Anorectal Malformations

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Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine 1065 Anorectal Malformations Long-term outcome and aspects of secondary treatment JOHAN DANIELSON ACTA UNIVERSITATIS UPSALIENSIS UPPSALA 2015 ISSN 1651-6206 ISBN 978-91-554-9140-6 urn:nbn:se:uu:diva-241243 Dissertation presented at Uppsala University to be publicly examined in Rosénsalen, Entrance 95/96, ground floor, Uppsala University Children’s Hospital, Uppsala, Friday, 27 February 2015 at 13:15 for the degree of Doctor of Philosophy (Faculty of Medicine). The examination will be conducted in English. Faculty examiner: Adjungerad Professor Olof Hallböök (Linköpings universitet ). Abstract Danielson, J. 2015. Anorectal Malformations. Long-term outcome and aspects of secondary treatment. Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine 1065. 109 pp. Uppsala: Acta Universitatis Upsaliensis. ISBN 978-91-554-9140-6. Faecal incontinence (FI) is defined as the inability to control bowel movements. The causes of FI are many and diverse. One of the more uncommon reasons for FI is Anorectal Malformations (ARMs). An ARM is a congenital anomaly that affects somewhere between 1/2500 and 1/5000 live born babies. Many ARM patients have persistent FI. Several different procedures have been utilised to address this issue. This thesis aims to evaluate (1) the long-term outcome in adulthood of ARMs in relation to the modern Krickenbeck classification, and (2) scope for treating FI with transanal injection with dextranomer in non-animal stabilised hyaluronic acid (NASHA/Dx), in patients both with and without ARMs. All patients treated for ARMs in Uppsala up to 1993 were invited to participate in a questionnaire study of quality of life and function. The study included 136 patients and compared them with 136 age- and sex-matched controls. The Krickenbeck classification was found to predict functional outcome, and ARM patients had more problems with incontinence and obstipation, as well as inferior Quality of Life (QoL), compared with controls. Thirty-six patients with FI, owing to causes other than ARMs, were treated with transanal submucous injection of NASHA/Dx. The patients were monitored for two years after treatment. Significant reductions in both their incontinence score and the number of their incontinence episodes were achieved. A significant improvement in QoL was observed in patients who had at least a 75% reduction in incontinence episodes. No serious complications occurred. A prospective study of transanal injection of NASHA/Dx was conducted on seven patients with persistent FI after ARMs. After six months a significant reduction in the number of incontinence episodes was obtained. A significant improvement in QoL was also found. No serious complications occurred. In conclusion, adult patients with ARMs have inferior outcome of anorectal function and QoL compared with controls. NASHA/Dx is effective and appears to be safe in treating FI in general. This effect seems to be the same in selected patients with persistent FI after ARMs. Keywords: anorectal malformation, faecal incontinence, long-term outcome, Krickenbeck, NASHA/Dx Johan Danielson, Department of Surgical Sciences, Akademiska sjukhuset, Uppsala University, SE-75185 Uppsala, Sweden. © Johan Danielson 2015 ISSN 1651-6206 ISBN 978-91-554-9140-6 urn:nbn:se:uu:diva-241243 (http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-241243) What we do in infancy echoes in eternity Author’s personal proverb List of Papers This thesis is based on the following papers, which are referred to in the text by their Roman numerals. I Outcome in adults with anorectal malformations in relation to modern classification: Which patients do we need to follow closely beyond childhood? Danielson J, Karlbom U, Graf W, Wester T Submitted II Submucosal injection of stabilised nonanimal hyaluronic acid with dextranomer: A new treatment option for faecal incontinence. Danielson J, Karlbom U, Sonesson AC, Wester T, Graf W. Dis Colon Rectum 2009 Jun;52(6):1101-1106 III Efficacy and quality of life 2 years after treatment for faecal incontinence with injectable bulking agents. Danielson J, Karlbom U, Wester T, Graf W. Tech Coloproctol. 2013 Aug;17(4):389-395 IV Injectable bulking treatment of persistent faecal incontinence after anorectal malformations. A preliminary report. Danielson J, Karlbom U, Wester T, Graf W. Manuscript Reprints were made with permission from the respective publishers. Contents Introduction ................................................................................................... 11 Anatomy of the rectum and surrounding structures ................................. 11 The anal canal ...................................................................................... 11 The external anal sphincter (EAS) ....................................................... 12 The internal anal sphincter (IAS) ........................................................ 12 The rectum ........................................................................................... 12 The levator ani ..................................................................................... 12 Physiology of the colon, rectum and anal canal ....................................... 12 The colon ............................................................................................. 13 The rectum ........................................................................................... 13 The anal canal and surrounding muscles ............................................. 13 Faecal incontinence .................................................................................. 14 Incidence and aetiology of FI .............................................................. 14 Treatment of FI .................................................................................... 15 Anorectal malformations .......................................................................... 18 History of ARMs ................................................................................. 18 Incidence of ARMs .............................................................................. 19 Associated anomalies........................................................................... 19 Genesis of ARM .................................................................................. 20 Classification of ARMs ....................................................................... 20 Classification used in this thesis .......................................................... 22 Primary surgical treatment of ARM ......................................................... 25 Low anomalies ..................................................................................... 25 High and intermediate anomalies ........................................................ 25 Outcome of ARM treatment ..................................................................... 25 Mortality .............................................................................................. 25 Short-term outcome of low anomalies ................................................. 26 Long-term outcome of low anomalies ................................................. 26 Short-term outcome of high and intermediate anomalies .................... 26 Long-term outcome of high and intermediate anomalies .................... 27 Conservative treatment of problems after ARM ...................................... 27 Secondary surgical treatment of persistent faecal incontinence after surgery ...................................................................................................... 28 Measuring and evaluating anorectal function .......................................... 29 Evaluation of the anatomy of the anorectal area.................................. 29 Evaluation of the physiology of the anorectum ................................... 30 Evaluation of faecal incontinence ........................................................ 30 Quality of Life ..................................................................................... 31 Background to the current thesis .............................................................. 31 Aims of the thesis.......................................................................................... 32 Materials and methods .................................................................................. 33 Basic methodology ................................................................................... 33 Paper I .................................................................................................. 33 Papers II and III ................................................................................... 33 Paper IV ............................................................................................... 33 Patients & controls ................................................................................... 34 Paper I .................................................................................................. 34 Papers II–III ......................................................................................... 36 Paper IV ............................................................................................... 37 Questionnaires utilised in the studies ....................................................... 38 Diary of bowel habits and incontinence episodes ................................ 38 Validated bowel-function questionnaire .............................................. 38 Non-validated questionnaire ................................................................ 39 Short form 36 (SF-36) ......................................................................... 39 Faecal Incontinence Quality of life questionnaire (FIQL) ................... 40 Clinical assessment (Papers II–IV) ...................................................... 40 Choice of injectable compound and technique for administration (II–IV) .................................................................................................. 42 Statistical methods ............................................................................... 43 Ethical and legal considerations .......................................................... 43 Results ........................................................................................................... 44 Outcome in adults with ARM in relation to the type of malformation (Paper I) .................................................................................................... 44 Continence ........................................................................................... 44 Constipation ......................................................................................... 45 Urogenital function .............................................................................. 45 QoL ...................................................................................................... 46 Spontaneous comments ....................................................................... 47 Efficacy and safety of perianal NASHA/Dx-injection for treatment of incontinence (Paper II) ............................................................................. 47 Effect on incontinence ......................................................................... 47 Effect in relation to dose given and pretreatment characteristics ........ 48 Side-effects of treatment ...................................................................... 49 Effect on continence and QoL two years after NASHA/Dx for treatment of incontinence (Paper III) ....................................................... 50 Effect on anal incontinence ................................................................. 50 Effect on QoL in the whole material ................................................... 51 Effect on QoL in patients with more than 50 per cent reduction in the number of incontinence episodes at 24 months ............................. 52 Effect on QoL in patients with more than 75 per cent reduction in the number of incontinence episodes at 24 months ............................. 52 Effect and safety of perianal NASHA/Dx-injection for treatment of persistent faecal incontinence in patients with ARM (Paper IV) ............. 54 Efficacy in terms of anal incontinence ................................................ 54 Effect on QoL ...................................................................................... 55 Side-effects of treatment ...................................................................... 55 Discussion ..................................................................................................... 56 Outcome and follow-up of patients with ARM ........................................ 56 The effect on incontinence and role of NASHA/Dx in treatment of FI in general .................................................................................................. 58 Improving QoL when FI is treated ........................................................... 61 The role of NASHA/Dx in treatment of FI in patients with ARM ........... 62 Conclusions ................................................................................................... 64 Future perspectives ....................................................................................... 65 Populärvetenskaplig sammanfattning (Summary in Swedish) ..................... 66 Acknowledgements ....................................................................................... 68 Appendices.................................................................................................... 73 Appendix 1: 2-week diary ........................................................................ 74 Appendix 2: Validated bowel function questionnaire .............................. 76 Appendix 3: Non-validated questionnaire ................................................ 85 Appendix 4: SF-36 QoL-questionnaire .................................................... 86 Appendix 5: FIQL .................................................................................... 89 Appendix 6: Full tables of the ARM-patients and their matched controls outcomes subgrouped according to the Krickenbeckclassification ............................................................................................. 91 References ................................................................................................... 100 Abbreviations ARM BP CI DGP EAS EMG FAMT FI FIQL GH HARM IAS LARM MH MRI MRP MSP NASHA/Dx PF PSARP QoL RAIR RE SF SF-36 SNS VACTERL VT Anorectal malformation Bodily pain(SF-36 subscale) Confidence interval Dynamic graciloplasty External anal sphincter Electromyography Free autogenous muscle transplant Faecal incontinence Faecal incontinence quality of life General health (SF-36 subscale) High anorectal malformation Internal anal sphincter Low anorectal malformation Mental health (SF-36 subscale) Magnetic resonance imaging Mean resting pressure Mean squeeze pressure Non-animal stabilised hyaluronic acid in dextranomer Physical function (SF-36 subscale) Posterior sagittal anorectoplasty Quality of life Recto-anal inhibitory reflex Emotional role function (SF-36 subscale) Social function (SF-36 subscale) Short form 36 Sacral nerve stimulation Combination of at least three of: Vertebral malformation, ARM, Cardiac malformation, TracheoEsophageal fistula, Renal malformation and Limb malformation Vitality (SF-36 subscale) Introduction Most people expect their ability to pass stool and control bowel function to work flawlessly. When they have either incontinence or constipation, it is uncommon for them to talk about these problems openly outside the family. Many patients with congenital anorectal malformations (ARMs) never experience ‘normal’ bowel control and seldom acknowledge this in adulthood either to close kin or to their physicians. The present thesis is an effort to shed light on the outcome of ARMs in adulthood, treatment of faecal incontinence (FI) in general and in particular treatment of patients with persistent FI after ARMs. Anatomy of the rectum and surrounding structures Knowledge of the normal anatomy of the rectum, anal canal and surrounding structures is crucial when dealing with FI and ARMs. The structures of interest are the anal canal, external anal sphincter (EAS), internal anal sphincter (IAS), rectum and levator ani muscle complex. The anal canal The ‘anatomical’ or ‘embryological’ definition of the anal canal is that it starts at the anal verge and ends at the pectinate line. The surface of the ‘anatomical’ anal canal is lined with stratified squamous epithelium. There is also a ‘surgical’ definition of the anal canal: that it starts at the anal verge and ends at the ‘anorectal ring’, which is the surgical term for the contracted puborectalis muscle (Milligan 1934). In this ‘surgical’ anal canal the upper part is lined with mucosa, which ends at the pectinate line, which is important because it represents the junction of tissues of different embryological origin (ectoderm and endoderm). This means that venous and lymphatic drainage take different routes and the nerve supply is highly differentiated. Below the pectinate line, sensitivity to pain is elevated (Williamson 1987, Fritsch 2002). In adults the anatomical anal canal is about 2 cm long, while the surgical anal canal measures approximately 4 cm. The normal location of the anal orifice is just in between the ischial tuberosities. 11 The external anal sphincter (EAS) The EAS is a striated voluntarily controlled muscle that extends from the perineal body to the anococcygeal ligament. It starts at the level of the pectinate line and ends close to the skin. It thus envelops the ‘embryological’ anal canal only. There is a difference between males and females: while in males the EAS is of the same strength anteriorly and posteriorly, in females its anterior strength is only half that of its posterior strength (Fritsch 2002). The internal anal sphincter (IAS) The IAS is a continuation and thickening of the inner circular muscle of the bowel wall. Within the circular muscle, residues of the longitudinal muscle of the bowel wall continue down and adhere to the EAS and the perineum. The lower rectum thus adheres to the perineum more broadly (Fritsch 2002). Being a continuation of the bowel wall musculature, the IAS is controlled involuntarily. The rectum The rectum is anatomically considered to start at the level of the third sacral vertebra, but surgeons usually refer to the rectum as starting at the promontory. It ends at the pectinate line. The rectum is easily distendable and can thus act as a reservoir for faeces. The levator ani The levator ani is a term for three distinct muscles: the iliococcygeus, pubococcygeus and puborectalis. With the pelvic diaphragm, they comprise the main muscular components of the pelvic floor. The levator ani is intimately associated with the muscles surrounding the urethra, vagina and anal canal. Regarding the levator ani’s effect on faecal continence, the most important function is that of the puborectalis muscle. This muscle forms a sling that angulates the rectum anteriorly. This angulation is considered important for the ability to maintain continence (Hajivassiliou 1996). Physiology of the colon, rectum and anal canal In dealing with FI and ARMS, knowledge of the normal physiology of the colon, rectum and anal canal is imperative. Maintaining continence and being able to defecate involve a complex system that includes the colon, rectum and anal canal, as well as the pelvic nerves and muscles. The factors affecting continence are stool consistency, rate of delivery of contents to the 12 rectum, rectal capacity and compliance, anorectal sensation, and IAS and EAS function. The colon The role of the colon is to absorb fluid from the faeces, as well as delivering it to the rectum. The latter is performed in two ways. The first is by intermittent low-pressure transition, a type of activity that occurs over approximately 5 cm of bowel (Kumar 1985). The second is by contracting a long segment of colon, approximately 30–50cm, pushing a larger amount of faeces rectally (Ritchie 1972). This in turn distends the rectum. The rectum The rectum is, as stated above, an organ that can be distended and is able to maintain a low intraluminal pressure when filled with faeces (up to a certain point, of course). This enables the rectum to store faeces and defer the need to defecate, by a mechanism known as ‘rectal compliance’. A decrease in compliance will result in higher intraluminal pressure, causing urgency and possibly incontinence (Denis 1979, Varma 1985). Sensation in the rectum is, like the rest of the bowel, indistinct. Pain and temperature are not perceived. Pressure is, however, perceptible and an increase in pressure will evoke a desire to defecate. Where the nerve endings that register this sensation are situated is not entirely clear, but they are probably located in the tissues surrounding the rectum (Scharli 1970, Varma 1972). The anal canal and surrounding muscles The anal canal is extremely sensitive to touch, pain and temperature. It has been said to be among the parts of the body with the highest density of sensory nerve endings (Duthie 1960). The IAS has the ability to temporarily relax, permitting the upper anal canal to come into contact with the contents of the rectum. At the same time a reflex contraction of the EAS occurs. This is known as the ‘sampling reflex’ or ‘rectoanal inhibitory reflex’ (RAIR) and enables us to discern the nature (gas, loose or solid) of the contents in the rectum (Gowers 1877, Miller 1988b). The resting tone of the anal canal depends on the EAS, IAS and the anal cushions. The IAS is responsible for 55–60% of the resting tone, the EAS for 25–30% and the anal cushions for approximately 15% (Gibbons 1986, Lestar 1989). As stated above, the EAS and the levator ani complex are voluntarily controlled striated muscles. However, they maintain an unconscious resting pressure. At times of ‘threatened continence’ they can contract both voluntarily and involuntarily, and delay defecation (Philips 1965). Owing to muscle fatigue, this 13 contraction can be sustained for only up to a minute and turns the contraction into ‘an emergency preserver of continence’. Faecal incontinence Incidence and aetiology of FI FI is defined as inability to control bowel moments, causing faeces to leak unexpectedly from the rectum. FI ranges from an occasional leakage of faeces when gas is passed to complete absence of bowel control. FI has been acknowledged as a medical problem for many years. However, its frequency was unknown until the beginning of the 1990s (Kiff, 1992). Studies have shown that around 1–2% of the adult population suffers from varying degrees of FI. This incidence rises with age and is as high as 7% in the population above 65 years of age (National Institute of Health 2007, Kamm 1998). The many and diverse causes of FI are summarised in Table 1. Table 1. Reasons behind congenital and acquired faecal incontinence. Congenital reasons Spina Bifida ARM Hirschsprung’s disease Acquired reasons 14 Colon • • • • • • Rectum • • • Anus • • • Chronic diarrhoea Entero-colic fistula Malabsorption Food allergy Excessive use of laxatives Endocrine tumours Loss of rectal sensation Loss of rectal reservoir Inflammation Poor anal tone Neurological damage Trauma Treatment of FI Conservative treatment of FI The role of conservative treatment in FI should not be underestimated. Many patients with mild symptoms can be helped substantially by changes in diet, training of the pelvic floor muscles and/or medication with loperamide, codeine phosphate and bulking agents for primary FI and oral laxatives and enemas for secondary FI due to impaction. Irrigation regimes may also be helpful, irrespective of the aetiology, by diminishing the amount of leakage. Behavioural techniques and biofeedback training can be effective, although scientific support is debatable (Norton 2003). Surgical treatment of FI Surgical treatment of FI is, of course, adapted to the underlying reasons of the FI. A damaged anal sphincter can be repaired surgically by suturing the defect. A non-functioning sphincter can be replaced by an artificial baloon or a neosphincter can be constructed with endogenous muscle tissue (free autogenous muscle transplantation, graciloplasty, dynamic graciloplasty or gluteus maximus transposition). Sacral nerve stimulation (SNS) can also be tried, to augment existing muscular tissue and modify bowel motility. A different concept for treating incontinence is the antegrade continence enema pioneered by PS Malone (Malone 1990). In this procedure a conduit is constructed to the proximal colon, through which the patient receives regular enemas. These enemas ensure that the colon and rectum are sufficiently empty for episodes of FI to be prevented. As for the secondary surgical treatment of ARMS, the techniques utilised have their inherent complications and none is guaranteed to improve continence. As a last resort the surgical option of a colostomy exists, but having a stoma is not uncomplicated. Injectable bulking treatment for FI The idea behind injectable bulking treatment is to increase the volume where the normal haemorrhoid venous plexus is situated or to fill up a defect after trauma or weakening. This is supposed to increase resistance in the anal canal and thus decrease FI. The first paper that described perianal injection treatment for FI was published in 1993 (Shafik 1993). To date, ten different substances have been described in the literature; these are presented in Table 2. It has been stated that ‘the optimal injectable bulking agent should be non-biodegradable, biologically non-reactive, non-migratory and easy to inject’ (Hussain 2011). However no compound with exactly these characteristics exists today and the search for the optimal bulking agent continues. 15 Table 2. Agents used for perianal injection therapy for treatment of FI. Agent Explanation of compound PTQ Durasphere Coaptite NASHA Dx Contigen Bulkamid Permacol Teflon EVOH Autologous fat Silicone suspended in a hydrogel Carbon coated zirconium beads suspended in a water-based gel Ceramic microspheres of calcium Dextranomer microparticles in hyaluronic acid Glutaraldehyde cross-linked collagen Cross-linked polyacrylamide in water Cross-linked porcine collagen matrix Teflon paste EVOH Co polymer in dimethyl sulphoxide Harvested from the patient Apart from the agent used, the injection technique is of the utmost importance. Seven different injection techniques have been described in the literature. These differ in two respects: the route for administering the injection (transanal, trans-sphincteric or intersphincteric) and the implant site for the agent (submucous, interphincteric or in the internal anal sphincter). In a systematic review it was found that a transanal injection technique reduces the risk of postoperative complications (Hussain 2011). The various techniques are presented in Figure 1. The results of injectable bulking treatment have, in general, been highly encouraging in the short term. Continence has improved in up to threequarters of the patients treated. However, in the medium term the effect has proved to decline and fewer than half the patients had improved continence two to three years after injection (Hussain 2011). Genuine long-term studies have yet to be published. Compared with many of the other surgical methods used in treatment of FI, there have been relatively few and mostly minor complications with the technique. This and the fact that the procedure is simple and often can be performed in an outpatient setting (depending on injected agent and route of administration) make it an interesting concept. 16 Rectum Puborectalis External sphincter Internal sphincter Pectinate line Anal canal A Injection into IAS, transsphincteric approach B Injection into IAS, intersphincteric approach C Submucosal injection, intersphincteric approach D Submucosal injection, transanal approach E Submucosal injection, transsphincteric approach F Intersphincteric injection, intersphincteric approach G Intersphincteric injection, transsphincteric approach Figure 1. Illustration of the seven different proposed injection sites and routes used for treatment with injectable bulking agents. 17 Anorectal malformations History of ARMs Anorectal malformations were known to the ancient Greeks. They were first described by the Greek scientist Aristotle in the third century BC. However, his observations were of animals (Aristotle). The first known treatment of an ARM in humans was carried out in the second century AD by a Roman paediatrician, who described dividing a thin anal membrane. Thereafter, ARM treatments are scarcely noted in medical literature until the 18th and 19th centuries, when modern surgery began to emerge. Amussat described the first real sutured proctoplasty in 1835 (Amussat 1835). A multitude of different techniques were described or suggested up to the start of the 20th century. At that point surgical textbooks recommended a one-stage perineal approach in the neonatal period. Colostomies were recommended only as lifesaving measures. This was probably a prudent approach in an era with no antibiotics or advanced anaesthesia. From the end of the Second World War increased availability of antibiotics, improved anaesthesia and greater knowledge of rectal anatomy and physiology had a profound impact on the surgical techniques employed. Simple anomalies were corrected with more standardised anoplasties. The inherent risks of bowel surgery decreased and opportunities arose to correct more complex anomalies in multi-stage procedures after implementation of a colostomy in the neonatal period. At the time, knowledge of perianal anatomy and physiology was not nearly as advanced as it is today. There was controversy regarding which muscles were important for future continence. This led to different surgeons advocating adoption of various procedures. Classification was also an area where several authorities on the subject advocated their own systems. The first textbook on the subject of ARMs was not published until 1963 (ed. DF Stephens). With the degree of dissenting opinion among leading authorities in the field, the first structured reports of outcomes of ARM surgery in the 1970s and ’80s were most welcome. These studies were, however, difficult to compare owing to the different grading systems. Nonetheless, it was evident that the results were far from satisfactory. The main problem was incontinence. The emergence of a plethora of different secondary surgical techniques to improve continence after failed primary surgery also indicates a high number of patients with unsatisfactory results. In 1982 the PSARP procedure was described by PA deVries and A Peña (deVries 1982). A technique similar to the PSARP procedure had been suggested back in 1834. But the novelty of the ‘modern’ PSARP procedure was that it incorporated the latest knowledge of the pelvic muscles and how 18 to reconstruct them during surgery. The technique is based on the embryological phenomenon of the pelvic muscles and nerves being fused laterally. Thus, a division of these structures strict in the midline does not damage their functionality. The PSARP technique proved to have substantially better results than its predecessors, but the number of patients with postoperative incontinence remained high. This incontinence is often attributed to overflow incontinence secondary to constipation. To solve this problem, various regimes of oral laxatives, retrograde enemas and antegrade enemas (through a conduit to the colon) have been developed, and the results have been good. The PSARP procedure has had a tremendous influence on how paediatric surgeons treat ARMs today, although other techniques are still used. With the rise in laparoscopic surgery performed by paediatric surgeons, it is natural that laparoscopically assisted operative techniques for ARMs have been developed. The initial results of these techniques have been encouraging (Lin 2003) and the current discussion concerns whether these techniques are superior to PSARP or not. Incidence of ARMs The incidence of ARMs has been reported to be between 1/1000 and 1/11500 live births. The most commonly stated figures are between 1/2500 and 1/5000. ARMs are somewhat more common in males, with about 57 per cent of cases. It is a diagnosis that encompasses a wide clinical spectrum, from mild manifestations requiring no or only minor surgery to complex forms that require multiple complex operative procedures. About half of all anomalies are classified as mild or ‘low’ (Stephens 1988, Endo 1999). Associated anomalies It is well known that ARMs are associated with malformations in other organs. Most of hese malformations are situated within the so called VACTERL-spectrum. The more complex the ARM, the higher the incidence of associated malformations (Kiesewetter 1981). Several studies have been published on the incidence of synchronous malformations (Gross 1953, Kiesewetter 1981, Smith 1988 and Ratam 2005). The figures show a rising incidence of vertebral anomalies. This is probably due to increased awareness of these anomalies and the fact that clinicians actively search for them. Vertebral malformations not only imply skeletal malformation but often include a synchronous malformation of the spinal cord. This malformation is often responsible for a relatively poor prognosis in terms of continence. Table 3 presents figures for synchronous malformations from the published studies. 19 Table 3. Incidence of synchronous malformations in patients with ARMs Anomaly Oesophageal/Tracheal Cardiovascular Vertebral/sacral/spinal cord Gastrointestinal Urinary Patients with one or more synchronous anomalies Incidence 7% 9% 19% 6% 29% 51% Genesis of ARM Most cases occur sporadically, but there are reports of a number of families with inherited cases. There is a link with chromosomal anomalies, and ARM is more common with trisomies 13, 18 and 21 (Mundt 2010). Nonetheless, the genetic mechanisms behind human ARM remain elusive. Several environmental factors have been postulated as part of the pathogenesis of ARM. No factors have been clearly shown to be connected with ARM. However, the animal models that exist for ARM are induced with environmental factors (adriamycin and all-trans-retinoic acid), which suggests that there may be undiscovered connections. Classification of ARMs Three influential meetings have been held to stratify the classification of ARMs. The first meeting with widespread impact on ARM classification was held in Melbourne, Australia, in 1970. As mentioned above, before this meeting most authorities in the field had their own classifications. The Melbourne meeting took into account several different authors’ classifications and set up an international classification of male and female, as well as low, intermediate and high malformations. The second was organised in Wingspread, Wisconsin, USA, in 1984. The classification was based on anatomical studies and the relationship between the levator ani and the rectal pouch. The advantage of the Wingspread classification is that it can be used to predict the best surgical approach (perineal or abdominal). The Wingspread classification is presented in Table 4 (Stephens 1988). 20 Table 4. Wingspread classification Cloaca Female Anorectal agenesis with recto-vaginal fistula Anorectal agenesis without fistula Rectal atresia Rectovestibular fistula Rectovaginal fistula Anal agenesis without fistula Anovestibular fistula Anocutaneous fistula Anal stenosis Common channel Rare malformations Various High anomaly (pouch above the levator ani) Intermediate anomaly (pouch at the level of the levator ani) Low anomaly Male Anorectal agenesis with recto-prostatic fistula Anorectal agenesis without fistula Rectal atresia Rectobulbar or urethral fistula Anal agenesis without fistula Anocutaneous fistula Anal stenosis N/A Various The third conference was in Krickenbeck, Germany, in 2005. This conference radically modified the former classification, removing the terms ‘low’, ‘intermediate’ and ‘high’ and the distinction between female and male anomalies. The grading is based on the presence and type of fistula. The Krickenbeck classification is fairly similar to the classification proposed by Dr Peña, one of the fathers of the PSARP procedure. The reason for this reclassification was the great difficulty of comparing the outcomes of different surgeries with the old Wingspread classification. In addition to the classification, the Krickenbeck conference also agreed on a grouping of surgical procedures and a classification of postoperative results. These changes were done to facilitate future comparisons of treatments. Today, the criteria adopted by the Krickenbeck conference are the gold standard for classification of ARMs. The Krickenbeck classification is presented in Table 5 (Holschneider 2005). 21 Table 5. Krickenbeck classification Major clinical groups Perineal (cutaneous) fistula Recto-urethral fistula Prostatic Bulbar Recto-vesical fistula Vestibular fistula Cloaca No fistula Anal stenosis Rare/regional variants Pouch colon Rectal atresia/stenosis Rectovaginal fistula H-type fistula Others Clincal pictures and drawings of the more common malformations according to the Krickenbeck classification are presented in Fig 2 and Fig 3. Several studies have been published where the patient material has been classified according to the Krickenbeck criterion (Shmiedeke 2012, de Blauuw 2012, Nah 2012, Brisighelli 2013). The reported incidence of the different subgroups is presented in Table 6. Table 6.Reported prevalence of each subtype according to the Krickenbeck classification Krickenbeck classification Gender Reported prevalence (%) Perineal fistula No fistula Rectal atresia Vestibular fistula Cloaca Recto-urethral fistula Bulbar fistula Prostatic fistula Rectovesical fistula Mixed Mixed Mixed Female Female Male Male Male Male 25-43 3-12 1-3 41 4-10 19-50 5-15 12-20 5-12 Classification used in this thesis Since most publications on the outcomes of ARM predate Krickenbeck, the Wingspread Classification has been used for the rest of the introductory section of this thesis. In the papers on ARM (I and IV) the Krickenbeck classification has been used. 22 Figure 2a. Boy with a visible fistula anterior to the normal site of the anus: perineal fistula. Figure 2b. Boy with no visible fistula in the perineum. Three plausible clinical diagnoses exist: no fistula, rectourethral fistula and recto-vesical fistula. No fistula Recto-urethral fistula Recto-vesical fistula 23 Figure 3a. Girl with a fistula anterior to the normal site of the anus: perineal fistula. Fig 3b. Girl without a visible fistula in the perineum or vestibule. but with normal urethra and vaginal opening: no fistula. Fig 3c. Girl with a fistula posterior to the vaginal opening but within the vestibule: vestibular fistula. Fig 3d. Girl with one common opening only: cloaca. 24 Primary surgical treatment of ARM Low anomalies Low malformations have been treated with more or less the same techniques for the last 50 years. Stenotic anal openings situated within the sphincter complex are gradually dilated with suitable dilators (most commonly Hegar dilators). The great difference in practices between the period before the mid-1980s and today is nowadays this dilation is carried out daily by the child’s parents and requires no anaesthesia. Before the mid-1980s, dilations were often done intermittently by a surgeon and under general anaesthesia. Dilations are continued up to a few weeks after age-appropriate anus size is reached. Anteriorly situated anal openings partially within or just outside the sphincter complex that have little clinical impact can be treated conservatively with dilations (if it is stenotic). Patients with anocutaneous fistula or low anomalies without fistula can be treated with cutback, Hendren’s procedure or minimal PSARP. These three procedures are fairly similar, in that the skin is split in the midline anterior to the correct site of the anal opening. The anal canal and distal rectum are then freed, mobilised and subsequently sutured in place. The techniques differ regarding whether the surgeon moves the anterior rim of the anus posteriorly or not. Both techniques require postoperative dilations of the anal canal, since the anal canal has a tendency towards stenosis. Dilations sometimes need to continue for up to a year after surgery. High and intermediate anomalies As noted above in the section on the history of ARM, treatment of the more complex anomalies has changed radically over the years, from abdominosacroperineal and abdominoperineal procedures to the currently most widespread technique, PSARP. The main difference between these procedures is that the older methods took ‘only’ the placement of the external sphincter into account. The bowel was subsequently pulled down into that position and a ‘perineal stoma’ was formed. The aspects of the deeper anatomy of the pelvic diaphragm and the bowel’s normal relation to the pelvic muscles were not addressed. Outcome of ARM treatment Mortality With the availability of modern surgery, antibiotics and intensive care, an ARM is not an intrinsically life-threatening condition. ARMs are, however, 25 often accompanied by associated anomalies that, in themselves or in combination, may be associated with significant mortality (especially cardiac malformations). Historically, however, mortality has been very high and before the advent of antibiotics often exceeded 50%. In the 1940s and ’50s it decreased to a level of about 25% and it continued to fall, to a level below 5%, until the end of the 1980s. Mortality is substantially lower in patients with low malformations than in the high lesions (Rintala 2005). The improvement is probably due to both improved neonatal intensive care and better surgery. But it must also be borne in mind that patients who used to be excluded owing to their severe malformations now have a chance. To reach a mortality rate approaching zero is probably difficult, owing to the incidence of severe associated malformations. Short-term outcome of low anomalies The most common early complication is constipation. It occurs in about 40% of the patients. The first two years of life are most troublesome and most patients require medication during this time. The age when affected children sare out of nappies and toilet-trained is similar to that of age-matched controls (Rintala 1997, Pakarinen 2006, Pakarinen 2007, Pakarinen 2010). Long-term outcome of low anomalies Traditionally, paediatric surgeons have considered the long-term outcome of these anomalies to be good. The basis for this view was a number of papers in the 1960s and ’70s, when the long-term outcome was reported to be more or less excellent (Partridge 1961, Trusler 1962, Nixon 1977, Kiesewetter 1977). In more recent papers these views have been strongly contested. It has been shown that only about half to two-thirds of older children with low ARM have normal bowel function compared with age-matched controls. The most common problems are constipation and soiling (Ong 1990, Yeung 1991, Rintala 1997). Outcome studies of adult patients are scarce and the most recent ones date from the early 1990s. These studies report good continence according to scoring systems, but 14–25% of the patients suffered from soiling and up to 49% from faecal smearing (Karkowski 1973, Nixon 1977, Ong 1990, Yeung 1991, Rintala RJ 1992, Kyrklund 2014). Short-term outcome of high and intermediate anomalies The outcome in this group is closely linked to the type of underlying malformation. In general, patients with high recto-urogenital connections (i.e. bladderneck fistulas or cloacas with a long common channel) have a 26 poor prognosis. The reason is thought to be the increased risk of sacral abnormalities and hypoplasia of the sphincter apparatus (Peña 1995). Several studies on the outcome in this group, including both ‘pre-PSARP’ and PSARP patients, have been published. Long-term outcome of high and intermediate anomalies Knowledge in this field is fairly limited and to date only three studies have been published, all on patients operated on with pre-PSARP procedures (Nixon 1977, Hassink 1993, Hassink 1994, Rintala 1994). These studies conclude that almost all patients who were operated on with pre-PSARP techniques had some form of faecal incontinence even if they had received secondary surgery. Nonetheless, many patients seemed to have adapted to their situation and were satisfied with their continence. Many seemed to have developed measures to tackle their situation in terms of soiling. Their QoL, on the other hand, was affected especially in social and occupational settings (Hassink 1994). Table 7 presents results from studies in the field. Table 7. Results of long term follow-up for high and intermediate ARM N Normal Good Fair Poor Nixon et al. 1977 47 15% 62% (Good/fair) * 23 Hassink et al. 1993 58 0% 36% 43% 21% Rintala et al. 1994 33 0% 18% 54% 27% Conservative treatment of problems after ARM As in other forms of FI, the role of conservative treatments of persistent FI and/or constipation after ARM should not be underestimated. Use of oral bulking agents, laxatives and/or enemas is standard in treatment of both incontinence and constipation. In recent years the idea of bowel management has been increasingly popular, especially in the paediatric population. The idea behind bowel management is that ‘an empty colon can’t leak’, so the regimen aims to empty the colon regularly either by oral laxatives or by the administration of enemas. Enemas can be given either in the standard retrograde fashion (i.e. 27 through the rectum) or by antegrade means (through a surgically constructed conduit to the colon). Secondary surgical treatment of persistent faecal incontinence after surgery The less than perfect postoperative outcomes of ‘older’ types of primary surgery for the more complex ARMs led to the evolution of secondary procedures. These procedures can be grouped into one of the following seven categories: 1) Secondary, or redo pull-through: i.e. realignment of the anus to the correct anatomical position of the anal sphincter and repairing the levator complex (i.e. the primary surgery failed and is redone). 2) Substituting or strengthening a weak levator complex. 3) Constructing an internal sphincter with bowel. 4) Using electric devices to augment the function of the levator complex. 5) Implantation of an artificial sphincter. 6) Excision of excess mucosa. 7) Construction of conduits into the caecum for administering antegrade enemas. The secondary procedures described are summarised in Table 8 where they have been grouped according to the seven groups above. None of the procedures described have proved to be the ‘salvation of failed ARM surgery’. Conduits for the administration of antegrade enemas have gained increased popularity in the paediatric surgical community. There are, however, data that imply that the utilisation of this conduit declines with time even if a majority still benefit from it (Koivusalo 2008). 28 Table 8. Compilation of the secondary procedures that have been used for improving anal continence in patients with persistent FI after ARM surgery Group Procedure 1. Redo surgery 2. Levator strengthening or substitution 3. Internal sphincter substitution 4. Electrical stimulation 5. Artificial sphincter 6. Excision of excessive mucosa 7. Conduits for antegrade enemas Stephens’ secondary pull-through Redo PSARP Kottmeir’s Levatorplasty Puri and Nixon’s Levatorplasty Free autogenous muscle transplantation (FAMT) Gracilis muscle transposition Dynamic gracilis muscle transposition (DGP) Gluteus Maximus transposition Free smooth muscle transplantation Flap smooth muscle transplantation Sacral nerve stimulation (SNS) Circular balloon devices Simple excision Nixon’s anoplasty Mollard-Laberge operation Appendicostomy Chait button Measuring and evaluating anorectal function Measuring and getting an objective evaluation of anorectal function is difficult. One can measure physiological parameters and discern the anatomy of the perirectal area but this alone does not tell us the anorectal function for a specific person. Objective measurements must therefore be combined with recording of bowel habits and the occurrence of FI and/or obstipation. Evaluation of the anatomy of the anorectal area Clinical investigation tells the examiner a great deal about the patient’s anatomy but is, of course, entirely dependent on the experience of the investigator. Endoanal ultrasound and magnetic resonance imaging (MRI) can improve the evaluation of the anatomical structures surrounding the anal canal and lower rectum. The most common use of the methods is to evaluate the IAS and EAS but it can also be used to evaluate pathology in the surrounding tissues. Modern anal endosonography generates 3D pictures that make interpretation easier than older types of equipment. MRI gives more detailed information of the anus and rectum as well as the surrounding tissues but has the disadvantage of being much more expensive and time consuming than endosonography (Williams 2002, West 2005). 29 Evaluation of the physiology of the anorectum Anorectal manometry is used to evaluate the physiological and anatomical function of the rectum and anal canal. With this procedure one can measure resting pressure and squeeze pressures, as well as whether the contraction is circumferent. To measure the innervation of the anorectum, EMG may be performed or pudendal nerve terminal motor latency measured (Van Koughnett 2013). Evaluation of faecal incontinence The most accurate way of measuring FI is diary registration of the bowel habits and episodes of FI. The diary often covers a period of two to four weeks. This is time consuming and is not always possible for the patient or the clinic to accomplish. Therefore several different scores for assessing the severity of FI have been constructed. Many of these scales take into account both the type and frequency of FI as well as the impact FI has on everyday life. In the international literature the most widespread scores are: 1. Miller’s Incontinence score (Miller 1988). Takes into account the frequency and type of FI-episode. 2. Pescatori score (Pescatori 1992). Takes into account the frequency and type of FI episode. 3. Cleveland Clinic FI score (commonly known as Wexner Score, Jorge 1993). Takes into account frequency and type of incontinence as well as the need to wear protection of underwear and whether this alters lifestyle. 4. St Mark’s Score (Vaizey 1999). Takes into account frequency and type of incontinence as well as the need to wear protection of underwear, oral medication and urgency of defecation. 5. Fecal Incontinence Severity Index (Rockwood 1999). Takes into account the frequency and type of FI episode but is more precise in its measurement than Miller’s and Pescatori’s scores. In recent literature the Wexner score and St Mark’s score have been the most commonly used. 30 Quality of Life One of the main aims of any kind of medical treatment should be to improve the patient’s Quality of life (QoL). The measurement of QoL is a difficult area where there are many variables to consider. A multitude of different scales have been suggested measuring both general as well as disease specific QoL. In general, QoL scales may be said to fall into three categories: 1. Generic scales that measure general changes in different areas and permit comparison of various groups with one another. 2. Specialised scales used in a group of similar conditions (such as psychiatric or oncologic diseases). 3. Condition-specific scales that measure QoL outcome in relation to a specific disease or symptom and treatment. Condition-specific QoL scales are much more sensitive to changes in what is considered as QoL in the measured group. However data from such scales are often not comparable with data from other groups of patients. Measurement of QoL can also be done with global single questions. A person’s ability to be continent obviously has a heavy impact on QoL. In the area of FI, a multitude of different scales have been constructed. Those most commonly used today are the Faecal Incontinence Quality of Life score (FIQL, Rockwood 2000), which is disease-specific, and SF-36 (Short Form 36), which is a generic scale. Background to the current thesis Over the last 30 years, surgical and postoperative care of patients with ARM has evolved dramatically. Publications regarding outcome during childhood are common and this outcome has clearly improved. At the same time, studies on outcome in adulthood have been scarce and international discussions on ARM are beginning to address how we take care of our patients in the longer term. Furthermore, there is an urgent need for further treatment options for physicians treating ARM patients with persistent faecal incontinence. 31 Aims of the thesis The general purpose of this thesis was to increase the knowledge on longterm functional results of ARM patients in adulthood. In addition, specific aims of each paper were: • To evaluate the long-term functional and QoL outcome of Swedish patients with ARM, subdivided according to the Krickenbeck classification, and compare them with an age- and gender-matched control group (I). • To evaluate the safety and effect on FI and QoL of NASHA/Dx as an injectable bulking treatment. In addition, the study aimed to discern the dose that should be used and whether the treatment seemed to be more effective or ineffective in any particular group of patients (II, III). • To assess the relationship between reduction in incontinence symptoms and change in quality of life, with reference to threshold levels for definition of response (III). • To evaluate the safety, and efficacy in terms of FI and QoL, of NASHA/Dx as an injectable bulking treatment for persistent faecal incontinence in patients with ARM (IV). 32 Materials and methods Basic methodology Paper I Paper I is a retrospective cohort study of a group of adult ARM patients. The patients were sent a validated bowel function questionnaire, a nonvalidated bowel function questionnaire and the validated SF-36 QoL questionnaire. Patients who did not respond were sent two reminders at sixweek intervals. Those who did not respond were designated as nonresponders. Once the included cohort of patients was defined, age- and sex-matched controls were recruited. The controls were sent the same set of questionnaires. Papers II and III Papers II & III are based on a non-randomised prospective study where the patients act as their own controls. The study is a proof of concept study that aimed to evaluate both the safety and effect of NASHA/Dx as a treatment for FI. Since the dose that should be used was unknown, an option for retreatment was devised in the protocol. Before treatment all patients underwent anal endosonography and anal manometry. All patients were followed at 3, 6, 12, 18 and 24 months after treatment. Before treatment and at follow-up all patients filled in a fourweek bowel diary, a validated bowel function questionnaire and SF-36 QoLinstrument. At treatment and subsequent follow-up visits the patients were examined with rectoscopy and palpation. Endosonography was not performed routine at follow-up, but was occasionally performed. Paper IV Paper IV is a non-randomised prospective pilot study where the patients act as their own controls. Patients were evaluated before treatment with a two-week bowel diary, a validated bowel function questionnaire as well as FIQL and SF-36 33 questionnaires. Anal manometry, endosonography and rectoscopy were also performed. Follow-up consists of the same set of questionnaires and diary at 3 and 6 months. Clinical evaluation with anal endosonography and rectoscopy was performed at 6 months. Patients & controls Paper I The case records and operative registry at the Department of Paediatric Surgery, University hospital, Uppsala, Sweden, were reviewed for patients diagnosed with ARM. The records and registry were searched from when the registration started 1961 to 1993 so that only adult and adolescent patients should be included. A total of 257 patients diagnosed with ARM were identified and clinical data extracted. Thirty patients were untraceable and 24 had died (23 in infancy and one in adulthood), leaving a cohort of 203 patients. Invitations to participate and questionnaires were sent to these 203 patients. In total, 136 patients (67 per cent) responded and were included in the present study (see Figure 4 for flow chart of inclusion). Figure 4. Flow chart of inclusion of patients into Paper I. Total material: 257 Traceable patients sent questionnaires: Untraceable patients: 203 30 Dead: 24 Non-responders: Study cohort: 67 136 The type of ARM was reclassified according to the Krickenbeck system, based on preoperative charts, drawings of the malformation, X-ray reports, radiographs and surgical reports. Since it was difficult to adequately 34 distinguish prostatic from vesical fistulas, these patients were included in a single group. Age- and sex-matched control subjects for every patient were randomly selected from the National Swedish population registry. They received the same questionnaires as the patients and an invitation to participate in the study. The study aimed to include two controls per patient, and five control subjects were therefore selected for every patient. The average response rate of control subjects was 24 per cent and hence only one control could be matched to each patient. The characteristics of the patients and the controls included in Paper I are presented in Table 9. Table 9. Characteristics of patients with ARM and controls included in Paper I All patients Controls Number of patients Sex Male Female Age (years) Median Mean Range Type of ARM (males) Anal stenosis Perineal fistula No fistula Recto-bulbar fistula Prostatic & vesical Type of ARM (females) Anal stenosis Perineal fistula No fistula Vestibular fistula Cloaca 136 136 80 56 80 56 31 30.4 18–60 31 30.5 18–60 5 24 16 30 5 N/A 6 17 4 26 3 N/A 35 Papers II–III Papers II and III are based on 34 patients, with FI analysed at one and two years after treatment. Patients were recruited consecutively from the surgical outpatient clinic in Uppsala. The inclusion criteria were: faecal incontinence (loose or solid stool) at least once weekly, age between 18 and 80, availability for follow-up and provision of written informed consent. The exclusion criteria were: total internal and external sphincter defect (i.e. seen at all levels of the anal canal) confirmed by ultrasound and/or clinical examination, pregnancy, rectal prolapse or significant mucosal prolapse, inflammatory bowel disease, anorectal surgery within the last year, anticoagulant medication/bleeding diathesis, and anorectal sepsis. The patients underwent rectoscopy, anal manometry and anal endosonography prior to inclusion. All patients had failed an initial attempt of conservative treatment including fibre supplements, loperamide and sphincter exercises. A total of 35 patients (6 male, 29 female) with a mean age of 61 years (range: 34–80) were included. One male patient with coronary heart disease died of myocardial infarction 3 months after inclusion, leaving a study group of 34 patients. Anal endosonography showed that 3 patients had a partial sphincter defect (i.e. a defect which was not observed at all levels of the anal canal), and 2 of these had undergone an external anal sphincter repair prior to the study. These defects were deemed unsuitable for surgical correction. The characteristics of the patients in Papers II and III are presented in Table 10. Table 10. Patient characteristics of patients included in Papers II and III Gender Male Female Cause of incontinence Iatrogenic Obstetric injury Neurogenic Idiopathic Type of incontinence Urgency Non-urgency Sphincter defect at ultrasound Yes No 36 Number % 5 29 15 85 1 1 25 7 3 3 73 21 17 17 50 50 3 31 9 91 Four weeks after treatment, the patients were evaluated by a telephone interview, and offered a second treatment if they fulfilled the criteria for retreatment (persistent faecal incontinence, absence of side-effects and the patient’s willingness to undergo a second procedure). Eighteen patients fulfilled these criteria and received a second treatment within 2 weeks. The procedure for retreatment was similar to the initial treatment, except that the injection sites were between the initial ones. No further implantations or biofeedback treatments were given during the follow-up period. One patient was lost to follow-up after 12 months. Paper IV Inclusion criteria for the study were persistent FI after ARM with a Miller incontinence score of more than 5 (meaning, at minimum, incontinence to loose stool at least once weekly). Exclusion criteria were age <18 years, pregnancy, rectal prolapse or significant mucosal prolapse, inflammatory bowel disease, anorectal surgery within the last year, anticoagulant medication/bleeding diathesis, anorectal sepsis, anal stenosis or immunosuppressive therapy. Forty-two patients in Paper I fulfilled the inclusion criteria and were offered a clinical evaluation at the surgical outpatient clinic in Uppsala. Seventeen accepted. Six of these were found to be suitable candidates for NASHA/Dx-treatment. Four of the patients accepted inclusion in the study. Two patients fulfilling the inclusion criteria were recruited from the surgical outpatient clinic in Uppsala (these patients were not originally operated for their ARM in Uppsala and were therefore not been included in Paper I). In addition, charts of 15 adult patients with persistent FI after ARM were sent by colleagues in Stockholm. Four patients were found to fulfil the inclusion criteria without having any contraindication and were invited to be evaluated for inclusion into the study. One of these patients was included in the study. The characteristics of the seven patients included in the study are presented in Table 11. 37 Table 11. Characteristics of patients included in paper IV Gender Male Female Age at treatment (years) Mean Range Type of ARM Recto-bulbar fistula Vestibular fistula 2 5 43.1 35–52 2 5 Questionnaires utilised in the studies Diary of bowel habits and incontinence episodes Two different diaries covering bowel habits and incontinence episodes have been used. In studies II and III a four-week diary and in study IV a two-week diary were utilised. In the diary, the patient noted normal bowel movements as well as episodes of FI and the consistency of the stool or FI episode. There were two reasons for changing the diary used in Paper IV. First, some patients found it a hard task to fill in the four-week diary. Second, the two-week diary had been used in a multicentre study of NASHA/dx (Graf 2011) and found to work very well. The two-week diary is found in the Appendix 1. The four-week version is not presented, but was similar in appearance and twice as long. Validated bowel-function questionnaire The bowel function questionnaire used in Papers I–IV was constructed and validated in Uppsala (Österberg 1996). The questionnaire consists of 49 questions relating to faecal incontinence, constipation and general bowel function symptoms, allowing calculation of the Miller incontinence score . The questionnaire also gives information of type of incontinence (classified as soiling, urge, non-urge or combination incontinence), medication, anal sensibility, deferring time and whether the anal continence affects social function in different ways. In the Miller incontinence score (Miller 1988), which is based on the type and frequency of incontinence episodes, 0 represents total continence and 18 represents total incontinence. The score is presented in Table 12. 38 Table 12. Miller’s incontinence score Flatus Less than weekly 1 incontinence Weekly 2 incontinence Daily incontinence 3 Fluid Solid 4 7 5 8 6 9 This scoring system is albeit somewhat old and omits the use of underwear protection or lifestyle changes, in contrast to more ‘modern’ incontinence scores (such as the Cleveland Clinic or St Mark’s incontinence scores). However the bowel function questionnaire utilised covers all these questions and the data are presented in a way that makes it easier to discern the individual variables than an ‘all-encompassing incontinence scale’. The bowel function questionnaire is found in Appendix 2. Non-validated questionnaire In the design of Paper I, some relevant questions that apply to patients with ARM were lacking in the validated questionnaires. A non-validated questionnaire was therefore added. This questionnaire contains seven questions regarding satisfaction with bowel function and sexual problems. The answers were graded on a scale of 1 to 4 (1=None, 2=Some, 3=Quite a lot, 4=Very much). The questionnaire is found in Appendix 3. Short form 36 (SF-36) SF-36 was utilised in Papers I, III and IV. SF-36 is a generic instrument for measuring QoL. It has been used in many different fields and has been validated and tested for reliability (Sullivan 1995, Sullivan 1998, Sullivan 2002). The questionnaire consists of 36 questions. The answers to these questions are then analysed in terms of eight different aspects of QoL. The eight subscales are further transformed into a mental health domain (mental component scores) and a physical health domain (physical component scores). The scale of each subscale is 0–100. Low scores imply poor function and/or health status. The eight subscales and the physical and mental health domains are presented in Table 13, and the questionnaire is displayed in Appendix 4. 39 Table 13. SF-36 subscales SF-36 subscale name Abbreviation Explanation Physical Function PF Physical Role Function RP Bodily Pain BP General Health GH Vitality VT Social Function SF Emotional Role Function RE Mental Health MH General Health GH Evaluates ability of performing daily physical activities. Evaluates limitations of performing work or similar activities. Evaluates amount of pain and limitations thereof. Evaluates the subjective feeling of general health status Evaluates feelings of energy or tiredness. Evaluates limitations in social activities. Evaluates limitations due to emotional problems Evaluates depression and nervousness Evaluates the subjective feeling of general health status Cluster score of the scores mirroring mental health Cluster score of the scores mirroring physical health. Mental Component Scores MCS Physical Component Scores PCS Faecal Incontinence Quality of life questionnaire (FIQL) FIQL was used in Paper IV. FIQL is a validated, disease-specific score published in 2000 (Rockwood 2000). It specifically evaluates how FI affects life. The questionnaire is composed of 29 questions that form four subscales; Lifestyle (ten questions), Coping/Behaviour (nine questions), depression/self-perception (seven questions) and embarrassment (three questions). Analysis of the questions yields a score between 1 and 4 for each subscale. A lower score implies a lower functionality. The FIQL questionnaire is found in Appendix 5. Clinical assessment (Papers II–IV) Clinical examination All patients were examined at the initial visit, as well as at the follow-up visits, according to the study protocol. Before examination all patients received a small enema. The clinical examination included inspection, 40 palpation as well as rectoscopy or proctoscopy with the patient in the left lateral position. Endoanal ultrasonography In brief, the following protocol was used. All patients received a small enema before examination (not because of the endosonography, but to perform a rectoscopy). The patient was placed in the left lateral position. A 12–16 MHz 3D probe (ultrasound scanner 2050, B-K Medical, Mileparken 34, Herlev, Denmark) was used. The probe was enclosed in a plastic cone containing degassed water, providing a circumferential view of the anal region. The probe was introduced and the lower rectum and anal canal were scanned. The image was then assessed by the physician performing the procedure. The IAS and EAS were always identified. Anal manometry A water-perfused catheter was used (Synetics VMC-8 Manometric Catheter), with an outer diameter of 5 mm, eight side holes and eight pressure detectors, radially oriented at 45-degree intervals. An inflatable rubber balloon was attached to the tip of the catheter. The perfusion rate was 0.5 ml/min. The catheter was connected to a compressor (Mui Scientific model PIP-4-8, Missauga, Ontario, Canada). The software used was Polygram 98 for PC (Medtronic Functional Diagnostics A/S). With the patient in the left lateral position, the catheter was fixed with the pressure detectors 6 cm above the anal verge. After stabilisation for 2 to 3 minutes, a recording was performed over 30 seconds. Thereafter, the catheter was retracted by 1 cm, the pressure allowed to stabilise and another recording was made. The last measurement was taken with the detector 1 cm above the anal verge. The level with highest resting pressure was noted as maximal resting pressure (MRP). The measurements were repeated during maximal squeeze, for maximal squeezing pressure (MSP). Next, the catheter was placed and fixed with the transducer in the zone with the highest resting pressure. The balloon was inflated with 10 ml air and if the initial inflation failed to induce the rectoanal inhibitory reflex (RAIR), the balloon was further inflated by increments of 10 ml (up to 60 ml) until RAIR was elicited. Finally, the balloon was gradually inflated with 10 ml doses of body-temperature water, to record the first sensations of rectal filling, constant sensation and maximal tolerated volume (maximum volume: 250 ml). 41 Choice of injectable compound and technique for administration (II–IV) NASHA/Dx NASHA/Dx is a gel consisting of dextranomer microspheres in stabilised hyaluronic acid-based gel of non-animal origin (NASHATM gel). Under the trademark DefluxR it has been CE-approved since December 1998, and FDA-approved for treatment of vesicoureteral reflux since September 2001. It has been used to treat more than 100,000 paediatric patients with this indication and has had a very good safety profile. It has proved to be an easily injectable substance with good clinical tolerability. Histopathologic examination of implants has shown fibrosis, i.e. collagen ingrowth and slight inflammatory reaction to the material, with no significant tissue changes or granuloma formation (Stenberg 1999, Stenberg 2003). When the study behind Papers III and IV started in 2004, NASHA/Dx was not approved for treatment of faecal incontinence. Since then it has been CE- and FDA-approved (in 2006 and 2010 respectively), under the trademark SolestaR, for treatment of faecal incontinence. Following the start and publication of the studies included in this thesis several studies have been published on NASHA/Dx as a treatment option for FI. Most importantly, a randomised sham controlled trial of NASHA/Dx has been proved to have a significant effect on FI and that the effect is stable for at least 36 months (Graf 2011, Mellgren 2014). Injection technique of NASHA/Dx in Papers II and III Since publications of other compounds injected intersphincterically have shown a risk of deep abscesses, it was decided that the injections should be administered submucously. This technique is also simpler since it does not need synchronous use of ultrasound. The treatment was administered as an outpatient procedure after a small enema, without anaesthesia or prophylactic antibiotics. An anoscope was used, with the patient in the left lateral position. Four 1 ml injections of NASHATM Dx gel were administered 5 to 10 mm above the dentate line in the submucosal layer, at the 3, 6, 9, and 12 o’clock positions (total dose: 4 ml). The intended puncture site was 3 to 5 mm above the dentate line and the needle was advanced further a few mm to place the implant well in the submucous layer. After injection the needle was retained in situ for 10 seconds in order to prevent leakage of the gel. The injections were always performed in the same order and by the same investigator to maintain standardisation. The patients were allowed to leave the hospital after 1 hour of observation and advised to avoid physical exercise for 2 weeks. Furthermore, activities involving pressure on the perineal region were not permitted for 4 weeks. 42 Retreatment utilised in Papers II–III was performed in the same manner but the injections were done in between the first injections (i.e. at the 1.30, 4.30, 7.30 and 10.30 clock positions). The dose at retreatment was also 1 ml x 4 giving a total dose of 8 ml. Injection technique and dosage of NASHA/Dx in Paper IV Since the patients in Paper IV had been operated for ARM, no real dentate line existed. In addition the anatomical findings were very variable. A dose of either 1 x 3 ml or 1 x 4 ml was therefore administered. The injection site selected was 3–5 mm above the mucocutaneous junction and the needle was advanced a few millimetres further so that the implant was well in the submucous layer. Statistical methods Statistical software (Statsfot, Tulsa, USA) was used for all statistical analyses. For Paper II version 9 was used, for Paper III it was version 10 and in Papers I and IV version 12 was used. Values are presented as proportions, means, medians, range or 95 per cent confidence intervals for means (95% CI) when appropriate. Fisher’s two tailed exact test was used to compare un-paired proportions. McNemar´s test was used to compare paired proportions. Wilcoxon’s signed rank test was used for paired comparisons and the Man-Whitney U-test for comparisons between groups. Spearman’s rank correlation test was used for evaluating correlations between variables. A P-value below 0.05 was considered statistically significant. Ethical and legal considerations All studies were approved by the Regional Ethics Review Board, Uppsala, Sweden. In addition the studies underlying Papers II, III and IV were approved by the Swedish Medical Products Agency. 43 Results Outcome in adults with ARM in relation to the type of malformation (Paper I) Continence The outcome of the total ARM group was significantly inferior in all nine parameters reflecting continence (Table 14). Table 14. Parameters reflecting continence for all ARM patients Values between brackets are corresponding values for matched controls. Patients with stomas have been excluded from the analysis except for the incidence of stomas. P-values <0.005 are marked with bold text and an asterisk (*). Data for all patients (N=136) Satisfied with bowel function (1-4) Permanent stoma (yes/no) Miller incontinence score Deferring time loose stool (max value =20, min) Deferring time solid stool (max value =20, min) Use of loperamid or equivalent Urgency of defecation Soiling of underpants Use of pad daytime 44 Mean P-value Yes P-value Mean Range P-value Mean Range P-value Mean Range P-value Yes P-value Yes P-value Yes P-value Yes P-value 2.8 (3.2) 0.0012* 15 (0) 0,0000* 3,8 (0,5) 0-17 (0-11) 0,0000* 8.0 (12,7) 0-20 (0-20) 0.0000* 15,3 (18,8) 0-20 (9-20) 0,0000* 21 (3) 0,0001* 60 (18) 0,0000* 39 (4) 0,0000* 25 (0) 0,0000* In total, 44 patients reported a Miller Incontinence Score of more than 5 (i.e. they had incontinence episodes of loose and/or solid stool at least once a week). Including the 15 patients with a permanent stoma, 60 patients (44 per cent of the total material) may be viewed as having unsatisfactory continence. In relation to the Krickenbeck classification, outcomes were significantly inferior for seven parameters in male recto-bulbar and female vestibular fistulas. The group with recto-prostatic or vesical fistulas had a higher Miller incontinence score (8.7 against 0.0, P=0.0369) and reduced deferring time to loose stool (4.8 against 14.8 minutes, P=0.0347). Among the Krickenbeck groups that in older classifications were categorised as low anomalies, only females with perineal fistulas had an inferior outcome for two parameters (Miller incontinence score and deferring time to loose stool, see Appendix 6 for details). Constipation The outcome of the total ARM group was significantly inferior in eight of ten parameters reflecting constipation (Table 15). Use of the Krickenbeck classification for subdivision purposes showed that male recto-bulbar fistulas had an inferior outcome in five variables and female vestibular fistulas in six variables. Female perineal fistulas had an inferior outcome in three parameters, whereas male perineal fistulas did not differ from the controls in any parameter; see Appendix 6 for details). Urogenital function Sexual function, as reflected by the two parameters measured, was significantly reduced for all ARM patients compared with the controls. On the question ‘Does your bowel function impair your interest in sexual activity?’ ARM patients scored 1.5, compared with 1.1 for the controls on the four-grade scale (P=0.0051). On the question ‘Does your bowel function reduce your sexual satisfaction?’ ARM patients scored 1.45, against 1.10 for the controls (P=0.0119). With the Krickenbeck classification, sexual function was impaired only in the female vestibular fistula group regarding both questions (see Appendix 6 for details). There were no significant differences regarding urinary incontinence or voiding problems. 45 Table 15. Parameters reflecting constipation for all ARM patients. Values in brackets are corresponding values for matched controls. All patients with permanent stomas and their matched controls have been excluded. All parameters were yes/no questions. P-values <0.05 are marked with bold text and *. Data for all ARM patients and controls Use of laxatives Use of enemas Bloating Problems with flatulence Digitation at defecation Supporting around anus at defecation Need to strain at defecation More than 10 minutes for defecation Rectum empty after defecation Several defecations for emptying Yes P-value Yes P-value Yes P-value Yes P-value Yes P-value Yes P-value Yes P-value Yes P-value Yes P-value Yes P-value 8 (3) 0.2156 18 (2) 0,0002* 43 (17) 0,0002* 29 (16) 0.0464* 15 (3) 0.0056* 9 (2) 0.0594 36 (8) 0.0000* 43 (20) 0.0011* 77 (106) 0.0000* 50 (13) 0.0000* QoL Three yes/no questions were asked: ‘Does your bowel function negatively affect your general well-being/social life/ability to go travelling?’ ARM patients reported significantly more ‘yes’ answers than their matched controls for effect on well-being (45 vs 9 for well-being P=0.0000), effect on social life (41 vs 3, P=0,0000) and ability to go travelling (10 vs 0, P=0.0016) In addition four of the SF-36 parameters were significantly lower in the ARM patients (Figure 5). When related to the Krickenbeck classification inferior outcomes were observed for male recto-bulbar and female vestibular fistulas regarding both effect on well-being and effect on social life. In addition, female vestibular fistulas had inferior outcome in both the SF-36 General Health and the Physical Cluster scale (see Appendix 6 for details). 46 Figure 5. SF-36 results for all ARM patients and their matched controls. PF=Physical Function, RP=Role Physical, BP=Bodily Pain, GH=General Health, VT=Vitality, SF=Social Functioning, RE=Role Emotional, MH=Mental Health, PCS=Physical Cluster Scale, MCS=Mental Cluster Scale. P-values below 0.05 are marked with *. 120 100 80 60 40 ARM 20 Controls 0 Spontaneous comments Twenty-seven patients provided comments, letters or emails in addition to the questionnaire responses. All these comments focused on the issue that they had no support to deal with their problems. Most of these patients had been told that there was nothing more to be done to relieve their problems except a permanent colostomy. Many had never been referred to an adult colorectal surgeon. Efficacy and safety of perianal NASHA/Dx-injection for treatment of incontinence (Paper II) Effect on incontinence At six months, 15/34 patients (44%) were defined as responders to treatment (i.e. had a 50% or more reduction in the number of incontinence episodes) and at 12 months there were 19 responders (56%). During the 4 weeks prior to treatment, the median number of incontinence episodes (loose or solid faeces) for the whole group was 22 (range: 2–77). At 12 months posttreatment the corresponding figure was 10 (range: 0–70, P=0.004 vs. baseline). 47 Before treatment, the median Miller’s incontinence score for the whole group was 14 (range: 6–18). At 6 months the corresponding figure was 12 (range 1–18, P=0.0173) and at 12 months it was 11 (range 1–16, P=0.0078). The number of patients reporting improvement and how they rated the result at 3, 6, and 12 months are presented in Table 16. Table 16. Patients’ reporting of improvement and rating of the result of treatment in relation to time after treatment Patients reporting improvement Patients’ rating of result Three months Six months Twelve months 27 (79%) 26 (77%) 25 (74%) Not measured Excellent: 3 (9%) Good: 13 (38 %) Acceptable: 14 (41%) Poor: 4 (12 %) Excellent: 4 (12%) Good: 11 (32%) Acceptable: 13 (38%) Poor: 6 (18%) Effect in relation to dose given and pretreatment characteristics At 12 months, 10 of the 16 patients treated once (62.5 per cent) were defined as responders to treatment, whereas 9 of the 18 patients treated twice (50 per cent) were defined as responders. The reduction in the number of incontinence episodes and MIS was more pronounced in the group treated twice (Table 17). Seventeen patients had clinical urge faecal incontinence, and treatment outcomes in this group were compared with those in the 17 patients with clinical non-urge faecal incontinence. No significant difference between the groups emerged from a comparison of the decrease in the number of incontinence episodes. However, there was a difference in MIS: the group with non-urge incontinence showed a significant decrease in relation to the baseline, whereas this was not evident in the group with urge incontinence (Table 17). No significant difference (P>0.05) in sensory thresholds or rectal volumes emerged from a comparison between the patients with urge and non-urge type incontinence. Neither were there any significant differences regarding those parameters evident from a comparison of responders and non-responders within these groups. The median resting pressure (MRP) and the median squeeze pressure (MSP) were calculated. The patients were then subdivided into groups according to whether they had levels higher or lower than the median value. The resulting four groups (low MRP, high MRP, low MSP and high MSP) were then compared. There were no significant differences between any of 48 these groups in terms of the decrease in the number of incontinence episodes or Miller’s incontinence score (P>0.05). The median volumes of first sensation and constant sensation were calculated. The patients were then subdivided into groups whether or they had values higher than the median value, on the one hand, or lower than or equal to it on the other. There was no clear difference in efficacy variables between these groups. There was no correlation between treatment effect and gender or age (data not shown). At each clinic visit, it was noted whether the submucosal implants could be palpated by digital examination (this was the case in 24 patients at 12 months), and whether they were visible upon rectoscopy (6 patients at 12 months). There were no significant differences between patients with or without visible implants, with regard to the decrease in incontinence episodes or Miller’s incontinence score (P>0.05). However, there was a significant decrease in the number of incontinence episodes and Miller’s incontinence score among the patients with palpable implants, in contrast to those without palpable implants (P<0.05, Table 17). Table 17. Efficacy variables in relation to number of treatments, type of incontinence and follow-up findings (values are median and range), P values for the change from pre-treatment to 12 months post-treatment are presented on the 12month figures (a=P<0.001, b=P<0.05, c=P>0.05). No. of Miller score episodes 12 months Pre 12 months Pre One treatment 21 (2-42) 7.5 (0–70)c 14 (6–18) 12 (11–16)b a Two treatments 26.5 (2–77) 12 (1–54) 14 (7–18) 9.5 (4–16)b Urge Non-urge 19 (1–72) 24 (9–77) 7 (1–54)b 15 (0–70)c 14 (16–18) 13 (7–18) 13 (6–16)c 8 (1–16)a Palpable implants 23 (1–77) 7.5 (0–54)a 14 (6–18) 9.5 (1–16)a Nonpalpable implants 20 (2–36) 16.5 (2–70)c 14 (9–18) 13.5 (6–16)c Side-effects of treatment The first injection procedure was associated with slight pain or discomfort in 26 per cent of patients, compared with 55 per cent for the second treatment. No patient reported loss of gel in the early post-treatment period. Three patients experienced symptoms of inflammation (urgency, diarrhoea and tenderness) during the first week after treatment. Two of these 49 patients were treated prophylactically with oral antibiotics since they had slightly elevated temperature (38–38.5°C). All of the symptoms resolved within one week. Rectoscopy showed evidence of a localised distal proctitis (edema and mucosal erythema) in one patient, but there were no signs of an abscess. Seven patients experienced mild pain or discomfort from time to time during the first 3 months. One patient reported periodic discomfort at 6 months, but this resolved spontaneously. Two patients experienced a feeling of obstruction at defecation, one during the first 3 months and one at 12 months. However, none of these patients had any problems defecating, and they perceived only a minor problem. Both of these adverse effects resolved uneventfully and without intervention. One patient inadvertently became pregnant some months after treatment. The pregnancy was uneventful and the child was healthy at birth. Effect on continence and QoL two years after NASHA/Dx for treatment of incontinence (Paper III) Effect on anal incontinence The median number of incontinence episodes decreased from 22 before treatment to 10 at 12 months (P=0.004) and to 7 at 24 months (P=0.0026). The median Miller’s incontinence score decreased from 14 before treatment to 11 at 12 months (P=0.0078) and to 10.5 at 24 months (P=0.0003). The changes were more pronounced in the group of patients treated twice than among the patients treated once. There was also an increase in the selfassessed satisfaction with bowel function (Table 18). No significant differences in efficacy emerged from a comparison of patients with high and low (above and below median) resting pressures or high and low (above and below median) squeeze pressures as measured on pretreatment manometry (data not shown). 50 Table 18. Treatment efficacy for all patients and for the groups treated once and twice respectively. Values are presented before treatment and at 24 months after treatment. P values <0.05 are marked in bold and *. All patients Before N=34 Number of incontinence episodes, median (range) Number of responders Miller score, median (range) Satisfaction with bowel function, mean (range) All patients 24 months N=33 One treatment Before N=16 One Two treatment treatments 24 months Before N=15 N=18 Two treatments 24 months N=18 22 (2–77) 7 (0–56) P=0.003* 22 (2–42) 11 (0–49) P=0.047* 26.5 (2– 77) 6 (0–56) P=0.018* N/A 14 (6–18) 20 10.5(1–16) P=0.000* N/A 14 (6–18) 8 12 (1–16) P=0.038* N/A 14 (7–18) 12 9.5 (3–16) P=0.003* 1.7 (1–3) 2.3 (1–4) P=0.006* 1.8 (1–3) 2.4 (1–4) P=0.067 1.6 (1–3) 2.2 (1–4) P=0.041* Effect on QoL in the whole material Before treatment, all 34 patients reported that their QoL was negatively affected by anal incontinence. At 12 and 24 months the corresponding figures were 29 (P=0.0631) and 27 (P=0.0294) patients respectively. Before treatment, 17 patients reported that they were unable to go on holiday owing to their anal incontinence. At both 12 and 24 months the corresponding figure was 10 patients (P=0.1370 and P=0.1633 respectively). There was a significant change in Physical Function at 6 months, Role Physical at 18 months and Mental Health at 6 and 18 months (Table 19). 51 Table 19. SF-36 figures for all patients. Figures are presented as median, range (within parenthesis) and p-values compared with the baseline. P values <0.05 are marked in bold figures. PF= Physical Function, RP=Role Physical, BP=Bodily Pain, GH=General Health, VT= Vitality, SF=Social Functioning, RE=Role Emotional, MH=Mental Health. PF RP BP GH VT SF RE MH Before 72.5 75 62 62 (10–100) (0–100) (0–100) (15–100) 60 (0–95) 75 (12,5–100) 100 (0–100) 68 (20–96) 6 months 75 75 64 66 (20–100) (0–100) (0–100) (15–97) P=0.041 P=0.467 P=0.478 P=0.175 62,5 (5–95) P=0.341 75 (12.5–100) P=0.313 83,3 (0–100) P=0.875 74 (16–100) P=0.046 55 (0–95) P=0.705 75 (25–100) P=0.600 50 (0–100) P=0.087 80 (20–96) P=0.071 75 75 74 67 65 (10–100) (0–100) (0–100) (20–100) (5–100) P=0.900 P=0.034 P=0.217 P=0.194 P=0.572 87,5 (12,5– 100) P=0.134 62,5 (25–100) P=0.920 100 (0–100) P=0.327 76 (20–100) P=0.010 66,7 (0–100) P=0.824 68 (24–100) P=0.084 12 months 18 months 24 months 62 75 72.5 (10–100) (0–100) (0–100) P=0.457 P=0.093 P=0.523 70 75 61,5 (15–100) (0–100) (0–100) P=0.786 P=0.820 P=0.456 61 (20–97) P=0.824 52 (10–97) P=0.388 55 (0–90) P=0.596 Effect on QoL in patients with more than 50 per cent reduction in the number of incontinence episodes at 24 months Twenty patients were responders to treatment, i.e. had a 50% or more reduction in the number of incontinence episodes. In this group there were no significant changes in SF-36 parameters at 24 months but there were increases in Physical Function scores at 6 and 18 months (P=0.005 and 0.010 respectively) and an improvement in Bodily Pain score at 18 months (P=0.037). Pre-treatment all 20 patients reported that their QoL was negatively affected by anal incontinence. At 12 and 24 months the corresponding figures were 15 patients (P=0.0558) and 13 patients (P=0.0125). Pretreatment 9 patients reported that they were unable to go on holiday owing to anal incontinence. At 12 months the corresponding figure was 4 patients (P=0.177) and at 24 months 3 patients (P=0.0845). Effect on QoL in patients with more than 75 per cent reduction in the number of incontinence episodes at 24 months Fifteen patients (six patients treated once and nine patients treated twice) had more than 75 per cent reduction in the number of incontinence episodes at 24 52 months. There were increases in the SF-36 Physical Function scores for this group at 6, 18 and 24 months (P=0.022, 0.021 and 0.038 respectively). There was also an improvement in Bodily Pain scores at 18 months (p=0.036) and in General Health scores at 6 and 18 months (P=0.046 and 0.041 respectively). Before treatment, all 15 patients reported that their QoL was negatively affected by their anal incontinence. At 12 and 24 months the corresponding figure was 10 patients (P=0.0501). Before treatment, six patients reported that they were unable to go on holiday because of their anal incontinence. At 12 and 24 months only two patients made this statement (P=0.2155). Analysis of the whole material revealed a clear correlation between the increase in SF-36 Physical Function and the decrease in the number of incontinence episodes. This correlation was significant (P<0.05) at 12, 18 and 24 months post treatment (see Fig. 6 for correlation at 24 months after treatment). There were no other clear correlations between outcome and other SF-36 parameters (data not shown). 53 Figure 6. Scatterplot of change in the number of incontinence episodes correlated to the change in SF-36 Physical function at 24 months after treatment. The line is the correlation (R=−0.596). Effect and safety of perianal NASHA/Dx-injection for treatment of persistent faecal incontinence in patients with ARM (Paper IV) Efficacy in terms of anal incontinence The mean number of incontinence episodes over two weeks before treatment was 20.7 (median 16, range 8–52). At three months the corresponding figure was 6.8 (median 4, range 0-22, P=0.0431), and at 6 months 5.3 (median 4, range 0–19, P=0.0180). The change in the number of incontinence episodes for each patient is presented in Figure 7. Six of the seven patients were defined as responders to treatment at six months (i.e. had a 50% or more reduction in the number of incontinence episodes). The mean Miller incontinence score was 13.7 (median 14, range 5–17) before treatment. At 3 months after treatment it was 10.0 (median 9, range 4–16, P=0.0679) and at 6 months after treatment it was 10.7 (median 14, range 5–15, P=0.1088). 54 60 52 50 40 Before 30 25 22 19 22 20 16 14 8 10 4 3 Pat 2 Pat 3 00 4 66 6 months 8 2 1 3 months 4 0 Pat 1 Pat 4 Pat 5 Pat 6 Pat 7 Figure 7. Change in the number if incontinence episodes over two weeks plotted for each of the seven patients. Three-month data are missing for patients 2 and 3. Effect on QoL At six months, five out of seven patients were very satisfied with the result and reported that the treatment had had a significant positive effect on their daily life. Significant improvement was found in the SF-36 Physical function subscale at six months (pre-treatment mean 74.3, 6-month mean 86.4, P=0.0431). No other significant changes could be found in either SF-36 or FIQL subscales at six months. Side-effects of treatment One patient had severe pain at injection and up to one month after treatment. This required treatment with analgetics but resolved uneventfully. Another patient had a mucous discharge, subfebrility and discomfort for three days after treatment. The patient was given antibiotics on the suspicion of local infection, but she did not take the prescribed drugs. These problems resolved uneventfully. 55 Discussion Outcome and follow-up of patients with ARM The fact that patients with ARM experience long-term problems was evident from older publications. It has also been clearly shown that patients with more complex ARMs have more problems throughout childhood and into adult life. What makes Paper I interesting in the field of ARM research is the size of the study, the matched controls and the application of the Krickenbeck classification. Paper I revealed that ARM patients as a group have more FI, constipation and sexual dysfunction, and lower QoL scores, than age- and sex-matched controls. Patients with more complex malformations have inferior functional outcomes and lower QoL scores. Forty-four per cent of the patients in Paper I had faecal incontinence at least once a week or a permanent stoma. This functional outcome was worse than that reported in earlier publications (Karkowski 1973, Nixon 1977, Kieswetter 1977, Puri 1977, Ong 1990, Yeung 1991, Rintala 1992, Hassink 1993, Rintala 1994, Rintala 1997, Rintala 2010). The definition of a poor outcome is however not clearly specified in those studies. Thus, the discrepancy may be attributable to differences in definition. This has been a continuous problem throughout the history of ARM research: most authors have had different definitions of outcome, as well as classifications, making comparisons between materials hazardous and fraught with interpretation errors. Increased use of the Krickenbeck classification in publications is therefore key for comparability of results. Paper I shows that the adult outcome of ARM can be predicted using the Krickenbeck classification. This is very important since it makes it possible to predict which patients need to be followed closely into adolescence and adulthood. Male patients with recto-bulbar fistulas and female patients with vestibular fistulas had a worse outcome than those with less complex types of ARM. The results in the groups of prostatic/vesical fistula and cloaca were proportionally worse than that of rectobulbar and vestibular fistulas. The absence of statistically significant differences in the prostatic/bladder neck fistula and cloaca patients, compared with the controls, is probably explained by the limited number of subjects in these groups. In contrast, patients with perineal fistulas and anal stenosis, which are quite simple anomalies, had outcomes that did not differ much from controls. One should however note that many patients with these ‘simple’ malformations still had 56 a suboptimal function and that female patients with perineal fistulas seem to have a slightly worse outcome. This difference may be attributed to the fact that a female perineal fistula is anatomically more similar to vestibular fistula than a male perineal fistula is to a rectobulbar fistula. The reported incidence of urological malformations, as well as associated secondary problems, has been high in the paediatric ARM population (Hamid 2007, Maerzheuser 2011). Looking at these historical figures it was surprising to see that the incidence of urological problems in Paper I was very low. Whether this was because the patients learnt to cope with their problems, the problems decreased over time or the questionnaire was too blunt is open to speculation. This area needs to be more thoroughly investigated in future studies. Sexual function is an area that paediatric surgeons in general have neglected. Paper I was not specifically designed to address this complex topic but the results indicate that patients with ARM have more sexual problems than controls. A few papers on this topic have been published in the last few years. A recent study on 15 Swedish adolescents reported that none of the eight female patients had any physical sexual problems. They did, however, report different coping strategies to minimise stigmatisation due to incontinence and/or scars during sexual intercourse. Of the seven male patients, one reported problems with impotence (Stenström 2014). A Japanese study reported a high incidence of impotence in male patients with more complex ARMs (Konuma 2006). Both these studies were based on small cohorts, which makes it hard to draw any firm conclusions. This issue needs to be addressed further The spontaneous comments recorded in Paper I show that almost a fifth of the patients spontaneously reported that there was no help available for their problems. They also reported that they were dissatisfied with the follow-up into adulthood. These patients had, for example, been told that there was nothing that could alleviate their problems except a permanent colostomy, although they were not receiving optimal conservative treatment. This is probably because ARM is such a rare condition that the average colorectal surgeon will encounter only a few cases during an entire career. Knowledge of ARM is therefore limited. These findings are in concordance with findings in adult materials from both Singapore and The Netherlands (Hartman 2005, Mantoo 2013). This issue is also debated in an article written by paediatric surgeons working in London and Los Angeles (Giuliani 2014), implying that the problems of follow-up into adolescence and adulthood are not confined to Sweden. Based on the results of Paper I and all earlier publications, it is clear that patients with ARM should be offered structured follow-up into adulthood. However, the lack of such follow-up is evident. So why is follow-up such a problem? First of all, most paediatric surgeons have historically been uninterested in helping to follow up their patients beyond adolescence. There 57 are many possible explanations for this, the most commonly stated being that paediatric surgeons need to ‘make room’ in their agenda for the newborn patients. Follow-up is then supposed to be carried out by ‘someone else’ (a general practitioner or a colorectal surgeon). This ‘someone else’, if such a person exists, seldom has both paediatric and general surgical training. Accordingly, there is no physician knowledgeable enough to take comprehensive responsibility for the patient’s problems. In the worst case scenario, patients are left without any follow-up. Paediatric surgeons therefore need to take the lead in designing a structured follow-up programme. This follow-up should preferably include gynaecological or urological consultation. Every centre that treats ARM in childhood should have either their own adolescent/adult follow-up programme or routine referral of patients to a centre that offers this service. This kind of structured follow-up would benefit not only the individual patient but also future research in terms of the long-term outcomes of ARM. Which patients should then be offered follow-up and when should it take place? The need to follow up patients with rectobulbar fistulas, vestibular fistulas and more complex malformations is clear. But considering that many patients with less severe malformations have recurrent problems, all patients should be offered follow-up so that they at least know where to contact if they encounter future problems or have questions. Patients should be transferred to an adolescent/adult follow-up programme as soon as they are discharged from the paediatric outpatient clinic (in Sweden, usually at the age of 15). If they have no special issues they should then be offered a follow-up at 18–20 years. This proposed timing takes into account the fact that many adolescent patients in their late teens may not easily be persuaded to address their problems. The effect on incontinence and role of NASHA/Dx in treatment of FI in general There is a tremendous difference in risk between conservative treatment of FI and most invasive procedures. The incidence of FI also increases with age, as does the incidence of synchronous diseases in the cardiac and respiratory systems. This in turn leads to an increase in the inherent risks of anaesthesia. Thus, many patients who would require additional treatment for their FI are disqualified from surgical treatments. In addition many younger and/or less unfit patients hesitate to undergo invasive surgery if their FI is not severe. Less invasive procedures requiring no anaesthesia are therefore called for. Injectable bulking treatment is one method that can fill the gap between conservative treatment and invasive surgery. 58 The results of Papers II and III show that submucous injection of NASHA/Dx in the anal canal significantly decreases the number of incontinence episodes, with over half of the patients experiencing a decrease of more than 50 per cent. There was a significant decrease in Miller’s incontinence score, and the great majority of the patients noted their improvement throughout the study period. In addition, global assessment indicated successful results in about 80 per cent of patients. Importantly, there was no sign of any reduction in treatment effect during the course of the study. These findings have since been confirmed by a larger, blinded and randomised multicentre study (Graf et al. 2011). There was a slight difference between patients treated once and those treated twice. The group treated twice showed significant reduction in both incontinence episodes and Miller’s incontinence score at 12 and 24 months, whereas those treated only once showed a significant decrease in Miller’s incontinence score at 12 months but significant reduction in both parameters at 24 months. Given that the group treated twice originally had higher Miller’s incontinence scores and more numerous incontinence episodes, this indicates that patients who do not experience adequate improvement following initial treatment might benefit from retreatment. In the light of the results it is, of course, arguable that every patient should be treated twice. This would, however, double the cost of treatment and probably increase its risks. Retreatment should therefore be reserved for patients with inadequate or declining effects of treatment. The results showed no significant differences between patients with high and low resting and/or squeeze pressures or between patients with differences in rectal volumes and sensory thresholds before treatment. This suggests that patients may benefit from NASHA/Dx treatment regardless of their initial manometric result. Accordingly, including anorectal manometry as a standard procedure before treatment is questionable. Patients with clinical non-urge faecal incontinence appeared to have a slightly better response to treatment than those with clinical urge faecal incontinence. However, several patients with clinical urge incontinence also showed a significant response to treatment and a larger material is probably needed before the prognostic importance of the clinical type of incontinence can be determined. In Paper II, age had no statistically significant effect on treatment outcomes. This is encouraging, since the incidence of FI increases with age. Treatment of FI with submucous injection of NASHA/Dx requires no anaesthesia and may therefore be possible in patients with multiple comorbidities who would otherwise be ineligible for any invasive treatment to be attempted. The results in Papers II–III show that the procedure of injecting into the anal canal is sometimes associated with pain or discomfort. However, the intensity of this pain or discomfort was low and no patient requested 59 cessation of the injection. In Paper II the incidence of pain was twice as common during the second treatment as during the first. The mechanism behind this is uncertain, but it may be attributable either to volume effects or to a tissue reaction following the first treatment. The only significant complications were inflammation at the injection site in three patients. These complications were treated with oral antibiotics in two cases and resolved uneventfully. An advantage of the submucous injection of NASHA/Dx is the simplicity of the procedure. It is completed in 15 minutes, and the patient is allowed to leave the hospital after an hour’s observation. This makes the treatment an attractive option for faecal incontinence patients in whom conservative treatment has failed. However, it is an invasive procedure in an anatomic location prone to chronic infections, and appropriate patient selection and correct injection technique are probably key to successful results. Moreover, it is essential to position the implants in the correct anatomical location. If they are sited too low, the patient will experience pain and the implant may prolabate through the anus. Placing them too high will create rectal elevations and probably render them ineffective. The reason for choosing four injection sites of injection was to create a symmetric ring-formed tissue expansion caused by the size of the bulges in the restricted anatomic space. The rationale for using 5–10 mm supra dentate injections was that a tissue expansion at this level is intended to cause a rise in pressure at the cephalad part of the high-pressure zone, preventing rectal pressure from exceeding anal pressure and thereby avoiding leaks. Another reason was that it is less painful because of the absence of somatic innervation. The volume injected was selected after a review of volumes used with other agents and in consideration of the available anatomic space. It was also decided to use a submucous injection since this is readily performed through the proctoscope under direct vision and avoids introduction of skin flora into the implant. Several agents have been tested as injectables for faecal incontinence. Of these, carbon-coated zirconium beads (Durasphere, Carbon Medical Technologies) and injectable silicone biomaterial (PTQ, Uroplasty, Geleen, Netherlands) have received most attention. Carbon-coated zirconium beads are injected into the submucosal layer but through the sphincters, as opposed to the injection technique described in this paper. Trans-sphincteric injection would be more cumbersome to perform and the location of the implant is difficult to define precisely. Injection of carbon-coated zirconium beads is associated with a reduction of approximately 30 per cent in incontinence score after a minimum follow-up of 10 months (Altomare 2008). Injectable silicone implants are placed in the intersphincteric layer and are also injected by the trans-sphincteric route, and the results appear to be superior when the injection is guided by ultrasound (Tjandra 2004). However, silicone treatment has been followed by abscess formation in a significant proportion of patients (Gett 2007). Collagen has also been tried as an injectable for 60 incontinence, with some success (Stojkovic 2006). Submucous injection of Permacol has been tried and the reported outcome has been variable (Maeda 2007, Hussain 2012). Compared with other injectable treatments, NASHA/Dx appears to be an easier and quicker procedure with similar, or possibly higher, efficacy. Possible reasons for an improved effect are the biodegradable nature of Hyaluronan and the fact that the remaining Dextranomer builds a framework for collagen ingrowth. NASHA/Dx is no miracle cure and physicians should inform the patients that it may elicit an improvement in their symptoms and QoL, but that it is unlikely to resolve all the symptoms. In view of this, NASHA/Dx may be a very useful adjunct in treating FI. Improving QoL when FI is treated In Paper III a positive effect on QoL, as measured by self-assessment, was observed. This change was significant for patients experiencing a more than 50 per cent reduction at 24 months. For the patients with a more than 75 per cent reduction in the number of incontinence episodes, there was a similar improvement but the difference was not significant. This is in concordance with studies of PTQ using visual analogue scales for evaluation of QoL (Tjandra 2004, Bartlett 2009). A decrease in the number of patients who felt inhibited to go on holiday owing to anal incontinence was observed. This reduction was not significant and it occurred first at 12 months. This may be because it takes time for the injected anal cushions to stabilise and possibly for the patients to start trusting the improvement in continence and daring to go on holiday. It should be noted that although the effect on self-assessed QoL was significant, it nonetheless improved only to a limited extent. Analysis of the whole material showed a modest impact on SF-36 scores. This was somewhat discouraging, but is similar to the results found in studies of PTQ (Soerensen 2009) and a study with Durasphere (Altomare 2008). Significant results on SF-36 have, however, been reported in studies of PTQ (Maeda 2007) and the Gatekeeper prosthesis (Ratto 2012). In Paper III it was found that a 75 per cent reduction in the number of incontinence episodes was required to obtain a significant rise in Physical Function scores over time. Several SF-36 subscales show improvements with just a 50 per cent reduction, but a larger material is needed to show whether a significant positive effect exists at this improvement level. Thecorrelation between the falling number of incontinence episodes and rising SF-36 Physical Function conforms to the findings in the 75 per cent reduction group. It also implies that there may be an effect on Physical Function for all patients. It should, however, be noted that all significant improvements in SF-36 scores except Physical Function disappeared at 24 months. Whether this depends on a diminishing effect on QoL over time or 61 not is hard to say. SF-36 was designed as a general instrument, and to obtain a significant change in SF-36 QoL subscales we conclude that highly substantial treatment effects must be attained. Faecal incontinence QoL (FIQL) is a more disease-specific instrument that is probably more suitable for analysing the effect on QoL of treating faecal incontinence. However, validated translated versions were not available when this study started. The normal definition of a ‘responder to treatment’ of FI is someone whose frequency of incontinence episodes falls by 50 per cent or more. The findings in Paper III raise an interesting question: whether the criterion should be raised to a 75 per cent reduction. This issue has great relevance for all procedures intended to improve continence, especially sacral nerve stimulation, where a 50 per cent reduction with the temporary electrode is used as a criterion for permanent implantation (Gourcerol 2007). It is tempting to speculate that the results after permanent stimulation would improve if this limit were increased to 75 per cent, thus improving costeffectiveness. The role of NASHA/Dx in treatment of FI in patients with ARM In Uppsala, six different secondary procedures for treating persistent FI after ARM have been employed over the years: FAMT, Stephens’ secondary pullthrough, local mucosectomy, implantation of artificial balloon-type sphincter, DGP and appendicostomy or Chait buttons. Today only three of these methods exist in clinical practice. At the department of general surgery in Uppsala local mucosectomy and the occasional DGP are performed in this group of patients. In the department of paediatric surgery, local mucosectomy is performed when needed but the most commonly utilised procedure is a formation of a conduit for antegrade enemas either as an appendicostomy (with or without an indwelling catheter) or through a permanently implanted catheter. The reduction in the arsenal utilised is due to the somewhat discouraging long-term efficacy of FAMT (Hakelius 1991, Danielson 2010) and Stephens’s secondary pull-through, as well as severe complications with artificial balloon sphincters. The use of DGP in patients with ARM is controversial after its efficacy in this patient group was reported as inferior to that in other types of FI and the incidence of severe complications as high (Koch et al. 2004). The Uppsala experience is, however, that more than half of the ARM patients found DGP most helpful and used it at median 11 years after surgery (unpublished data in manuscript form). In addition, DGP is able to restore anatomy and provide the patient with a more ‘normal-looking’ anus. Hence DGP is still offered to selected adult patients with severe persistent FI after ARM. 62 Antegrade enemas are a convenient procedure in the way that it produces a reproducible time of social continence. Therefore it is relatively ‘safe’ for the patient. It is however a procedure that has possible drawbacks and it is not a perfect way of dealing with FI for all patients. Considering the small arsenal available to treat patients persistent FI after ARM, the option of treating FI with injectable bulking agents would be a welcome addition. In particular it is an option for patients with moderate FI who would not accept the inherent risks and time consumption of treating their FI with antegrade enemas or an operation with DGP. The preliminary data presented in Paper IV suggest that NASHA/Dx has a significant effect on the number of incontinence episodes in selected adult patients with persistent FI after ARM. The reduction in incontinence episodes appears to be at least of the same magnitude as that reported after injection treatment with NASHA/Dx for FI of other aetiologies. The incidence of adverse events was low and comparable to that reported in other studies. The patients included in Paper IV were carefully selected, which limits the external validity of the data. It should be stressed that Paper IV does not show that injectable bulking therapy with NASHA/Dx is an ideal procedure for all patients with persistent FI after ARM. Anorectal anatomy is highly variable in these patients and it is essential to consider the anatomy regarding stenosis, scarring and prolapse in the pre-treatment evaluation. In addition, Paper IV is a pilot study and a larger patient material is needed to draw definite conclusions. However, it seems that NASHA/Dx has a potential of being a good adjunct for selected patients. Further studies are required to confirm the data presented and see whether the treatment can be used in adolescence and older children. 63 Conclusions Overall, the outcome of adult ARM is far from satisfactory and many patients have suboptimal function and QoL which indicate an urgent need for structured follow-up into adulthood (I). The Krickenbeck classification can be used to predict the functional result into adulthood and thus the need for structured follow up after ARM surgery (I). NASHA/Dx is effective as a compound for perianal, submucous injection therapy for treatment of FI. It reduces the number of faecal incontinence episodes by more than 50%. The effect lasts at least two years after treatment (II, III). NASHA/Dx seems to have the potential to improve QoL. The reduction in incontinence episodes need to 75% or more to accomplish this (III). NASHA/Dx is a compound that that seems safe as a submucous injectable bulking treatment for anal incontinence (II, III). NASHA/Dx seems to be as safe and effective in treatment of persistent faecal incontinence after ARM as it is in other categories of patients with FI (IV). 64 Future perspectives The area of ARM care into adolescence and beyond is a neglected field. Paper I pointed out several areas in which future research is needed: gynaecological, urinary, functional studies on anorectal function etc. There is also another group of paediatric surgical patients that often have anorectal problems into adulthood: patients with Hirschsprung’s disease. Do we really know how they are doing in adulthood? Are they also in need of more specialised care? Could they benefit from modern treatment options for FI and/or constipation? A study of the bowel function of patients operated for Hirschsprung’s disease in Uppsala is currently under way. Treatment of FI with NASHA/Dx has proved effective for adult patients. The preliminary results of Paper IV imply that it also could be effective for adult patients with ARM. The pilot study needs to be enlarged and the patients followed over a longer period of time. . There are also the adolescent and older paediatric patients with ARM and persistent FI. Could they benefit from treatment with NASHA/Dx at a younger age or should they have to wait until their 18th birthday? Injectable bulking therapy is one of the two relative novelties in the treatment arsenal of FI. The other is sacral nerve stimulation. Could patients with persistent FI after ARM benefit from this treatment as well? The problem here is that patients with ARM often have sacral deformities that make sacral nerve stimulation difficult. To date there have been no major studies published on this subject, and further research needs to be done. 65 Populärvetenskaplig sammanfattning (Summary in Swedish) Anorektal missbildning (ARM) innebär att det finns en missbildning av ändtarmens läge eller dess anatomi. Ungefär 1/2500-1/5000 barn föds med ARM. Av de drabbade är något mer än hälften pojkar. ARM innehåller ett spektrum av missbildningar: allt från en försnävning av ändtarmsmynningen till tillstånd där ändtarmen sitter ihopkopplad med urinblåsan hos pojkar och till urinblåsan/slidan hos flickor (s.k. kloakmissbildning). Beroende på missbildningens allvarlighetsgrad behöver man göra olika medicinska och kirurgiska insatser. Allt från att enbart observera tillståndet till att göra komplexa flerstegsoperationer. ARM är också kopplat till en ökad risk för missbildningar i andra organsystem (hjärta, matstrupe, rygg, njurar och skelettet i armar och ben). Möjligheterna att göra något åt dessa missbildningar innan antibiotikan och modern narkos utvecklades var mycket begränsade. Det är därför först från 1930-talet och framåt som man har förfinat kirurgiska metoder för att åtgärda problemet. Resultatet efter ARM i barnaåren har studerats relativt mycket de senaste 30 åren. Patienter med mer komplicerade missbildningar har inte haft några lysande resultat med både läckage och förstoppning. Det har därför tagits fram ett stort antal kirurgiska operationsmetoder för att försöka förbättra detta. Inga av dessa har varit inneburit någon succé och har ofta inneburit relativt stora kirurgiska eller infektiösa risker. Mer moderna behandlingsmetoder för anal inkontinens har däremot inte prövats på patienter med ARM. Hur patienter med ARM har det i vuxen ålder har däremot inte studerats mycket. Man vet från de studier som gjorts att resultaten har varit tämligen nedslående för patienter med allvarligare missbildningar. De studierna har dock gjorts med äldre klassificeringssystem vilket gör det mycket svårt att förutsäga enskilda patienters prognos. Utan en säker prognos är det givetvis svårt att veta vilka patienter man ska följa mer intensivt från sjukvårdens sida. Målet med denna avhandling var tre: 1. Att ta reda på hur de patienter som opererats för ARM i Uppsala mår som vuxna och jämföra detta med personer som inte hade ARM. 2. Ta fram en injektionsbehandling för att behandla anal inkontinens hos vuxna som inte hade ARM. 3. Utvärdera 66 denna behandling på vuxna patienter med ARM som hade stora problem med anal inkontinens. Avhandlingen består av fyra delarbeten. I delarbete I följde man upp de patienter som opererats för ARM i Uppsala fram till 1993. 203 patienter kunde spåras och 136 av dessa deltog i uppföljningen. Patienterna utvärderades med tarmfunktions- och livskvalitetsenkäter. Resultaten från dessa jämfördes sedan med 136 friska köns och åldersmatchade kontrollpersoner. Man återfann att patienter med ARM hade signifikant mer problem med inte bara anal inkontinens men också förstoppning, påverkan på sexuallivet och livskvalitet. Patienter med mer komplexa missbildningar hade betydligt mer problem inom samtliga områden. Baserat på de symptom som rapporterades kan man tolka att det finns ett stort behov för strukturerad uppföljning av denna patientgrupp ända upp i vuxen ålder. I delarbete II och III undersökte man hur injektion av en substans kallad NASHA/Dx (enkelt beskrivet stora sockermolekyler uppblandade i hyaluronsyra) kan användas för att förbättra anal inkontinens. Behandlingen går till så att man sprutar in 4 x 1 ml av läkemedlet under slemhinnan någon cm upp i ändtarmen. Man behandlade 34 vuxna patienter med anal inkontinens. Patienterna följdes sedan med regelbundna kontroller under två år. Resultaten visade att man kunde minska antalet inkontinensperioder signifikant och att effekt höll i sig i åtminstone två år. Man kunde också visa att man signifikant kunde påverka livskavlitetsparametrar i positiv riktning, Dock krävdes det då att man minskade antalet inkontinensperioder med 75% eller mer. I delarbete IV behandlade man sju vuxna patienter som hade ARM och anal inkontinens med NASHA/Dx. Patienterna följdes med kontroller i sex månader och man kunde se en signifikant minskning av antalet inkontinensepisoder. Avhandlingens resultat visar att behovet av regelbundna kontakter med sjukvården för patienter med ARM sannolikt inte försvinner i och med att de blir vuxna. Många har handikappande problem och är i behov av att kunna komma i kontakt med specialisthjälp. En specialisthjälp som tyvärr inte finns organiserad i Sverige idag. Vidare visar den att injektion av NASHA/Dx kan vara en enkel och effektiv behandling vid anal inkontinens i allmänhet och att denna metod även verkar effektiv på vuxna patienter med ARM och anal inkontinens. 67 Acknowledgements A thesis can never come into existence without substantial support from the people surrounding the writer. This thesis was no exception to this rule. I owe great gratitude to most of my surroundings in different ways for both support in research and my parallel surgical education. I would especially like to thank the following. Wilhelm Graf, my main supervisor; for sharing your vast experience in the field of science and for your uncanny ability to show me that what I thought was good was actually mediocre and could always become better. Without you the scientific content of this thesis would not have been close to what it is today. Tomas Wester, my co-supervisor, clinical supervisor and guide into the international paediatric surgical community; words are not enough. Without you this thesis would have been something completely different. You have opened both windows for my eyes and doors for me to pass through, with tremendous generosity. Urban Karlbom, my co-supervisor; for being the voice of reason in our research group. Whenever Wille, Tomas and I were on the verge of going overboard with something you always managed to get us back on track with a few choice words. Staffan Meurling, Arne Stenberg, Erik Sköldenberg, Ewa Lundgren, Staffan Wollert and Claes Juhlin, former and present heads of the Departments of paediatric and general surgery for providing working conditions that made this work possible. Lars Wiklund and Olle Nilsson, former and present heads at the Department of Surgical Sciences for providing conditions that made this work possible. Ann-Cathrine Sonnesson, a specialist nurse at the surgical outpatient clinic and co-writer, for passing on the torch to me and giving me invaluable advice in the beginning of my work with Wille. 68 Liselotte Zetterlind and Kerstin Lindblad, specialist nurses at the paediatric bowel and stoma outpatient clinic, for all your support in my efforts to bring specialist care to adult patients with ARM. The staff at the adult surgical outpatient clinic: Without your help and hands-on support, Paper IV could not have come into existence. Tomas Lorant – friend and supporter in all aspects regarding red tape when it comes to Uppsala University. Britt Husberg, paediatric and colorectal surgeon, Stockholm, for believing in and supporting my plans for establishing structured follow-up of adult patients with ARM. The members of the colorectal research collaboration at the department of surgical sciences: during the time it has taken for me to complete this thesis, the members have shifted far too many times. None mentioned, none forgotten. Thank you for the interesting and fruitful discussions on various research topics. The members of Tomas Wester’s research group in Stockholm who have welcomed me into their midst, for adding that important paediatric surgical point of view to my insights into research. Working in an ‘adult research environment’ has been more than helpful. All my current and former colleagues at the department of paediatric surgery (in no special order); Staffan Meurling: for calling me at 22.00 20031223 and offering me a job. If not for that I would probably not have stayed in paediatric surgery and I would not have met my wife. I also think I owe thanks to you for having put in a good word for me regarding research funding. Elisabet Gustavson: my clinical supervisor during the latter part of my residency; for always being supportive on my road from residency to specialist paediatric surgeon and beyond. Gertrud Angsten: for all that we have accomplished by working together regarding gastrostomies and for the knowledge that you have shared. Helene Engstrand-Lilja: for the knowledge of neonatal surgery that you have shared with me. Rolf Christofferson: for all our interesting discussions, scientific support and coaching me in ARM surgery. Ammar Al-Mashadi: for the hands on learning of ARM surgery. Kai Arnell: for teaching me the basics of paediatric surgery all those years ago. Gillian Barker: for hands-on teaching of paediatric urology and supporting me on my minimal-invasive ramblings. Göran Läckgren: for always coming when we need him and showing me what a surgeon can do in open surgery. I bow in the presence of the master. Arne Stenberg: for always being a friendly colleague and starting to believe 69 in my ramblings regarding adolescent surgery. Nils Wåhlin: for showing me how a surgeon should behave, no matter what the circumstances are, you are my beacon. Erik Sköldenberg: for all the laughs in the past and present, as well as your magnificent way of trying to realise my dreams of an outpatient clinic for adolescent and adult patients with malformations. Anders Stenbäck: my friend and pair-horse during residency. For all the good times and all the support we have given each other during the rough times. Niclas Högberg: for showing me that a thesis could be put together in our environment and sparring with me about minimal invasive surgery. Peter Flacker: the ever friendly and enthusiastic worker who will brighten one’s day just by turning up. Thora Olafsdottir: For putting up with my ‘endless complaining’ and just being such a wonderful and positive person to work with. Fanny Fredriksson and Filippe Donoso: As the newest additions to our merry band you add that vitamin injection that all workplaces need. My former colleagues at the department of general surgery. You are too many to name but a few of you. Staffan Wollert and Mikael Ljungdahl: for really igniting my interest in minimally invasive surgery. Haile Mahteme: the father of a lion’s share of my surgical skills acquired during my residency in general surgery. Ib Rasmussen: for listening to a young colleague’s gut feeling. Ola Hessman: my clinical supervisor in general surgery. Eva Lundgren: who in 2007 gave me the advice that one should not try to finish residency and a thesis at the same time. Obviously I took that advice to heart. All my dear friends: I would not like to take the risk of leaving anyone out by mistake. You know who you are. You have had the good sense to distract me from my research over the years. As a result this thesis, like a good whisky, has had the time to mature and ripen. Last but definitely not least, my close family. My mother Birgitta Danielson, for always believing in me and supporting me no matter the circumstance. To my late father Ebbe Danielson for all the support and for showing me that no matter how hard you fall you can always rise and conquer. My dear brother Peter Danielson, who has always been the most avid supporter of his baby brother. My family-in-law – Eje, Ingrid, Nicklas, Klas and Teres for including me in your family and helping us to get the puzzle of life together. 70 My wonderful wife Nathalie. Without you and the life we have created together, life would be dull and grey. I love you more than words can say. My stepdaughter Emma and daughters Amanda and Alva: you have done the same thing as my friends: kept me away from completing this thesis in a reasonable time. But it has always been an easy thing to choose between pretending to write science and spending time with you. You show me aspects of the world that I would otherwise miss and then I would be less of a man. Together with your mother you are the centre of my universe. 71 Appendices 73 2-veckors ”dagbok ” över inkontinensepisoder Markeringen gör du på aktuell dag och under vilket tidsintervall du var på toaletten. N för normalt toalettbesök, G för gasinkontinens, L för inkontinens av lös avföring F för inkontinens av fast avföring Vid varje episod av normal avföring eller inkontinens gör du en markering i form av en bokstav: Dagboken är designad för att ta reda på inkontinensmönster samt hur dina avföringsvanor ser ut. Med inkontinens menas en episod av ofrivilligt gasläckage eller läckage av lös eller fast avföring. Instruktion Dagboken ska fyllas i under en tvåveckorsperiod. Denna period ska ligga så nära din behandling/ditt besök som möjligt Inför behandlingen och uppföljningen med Solesta är det mycket viktigt att du fyller i denna dagbok. Resultaten hjälper oss att utvärdera effekten av din behandling. Appendix 1: 2-week diary Klockan 23-07 Natt Klockan 18-23 Eftermiddag Klockan 12-18 Förmiddag Klockan 7-12 Morgon Veckodag Datum Tid Namn: Dag 1 Dag 2 Dag 3 Dag 4 Dag 5 Dag 6 Dag 7 Dag 8 Personnummer: Dag 9 Dag10 Dag 11 Dag 12 Dag 13 Dag14 Appendix 2: Validated bowel function questionnaire Var vänlig fyll i ditt födelsedatum (år, månad, dag): ……………………. Var vänlig fyll i dagens datum (år, månad, dag): …………………….. Kön Man Kvinna Längd …………………….. Vikt …………………….. Släkting med Hirschsprungs sjukdom? Ja Nej Släktrelation………………………………………………………………………… …… Släkting med anorektal missbildning? Ja Nej Släktrelation………………………………………………………………………… …… Släkting med inflammatorisk tarmsjukdom Ja Nej Släktrelation………………………………………………………………………… …… Frågor rörande yrke 1. Är Du idag yrkesverksam?       76 Ja, arbetar som ………………………………………………………………….. Nej, studerar …………………………………………………….……………… Nej, är långtidssjukskriven Nej, uppbär sjukpenning Nej är förtidspensionerad Nej, är arbetssökande 2. Har Dina ändtarmsbesvär i barnaåren haft någon inverkan på ditt yrkesval?   Ja Nej Frågor rörande tarmfunktion 1. Har Du stomi?     2. Nej Ja, ileostomi (hoppa över fråga 11-36) Ja, colostomi (hoppa över fråga 11-36) Ja, oklart vilken sort (hoppa över fråga 11-36) Hur ofta har Du avföring/behöver du tömma stomipåsen?        3. Använder Du piller, droppar, pulver eller vätska för att hålla tarmen igång?   4. Ja, i så fall vad? ……………………………………………………… Nej Använder Du lavemang?    5. Mer än 2 ggr/dag 2 ggr/dag 1 gång/dag Ungefär varannan dag Ungefär 2 ggr/vecka Ungefär 1 gång/vecka Mer sällan än 1 gång/vecka Ja, via ändtarmen ………..ggr per vecka Ja, via ”appendicostomi eller knapp” ………….ggr per vecka Nej Använder Du mikrolavemang (Toilax, Microlax etc?)?   Ja, i så fall hur ofta? ………………………………………………….. Nej 77 6. Använder Du någon form av stoppande medicin (imodium, loperamid el dyl)   7. Hur är avföringens konsistens?     8.  Ja Nej Besväras Du av mycket gaser?   11. Ja, i så fall hur ofta/när kommer de och var i magen sitter de? …………………………………………………………… ………………. …………………………………………………………… ………………. Nej Besväras Du av uppblåsthet i buken?   10. Lös, dvs ej formad Normal, dvs mjuk och formad Hård Växlande mellan lös och hård Besväras Du av smärtor i buken/bäckenet?  9. Ja Nej Måste Du hjälpa till med fingret eller annat föremål för att få ut avföringen? Ja Nej Måste Du stödja med fingrarna kring ändtarmen eller i slidan för att få ut avföringen?   12.   78 Ja, i så fall hur ofta? ………………………………………………….. Nej Ja Nej 13. Måste Du krysta hårt för att få ut avföringen?   14. Behöver Du sitta länge för att tömma tarmen?     15. Ja Nej Nej Ja, cirka 10 minuter Ja, cirka 20 minuter Ja mer än 20 minuter Försök uppskatta under hur stor del av tarmtömningen som Du behöver krysta. ---------------------------------------------------------------------------------Ingen Halva Hela 16. Tycker Du att det är svårt att få tarmen att kännas tom efter toalettbesök?   17. Måste Du gå flera gånger på toaletten samma dag för att det ska kännas tomt?   18. Ja Nej Har Du ofrivilligt läckage av gaser?      19. Ja Nej Nej Ja, enstaka gånger Ja, minst 1 gång/vecka Ja, dagligen Har Du ofrivilligt läckage av lös avföring?     Nej Ja, enstaka gånger Ja, minst 1 gång/vecka Ja, dagligen 79 20. Har Du ofrivilligt läckage av fast avföring?     21. Om Du besväras av avföringsläckage vilken beskrivning passar bäst in på de läckage Du upplevt?    22. Ja Nej Kan Du skillnad på om det är gas eller avföring i tarmen?   80 Ja Nej Känner Du när avföringen kommer?   27. Ja Nej Har Du besvär med klåda kring ändtarmen?   26. Ja Nej Har Du problem med nedsmutsning av trosor/kalsonger?   25. Ja Nej Bär Du någon form av skydd mot avföringsläckage dagtid?   24. Plötsligt har det inträffat ett läckage utan att jag har känt det? Jag får trängningar till avföring men kan ej hålla emot Läckage av avföringsfärgat slem och nedsmutsning av underkläder Bär Du någon form av skydd mot avföringsläckage nattetid?   23. Nej Ja, enstaka gånger Ja, minst 1 gång/vecka Ja, dagligen Ja Nej 28. Måste Du snabbt till en toalett när Du känner att Du behöver?   29. Ja Nej Från det att Du fört känner behov av att tömma tarmen hur, hur länge kan du hålla Dig? Vid lös avföring -------------------------------------------------------------0 5 10 15 20 minuter 30. Från det att Du fört känner behov av att tömma tarmen hur, hur länge kan du hålla Dig? Vid fast avföring -------------------------------------------------------------0 5 10 15 20 minuter 31. Besväras Du av smärtor i eller kring ändtarmen?   32. Har Du smärtor i tarmen/bäckenet/buken i samband med avföring?   33. Ja Nej Besväras Du av blödning från tarmen eller tarmöppningen?   35. Ja Nej Har Du smärtor i tarmen/bäckenet/buken efter avföring?   34. Ja Nej Ja Nej Försök att uppskatta ungefär hur många gånger Du har avföring under en ”vanlig” vecka ………..ggr 81 36. Försök att uppskatta ungefär hur många gånger Du skulle ha avföring under en vecka ifall du inte tog några lavemang eller mediciner för att reglera avföringsfrekensen ………..ggr 37. Är Din tarmfunktion besvärande för Ditt allmänna välbefinnande?   38. Är Din tarmfunktion besvärande för Ditt umgängesliv?   39. Ja Nej Behöver Du hålla diet på grund av Dina tarmbesvär   40. Ja Nej Ja, i så fall vad undviker Du att äta? …………………………………………………………… ………………. Nej Är Dina besvär med tarmen så svåra att de hindrar Dig från att resa på semester?   Ja Nej Frågor rörande urinvägsfunktion 1. Kan Du hålla tätt för urin vid hosta, nysning, skratt eller tunga lyft?   2. Tycker Du att Du har svårt att tömma urinblåsan?   82 Ja Nej Ja Nej Frågor enbart gällande kvinnor 1. Hur många vanliga förlossningar har Du genomgått? …………stycken 2. Användes tång vid någon förlossning?   3. Användes sugklocka vid någon förlossning?   4. Ja Nej Har Du skötts av gynekolog på grund av underlivsframfall?   7. Ja Nej Är det känt om Du fick en skada på slutmuskeln vid någon förlossning?   6. Ja, vid …………stycken förlossningar Nej Blev Du sydd i underlivet i samband med någon förlossning?   5. Ja, vid …………stycken förlossningar Nej Ja Nej Har Du opererats på grund av underlivsframfall?   Ja Nej 83 Frågor rörande operationer på tarmen/ändtarmen 1. Har Du vårdats för besvär i tarmen/ändtarmen vid något annat sjukhus/vårdcentral än Akademiska sjukhuset?   Ja Nej Om ja: Vid vilket/vilka sjukhus? …………………………………………… 2. Har Du opererats i tarmen/ändtarmen på något annat sjukhus än Akademiska Sjukhuset i Uppsala?   Ja Nej Om ja: Vid vilket/vilka sjukhus? …………………………………………… Om ja: Med vilken sorts operation? ……………………………………….… 84 Appendix 3: Non-validated questionnaire Instruktioner: I denna enkät tillkommer några frågor till den tarmfunktionsenkät som du besvarade ovan. Svaren är graderade 1-4. 1 = Inte alls, 2 = Lite, 3 = En hel del, 4= Mycket. Besvara frågorna genom att sätta en ring runt den siffra som stämmer in bäst på Dig. 1. Är Du nöjd med hur din tarm fungerar? 1 2 3 4 2. Har Du haft svårigheter tömma urinblåsan? 1 2 3 4 3. Besväras Du av urinläckage? 1 2 3 4 4. Begränsar Din tarmfunktion Ditt intresse för sex? 1 2 3 4 5. Påverkar Din tarmfunktion Dig i njutningen av sex? 1 2 3 4 6. Är Du begränsad i din förmåga att få erektion? 1 2 3 4 7. 1 2 3 4 Frågorna nedan enbart för män: Har du problem att få sädesuttömning? 85 Appendix 4: SF-36 QoL-questionnaire 86 87 88 Appendix 5: FIQL Frågeformulär för mätning av livskvalitet vid avföringsinkontinens Besvara frågorna genom att sätta en ring runt den siffra som stämmer in bäst på Dig. F1: Din hälsa kan i allmänhet beskrivas som: 1. 2. 3. 4. 5. F2: Utmärkt Mycket god God Måttligt god Dålig Vänligen ange för varje påstående hur stor del av tiden frågan är till bekymmer för dig pg.a. ofrivilligt avföringsläckage. Pga ofrivlligt avföringsläckage: Jag är rädd för att gå ut. Jag undviker att besöka vänner Jag undviker att övernatta borta från hemmet Det är svårt för mig att komma ut och göra saker som att gå på bio eller på konsert. Jag drar ner på hur mycket jag äter innan jag går ut. Jag försöker att hålla mig i närheten av en toalett så mycket som möjligt när jag är borta från hemmet. 1 1 1 En del Av tiden 2 2 2 1 2 3 4 1 2 3 4 1 2 3 4 Det är viktigt att planera mitt schema (dagliga aktiviteter) runt mina avföringsvanor. 1 2 3 4 h. Jag undviker att resa. 1 2 3 4 i. Jag oroar mig för att inte kunna ta mig till toaletten i tid. 1 2 3 4 j. Jag känner att jag inte har någon kontroll på min tarmfunktion. 1 2 3 4 k. Jag kan inte hålla mig tillräckligt länge för att nå toaletten. 1 2 3 4 l. Jag läcker avföring utan att jag märker det. 1 2 3 4 m. Jag försöker undvika olyckor genom att hålla mig väldigt nära en toalett. 1 2 3 4 a. b. c. d. e. f. g. För det mesta En liten del av tiden 3 3 3 Aldrig 4 4 4 89 F3: P.g.a. ofrivilligt avföringsläckage, ange i vilken utsträckning du HÅLLER MED eller INTE HÅLLER MED vart och ett av följande påståenden. F3. P.g.a. ofrivlligt avföringsläckage: Håller Håller Håller Håller Med med till inte med inte helt viss del till viss med alls del a. Jag skäms. 1 2 3 4 b. Jag kan inte utföra många av de 1 2 3 4 aktiviteter jag skulle vilja utföra. c. Jag oroar mig för olyckor. 1 2 3 4 d. Jag känner mig nedstämd. 1 2 3 4 e. Jag oroar mig för att amdra känner 1 2 3 4 att jag luktar avföring. f. Jag känner mig inte som en frisk 1 2 3 4 person. g. Jag njuter mindre av livet. 1 2 3 4 h. Jag har sex mindre ofta än vad jag 1 2 3 4 skulle vilja ha. i. Jag känner mig annorlunda från 1 2 3 4 andra människor. j. Jag tänker hela tiden på att en 1 2 3 4 olycka kan inträffa. k. Jag är rädd för att ha sex. 1 2 3 4 l. Jag undviker att resa med flyg eller 1 2 3 4 tåg. m. Jag undviker att gå ut och äta. 1 2 3 4 n. Varje gång jag kommer till en ny 1 2 3 4 plats, tar jag reda på var toaletterna finns. F4: Under den senaste månaden, har du känt dug så ledsen, modfälld, utanhopp, eller haft så många problem att du undrat om det var värt att göra något över huvud taget? 1. 2. 3. 4. 5. 6. 90 Extremt mycket – Till den grad att jag nästan gett upp Väldigt mycket En hel del Något – Tillräckligt för att besvära mig Lite grann Inte alls Appendix 6: Full tables of the ARM-patients and their matched controls outcomes subgrouped according to the Krickenbeck-classification 91 Mean P-value Yes No P-value Mean Range P-value Mean Range P-value Mean Range P-value Yes No P-value Yes No P-value Yes No P-value Yes No P-value RBF (N=30) 2,7 (2,8) 0,09941 5 (0) 25 (30) 0,0522 5,6 (0,7) 0-16 (0-8) 0,0000* 6,1 (13,4) 0-20 (1-20) 0,0003* 14,7 (19,1) 2-20 (9-20) 0,0162* 9 (1) 16 (24) 0,0106* 15 (3) 10 (22) 0,0009* 12 (1) 13 (24) 0,0008* 9 (0) 16 (25) 0,0016* PF (N=24) 3 (3,5) 0,1975 1 (0) 23 (24) 1,0000 1,2 (0,1) 0-11 (0-1) 0,0680 11,9 (12,6) 0-20 (5-20) 0,08518 17,3 (19,0) 0-20 (15-20) 0,9650 0 (1) 24 (23) 1,0000 7 (2) 16 (21) 0,1346 3 (0) 20 (23) 0,2333 1 (0) 22 (23) 1,0000 NF (N=16) 2,9 (3,3) 0,1178 1 (0) 15 (16) 1,0000 2,8 (0,5) 0-15 (0-1) 0,2517 9,3 (15,3) 2-20 (5-20) 0,0465* 15 (19,3) 5-20 (10-20) 0,0890 1 (0) 14(15) 1,0000 5 (1) 10 (14) 0,1686 3 (0) 12 (15) 0,2241 4 (0) 11 (15) 0,0996 AS (N=5) 3,4 (3,4) 0,5309 0 (0) 5 (5) 1,0000 0,2 (0,4) 0-1 (0-1) 0,2517 11,4 (11,4) 2-20 (4-20) 1,0000 20 (18) 20 (10-20) 0,6761 0 (0) 5 (5) 1,0000 1 (0) 4 (5) 1,0000 0 (1) 5 (4) 1,0000 0 (0) 5 (5) 1,0000 Parameters regarding continence for male patient-subgroups, VPF=Vesical and prostatic fistula, RBF= Recto-bulbar fistula, NF= No Fistula, AS= Anal Stenosis. Values between brackets are corresponding values for matched controls. All patients with permanent colostomies and their matched controls have been excluded in the analysis of all parameters except the incidence of permanent stomas. Use of pad daytime (yes/no) Soiling of underpants (yes/no) Need to rush to toilet (yes/no) Use of loperamid or equivalent (yes/no) Deffering time solid stool (max value =20, min) Deffering time loose stool max value =20, min) Miller incontinence score Satisfied with bowel function (1-4) Permanent stoma VPF (N=5) 3 (3,5) 0,5309 2 (0) 3 (5) 0,4444 8,7 (0) 5-14 (0-0) 0,0369* 4 (14,8) 2-5 (6-20) 0,0347* 14 (18) 12-15 (15-20) 0,0651 1 (0) 2 (3) 1,0000 3 (0) 0 (3) 1,0000 2 (0) 1 (3) 0,4000 2 (0) 1 (3) 0,4000 4 (0) 21 (26) 0,0506 5,7 (0,7) 0-14 (0-7) 0,0000* 6,8 (10,4) 0-20 (2-20) 0,0283* 13,6 (17,9) 4-20 (11.20) 0,0123* 7 (0) 15 (22) 0,0089* 15 (8) 7 (14) 0,0690 11 (0) 11 (22) 0,0002* 9 (0) 13 (22) 0,0014* 1 (0) 2 (3) 1,0000 4 (0,3) 1-7 (0-1) 0,1266 7 (16,7) 3-10 (10-20) 0,2482 11 (19,7) 7-15 (19-20) 0,1489 1 (0) 1 (2) 1,0000 1 (0) 1 (2) 1,0000 1 (0) 1 (2) 1,0000 1 (0) 1 (2) 1,0000 Mean P-value Yes No P-value Mean Range P-value Mean Range P-value Mean Range P-value Yes No P-value Yes No P-value Yes No P-value Yes No P-value 0 (0) 17 (17) 1,0000 3,0 (1,1) 0-9 (0-11) 0,0237* 7,7 (13,6) 1-20 (1-20) 0,0095* 15,8 (19,1) 3-20 (12-20) 0,1262 1 (0) 16 (17) 1,0000 9 (3) 8 (14) 0,0707 5 (1) 12 (16) 0,1748 0 (0) 17 (17) 1,0000 PF N=17) 2,9 (3,2) 0,4975 0 (0) 4 (4) 1,0000 3,5 (0,3) 0-7 (0-1) 0,1939 3,3 (9,5) 0-10 (4-20) 0,2159 15 (17) 5-20 (11-20) 0,8597 1 (0) 3 (4) 1,0000 2 (0) 2 (4) 0,4286 2 (0) 2 (4) 0,4286 1 (0) 3 (4) 1,0000 NF (N=4) 1,7 (4,0) 0,1124 1 (0) 5 (6) 1,0000 0,3 (0,3) 0-1 (0-2) 0,8312 6,3 (10,7) 5-10 (5-20) 0,2864 15,5 (19,8) 7-20 (19-20) 0,3374 0 (0) 5 (5) 1,0000 1 (1) 4 (4) 1,0000 0 (1) 5 (4) 1,0000 0 (0) 5 (5) 1,0000 AS (N=6) 2,8 (2,8) 0,9362 Parameters regarding continence for female patient-subgroups C= Cloaca, VF= Vestibular fistula, PF=Perineal Fistula, NF= No Fistula, AS=Anal Stenosis. Values between brackets are corresponding values for matched controls. All patients with permanent colostomies and their matched controls have been excluded in the analysis of all parameters except the incidence of permanent stomas. P-values >0.05 are marked with bold text and *. Use of pad daytime (yes/no) Soiling of underpants (yes/no) Need to rush to toilet (yes/no) Use of loperamid or equivalent (yes/no) Deffering time solid stool (max value =20, min) Deffering time loose stool max value =20, min) Miller incontinence score Satisfied with bowel function (1-4) Permanent stoma VF (N=26) 2,5 (3,3) 0,0055* C (N=3) 3,0 (4,0) 0,2752 Yes No P-value Several defecations for emptying (yes/no) 4 (4) 1 (1) 1,0000 1 (1) 4 (4) 1,0000 14 (14) 1 (1) 1,0000 1 (1) 14 (14) 1,0000 19 (22) 4 (1) 0,3463 4 (1) 19 (22) 0,3463 14 (24) 11 (1) 0,0019* 10 (1) 15 (24) 0,0046* 3 (0) 0 (3) 1.0000 AS (N=5) 0 (0) 5 (5) 1,0000 0 (0) 5 (5) 1,0000 1 (1) 4 (4) 1,0000 1 (0) 4 (5) 1,0000 0 (2) 5 (3) 0,4444 0 (0) 5 (5) 1,0000 0 (0) 5 (5) 1,0000 1 (2) 4 (3) 1,0000 2 (3) 1 (0) 1,0000 NF (N=15) 2 (0) 13 (15) 0,4828 3 (0) 12 (15) 0,2241 2 (1) 13 (14) 1,0000 2 (0) 13 (15) 0,4828 1 (0) 14 (15) 1,0000 1 (0) 14 (15) 1,0000 4 (0) 11 (15) 0,0996 3 (4) 12 (11) 1,0000 Parameters regarding constipation for male patient-subgroups, VPF= Vesical and prostatic fistula, RUF= Recto-bulbar fistula, NF= No Fistula, AS= Anal Stenosis. Values between brackets are corresponding values for matched controls. Values between brackets are corresponding values for matched controls. All patients with permanent stoma and their matched controls have been excluded. P-values >0.05 are marked with bold text and *. Yes No P-value Yes No P-value Yes No P-value Yes No P-value Yes No P-value Yes No P-value Yes No P-value Yes No P-value Yes No P-value Rectum emplty after defecation (yes/no) More than 10 minutes for defecation (yes/no) Supporting around anus at defecation (yes/no) Need to strain at defecation (yes/no) Digitation at defecation (yes/no) Problems with flatulence (yes/no) Bloating (yes/no) Use of enemas (yes/no) Use of laxatives (yes/no) PF (N=23) 0 (0) 23 (23) 1,0000 2 (1) 21 (22) 1,0000 4 (1) 19 (22) 0,3463 2 (1) 21 (22) 1,0000 0 (0) 23 (23) 1,0000 0 (0) 23 (23) 1,0000 3 (2) 20 (21) 1,0000 7 (3) 16 (20) 0,2837 RBF (N=25) 1 (0) 24 (25) 1,0000 8 (0) 17 (25) 0,0040* 8 (3) 17 (22) 0,1706 3 (2) 22 (23) 0,6743 2 (0) 23 (25) 0,4898 2 (1) 23 (24) 1,0000 8 (1) 17 (24) 0,0232* 12 (3) 13 (22) 0,0054* VPF (N=3) 0 (0) 3 (3) 1,0000 0 (0) 3 (3) 1,0000 0 (0) 3 (3) 1,0000 2 (0) 1 (3) 0,4000 0 (0) 3 (3) 1,0000 0 (0) 3 (3) 1,0000 0 (0) 3 (3) 1,0000 0 (0) 3 (3) 1,0000 Yes No P-value Several defecations for emptying (yes/no) 5 (4) 0 (1) 1,0000 0 (2) 5 (3) 0,4444 2 (4) 2 (0) 0,4286 2 (0) 2 (4) 0,4286 10 (13) 7 (4) 0,4646 7 (4) 10 (13) 0,4646 6 (20) 16 (2) 0,0000* 15 (3) 7(19) 0,0005* 1 (0) 1 (2) 01,0000 AS (N=5) 0 (1) 5 (5) 1,0000 0 (1) 5 (5) 1,0000 1 (2) 4 (3) 0,5455 0 (2) 5 (3) 0,4444 0 (0) 5 (5) 1,0000 0 (0) 5 (5) 1,0000 0 (1) 5 (4) 1,0000 0 (0) 5 (5) 1,0000 1 (2) 1 (0) 1,0000 NF (N=4) 0 (0) 4 (4) 1,0000 1 (0) 3 (4) 1,0000 2 (0) 2 (4) 0,4826 1 (0) 3 (4) 1,0000 0 (0) 4 (4) 1,0000 0 (0) 4 (4) 1,0000 1 (0) 3 (4) 1,0000 1 (0) 3 (4) 1,0000 Parameters regarding constipation for female patient-subgroups C= Cloaca, VF= Vestibular fistula, PF=Perineal Fistula, NF= No Fistula, AS=Anal Stenosis. Values between brackets are corresponding values for matched controls. All patients with permanent colostomies and their matched controls have been excluded in the analysis. P-values >0.05 are marked with bold text and*. Yes No P-value Yes No P-value Yes No P-value Yes No P-value Yes No P-value Yes No P-value Yes No P-value Yes No P-value Yes No P-value Rectum emplty after defecation (yes/no) More than 10 minutes for defecation (yes/no) Supporting around anus at defecation (yes/no) Need to strain at defecation (yes/no) Digitation at defecation (yes/no) Problems with flatulence (yes/no) Bloating (yes/no) Use of enemas (yes/no) Use of laxatives (yes/no) PF (N=17) 2 (1) 15 (16) 0,6136 0 (1) 17 (16) 1,0000 8 (4) 9 (13) 0,2818 5 (4) 12 (13) 1,0000 7 (1) 10 (16) 0,0391* 1 (0) 16 (17) 1,0000 7 (1) 10 (16) 0,0391* 7 (1) 10 (16) 0,0391* VF (N=22) 3 (1) 19 (21) 0,6069 3 (0) 19 (22) 0,2326 16 (5) 6 (17) 0,0022* 12 (7) 10 (15) 0,2231 5 (0) 17 (22) 0,0485* 5 (1) 17 (21) 0,1853 13 (1) 9 (21) 0,0002* 10 (2) 11 (20) 0,0157* C (N=2) 0 (0) 2 (2) 1,0000 1 (0) 1 (2) 1,0000 1 (0) 1 (2) 1,0000 1 (0) 1 (2) 1,0000 0 (0) 2 (2) 1,0000 0 (0) 2 (2) 1,0000 0 (0) 2 (2) 1,0000 1 (0) 1 (2) 1,0000 Yes No P-value Yes No P-value Mean Range P-value Mean Range P-value Mean Range P-value Mean Range P-value RBF (N=30) 4 (2) 26 (28) 0,6707 5 (4) 25 (26) 1,0000 1,4 (1,1) 1-4 (1-3) 0,0963 1,2 (1,1) 1-4 (1-2) 0,3555 1,5 (1,0) 1-4 (1-1) 0,0773 1,4 (1,1) 1-3 (1-4) 0,1316 PF (N=24) 1 (0) 23 (24) 1,0000 1 (2) 23 (22) 1,0000 1,0 (1,0) 1-2 (1-1) 0,8149 1,0 (1,0) 1-1 (1-2) 0,8149 1,1 (1,0) 1-3 (1-1) 0,6170 1,1 (1,0) 1-3 (1-2) 1,0000 NF (N=16) 0 (2) 16 (14) 0,4839 1 (0) 15 (16) 1,0000 1,5 (1,0) 1-4 (1-1) 0,2530 1.2 (1,0) 1-3 (1-1) 0,7669 1,53 (1,0) 1-4 (1-1) 0,3529 1,3 (1,0) 1-4 (1-1) 0,5892 AS (N=5) 1 (0) 4 (5) 1,0000 0 (0) 5 (5) 1,0000 1,4 (1,2) 1-2 (1-2) 0,6761 1.2 (1,0) 1-2 (1-1) 0,6761 1,2 (1,0) 1-2 (1-1) 0,6761 1,2 (1,0) 1-1 (1-2) 0,6761 Parameters regarding urinary continence and sexual function for all male patient-subgroups. VPF=Vesical and prostatic fistula, RUF= Recto-bulbar fistula, NF= No Fistula, AS= Anal Stenosis. Values between brackets are corresponding values for matched controls. Values between brackets are corresponding values for matched controls. Bowel function reduces sexual satisfaction (1-4, 1=none, 4=very much) Problems with ejaculation (1-4, 1=none, 4=very much) Bowel function impairs interest for sexual activity (1-4, 1=none, 4=very much) Problems with erection (1-4, 1=none, 4=very much) Problems to empty bladder (yes/no) Urine incontinence (yes/no) VPF (N=5) 1 (0) 4 (5) 1,0000 1 (0) 4 (5) 1,0000 1,8 (1,0) 1-4 (1-1) 0,3472 1,4 (1,0) 1-3 (1-1) 0,4351 1,2 (1,0) 1-2 (1-1) 0,4178 1,6 (1,4) 1 -4 (1-1) 0,3472 N/A 1,3 (1,1) 1-3 (1-2) 0,5757 N/A 2,0 (1,2) 1-4 (1-3) 0,0107* N/A 1,7 (1,0) 1-2 (1-1) 0,8660 Mean Range P-value Mean Range P-value Bowel function reduces sexual satisfaction (1-4, 1=none, 4=very much) N/A N/A 1 0 (1,7) 1-1 (1-4) 0,4113 2,0 (1,0) 1-3 (1-1) 0,4874 N/A 1 (0) 5 (6) 1,0000 1 (1,3) 1-1 (1-2) 0,3785 AS (N=6) 1 (1) 5 (5) 1,0000 N/A N/A 1 (0) 3(4) 1,0000 1,7 (1,0) 1-3 (1-1) 0,8770 NF (N=4) 0 (0) 4 (4) 1,0000 Parameters urinary continence and sexual function for female patient-subgroups C= Cloaca, VF= Vestibular fistula, PF=Perineal Fistula, NF= No Fistula, AS=Anal Stenosis. Values between brackets are corresponding values for matched controls. P-values below 0,05 are marked with * and bold text. N/A Problems with ejaculation (1-4, 1=none, 4=very much) N/A Mean Range P-value 1 (1) 16 (16) 1,0000 1,3 (1,1) 1-2 (1-2) 0,3973 Problems with erection (1-4, 1=none, 4=very much) 4 (3) 22 (23) 0,7095 2,0 (1,3) 1-4 (1-4) 0,0109* Yes No P-value Mean Range P-value Problems to empty bladder (yes/no) Bowel function impairs interest for sexual activity (1-4, 1=none, 4=very much) 0 (0) 3 (3) 1,0000 1,3 (1,0) 1-2 (1-1) 0,6625 Yes No P-value PF N=17) 3 (2) 14 (15) 0,6581 Urine incontinence (yes/no) VF (N=26) 5 (6) 21 (20) 0,7411 C (N=3) 0 (0) 3 (3) 1,0000 1 (0) 4 (5) 1,0000 1 (0) 4 (5) 1,0000 97 (98) 1,0000 95 (90) 1,0000 84,4 (88,4) 0,5309 71,2 (85) 0,9168 76 (48) 0,1172 80 (85) 0,9168 66,7 (73,3) 1,0000 87,2 (74,4) 0,1745 54,5 (56,8) 1,0000 46,3 (41,5) 0,4034 4 (0) 12 (16) 0,1212 3 (0) 13 (16) 0,2258 95 (96,3) 0,4070 93,8 (84,4) 0,5591 90,8 (89,8) 0,7487 82,8 (81,5) 0,8125 72,6 (74,1) 0,7630 89,8 (91,4) 0,8065 93,8 (97,9) 0,7774 87,8 (82,3) 0,6647 53,9 (53,2) 0,7972 51,5 (50,8) 0,7369 2 (0) 22 (24) 0,4894 0 (0) 24 (24) 1,0000 96,0 (97,9) 0,6134 100 (94,8) 0,4693 87,3 (93,2) 0,1942 84,0 (77,5) 0,3276 77,7 (75,4) 0,7576 98,4 (86,9 ) 0,8398 95,6 (94,4) 0,8315 86,6 (85,5) 0,8481 54,6 (54,5) 0,7096 52,9 (51,8) 0,7415 11 (1) 19 (29) 0,0025* 0 (0) 30 (30) 1,0000 96 (95,7) 0,4543 91,4 (91,7) 0,8735 92,7 (89,2) 0,5946 75,7 (83,9) 0,1071 72,7 (77,7) 0,2612 92,5 (96,3) 0,1120 93,3 (93,3) 0,8303 80,4 (83,3) 0,3147 54,5 (54,4) 0,8497 50 (51,1) 0,8496 2 (0) 3 (5) 0,4444 1 (0) 4 (5) 1,0000 83.0 (100) 0,0472* 100 (100) 0,9682 87 (100) 0,3472 80 (85) 0,2101 85 (76) 0,4034 88 (100) 0,3472 87 (100) 0,6761 88 (90) 0,8345 51,7 (56,5) 0,1437 52,9 (53,4) 0,8345 Yes No P-value Yes No P-value Yes No P-value Mean P-value Mean P-value Mean P-value Mean P-value Mean P-value Mean P-value Mean P-value Mean P-value Mean P-value Mean P-value Bowel function affects well being (yes/no) Bowel function affects social life (yes/no) Bowel function impairs travelling (yes/no) SF-36 Physical Function SF-36 Role Physical SF-36 Bodily Pain SF-36 General Health VF-36 Vitality SF-36 Social Function SF-36 Role Emotional SF-36 Mental Health SF-36 Physcial Cluster Scale Sf-36 Mental Cluster Scale Parameters regarding QoL for all male patient-subgroups. VPF= Vesical and prostatic fistula, RBF= Recto-bulbar fistula, NF= No Fistula, AS= Anal Stenosis. Values between brackets are corresponding values for matched controls.Values between brackets are corresponding values for matched controls. P-values below 0,05 are marked with * and bold text. AS (N=5) 1 (0) 4 (5) 1,0000 NF (N=16) 4 (1) 12 (15) 0,3326 PF (N=24) 3(2) 21 (22) 1,0000 RBF (N=30) 11 (1) 19 (29) 0,0025* VPF (N=5) 3 (0) 2 (5) 0,1667 Mean P-value Sf-36 Mental Cluster Scale 31,5 (44,4) 0,3011 53,3 (53,3) 0,6625 45,0 (47,8) 0,4387 PF (N=17) 5 (1) 12 (16) 0,1748 3 (0) 14 (17) 0,2273 0 (0) 17 (17) 1,0000 93,8 (97,8) 0,1130 89,7 (96,4) 0,7732 80,9 (97,2) 0,6525 73.2 (83,7) 0,2074 60,9 (63,8) 0,7187 85,3 (94,5) 0,1089 84,3 (91,7) 0,4602 72,2 (77) 0,4074 53,2 (55,8) 0,2140 53,5 (41,1) 0,3123 NF (N=4) 3 (0) 1 (4) 0,1429 3 (0) 1 (4) 0,1429 1 (0) 3 (4) 1,0000 81,3 (100) 0,1124 81,3 (100) 0,6650 80,5 (93,5) 1,0000 62,3 (87,0) 0,1489 67,5 (60,0) 0,6650 75 (87,5) 0,8852 100 (75) 0,6650 91 (69) 0,1489 42,7 (59,9) 0,0606 37,6 (42,2) 0,6889 AS (N=6) 1 (2) 5 (4) 1,0000 1 (0) 5 (6) 1,0000 0 (0) 6 (6) 1,0000 85,8 (99,2) 0,3367 79,2 (77,8) 0,8728 76,0 (76,3) 0,6889 80,8 (66,3) 0,9362 61,7 (58,3) 1,0000 77,1 (87,5) 0,7488 44,4 (72,2) 0,3785 65,3 (68,7) 0,9362 54,0 (52,9) 0,2980 Parameters regarding QoL for female patient-subgroups C= Cloaca, VF= Vestibular fistula, PF=Perineal Fistula, NF= No Fistula, AS=Anal Stenosis. Values between brackets are corresponding values for matched controls. P-values below 0,05 are marked with * and bold text. Yes No P-value Yes No P-value Yes No P-value Mean P-value Mean P-value Mean P-value Mean P-value Mean P-value Mean P-value Mean P-value Mean P-value Mean P-value Bowel function affects well being (yes/no) Bowel function affects social life (yes/no) Bowel function impairs travelling (yes/no) SF-36 Physical Function SF-36 Role Physical SF-36 Bodily Pain SF-36 General Health VF-36 Vitality SF-36 Social Function SF-36 Role Emotional SF-36 Mental Health SF-36 Physcial Cluster Scale VF (N=26) 15 (2) 11 (24) 0,0002* 14 (2) 12 (24) 0,0006* 4 (0) 22 (26) 0,1104 90,2 (92,6) 0,0182* 78,8 (85,2) 0,3234 72,9 (81,2) 0,2623 57,5 (80,9) 0,0008* 53,5 (59,4) 0,2738 78,9 (81,5) 0,4549 70,5 (80,3) 0,0927 68,0 (75,1) 0,0927 49,3 (53,6) 0,0471* C (N=3) 1 (0) 2 (3) 1,0000 1 (0) 2 (3) 1,0000 0 (0) 3 (3) 1,0000 91,7 (100) 0,2572 66,7 (100) 0,6625 75 (91,3) 0,6625 79,7 (98) 0,1904 70 (80) 0,6625 87,5 (100) 0,6625 100 (100) 0,8273 85,3 (86,7) 0,8273 47,7 (57,3) 0,3827 References Amussat JZ. 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(Prior to January, 2005, the series was published under the title “Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine”.) Distribution: publications.uu.se urn:nbn:se:uu:diva-241243 ACTA UNIVERSITATIS UPSALIENSIS UPPSALA 2015