Anal Acoustic Reflectometry in the Evaluation of the Anal Sphincter and the Response to Treatment of Faecal Incontinence

Anal acoustic reflectometry in the evaluation of the anal sphincter and the response to treatment of faecal incontinence

A thesis submitted to The University of Manchester for the degree of

Doctor of Medicine

in the Faculty of Medical and Human Sciences

2012

Benjamin Robert Hornung

School of Medicine Table of Contents

Table of Figures ...... 6 List of Tables ...... 7 List of Abbreviations ...... 8 Abstract ...... 9 Declaration ...... 10 Copyright Statement ...... 11 Acknowledgements ...... 12 Publications and Presentations ...... 13 Chapter 1 ...... 15 Introduction ...... 15 1.1 Anatomy ...... 16 1.1.1 Pelvis ...... 16 1.1.2 The Pelvic Floor ...... 16 1.1.3 Rectum and Anal Canal ...... 17 1.1.3.1 The Internal Anal Sphincter ...... 18 1.1.3.2 The External Anal Sphincter ...... 19 1.1.3.3 The Conjoined Longitudinal Muscle ...... 21 1.2 Nerve Supply ...... 22 1.2.1 Somatic Nervous System ...... 22 1.2.2 Autonomic Nervous System ...... 22 1.3 Physiology ...... 23 1.3.1 Anal Sphincter Tone ...... 23 1.3.2 Anal Motility ...... 24 1.3.3 Anal Reflexes ...... 25 1.3.3.1 The Recto-Anal Inhibitory Reflex ...... 25 1.3.3.2 The Closing Reflex ...... 26 1.3.3.3 The Cough Reflex ...... 26 1.3.3.4 The Classical Anal Reflex ...... 27 1.3.4 The Anal Stretch Receptor ...... 27 1.3.5 Maintenance of continence ...... 28 1.3.6 Defaecation ...... 29 1.4 Faecal Incontinence ...... 31

1.4.1 Definition and Prevalence ...... 31 1.4.2 Aetiology ...... 32 1.4.3 Scoring Systems ...... 33 1.4.4 Anorectal Investigations ...... 34 1.4.4.1 Anal Manometry ...... 34 1.4.4.2 Neurophysiological Investigations ...... 34 1.4.4.3 Endoanal Ultrasonography ...... 35 1.4.5 Management ...... 36 1.4.5.1 Conservative Treatment ...... 37 1.4.5.2 Surgical Treatment ...... 37 1.4.6 Sacral Nerve Stimulation ...... 38 1.4.7 Faecal Incontinence in Males ...... 40 1.5 Acoustic Reflectometry ...... 42 1.5.1 Background ...... 42 1.5.2 Urethral Pressure Reflectometry ...... 42 1.5.3 Anal Acoustic Reflectometry ...... 47 1.6 Aims ...... 51 Chapter 2 ...... 52 Materials and Methods ...... 52 2.1 Ethical Approval ...... 53 2.2 Patients ...... 53 2.3 Anal Acoustic Reflectometry ...... 54 2.4 Anal Manometry ...... 56 2.5 Experimental Learning Curve ...... 57 Chapter 3 ...... 58 A Comparative Study Of Anal Acoustic Reflectometry And Anal Manometry In The Assessment of Faecal Incontinence ...... 58 3.1 Introduction ...... 59 3.2 Aims ...... 60 3.3 Methods ...... 60 3.4 Results ...... 62 3.5 Discussion ...... 68 3.6 Conclusions ...... 71 Chapter 4 ...... 73 3

Anal Acoustic Reflectometry – A Novel Method For Predicting Outcome Of Sacral Nerve Stimulation For Faecal Incontinence ...... 73 4.1 Introduction ...... 74 4.2 Aims ...... 75 4.3 Methods ...... 76 4.4 Results ...... 78 4.5 Discussion ...... 83 4.6 Conclusions ...... 88 Chapter 5 ...... 89 Anal Acoustic Reflectometry In The Evaluation Of Sacral Nerve Stimulation . 89 5.1 Introduction ...... 90 5.2 Aims ...... 91 5.3 Methods ...... 91 5.4 Results ...... 94 5.5 Discussion ...... 98 5.6 Conclusions ...... 100 Chapter 6 ...... 101 Anal Acoustic Reflectometry In The Evaluation Of Male Patients With Faecal Leakage ...... 101 6.1 Introduction ...... 102 6.2 Aims ...... 103 6.3 Methods ...... 103 6.4 Results ...... 105 6.5 Discussion ...... 110 6.6 Conclusions ...... 116 Chapter 7 ...... 117 Anal Acoustic Reflectometry In The Evaluation Of Anal Sphincter Function During General Anaesthesia And Neuromuscular Blockade ...... 117 7.1 Introduction ...... 118 7.2 Aims ...... 119 7.3 Methods ...... 119 7.4 Results ...... 121 7.5 Discussion ...... 127 7.6 Conclusions ...... 134

Chapter 8 ...... 135 Overall Conclusions and Future Work ...... 135 References ...... 139 Appendices ...... 149

Final Word Count: 39, 212 (including references and appendices)

Table of Figures

Figure 1.1 The Pelvic Floor Muscles...... 17 Figure 1.2 The Internal and External Anal Sphincter...... 20 Figure 1.3. A normal endoanal ultrasound scan...... 36 Figure 1.4 Polyurethane bag and reflectometry probe ...... 44 Figure 1.5. Graphs of cross-sectional area vs. Distance into the urethra are plotted initially for each pressure step...... 45 Figure 1.6 Area vs. Pressure graph for HPZ showing opening and closing traces, demonstrating the acoustic parameters...... 46 Figure 2.1 Equipment set up with acoustic reflecometry digital signal processor, pump and probe ...... 54 Figure 2.2. Manometry catheter connected to pressure transducer ...... 56 Figure 4.1 ROC curve for Opening Pressure ...... 81 Figure 6.1 Area vs. Pressure graph showing opening and closing traces, demonstrating the acoustic parameters ...... 112 Figure 7.1. Line plots demonstrating trends in measured variables ...... 123 Figure 7.2 Line plots demonstrating trends in measured variables ...... 125

List of Tables

Table 1.1 Causes of faecal incontinence...... 32 Table 3.1 Demographics of female patients undergoing assessment with AAR and anal manometry ...... 62 Table 3.2 Spearman correlation between anal acoustic reflectometry and anal manometry variables ...... 63 Table 3.3 Spearman correlation between Vaizey incontinence score and measured variables ...... 64 Table 3.4. Comparison of measured variables between subgroups of incontinent subjects ...... 65 Table 3.5. Comparison of AAR and anal manometry in incontinent females with and without anal sphincter defects...... 67 Table 4.1 Pre-operative demographics of successful and unsuccessful groups...... 78 Table 4.2 Comparison of AAR and manometry variables between successful and unsuccessful groups...... 80 Table 5.1 Demographics of female patients undergoing permanent SNS ...... 94 Table 5.2 Comparison of effect of SNS at follow-up compared with baseline ...... 95 Table 5.3 Comparison of AAR and manometry variables before and after permanent SNS...... 97 Table 6.1 Demographics of continent males and males with faecal leakage...... 105 Table 6.2 Comparison of measured variables in age-matched continent males and male leakers...... 106 Table 6.3 Comparison of AAR and manometry variables before and after proctoscopy in the male leakers...... 108 Table 6.4 Comparison of AAR and manometry variables before and after proctoscopy in the continent males...... 109 Table 7.1 Type of surgery undertaken ...... 121 Table 7.2 Comparison of measurement timings between protocol subsets ...... 126

List of Abbreviations

AAR anal acoustic reflectometry

Ca2+ calcium cGMP cyclic guanosine – 3’5’-monophosphate

CI confidence interval

CNS central nervous system

EAS external anal sphincter

EAUS endo-anal ultrasound

EMG electromyography

FI faecal incontinence

GA general anaesthesia

HPZ high pressure zone

IAS internal anal sphincter

ICS International Continence Society

MRP maximum resting pressure

MSP maximum squeeze pressure

NMB neuromuscular blockade

NO nitric oxide

PNE percutaneous nerve evaluation

PNTML pudendal nerve terminal motor latency

RAIR recto-anal inhibitory reflex

ROC receiver operator characteristic

SNS sacral nerve stimulation

Abstract

Anal Acoustic Reflectometry (AAR) is a novel technique providing a dynamic physiological assessment of anal sphincter function. In AAR wide band sound waves are transmitted into a thin polyurethane bag placed within the anal canal. The reflection of these sound waves allows calculation of the cross-sectional area of the anal canal. The bag is slowly inflated and deflated, during which simultaneous cross-sectional area and pressure measurements are taken along the entire length of the anal canal. This allows Opening Pressure, Opening Elastance, Closing Pressure, Closing Elastance and Hysteresis to be calculated, representing a physiological assessment of anal canal function at rest. During voluntary contraction Squeeze Opening Pressure and Squeeze Opening Elastance can be measured. AAR has been shown to be a reproducible and clinically reliable technique in the assessment of women with faecal incontinence. The aims of this study were to: (i) compare AAR with conventional anal manometry in the assessment of women with faecal incontinence, (ii) evaluate the use of AAR in patients undergoing percutaneous nerve evaluation (PNE) and sacral nerve stimulation (SNS), (iii) determine whether male patients with faecal leakage have an identifiable abnormality in anal sphincter function using AAR and (iv) determine the relative contributions of the EAS and IAS to anal tone by using AAR to study anal sphincter function during general anaesthesia with and without neuromuscular blockade. In a comparative study of AAR and anal manometry, AAR provided a more sensitive assessment of anal sphincter function in women with faecal incontinence. Unlike anal manometry, AAR variables correlated with symptom severity and were able to distinguish between different symptomatic subgroups of incontinence. Patients undergoing PNE for faecal incontinence were assessed pre-operatively. The AAR variable Opening Pressure was significantly greater in those patients with a successful outcome than in those with an unsuccessful outcome, whereas no difference was seen with the manometric equivalent of maximum resting pressure (MRP). Furthermore, Opening Pressure was shown to be an independent predictor of success in PNE, which suggests that AAR may allow better patient selection for this expensive treatment. In patients undergoing insertion of a permanent sacral nerve stimulator no change in anal sphincter function was identified at follow up and the exact mode of action of SNS remains unclear. Male patients with faecal leakage were compared with continent controls. No difference in anal manometry was found, but AAR was sensitive enough to detect a measurable difference in anal sphincter function. Both Opening and Closing Pressure were significantly lower in the male leakers which suggest that reduced anal closing forces may account for the post-defaecatory leakage. The relative contributions of the anal sphincter muscles to resting anal canal function was investigated by measuring male subjects while conscious and while under general anaesthesia with and without neuromuscular blockade. General anaesthesia resulted in a significant reduction in resting sphincter function. Neuromuscular blockade resulted in a significant increase in Opening Pressure, which has not been previously reported. AAR is a promising new technique which has advantages over conventional anal manometry and allows a sensitive assessment of anal sphincter function.

Declaration

I declare that 50% of the data used in Chapter 3 was collected by Peter Mitchell and submitted as part of a MD thesis with the University of Manchester. No other portion of the work referred to in the thesis has been submitted in support of an application for another degree or qualification for this or any other university or other institute of learning.

i. The author of this thesis (including any appendices and/or schedules to this thesis) owns certain copyright or related rights in it (the “Copyright”) and s/he has given The University of Manchester certain rights to use such Copyright, including for administrative purposes.

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Acknowledgements

I would like to express my sincere gratitude to my supervisors, Mr Edward Kiff and Professor Gordon Carlson. They have both provided expert help and advice and have supported the research project with great enthusiasm. Mr Kiff’s wealth of experience and knowledge of pelvic floor pathology was invaluable in facilitating the research and in providing many of the answers to problems encountered over the past two years. Professor Carlson’s expertise in research methodology and his tireless attention to detail was of great help and his guidance ensured that the studies conducted were of sound scientific foundation. I would also like to thank my predecessor, Peter Mitchell, from whom I learnt the technique of anal acoustic reflectometry. He provided great support and was always on the end of the telephone for helpful advice.

Other notable contributors I would like to thank include John Cooley, for his technical assistance, Julie Morris, for her statistical advice, and Miss Gemma Faulkner, for sharing the trials and tribulations of research with me.

Finally, I would like thank my friends and family for their endless support. Above all, my wife Sarah, who has always listened, supported and encouraged me, and who is blessed with incredible patience. Special thanks also must go to my little boy, James, who was born during the first year of the research and whose little face always motivated me and made me smile.

Publications and Presentations

Published Papers

Hornung BR, Mitchell PJ, Carlson GL, Klarskov N, Lose G and Kiff ES. Comparative Study Of Anal Acoustic Reflectometry And Anal Manometry In The Assessment Of Faecal Incontinence. Br J Surg 2012; 99(12): 1718-24.

Published Abstracts

Hornung BR, Mitchell PJ, Klarskov N, Lose G, Carlson GL and Kiff ES. Anal acoustic reflectometry – a novel method for predicting outcome of sacral nerve stimulation for faecal incontinence. Colorectal Disease 2012, 14(S1): 33.

Hornung BR, Mitchell PJ, Klarskov N, Lose G, Carlson GL and Kiff ES. Anal acoustic reflectometry: a novel technique in the evaluation of male patients with faecal leakage. Br J Surg 2012; 99(S4): 27.

Hornung BR, Mitchell PJ, Klarskov N, Lose G, Carlson GL and Kiff ES. Anal acoustic reflectometry: a novel technique in the evaluation of male patients with faecal leakage. Colorectal Disease 2011, 13(S6): 54.

Oral Presentations

Hornung BR. Anal Acoustic Reflectometry: a new technique of assessing anal sphincter function. Oral presentation at ACPGBI Northwestern Chapter Meeting, Manchester, March 2012.

Hornung BR, Mitchell PJ, Klarskov N, Lose G, Carlson GL and Kiff ES. Anal acoustic reflectometry: a novel technique in the evaluation of male patients with faecal leakage. Oral presentation at Society of Academic and Research Surgery (SARS), University of Nottingham, January 2012.

Hornung BR. Anal Acoustic Reflectometry: a new technique of assessing anal sphincter function. Oral presentation at Northern Functional Bowel Meeting, Manchester, April 2011.

Poster Presentations

Hornung BR, Mitchell PJ, Klarskov N, Lose G, Carlson GL and Kiff ES. Anal acoustic reflectometry: a novel technique in the evaluation of male patients with faecal leakage. Poster presentation at the European Society of Coloproctology, Copenhagen, September 2011.

Chapter 1

Introduction

1.1 Anatomy

1.1.1 Pelvis

The pelvis is infero-posterior to the abdomen and the area of transition from the trunk to the lower limbs. It is funnel-shaped and enclosed by bony, ligamentous, and muscular walls. The bony pelvis is formed by the two hip bones (ilium, ischium, and pubis), sacrum and coccyx. The hip bones are joined anteriorly at the pubic symphysis to form a pelvic girdle that is firmly attached to the sacrum for support of the lower limbs. This girdle is a weight bearing, protective structure that also forms the skeletal frame-work of the birth canal.1

1.1.2 The Pelvic Floor

The floor of the pelvis supports the pelvic viscera and is formed by the pelvic diaphragm. The pelvic diaphragm stretches between the pubis anteriorly and the coccyx posteriorly and from one lateral pelvic wall to the other, dividing the pelvis into the main pelvic cavity above and the perineum below. The pelvic diaphragm is formed by the levator ani and coccygeus muscles and the fascia that cover their superior and inferior surfaces. It is incomplete anteriorly to allow passage of the urethra in males and the urethra and the vagina in females. The levator ani is formed by overlapping paired musculotendinous sheets of predominantly striated muscle fibres. Anteriorly the levator prostatae or sphincter vaginae form a sling around the prostate or vagina inserting into the perineal body anterior to the anal canal. The puborectalis muscle forms a powerful sling around the anorectal junction angulating it anteriorly. Puborectalis is an integral part of both the levator ani and external anal sphincter complexes.2 It, together with the superior borders of the internal and external sphincters, forms the anorectal ring, which delineates the anal canal from the rectum. The pubococcygeus then passes posteriorly inserting into a fibrous mass between the coccyx and the anal canal known as the anococcygeal body. The ileocoocygeus, the most posterior part of levator ani, inserts into the anococcygeal body and the coccyx. The coccygeus is a small triangular muscle arising from the ischial spine and inserting into the lower sacrum and coccyx. Figure 1.1 is a diagrammatic representation of the pelvic floor musculature.

Figure 1.1 The Pelvic Floor Muscles. Adapted from Bharucha (2006).3

The muscles of the levator ani work together to resist increases in intra-abdominal pressure and have an important sphincter action on the anorectal junction contributing to the continence mechanism.4

1.1.3 Rectum and Anal Canal

The rectum begins anterior to the third sacral vertebra following the sacral curvature for its entire length of 12 to 15cm. It ends antero-inferior to the tip of the coccyx by turning posteroinferiorly and becoming the anal canal. There are three lateral curves, the upper and lower ones being convex to the right and the middle one being convex to the left. When the lumen is inspected three folds comprising mucosa and circular smooth muscle can be seen corresponding to these curvatures (the circular valves of

Houston).5 The taeniae coli of the sigmoid colon spread out to form the outer longitudinal muscle layer of the rectum which surrounds the inner circular muscle layer. The peritoneum covers the anterior and lateral surfaces of the upper third of the rectum and only the anterior surface of the middle third, leaving the lower third entirely below the peritoneal reflection. The posterior wall of the rectum is covered with a thick layer of pelvic fascia. Laterally, the lower portion of the rectum is supported on each side by reflections of endopelvic fascia known as the lateral ligaments of the rectum. The anterior extra-peritoneal surface of the rectum is separated from anterior structures by Denonvilliers’ pelvic fascia.2

The anal canal begins as the rectum passes through the pelvic diaphragm at the level of the anorectal ring. It extends for approximately 4cm passing downwards and backwards to the anal verge. In the ‘resting’ state the puborectalis sling is contracted, creating an 80° angulation between the anal canal and rectum, contributing to the continence mechanism.6 The lining of the anal canal is complex. Several longitudinal mucosal folds, the columns of Morgagni, arise in the proximal anal canal and end at the dentate line, where they surround the anal sinuses, into which open the anal glands. The epithelium of the upper half of the anal canal is columnar epithelium, but at a point about midway down the canal, just below the dentate line, the epithelium changes to stratified squamous epithelium. The mucosa proximal to the dentate line lacks somatic innervation, but that below is richly supplied with cutaneous sensory nerve endings. In addition, the mucosal lining is thick and folded to form anal cushions which are highly vascular and some authors state help plug the anus at rest aiding the continence mechanism.7 The anal canal is surrounded by a complex arrangement of sphincters consisting of smooth and striated muscle. The anal sphincters form two cylindrical layers between which lies the longitudinal muscle.

1.1.3.1 The Internal Anal Sphincter

The internal anal sphincter (IAS) comprises smooth muscle and is a continuation of the involuntary circular smooth muscle of the rectum. It extends from the anorectal ring to approximately 1.5cm below the dentate line, lying medial and just proximal to the caudal extension of the external anal sphincter. The intersphincteric groove is palpable at this level and is an important surgical landmark.8 In recent times

18 imaging techniques such as ultrasonography and magnetic resonance imaging have added to our understanding of the functional anatomy of the anal sphincter complex. Williams et al (2000), using three dimensional endosonography, showed no significant difference in the length of the IAS between males and females and no difference in the proportion of the anal canal that it occupied.9 The thickness of the internal sphincter has been shown to increase with age, accounted for by degeneration of muscle and replacement by fibrous tissue.10,11 However it is abnormally thinned in patients with idiopathic degeneration and abnormally thick in patients with solitary rectal ulcer syndrome.12 The internal sphincter, like the puborectalis, is tonically contracted at rest.

1.1.3.2 The External Anal Sphincter

The external anal sphincter (EAS) is the outermost muscle of the anal canal and is composed of a group of muscles surrounding the anal canal, continuous above with the fibres of puborectalis. The earliest anatomical description of the EAS came from Santorini in 1715, proposing a three part structure – subcutaneous, superficial and deep.13 This three tiered arrangement has been supported by many authors since.14, 15, 16 The subcutaneous part is described as an annular muscle lying in the perineal space inferolateral to the IAS. The superficial part is elliptical and lies slightly above and lateral to the subcutaneous sphincter, separated from it by lateral fibres of the conjoined longitudinal muscle. The deep part of the EAS is annular and blends with the inferior fibres of puborectalis. This arrangement is shown in figure 1.2.

Figure 1.2 The Internal and External Anal Sphincter. A: Subcutaneous EAS; B: Superficial EAS; C: Deep EAS; S: IAS; P.R.: Puborectalis. Fibres of the longitudinal muscle can be seen piercing the subcutaneous EAS. Adapted from Floyd and Walls (1953).17

Other authors however have failed to demonstrate three separate subdivisions and instead divide the sphincter into two parts, superficial and deep.18,19 Oh and Kark (1972), in an anatomical and histological study of 48 adult specimens, describe the EAS as being composed of a deep compartment (deep sphincter and puborectalis) and a superficial compartment (superficial and subcutaneous sphincter).20 More recent work by Fritsch et al (2002) also supports this bilaminar arrangement.21 The precise anatomy of the EAS remains controversial and this is partly due to disagreement on the layout of the fibres of the conjoined longitudinal muscle which bind together the EAS.

The EAS has been shown to be thicker in men and shorter anteriorly in females.22 In cross sectional imaging the infero-medial sloping fibres of the EAS produce an apparent anterior defect in females.22 Bollard et al (2002) also describe a natural variable defect occurring along its anterior length in women.23 This must be distinguished from a pathological defect secondary to obstetric trauma. The deficiency in the EAS at this level may explain the vulnerability of the IAS to obstetric damage even in the presence of an intact EAS.

The EAS is a voluntary striated muscle acting as a single functional unit. The muscle fibres of the EAS are composed of slow and fast twitch types. The slow twitch type 1 muscle fibres are responsible for the sustained tonic contraction of the EAS which aids the IAS in maintaining closure of the anal canal. The fast twitch type 2 muscle fibres allow the EAS to contract rapidly with voluntary squeeze.24 These fibres can only maintain this maximal level of contraction for a short time before they become fatigued.

1.1.3.3 The Conjoined Longitudinal Muscle

Running in between the anal sphincters is the conjoined longitudinal muscle, a complex structure with both smooth and striated muscle bundles and fibroelastic tissue that invests the entire sphincter complex and fixes it in place.25 It is described as a direct continuation of the outer muscle coat of the rectum receiving striated muscle contributions from the pelvic floor muscles. The exact anatomy is disputed but most authors state that the conjoined longitudinal muscle runs down in the intersphincteric plane with inferior extensions that pierce and divide the subcutaneous external anal sphincter to attach to the perianal and perineal skin.26, 27 The muscle contracts to shorten and widen the anal canal during defaecation everting the anal orifice. It has also been implicated in the pathogenesis of haemorrhoids and prolapse and, due to its fibrous extensions to the perianal skin, it is thought to contain sepsis within the perianal space.27

1.2 Nerve Supply

1.2.1 Somatic Nervous System

The pelvic floor muscles are innervated by branches from the sacral nerve roots of S2, S3 and S4. The motor fibres that innervate these muscles and the EAS originate from cells lying in Onuf’s nucleus. Onuf’s nucleus is a specialised group of anterior horn cells spanning the second and third sacral spinal segments, which also contains nerve cells belonging to the parasympathetic nervous system.28 The pudendal nerve arises from the sacral plexus by branches of the ventral rami of S2-S4. It travels with the internal pudendal artery leaving the pelvis through the greater sciatic foramen between the piriformis and coccygeus muscles. It then hooks around the sacrospinous ligament and enters the perineum through the lesser sciatic foramen. The nerve then runs forward in the pudendal canal and, via its branches supplies the muscles and skin of the perineum and the external anal sphincter. The inferior rectal nerve branches from the pudendal nerve at the start of the pudendal canal crossing the ischioanal fossa to the anus. It supplies the motor innervation to the external anal sphincter, and the afferent sensory innervation to the mucous membrane of the lower half of the anal canal and the perianal skin. The external anal sphincter has dual innervation from both the right and left pudendal nerves. Stimulation of the right pudendal nerve causes circumferential contraction of the external sphincter.3 The pudendal nerve then splits to form the dorsal nerve of the penis (or clitoris) and the perineal nerve.1, 29

1.2.2 Autonomic Nervous System

The rectum, upper half of the anal canal and the bladder are innervated by fibres of the autonomic nervous system. The sympathetic supply to the rectum derives from the lumbar part of the sympathetic trunk and the superior hypogastric plexus. The parasympathetic supply derives from the pelvic splanchnic nerves. The rectum and upper half of the anal canal are only sensitive to stretch. The involuntary internal anal sphincter is supplied by sympathetic fibres from the inferior hypogastric plexuses and by parasymapathetic fibres from the pelvic splanchnic nerves. At rest the sympathetic supply has a tonic, excitatory effect on internal sphincter tone.30, 31 Parasympathetic innervation does not appear to affect internal sphincter tone.32

1.3 Physiology

1.3.1 Anal Sphincter Tone

In the resting state the anal canal is kept closed by the anal sphincter muscles. The pressure recorded within the anal canal is higher than that in the rectum and this pressure is a major determinant of the strength of the anal continence mechanism.33 The concentric anatomy of the anal sphincter complex makes attributing pressure recordings to one or other of the sphincters problematic. It is however widely accepted in the literature that the resting pressure in the anal canal is largely attributable to the IAS, with minimal contribution from the EAS, and that voluntary contraction of the EAS is responsible for the rise in pressure during squeeze manoeuvres. Duthie and Watts (1965) studied the pressure in the anal canal with simultaneous electromyographic (EMG) recordings of the EAS before and after muscle paralysis in twenty male patients without anorectal pathology. The results from this study suggested that the EAS contributes little to the pressure within the anal canal at rest and only plays a part when a bolus is present within the anal canal.34 Frenckner and Euler (1975) studied the function of the anal sphincters by obtaining anal canal pressure recordings and EMG activity in the EAS, before and after bilateral pudendal nerve block. The EAS is supplied by the pudendal nerve, therefore after blockade the authors reported the pressure in the anal canal to be due to IAS function alone. They found that after bilateral pudendal nerve block the maximal anal pressure decreased from a mean of 64 mmHg to 54 mmHg, concluding that the smooth IAS contributed approximately 85% of the anal pressure at rest.35

IAS tone seems to be mediated by continuous excitatory sympathetic activity, together with the intrinsic myogenic properties of the smooth muscle. The precise involvement of the parasympathetic and enteric nervous systems is poorly understood. Frenckner and Ihre (1976) investigated the effect of the autonomic nerves on the human IAS by comparing anal canal pressures in patients after a high or low spinal anaesthetic. A high spinal anaesthetic inhibits autonomic and somatic nerve supply to the sphincter complex, whereas a low spinal anaesthetic inhibits parasympathetic and somatic supply leaving the sympathetic nerve supply intact. Anal pressure at rest decreased significantly more after high spinal anaesthesia (32 mmHg) than with low (11 mmHg) supporting the proposal of a tonic excitatory

23 sympathetic drive to the IAS in man.30 Moreover, Carlstedt et al (1988) studied the effect of sympathetic nerve block and efferent stimulation of the sympathetic nerves on anorectal motility in patients undergoing surgery for cancer of the proximal two thirds of the rectum.31 They showed that electrical stimulation of the sympathetic hypogastric nerves elicited a contraction of the IAS in 13 out of 15 patients.31 Other authors have found, however, that stimulating the hypogastric nerves resulted in relaxation of the IAS suggesting the involvement of inhibitory β-adrenergic receptors.36, 37 The over-riding view however, is that of a tonic excitatory sympathetic drive to the IAS.28

The tonic contraction of the IAS is maintained by the extrinsic neural influences mentioned above, but also by the intrinsic myogenic properties of the smooth muscle. Rattan (2005) believes that this basal IAS tone is predominantly myogenic due to the specialised properties of the smooth muscle cells in the IAS.38 Lestar et al (1989), as part of a larger study, investigated basal resting pressures in the anal canal of 7 patients before and after abdomino-perineal resection for low rectal cancers. None of the tumours were involving the anal canal clinically or manometrically and measurements were taken pre-operatively first. Post-operative measurements were then taken from the resection specimen after it had been soaked in oxygenated Hartmann’s solution for 15 minutes at 37 0C. The authors reported that under these circumstances the muscle was extrinsically denenervated leaving the intrinsic myogenic activity of the IAS intact. They concluded that at rest 55% of the anal basal pressure is made up of IAS activity, with 45% being nerve induced activity and 10% being purely myogenic IAS activity. They attributed 30% of resting pressure to tonic activity of the striated EAS and the remaining 15% to expansion of the haemorrhoidal plexuses.39

1.3.2 Anal Motility

Anal motility can be visualised at manometry. Superimposed on the tonic state of the IAS is intermittent slow and ultraslow wave activity. Slow waves are of low amplitude and occur about 10-20 times per minute. They represent basal activity of the IAS as they are present under anaesthesia with the EAS paralysed and can be recorded from isolated IAS strips.32, 40 Slow waves occur more frequently in the distal anal canal and it is proposed that they may serve to keep the anal canal empty

24 and prevent desensitisation of the anoderm.41 Ultraslow pressure waves, occurring at a frequency of less than 2 per minute, can also be seen. They are also related to IAS activity.40 It has been reported that these ultraslow waves disappear after haemorrhoidectomy and after anal dilatation.40, 42 Both these intermittent anal pressure waves are often deranged in patients with faecal incontinence. It is not clear whether this is a result of, or a contributor to, incontinence.41

1.3.3 Anal Reflexes

A reflex is a simple motor response to a defined sensory input.43 Information from a stimulus is carried in an afferent neuron to the central nervous system (CNS), from where an efferent neuron transmits nerve impulses to an effector. This reflex arc is often modulated by higher cerebral centres.44 A number of reflexes involving the anorectum have been described, but the exact nature of the neural pathways and the receptors involved is still unclear.

1.3.3.1 The Recto-Anal Inhibitory Reflex

The recto-anal inhibitory reflex (RAIR) was first described by Gowers in 1877 and subsequently by Denny-Brown and Robertson in 1935.45, 46 During distension of the rectum there is a rapid fall in anal canal pressure due to IAS relaxation, followed by a steady return to the initial resting pressure. The extent of the relaxation depends on the degree of distension, with larger volumes of rectal distension leading to larger and longer reductions in anal canal pressure. It is a reproducible pressure decrease associated with a decrease in IAS electrical activity, although the phenomenon is more complex, often being preceded by a transient increase in anal canal pressure due to EAS contraction.47 The contractile response of the striated EAS to rectal distension is known as the ‘inflation’ response.48 The presumed physiological significance of the reflex is that of ano-rectal sampling. The transient IAS relaxation in response to rectal distension brings the rectal contents into contact with the sensory epithelium of the proximal anal canal, allowing discrimination between solids, liquids and gas. The excitatory response of the EAS as part of the RAIR is critical in preventing passive loss of rectal contents and, together with anal slow waves, serves to return the contents back to the rectum.49 This reflex, composed of

IAS relaxation and EAS contraction is frequently abnormal in patients with faecal incontinence.50, 51

The RAIR is absent in Hirshsprung’s disease, which is characterised by a lack of intramural ganglia in a variable length of colon or rectum.52 It is however present in patients with spinal cord transection or after extrinsic denervation of the the rectum suggesting that the pathways for this reflex are entirely within the wall of the rectum and anal canal.37, 53 The reflex contraction of the EAS during rectal distension does, however, appear to be modulated by higher cerebral centres, demonstrated by the fact that normal subjects showed sustained and increased activity of the EAS during rectal distension compared to patients with transverse spinal cord lesions.53 It has also been shown that the RAIR initially disappears after rectal excision, but then returns 1-3 years after a colo-anal or ileo-anal anastomosis, enabling discrimination of flatus from stool.54, 55 This suggests that the intramural enteric neurones involved in the reflex regenerate across anastomoses.

1.3.3.2 The Closing Reflex

The closing reflex is another physiological phenomenon displayed by the external anal sphincter. When traction is applied to the EAS there is an initial contractile response which is heightened on release of the traction. This forms the basis of anal canal closure following defaecation and prevents post defaecation leakage.49

1.3.3.3 The Cough Reflex

During coughing there is a transient rise in intra-abdominal pressure accompanied by a reflex contraction of the external anal sphincter. This leads to a sudden rise in pressure in the anal canal preventing faecal incontinence. This reflex response is seen in paraplegics.6 Deffieux et al (2006) investigated this reflex by measuring EMG activity of the EAS and external intercostal muscle during coughing. They demonstrated that contraction of the EAS occurred prior to activation of the muscles involved in coughing concluding that this response is a specialised spinal reflex involving higher or more complex integrative centres.56

1.3.3.4 The Classical Anal Reflex

The classical anal reflex is described as a contraction of the anal sphincter in response to pricking or scratching the perianal skin or anal mucosa. This anal response is a spinal reflex and is always present in normal subjects, forming part of routine neurological assessment of the anorectum.57, 58

1.3.4 The Anal Stretch Receptor

The presence of stretch receptors in the levator ani and the EAS has been reported in several studies.59-61 Muscle spindles are proprioceptive endings acting as stretch receptors to detect variation in length and tension of the muscle in which they are situated. In 1960 Chennells et al demonstrated the presence of muscle spindle stretch receptors in the EAS of the cat.59 Other feline studies have failed to demonstrate the presence of EAS muscle spindles, but suggest there may be non- spindle sensory receptors present in the anal canal.62 In human studies muscle spindles were identified in the EAS by Walls in 1959.61 Li et al (1992) demonstrated that the puborectalis and EAS are abundantly supplied with muscle spindle stretch receptors.60 The puborectalis and EAS are in a constant state of tonic contraction, in stark contrast to other skeletal muscles. The abundance of red type 1 muscle fibres found in the puborectalis and EAS allow this sustained tonic activity.63 This resting EAS tone is reliant on a spinal reflex arc. Parks et al studied patients with tabes dorsalis, a condition in which dorsal root nerve fibres are destroyed and thus afferent sensory pathways are blocked, leaving motor units intact. They found no EMG activity in the EAS at rest in these patients but normal activity on voluntary contraction.64 This suggests that the tonic resting activity of the EAS is reliant on intact afferent pathways involved in a reflex mechanism. The same authors also studied patients with complete cord transection above the 3rd lumbar segment. They found that the resting EMG activity of the EAS was normal in these patients, confirming the theory of a spinal reflex arc being responsible for the resting EAS activity.64 This tonic EAS activity appears to be mediated by sensory receptors found in the muscle itself.54, 64 Lane and Parks (1977) demonstrated normal EAS activity after rectal excision suggesting that the receptors lie not in the rectum but in the pelvic floor musculature itself.54 Like other muscle reflexes these receptors are very likely to be activated by stretch. Indeed, as mentioned above muscle spindle

27 stretch receptors have been found in the EAS and Chennells work demonstrated that the impulse from the feline EAS at rest increased when the sphincter was stretched.59 Certainly the rise in intra-abdominal pressure that precedes a cough will stretch the pelvic floor musculature leading to an increase in activity likely mediated by these stretch receptors.64 It therefore seems reasonable to conclude that the resting tonic activity of the EAS and the reflex increase in activity seen with increases in intra- abdominal pressure are mediated by these pelvic floor stretch receptors. The specific effect of distension and stretch on the anal canal is relatively understudied and an area that requires further investigation.

1.3.5 Maintenance of continence

The maintenance of continence is a multifactorial process involving mental function, colonic motility, volume and consistency of stool, rectal compliance, anorectal angle, nerve supply and structure and function of the anorectal musculature. Consequently, any disruption to the normal anatomy or physiology of the anorectal unit may lead to faecal incontinence. As continence is reliant on several factors, some of the mechanisms may be able to compensate and maintain clinical continence when one factor is impaired.

The ano-rectal angle, maintained by the puborectalis sling, is generally considered to be responsible for maintaining gross faecal continence.39 In children with congenital abnormalities involving absence of the anal sphincter complex, continence can be maintained by the puborectalis. However, the fine tuning of continence and the barrier to passage of material through the anal canal is maintained by the concentrically arranged internal and external anal sphincters. In order to retain gas and liquid stool in the rectum the anal canal has to be closed with adequate pressure. This pressure is generated by both the rhythmic activity of the IAS and the tonic activity of the EAS. At rest it is generally accepted that the IAS plays the predominant role in maintaining this pressure and thus anal continence with some contribution from the tonically active EAS. The EAS has the ability to greatly increase anal canal pressure during voluntary contraction, thus maintaining continence when an individual experiences a call to stool.65

Although the active forces generated from the smooth and striated sphincter muscles keep the anal canal closed, the presence of the anal cushions is required for perfect

28 anal continence. The anal lining is thick and folded to form highly vascular anal cushions. The anal cushions consist of epithelium, sub-epithelium and the underlying haemorrhoidal plexuses. These vascular anal cushions seem to provide an autoregulation system that fills up the IAS ring plugging the anal canal at rest.7, 66

For these barrier mechanisms of continence to function effectively the rectum has to be sufficiently compliant so that it can accommodate large volumes of stool without significant increases in pressure. Patients with colitis or those suffering with radiation proctitis can have a reduction in rectal capacity which may present with faecal urgency and incontinence.67

The maintenance of continence is also reliant on higher cortical function. The frontal cortex of the brain is important for the conscious awareness of the desire to defaecate and appropriate social behaviour.67 Many patients with dementia are incontinent because they have no interest in, or awareness of bowel function.

1.3.6 Defaecation

Defaecation is a complex process involving both reflex and voluntary actions. The rectum serves as both a storage reservoir for faeces and also as a pump for the evacuation of faeces. Faecal material, driven by peristaltic waves, enters the rectum causing distension. The rectum is initially compliant and distends passively until a certain threshold, when a desire to defaecate is experienced. As further rectal filling occurs this urge to defaecate intensifies. This rectal distension also leads to the recto-anal inhibitory reflex (RAIR), whereby the internal anal sphincter relaxes simultaneously with external anal sphincter contraction allowing rectal contents to move down to the proximal anal canal. This “sampling” by the anal mucosa allows the nature of the rectal contents to be determined without causing incontinence. If defaecation is socially acceptable there is conscious inhibition of tonic pelvic floor activity allowing puborectalis to relax and thus straightening out of the ano-rectal angle. This coupled with pelvic floor descent, prolonged internal sphincter relaxation, reflex and voluntary external sphincter relaxation causes the anal pressure to fall and defaecation to proceed.68 Voluntary contraction of the abdominal muscles and diaphragm increases intra-abdominal pressure and thus intra-rectal pressure, assisting defaecation to a variable degree. Recently it has been shown that contraction of the smooth muscle of the rectum is also important in defaecation and

29 specific rectal contractile activities also play a role. Disturbances in these motility patterns may be implicated in the pathophysiology of constipation.69 After defaecation is complete, the closing reflex occurs, whereby the external anal sphincter temporarily contracts, puborectalis contracts restoring the ano-rectal angle and internal anal sphincter tone recovers. These processes, together with passive distension of the anal cushions serve to close the anal canal.69

1.4 Faecal Incontinence

1.4.1 Definition and Prevalence

Anal incontinence is defined by the International Continence Society (ICS) collaboration as the involuntary loss of flatus, liquid or stool that is a social or hygienic problem.70 The definition of faecal incontinence (FI) is similar but does not include incontinence to flatus. It is a socially embarrassing condition with devastating effects on personal self confidence and quality of life. It can lead to family isolation and is a leading cause of nursing home placement. FI mainly affects elderly or institutionalised patients, although many young patients are increasingly affected. Reported prevalence varies widely amongst published studies, ranging from 1% to 21%.71 In the UK, Perry et al (2002) conducted a cross sectional postal survey of 10116 adults aged over 40 years. Residential and nursing home residents were excluded. The prevalence of major FI was found to be 1.4% in the total sample and 2.3% in those over 65 years.72 More recent studies from the US have reported higher prevalence rates in the community, estimating FI to affect 15% of people over 50 years of age.73, 74 FI in the nursing home population has been estimated to be 47%.75 Prevalence and severity of FI increase with advancing age and the impact on quality of life is known to be a considerable problem in those over 65.72

Perry et al found no significant difference in prevalence between the sexes and this is in agreement with other large studies.72, 74 Although female predominance is found in specialist clinics, this is likely to reflect different consultation behaviour and referral patterns rather than the actual prevalence of FI in the general population. Men tend to seek help less and as such male faecal incontinence has received very little attention in the literature.

Faecal incontinence has a detrimental effect on quality of life, leading to embarrassment, social isolation, negative self image and financial hardship. As patients with this problem are less likely to present, prevalence data are likely to be under-estimated and therefore the overall impact on quality of life and cost to society is unknown.75

1.4.2 Aetiology

The maintenance of continence is multi-factorial and this is reflected in the large number of aetiological factors involved in incontinence. The main causes of faecal incontinence are shown in Table 1.1 below.

Table 1.1 Causes of faecal incontinence.

Traumatic Medical Obstetric injury Inflammatory bowel disease Ano-rectal surgery Diabetes Mellitus Haemorrhoidectomy Malabsorption Sphincterotomy Radiation proctitis Anal stretch Dementia Fistula surgery Psychiatric disorders Bowel resection Spinal cord injury Neurological

Congenital Multiple Sclerosis Imperforate anus Stroke Rectal agenesis Spina bifida Hirschsprung’s disease Meningocele/Myelomeningocele

Colorectal Rectal prolapse Haemorrhoids Rectal/anal tumour

Adapted from Madoff et al (2004).76

The majority of cases of faecal incontinence are acquired. Obstetric perineal trauma is a major cause and remains the commonest identifiable aetiological factor in young women. The development of endoanal ultrasonography has greatly enhanced our understanding of anal incontinence and allowed a much improved assessment of the structural integrity of the anal sphincter complex. It has been demonstrated that 35% of primiparous women and 44% of multiparous women develop sonographic evidence of anal sphincter injury during vaginal delivery, with anal incontinence developing in 13% and 23% respectively.77 In 2003 Oberwalder et al, in a meta- analysis of 717 vaginal deliveries, reported a 26.9% incidence of anal sphincter defects in primiparous women and an 8.5% incidence of new sphincter defects in

32 multiparous women.78 Forceps delivery is associated with increased risk.77 Other causes of trauma to the sphincters include surgery for haemorrhoids, lateral internal sphincterotomy, fistulotomy and the notorious Lord’s stretch.70

Injury to the pudendal nerve can occur during obstetric perineal trauma potentially contributing to resulting symptoms. Pudendal neuropathy leading to neurogenic or idiopathic faecal incontinence can also occur during chronic straining at stool, pelvic floor descent and rectal prolapse. In these situations the pudendal nerve is stretched over a number of years leading to a neuropathy that affects the striated anorectal musculature.79

Increasing age is a major risk factor with its concomitant effects of sphincter degeneration, progression of pudendal neuropathy, collagen weakness, sequelae of faecal impaction, stroke and dementia. Deterioration in anorectal function is frequently a result of more than one factor. The majority of cases of faecal incontinence develop later in life and many women with peri-partum sphincter injury do not become symptomatic until their 60’s or 70’s. These observations suggest a cumulative, multifactorial process in the development of faecal incontinence making a thorough assessment vital.

1.4.3 Scoring Systems

A number of scoring systems have been developed for the assessment of patients with FI, mainly because no physiological measure accurately reflects clinical severity. These tools assess symptom severity and impact on quality of life. Symptom severity is scored by assessing frequency and type of incontinence, the extent of lifestyle changes and the use of pads and anti-diarrhoeal medication. Commonly used symptom severity questionnaires include the Wexner continence score80, the faecal incontinence severity index (FISI)81 and the Vaizey incontinence score.82 The impact of FI on quality of life should be assessed as this often does not correlate with symptom severity.76 The Fecal Incontinence Quality of Life Scale (FIQL)83 and the Manchester Health Questionnaire84 are both validated FI-specific quality of life questionnaires in common use.

1.4.4 Anorectal Investigations

In conjunction with a thorough history and examination, the investigation of anorectal structure and function can aid the clinician in the assessment of patients with FI and help in guiding management. Useful laboratory studies include anal manometry, neurophysiological testing and endoanal ultrasonography.

1.4.4.1 Anal Manometry

Anal manometry provides an assessment of both the resting tone and voluntary contraction of the anal sphincters. It can be performed using micro-balloons, water- perfused catheters or solid state transducers. Measurements are taken either using a simultaneous channel recording technique that records the pressure at sites along the catheter simultaneously, or by using a station pull through technique. In the station pull through technique measurements are taken along the anal canal from the rectum to anal verge normally in centimetre intervals.85 At each station interval a period of a few seconds rest is observed to allow accommodation before measuring basal resting pressure and then squeeze pressure produced by voluntary anal contraction. The resting pressure generally reflects the function of the internal anal sphincter whereas the squeeze pressure represents voluntary contraction of the external anal sphincter. There is great variation in methods adopted between investigators, no agreed method of interpretation of results and no consistency in units of pressure used. Consequently there is no defined ‘normal’ range of values for resting pressure or squeeze pressure. This concept of normality is to be used with caution when interpreting manometry values as there is frequently considerable overlap in results when comparing continent and incontinent subjects.86, 87 Incontinent patients will frequently have ‘normal’ manometry results and similarly continent subjects will frequently have ‘abnormal’ results. It is therefore advisable to interpret manometry results with caution and only in conjunction with a full clinical assessment and other anorectal physiology results.

1.4.4.2 Neurophysiological Investigations

Neurophysiological assessment is achieved by electromyography (EMG) or pudendal nerve terminal motor latency (PNTML) testing. EMG provides a

34 sensitive measure of denervation, is able to identify areas of sphincter injury by mapping the sphincter and can determine whether the muscle contracts or relaxes by the number of motor units firing.88 EMG is performed either using a needle electrode, a surface electrode on the perianal skin or an anal plug. Needle electrodes can either be single fibre electrodes, which record a single motor unit at a time, or concentric needle electrodes, which record the activity of up to 30 motor units around the needle. EMG has largely been superseded by endoanal ultrasonography in detecting sphincter injury, but surface EMG still provides a valuable role in assessing appropriate sphincter relaxation or contraction. This makes it useful in biofeedback techniques.

A glove mounted stimulating and recording electrode has been developed to measure the conduction of the pudendal nerves, the PNTML.89 Delayed PNTML is used to identify pudendal nerve injury. The technique involves measuring the conduction time from stimulating the nerve at the ischial spine to contraction of the external anal sphincter. PNTML’s have been shown to be prolonged in patients with idiopathic faecal incontinence compared to normal controls.89 Questions have been raised over the test’s reproducibility owing to operator dependence.90 PNTML measures only the fastest conducting fibres and therefore latencies may be normal in a damaged nerve if a few normally conducting fibres remain.90 The clinical usefulness of the test remains controversial, but it remains commonly performed and important in the research setting.

1.4.4.3 Endoanal Ultrasonography

Endoanal ultrasonography (EAUS) is now a widely used, simple and quick test that provides an accurate picture of anal sphincter anatomy. Figure 1.3 is a typical normal endoanal ultrasound scan demonstrating the anal sphincter muscles in cross section.

Figure 1.3. A normal endoanal ultrasound scan. The darker inner ring represents the IAS (I) and the whiter ring surrounding this is the EAS (E). Taken from Diamant et al (1999).88

EAUS can accurately identify anatomical defects in both the IAS and EAS and can also demonstrate more subtle abnormalities in IAS smooth muscle texture and composition. It has been shown to have excellent sensitivity and specificity in detecting IAS and EAS defects when performed by an experienced ultrasonographer.91 As a result EAUS has become the imaging modality of choice when evaluating the anal sphincters of a patient with faecal incontinence.

1.4.5 Management

The management of faecal incontinence is dependent on the type and severity of symptoms, the effect on quality of life and the underlying structural or functional abnormalities. Treatment can be divided into conservative non-surgical options and surgical options.

1.4.5.1 Conservative Treatment

In addition to the exclusion of gut stimulants such as caffeine, alcohol and artificial sweeteners, conservative treatment options often involve a combination of pharmacological, behavioural and physical therapies.

Constipating agents such as loperamide, codeine, atropine and diphenoxylate lead to a harder stool consistency and less frequent call to stool, allowing easier control. A Cochrane review examined the effects of the anti-diarrhoeal agents compared to placebo. The review concluded that there is evidence to support the use of anti- diarrhoeals but that adverse events were common.92

Biofeedback is a technique that allows pelvic floor retraining using visual or auditory feedback to achieve coordinated and improved muscle function.93 It is a simple and safe treatment with few adverse side effects. In a systematic review Norton and Kamm (2001) reported 275 out of 566 patients (49%) were cured of faecal incontinence symptoms following biofeedback treatment and 617 out of 861 patients (72%) were improved after treatment.94 The same authors also state that biofeedback is most useful in the treatment of patients with urge incontinence but also improves symptoms in those with passive leakage.95 However, questions still exist about the long term usefulness of the technique and who it will benefit the most. The large variability of biofeedback techniques used, lack of uniformity in outcome measures and limitations in trial sizes and design have meant that the role of biofeedback in the treatment of faecal incontinence is not clearly defined.96

Anal plugs and pads can help those with passive anal leakage. Anal plugs are self- expandable devices that block the passage of stool. They are poorly tolerated and mainly used in patients who are institutionalised.93

1.4.5.2 Surgical Treatment

The aim of surgery is to correct any mechanical defect or to augment a functionally deficient continence mechanism.

Injectable bulking agents can be used to augment a deficient IAS in cases of passive faecal leakage. Results are encouraging in the short term but the implants are expensive and only patients with mild symptoms are likely to benefit.96

Patients with an anterior EAS defect, often after obstetric perineal trauma, are amenable to an overlapping anterior sphincteroplasty. A recent case series of 172 patients undergoing overlapping anterior sphincteroplasty demonstrated acceptable to excellent long term outcome in 60% of patients.97 Other reports however suggest the results from sphincteroplasty deteriorate with time and some patients may develop new evacuation disorders.98, 99 Co-existing pudendal neuropathy is common with sphincter injuries and some authors state that this adversely affects the long- term outcome of sphincteroplasty.76

Other surgical options include dynamic graciloplasty, artificial sphincter, defunctioning stoma and more recently sacral nerve stimulation.

1.4.6 Sacral Nerve Stimulation

Sacral nerve stimulation (SNS), originally described for use in urinary disorders has been used to treat faecal incontinence since 1995.100 The procedure involves placing an electrode in a sacral foramen (usually S3) to stimulate the sacral nerves. Stimulation to the sacral nerves is initially provided by a portable stimulator for a 2 week test period. Generally if a patient reports a 50% improvement in their symptoms or faecal incontinence severity score they are offered implantation of a permanent stimulator. The mode of action is poorly understood but it is thought to involve neuromodulation of the anal sphincter complex and improvement of rectal sensitivity.93 Studies investigating SNS in patients with urinary incontinence have suggested that it may also affect central nervous pathways.70

The use of SNS for patients with idiopathic faecal incontinence was approved by the National Institute for Clinical Excellence (NICE) in 2004. Initially SNS use was restricted to patients with an intact EAS but indications have evolved with time. It has now been shown to be successful in patients with faecal incontinence associated with EAS and IAS injury, idiopathic sphincter degeneration, spinal cord injury and after low anterior resection.101, 102 In a systematic review 41-75% of patients reported complete faecal continence after implantation and 75-100% reported improvement in symptoms and episodes of incontinence.101 Despite this, adverse effects are not uncommon. A recent study by Maeda et al (2011) reported loss of efficacy, lack of efficacy and pain as the most common adverse effects.103 Reprogramming or lead repositioning were the commonest interventions.103 Long

38 term functional data about the efficacy of SNS is lacking. In 2009 Matzel reported the outcome of a cohort of patients who were the first to have SNS from 1994-1999. 9 patients were followed up for > 7 years and all reported sustained improvement in symptoms and quality of life.104 In the UK a recent study reported continued success in 15 out of 18 patients (83%) followed up for 5 years and continued success in all 3 patients followed up for 10 years.102 These initial results suggest that SNS is an effective treatment in the long term, however, larger long term follow up studies are needed. Despite lack of long term data SNS has now become a first line treatment in patients where conservative measures have failed.

The effect of SNS on anal sphincter function is not clear cut. Despite successful results no significant changes in anal resting pressure or squeeze pressure have been reported in a number of studies.105, 106 Conversely, other studies have shown no change in resting anal pressure but significant increases in anal squeeze pressure after SNS 107, 108, and others have shown significant increases in both resting and squeeze pressures.109 The effect of SNS on anal manometry therefore remains uncertain and variations in findings are probably the result of differences in stimulation settings and non-standardised methods of measurement.

As the precise mode of action of SNS is not known, the type of patient who will benefit the most is unpredictable. Indeed, some patients report no improvement at all. For this reason a trial period with temporary stimulation (percutaneous nerve evaluation, PNE) is necessary to identify those who are likely to have a successful result. A number of authors have attempted to establish specific factors that may predict the success or failure of PNE in the treatment of faecal incontinence. In a large study by Maeda et al (2010) no pre-operative predictor of PNE outcome could be identified. Prospectively collected data were reviewed retrospectively in 244 patients. None of the preoperative variables including demographic data, type of incontinence, and preoperative anorectal physiology results could predict the outcome of PNE. Only low amplitude of sensory threshold during PNE and lead placement anterior to the sacral cortex had a significantly positive correlation with a successful test.110 Other studies have shown that success from PNE is associated with age (successful responders being significantly younger than non-responders) and low stimulation amplitude to achieve a motor response.111, 112 In all the published reports however there is no difference between those who have a

39 successful test and those who have an unsuccessful test in terms of clinical features, anorectal physiology findings and presence or absence of sphincter defects on EAUS.110-113

Despite the exact mechanism of action of SNS remaining unclear, it has been shown to substantially improve continence in all aetiological subgroups and can be used as a minimally invasive alternative to surgery. Further neurophysiological research is needed to fully understand the mechanism of SNS and the changes it effects on the physiology of defaecation and continence.

1.4.7 Faecal Incontinence in Males

As mentioned earlier the prevalence of faecal incontinence in the general population increases with advancing age and is thought to affect 15% of people over 50 years of age.73, 74 Large studies in both the UK and US have reported no significant difference in prevalence between the sexes.72, 74 Despite this finding the majority of reports in the literature concern faecal incontinence in females. This disparity is likely because the majority of patients seen in specialist pelvic floor clinics are women with child birth related trauma being the most common aetiological factor. Male incontinence has received very little coverage in the literature.

Faecal incontinence in men is often viewed as less severe without conclusive scientific evidence to corroborate this. Two studies have reported severity and quality of life data in male incontinent patients. Christoforidis et al (2010) reported no significant difference in Faecal Incontinence Severity Index (FISI) and quality of life scores between males and females.114 In a UK study, Maeda et al (2009) found similar results with no difference in the Short-Form 36 (SF-36) and Hospital Anxiety and Depression Scale (HADS) scores.115 Male incontinence should therefore not be overlooked as the social and behavioural effects are just as devastating.

A particular sub-group of male incontinence is seen in specialist clinics and has been defined in the literature. Some patients complain of faecal leakage or seepage particularly in the hours following defaecation, as opposed to the usual symptoms of urge and passive incontinence throughout the day. Sentovich and colleagues defined faecal leakage as “the loss of small amounts of liquid stool or solid smears of stool, resulting in minor staining of underclothes”.116 They classified “leakers” as a

40 separate clinical and physiological entity that should be treated differently. In a retrospective review of the records of 25 men with faecal incontinence, 14 men were defined as leakers. They were found to have significantly lower anal sphincter resting and squeeze pressures than normal males, but higher pressures than incontinent males. Incontinent males were defined as those with involuntary loss of gas, liquid or solid stool.116 The leakers were also found to have a significantly longer anal sphincter length than both the normal males and incontinent males. This prompted the authors to propose that a long sphincter length of intermediate pressure allows residual stool to remain in the anal canal after defaecation, only to leak thereafter. They advocated treatment with post-defaecation enemas and constipating agents for this group of males.116 In a similar retrospective study Parellada et al also found significantly longer anal sphincters in men with leakage compared to normals, but conversely significantly higher anal resting pressures.117 They proposed that a long high pressure sphincter traps faecal material during defaecation which may then leak out causing soiling and perianal discomfort.117 In a more recent, prospective study Titi et al found no significant difference in anal sphincter pressures between male “leakers” and normal controls. They also found no significant difference in anal sphincter length and the vast majority had structurally normal sphincters on EAUS. Indeed other studies report that the majority of incontinent men do not have a sphincter injury on EAUS.118 The authors agreed that males with faecal leakage are a separate clinical group but in view of the normal morphological and physiological findings they felt that investigating them was unhelpful and could be omitted.119 These three studies have attempted to provide a pathophysiological basis to faecal leakage but the results are conflicting. The exact causative mechanism remains unclear. There is a large percentage of incontinent men that do not have any physiological or anatomical abnormality when tested with current investigative techniques. These patients represent a difficult group to treat. There may be reasons for the incontinence that we do not yet understand or it may reflect the relative insensitivity of our current investigative regime. Further development of more dynamic physiological testing may improve our understanding of the pathophysiological processes involved in incontinence.

1.5 Acoustic Reflectometry

1.5.1 Background

Acoustic reflectometry was originally developed by seismologists for study of the earth’s crust. An explosion at the earth’s surface produces an impulsive acoustic wave which travels into the core, the reflections of which can be measured at the surface. The reflections measured at the surface, termed the input impulse response are dependent on the densities of the different rock layers. Ware and Aki developed a complex algorithm allowing the calculation of reflection coefficients of these layers from this impulse response.120 This technique was then adapted and used as a method for measuring airway dimensions. By applying a pulse of sound into the mouth of a subject, and recording the resulting reflections at the lips, the cross- sectional area of the airway could be calculated. Jackson et al (1977) then took this technique further using an acoustic pulse reflectometer to measure the area profiles of excised dog tracheas and lungs.121 Human studies then followed and since the 1980’s there have been many published reports describing the successful use of acoustic reflectometry to measure area profiles of the airways.122-125 Its use has also become established in the diagnosis of middle ear pathology, particularly otitis media and middle ear effusion.126, 127 It has proved helpful in the confirmation of endotracheal intubation128 and is also used in the assessment of sleep apnoea.129

1.5.2 Urethral Pressure Reflectometry

Acoustic reflectometry was initially limited to the investigation of open cavities. Klarskov et al modified the technique by adding a thin distensible polyurethane bag and a pressure pump.130 This adaptation allows the simultaneous measurement of cross-sectional area and pressure within a collapsible tube. The polyurethane bag is first placed into the cavity to be measured. Wide band sounds (100Hz – 16kHz) produced by a digital signal processor are then transmitted into the cavity and the reflections are detected by a microphone. Variations in cross sectional area cause impedences to the acoustic impulse response. These variations in acoustic impedence determine the reflection coefficients which in turn govern the acoustic impulse response of a cavity. By applying the Ware-Aki algorithm to the impulse response the cross-sectional area profile of the tube under investigation can be calculated. A pump is connected to the system to apply known pressures to the

42 polyurethane bag. The actual pressure is measured by a transducer, allowing simultaneous pressure and cross-sectional area measurements along the entire length of the tube under investigation.130 In vitro testing was carried out examining the accuracy and reproducibility in measuring 8 different models (some with constrictions) with known cross-sectional areas. Measurements were found to be reliable from 1-5 cm within the cavity and at pressures ranging from 10 – 200 2 cmH2O. The absolute error in measuring the models did not exceed 1.2mm . Reproducibility was not affected significantly by change in background noise, temperature, catheters or area profile of the cavity.130

Klarskov and Lose then used this technique for simultaneous measurement of pressure and cross-sectional area in the female urethra.131 Techniques for measuring pressure and cross-sectional area in the female urethra have already been described but none have become common practice. The most widely used technique is based on the field gradient principle, using a standard pressure catheter containing 4 ring electrodes surrounded by a balloon containing an electrolyte solution. The main disadvantages to this are that the urethra is inevitably opened and distorted by the relatively thick (~10mm2) and stiff catheter and measurements can only be performed at one site along the urethra at any one time. Urethral pressure reflectometry offered an optimal technique of measuring urethral physiology. The polyurethane bag is very thin (0.025mm) and highly flexible so once placed in the urethra causes minimal distortion. When collapsed the bag only occupies an area of 0.4mm2 allowing more physiological measurements to be taken. Also, during reflectometry cross-sectional area measurements of the urethra are taken every millimetre along the entire length of the bag at the same time allowing a more accurate assessment of the high pressure zone.131

The measuring catheter consists of the thin distensible polyurethane bag connected to a length of polyvinyl chloride (PVC) tubing. This tubing then attaches to the acoustic reflectometry probe containing the microphone and loud speaker, as shown in figure 1.4.

Figure 1.4 Polyurethane bag and reflectometry probe.132

The bag is placed in the urethra using an infant feeding tube as a guide wire preventing it becoming deformed. The feeding tube is then removed and the PVC tubing attached to the probe. The pump and digital signal processor are activated and a cycle of incremental pressure steps inflates the bag to the set pressure as cross- sectional area measurements are taken along the entire length. The pressure then decreases sequentially and as the bag deflates measurements are repeated. The minimum cross-sectional area along the bag at each pressure step represents the high pressure zone (HPZ) of the urethra, i.e. the part of the urethra that resists opening the greatest. Curves are plotted showing distance into the urethra (X-axis) against cross-sectional area (Y-axis) at each pressure level. From these curves computer generated graphs are plotted showing cross-sectional area (X-axis) against pressure (Y-axis) from the HPZ, demonstrated in figure 1.5.

Figure 1.5. Graphs of cross-sectional area vs. Distance into the urethra are plotted initially for each pressure step. Values taken from the HPZ are then plotted on a graph of Pressure vs. Cross-sectional area.132

Points are plotted on the graph during increasing pressure steps when the bag inflates and during decreasing pressure when the bag deflates. This produces opening and closing traces shown in figure 1.6.

Figure 1.6 Area vs. Pressure graph for HPZ showing opening and closing traces, demonstrating the acoustic parameters.133

From this graph, 5 physiological parameters can be determined. The opening and closing pressure represent the pressure where the urethra just begins to open and close respectively. The opening elastance is an expression of the resistance of the urethra to open, and the closing elastance is an expression of the ability of the urethra to close against a pressure. Both these measurements are calculated as the gradient of the opening and closing traces respectively. The hysteresis is then calculated as the difference between the area under the increasing (inflating) curve and the area under the decreasing (deflating) curve. The hysteresis represents the amount of energy dissipated while inflating and deflating the bag.131

Klarskov and Lose compared this technique to standard urethral pressure profilometry in 143 women.134 It was found to be equally as accurate, however reflectometry was found to be more reproducible. In a later study, urethral pressure reflectometry was compared to pressure profilometry in measuring healthy volunteers and stress incontinent women. It was shown to be a clinically reliable technique and was able to discriminate between continence and incontinence with more accuracy.135 Since these initial trials urethral pressure reflectometry has been shown to be useful in both the detection of physiological changes and understanding the mechanism of action following injection bulking therapy and pharmacological treatment.136, 137 It represents a clinically reliable technique providing useful physiological parameters which aid our understanding of both continence and incontinence.

1.5.3 Anal Acoustic Reflectometry

The technique of urethral pressure reflectometry has been adapted for use in the anal canal. Mitchell et al were the first investigators to adapt this technique and use it successfully in the evaluation of the anal canal.132 The methodology is very similar to urethral reflectometry, with the acoustic reflectometry bag being introduced into the anal canal with the patient in the left lateral position. The computer generated graphs are the same as those in urethral recflectometry and the same physiological parameters are measured. Anal Acoustic Reflectometry (AAR) may offer a number of advantages over conventional anal manometry. In anal manometry a rigid catheter is inserted into the anal canal and measurements are recorded in a station pull through technique along the length of the anal canal. This inevitably distorts the anal canal whereas the AAR bag is completely collapsible and flexible, and when collapsed occupies an area of only 0.4mm2. This means the anal canal is essentially closed at the beginning of measurements representing a more physiological assessment with minimal distortion. In AAR the thin polyurethane bag is slowly inflated, allowing an assessment of the ability of the anal canal at rest to remain closed against an increasing pressure. Also, reflected sound waves are analysed along the entire length of the bag allowing accurate measurement of the HPZ (point of minimal cross-sectional area), ensuring the associated acoustic parameters are based on the most functional part of the sphincter complex.

In addition to these methodological advantages, AAR offers the investigator a unique analysis of the physiological functioning of the anal continence mechanism. During defaecation the anal canal opens and dilates to allow the passage of stool. It then closes after the stool is passed and returns to its resting state to maintain continence. During AAR the anal canal is essentially opened, dilated and then allowed to return to its closed state during inflation and deflation of the bag. The measurements taken during this process, unlike other forms of assessment, thus represent a dynamic physiological assessment of the anal sphincter mechanism. At the start of AAR the anal canal is essentially closed as the bag takes up such a minimal area. As the pressure within the bag increases the anal canal initially resists opening up to a point where it can no longer remain closed. It then begins to open as the closing forces in the anal canal are unable to resist the increasing pressure. After the incremental steps of inflation are complete, the bag then deflates and the anal canal returns to its closed state. The five acoustic parameters that are recorded at rest represent a dynamic assessment of anal sphincter function which until now has been unavailable to investigators (Figure 1.6). The Opening Pressure represents the pressure at which the anal canal just starts to open. Functionally it represents the ability of the anal canal to remain closed against an increasing pressure. It is therefore a measure of the closing forces generated from the tissues and structures in and around the anal sphincter complex that contribute to the continence mechanism. Elastance is the resistance of an object to deformation by an external force and is the inverse of compliance.138 The Opening Elastance is a measure of the anal canal’s resistance to dilatation once the opening pressure has been reached, i.e. once the closing forces have been overcome. It is calculated as the gradient of the opening curve during anal canal opening. The Closing Elastance represents the ability of the anal canal to close against a reducing pressure and is calculated as the gradient of the closing curve. The Closing Pressure is the pressure at which the anal canal just closes after dilatation. It represents the pressure level at which the components in and around the anal sphincter complex are just able to close the anal canal lumen again after a period of dilatation. Finally Hysteresis is measured which is the difference between the area under the inflation curve and the area under the deflation curve expressed as a percentage. It represents the energy dissipated during opening and closing of the anal canal and reflects the viscoelastic characteristics of the anal canal. After these resting parameters are measured, AAR is then repeated with the patient performing a 48 voluntary contraction at each pressure step during inflation only. This allows the calculation of Squeeze Opening Pressure, the pressure at which the anal canal just opens during an assessment of voluntary contraction, and squeeze opening elastance, the resistance of the anal canal to opening during voluntary contraction. These variables reflect the voluntary function of the EAS.

Attempts at measuring cross-sectional area and pressure simultaneously during distension of the anal canal have previously been reported.139, 140 These studies however were limited as they used the field gradient principle to measure cross- sectional area. This meant that measurement was only possible at one particular point in the anal canal and in Rasmussen’s work the data presented with regard to the accuracy of this technique in measuring tubes of known cross-sectional area were very unclear.139 The main disadvantage of this technique however, is the inability to measure cross-sectional area simultaneously along the entire length of the anal canal. Cross-sectional area measurements are made at one particular part of the anal canal and in Rasmussen’s work this occurred at “the middle of the anal canal”.139 There is no accurate way to check that the position of the probe is correct and recording data from the HPZ, where the most active part of the anal sphincter complex resides. The advantage of AAR is that cross-sectional area measurements are taken simultaneously along the entire length of the anal canal at each pressure step. This ensures that data can be confidently recorded from the HPZ with more meaningful results.

AAR has been shown to be a reproducible technique. Initial work by Mitchell (2010) assessed inter-rater reliability and test-retest reliability with AAR. Comparison was made with conventional anal manometry for measurements taken at rest and during voluntary contraction. All of the measured AAR variables had acceptable mean differences and repeatability coefficients.133, 141 AAR was shown to have a similar reproducibility to conventional anal manometry in terms of both inter- rater and test-retest reliability.133, 141

In a study of continent subjects, the resting AAR variables were reported to be similar between the sexes, however during voluntary contraction men had a significantly greater Squeeze Opening Pressure than women.133 Opening Pressure, Opening Elastance and Closing Elastance were found to decrease with age in the

49 continent men, whereas only Opening and Closing Pressure demonstrated this trend in the continent women.133 In women with faecal incontinence, Opening Pressure and Closing Pressure again were found to decrease with advancing age, but in addition, Squeeze Opening Pressure was also shown to be negatively correlated with age, a finding not demonstrated in the continent males or females.133

AAR has been shown to be a clinically reliable technique in the assessment of FI. In a comparative study of continent and incontinent women, the resting AAR variables of Opening Pressure, Closing Pressure and Closing Elastance were all found to be significantly lower in the incontinent females.142 During the squeeze assessment both Squeeze Opening Pressure and Squeeze Opening Elastance were also significantly lower in incontinent women when compared with continent women.142 Receiver Operator Characteristic (ROC) curves demonstrated that at rest, the AAR variable Opening Pressure had a significantly superior ability to discriminate between continent and incontinent females than the anal manometry equivalent of Maximum Resting Pressure.142 This challenges the status of anal manometry as the first line investigation of sphincter function. During assessment of voluntary contraction, AAR was shown to be equal to manometry in discriminating between continent and incontinent subjects.142

These initial reports of AAR have shown the technique to be clinically reliable and reproducible in the assessment of anal sphincter function. AAR also provides an alternative physiological insight into the biomechanical processes involved during opening and closing of the anal canal. Further investigation will provide invaluable additional understanding to the physiology and pathophysiology of the anal sphincter mechanism and the maintenance of continence.

1.6 Aims

Anal acoustic reflectometry (AAR) is a reproducible and clinically validated technique, which provides a novel assessment of anal sphincter function. It also allows an insight into the physiological functioning of the anal sphincter mechanism during distension and stretch, knowledge which is currently lacking in the literature.

Individual aims and hypotheses are given at the beginning of each of the chapters, however in summary this study has the following aims:

1. To determine the ability of AAR and anal manometry to identify changes in anal sphincter function in patients with FI and to relate these changes to the severity of FI.

2. To identify whether the outcome from percutaneous nerve evaluation (PNE) for faecal incontinence is related to the variables measured using AAR in an attempt to identify a potential predictor of success that might allow better patient selection.

3. To evaluate the effect of SNS on anal sphincter function using AAR.

4. To investigate the pathophysiology of male faecal leakage and to determine whether men with faecal leakage have a measurable difference in anal sphincter function compared with continent males using AAR. 5. To determine the relative contributions of the EAS and IAS to anal tone by using AAR to study anal sphincter function during general anaesthesia with and without neuromuscular blockade.

Chapter 2

Materials and Methods

2.1 Ethical Approval Ethical approval for the study was granted on the 7th September 2010 by the North West 8 Research Ethics Committee – Greater Manchester East (08/H1012/47).

2.2 Patients

All participants were recruited from out-patient clinics, elective operating lists and ano-rectal physiology clinics. Both normal continent subjects and patients with faecal incontinence were recruited. Continent subjects were excluded if they reported any ano-rectal symptoms such as rectal bleeding, peri-anal pain, faecal incontinence, difficult defaecation or rectal prolapse. Patients with faecal incontinence were excluded if they had co-existing features of difficult defaecation, anismus or rectal prolapse.

Participants were invited to take part in the study via an invitation letter sent prior to their hospital appointment. All participants received an information leaflet and signed a research study consent form giving their informed consent to take part in the study.

An Excel database was used to record data from each patient recruited to the study. Data were recorded detailing study identification number, date of birth, age, weight, date of test, continence status, symptoms (urgency, urge incontinence, passive incontinence, difficulty wiping clean), parity, number of vaginal deliveries, number of caesarean sections, use of forceps/ventouse, perineal tears, previous gynaecological surgery, time since last bowel movement, stool consistency, previous anorectal or abdominal surgery, previous haemorrhoidal rubber band ligation, Vaizey Incontinence Score, and the results of any previous anorectal physiology investigations (manometry, rectal sensation, PNTML, and EAUS). The experimental results of AAR and anal manometry were then recorded, including the reason for the test.

2.3 Anal Acoustic Reflectometry

Materials

A very thin (0.025mm), collapsible polyurethane bag (Oticon A/S, Copenhagen, Denmark) measuring 6cm in length and 5mm in diameter (when fully inflated) is placed within the anal canal. The acoustic reflectometry digital signal processor produces wide band sounds (100Hz – 16kHz) which are sent into the polyurethane bag via rigid walled polyvinyl chloride (PVC) tubing by a transmitter (ED-1932, Knowles Electronics Inc., Itasca, Il, USA). These sounds are reflected and recorded by a microphone (FG-3329, Knowles Electronics Inc., Itasca, Il, USA). The reflected acoustic impulses allow the calculation of cross-sectional area every millimetre along the length of the bag by application of the Ware-Aki alogorithm. An integrated pressure pump inflates and deflates the polyurethane bag and the pressure within the bag is recorded by a transducer (SX30DN, Sensym sensor system). The equipment set up is shown below in figure 2.1.

Figure 2.1 Equipment set up with acoustic reflecometry digital signal processor, pump and probe.132

Protocol

AAR was performed with the patient in the left lateral position. No bowel preparation is needed. At the start of each measurement the polyurethane bag was inserted into the anal canal with the help of a narrow low friction introducer which was then removed. Once the bag was in the correct position the PVC tubing was connected to the reflectometry probe. The pump was set to apply a pressure of 100 cmH2O in the first instance to check the equipment was set up and recording properly. This pressure was then reduced to 0 cmH2O. The resting profile was then commenced with the pump applying increasing pressures from 0 – 100 cm H2O, inflating the bag until it was fully open. The pressure increased in steps of 5 cm

H2O, with 3 seconds at each pressure level. At each pressure level simultaneous pressure and cross-sectional area measurements were made along the entire length of the polyurethane bag. The pressure then decreased in a similar step-wise manner until the bag was fully collapsed inside the anal canal. This cycle was repeated three times. The strain profile was then commenced in which the pressure within the polyurethane bag was increased in steps of 10 cm H2O from 0 to 200 cm H2O. The patient performed a voluntary contraction of the anal sphincter when being asked to “squeeze” at each pressure level. After each voluntary contraction there was a rest period of 10 seconds before the pressure was increased to the next level. Graphs of cross-sectional area against pressure for the high pressure zone of the anal canal were then generated. From these graphs the acoustic parameters were determined. During the rest assessment, opening pressure, opening elastance, closing elastance, closing pressure and hysteresis were measured. During the strain assessment, only opening pressure and opening elastance were measured as cross-sectional area measurements were only taken during inflation of the polyurethane bag. AAR was performed first, followed by assessment with standard anal manometry.

The acoustic reflectometry balloons were sterilised in the Sterilox endoscopy sterilisation system in the hospital after use. Previous work by Mitchell (2010) had confirmed that, with repeated use and sterilisation, the acoustic reflectometry balloons remain accurate up to a maximum of ten cycles.133 The balloons were therefore discarded after being used on ten occasions.

2.4 Anal Manometry

Materials

Anal manometry was performed using a portable, closed water-filled system. The manometry balloons are disposable and were made by gluing a microballoon (Precision Dippings Marketing Ltd, UK) to the end of a 15cm length of ‘A-Line’ tubing (Protect-A-Line, Vygon Ltd, UK). A small piece of heat shrink then covered the end of the tubing leaving just the microballoon visible. The manometry catheter was then marked with 1 cm graduated markings from the base of the balloon for a distance of 5 cm. The proximal end of the ‘A-Line’ tubing was then connected to a three-way luer lock tap (BD ConnectaTM, Sweden). The manometry catheter was then flushed through with water ensuring that all air bubbles were removed. The catheter was then connected to the manometry system incorporating the pressure transducer (SensoNOR840), ensuring that the entire circuit was water-filled and free of air bubbles. The transducer sent the signal through an amplifier to the computer. Analysis was performed using DasyLab computer Software (DASYLab ‘Data Acquisition System Laboratory’ Version10.0, Adept Scientific UK). The manometry equipment set up is shown below in figure 2.2.

Figure 2.2. Manometry catheter connected to pressure transducer.

Protocol

Anal manometry was perfomed after AAR, ensuring a minimum rest period of 2 minutes. Again the patient was positioned in the left lateral position and the pressure

56 zeroed with the balloon held level with the anus. The manometry catheter was inserted into the anal canal and positioned with the 5cm mark level with the anal verge. After a 10 second pause the resting pressure was recorded. The patient was then asked to “squeeze”, performing a voluntary contraction of their anal sphincter muscle. A resting pressure measurement and a measurement during voluntary contraction were recorded at 5, 4, 3, 2, and 1 cm from the anal verge (station pull through technique). The command to squeeze was identical at each level. From these readings maximum resting pressure and maximum squeeze pressure, both relative to atmospheric pressure, were recorded in cmH2O.

Calibration of the manometry system was performed by connecting the system to the acoustic reflectometry pump and applying a known pressure.

2.5 Experimental Learning Curve

Prior to commencement of the study a period of overlap between the previous and current investigator ensured that the necessary level of experience was reached. The technique was learnt and accurate interpretation of the data was confirmed. After this period of learning a randomly selected group of nineteen patients previously investigated by Mitchell (2010) were re-analysed to ensure accuracy in interpretation of the data.133 The comparative results are shown in Appendix I. Very little variation occurred allowing accurate progression of the research.

Chapter 3

A Comparative Study Of Anal Acoustic

Reflectometry And Anal Manometry In The

Assessment of Faecal Incontinence

3.1 Introduction

The prevalence of faecal incontinence (FI) increases with age and in the community is estimated to affect 15% of people over 50 years of age.73, 74 Many of these patients will undergo ano-rectal physiology testing, including assessment of the structure and function and of the anal sphincter mechanism. In recent years the number of treatment options for patients with FI has increased, making a thorough assessment of the cause an important step in determining optimum treatment. Anal manometry is the most widely used method of objectively assessing anal sphincter function, but it has significant limitations. Specifically, considerable overlap between the values of anal manometry results of continent and incontinent subjects has been reported.86, 87 The relationship between the results of anal manometry and the severity of FI is also inconsistent. Some authors have reported a linear correlation between symptom severity and anal manometry variables,143 whereas others have shown no relationship.144 This has led some specialists to view anal manometry testing as unhelpful when deciding on treatment options.145

Anal acoustic reflectometry (AAR) is a new, recently validated technique which provides a dynamic physiological assessment of anal sphincter function.132 AAR has been previously shown to have comparable reproducibility to anal manometry in the assessment of anal sphincter function141 but it is currently unclear whether AAR findings correlate with symptom severity in FI and whether AAR is more sensitive than anal manometry for detecting differences in anal sphincter function in FI.

3.2 Aims

The aims of the present study were to determine the ability of AAR and anal manometry to identify changes in anal sphincter function in patients with FI and to relate these changes to the severity of FI. Specifically the following hypotheses were tested: i) The variables of anal sphincter function measured by AAR correlate with FI symptom severity. ii) AAR can detect differences in anal sphincter function between different symptomatic subgroups iii) AAR can detect differences in anal sphincter function between patients with an anal sphincter defect and those without.

3.3 Methods

Data were collected prospectively from female patients with symptoms of faecal incontinence. All participants in the study were recruited from surgical outpatient clinics and elective operating lists. A clinical history of incontinence was clarified with every patient, such that a patient was excluded if they had any concomitant symptoms of difficult defaecation or prolapse. Patients were classified based on their symptoms into three sub-groups as follows, in accordance with Engel et al (1995)146: i) Passive incontinence – faecal soiling without awareness ii) Urge incontinence – inability to defer defaecation with the awareness of call to stool iii) Mixed incontinence – a combination of passive and urge incontinence

Demographic data were recorded including age, parity, history of ano-rectal or gynaecological surgery and history of obstetric perineal trauma. Endoanal ultrasonography (EAUS) was performed by a trained clinical scientist using a three- dimensional 10-MHz endoanal ultrasound probe (BK Medical, Herlev, Denmark). A

60 defect in the internal anal sphincter (IAS) was identified as a hyperechoic loss of continuity of the normal hypoechoic internal ring, and a defect of the external anal sphincter (EAS) as a hypoechoic loss of continuity of the normal hyperechoic external ring147. Additionally, all patients completed the Vaizey FI questionnaire, providing a faecal incontinence symptom severity score82. AAR followed by conventional anal manometry, was then performed with the patient in the left lateral position. These techniques were identical to those previously described in the Methods section (pages 52-57).

Statistical Analysis

Continuous data are presented as median (range) unless indicated otherwise. Correlation analysis was carried out using Spearman’s correlation, and subgroup comparison was performed using the Mann–Whitney U test, one-way ANOVA or Kruskal–Wallis test as appropriate. SPSS® software version 15.0 (Armonk, New York, USA) was used for all statistical analysis.

3.4 Results

One hundred women with FI, mean age 57 (range 31–83) years, were studied. Demographic data is presented in Table 3.1 below. Six patients had previously undergone haemorrhoidectomy, one a lateral sphincterotomy and 72 patients had sustained a perineal tear during labour. Median Vaizey incontinence score was 17

(8–22). Median MRP (range) was 53 (8–295) cmH2O and median MSP (range) was

85 (14–326) cmH2O.

Table 3.1 Demographics of female patients undergoing assessment with AAR and anal manometry

Variable Patients undergoing assessment

(n=100)

Mean Age (range) 57 (31-83)

Parity 2 (0-5)

Vaizey Score 17 (8-22)

Type of incontinence Urgea 32 Passiveb 7 Mixed 61 Previous gynaecological surgery

Hysterectomy 34 Transvaginal tape 3 Anterior Repair 6 Posterior Repair 10 Values shown are median (range) unless otherwise stated. Raw data presented for categorical variables. a = inability to defer defaecation, b = faecal soiling without awareness.

Median (range) values for the variables measured by AAR, together with their correlation with anal manometry are presented in Table 3.2.

Table 3.2 Spearman correlation between anal acoustic reflectometry and anal manometry variables

Variable Median (range) rs p value

Rest

Opening pressure (cmH2O) 25.9 (4.1–107.9) 0.71 < 0.001*

2 Opening elastance (cmH2O/mm ) 1.01 (0.32–2.90) 0.32 0.002*

Closing pressure (cmH2O) 19.0 (2.0–92.8) 0.69 < 0.001*

2 Closing elastance (cmH2O/mm ) 0.84 (0.25–3.15) 0.41 < 0.001*

Hysteresis (%) 20.5 (–20.6 to –0.24 0.020* 56.8) Squeeze

Squeeze opening pressure (cmH2O) 41.5 (4.4–200) 0.61 < 0.001*

Squeeze opening elastance 1.36 (0.55–3.44) 0.29 0.005* 2 (cmH2O/mm )

Anal acoustic reflectometry (AAR) variables at rest were correlated with maximum resting pressure and squeeze AAR variables with maximum squeeze pressure. rs = Spearman Correlation Coefficient. * = significant at 0.05 level.

All the resting AAR variables (apart from Hysteresis) were found to positively correlate with the resting manometry assessment of maximum resting pressure (MRP). During the squeeze assessment the Squeeze Opening Pressure and Squeeze Opening Elastance were found to positively correlate with maximum squeeze pressure (MSP).

Correlation with Vaizey Incontinence Score

Correlation between the measured parameters of anal sphincter function (AAR and anal manometry) and the Vaizey Incontinence Score (Table 3.3) was performed using Spearman’s Correlation.

Table 3.3 Spearman correlation between Vaizey incontinence score and measured variables

Variable correlated with Vaizey Score rs p value

AAR Opening Pressure (cmH2O) -0.20 0.04*

2 Opening Elastance (cmH2O/mm ) -0.22 0.03*

Closing Pressure (cmH2O) -0.14 0.18

2 Closing Elastance (cmH2O/mm ) -0.28 0.005*

Hysteresis (%) 0.03 0.75

Squeeze Opening Pressure (cmH2O) -0.27 0.006*

2 Squeeze Opening Elastance (cmH2O/mm ) -0.14 0.18

Anal Manometry MRP (cmH2O) -0.11 0.29

MSP (cmH2O) -0.18 0.09

rs= Spearman Correlation coefficient, * = significant at 0.05 level.

There was a statistically significant relationship between the AAR variables of Opening Pressure, Opening Elastance, Closing Elastance and Squeeze Opening Pressure and Vaizey Incontinence Score. Increasing Vaizey score, indicating greater severity of incontinence symptoms, was associated with lower values of these above measurements. Closing pressure, Hysteresis and Squeeze Opening Elastance failed to correlate with severity of FI symptoms. No significant correlation was seen between the manometry variables of MRP and MSP and Vaizey Incontinence Score.

Comparison of AAR and anal manometry in distinguishing between patients with urge incontinence, passive incontinence and mixed incontinence.

Of the 100 female patients studied, 32 experienced urge incontinence only, 7 experienced passive incontinence only and the remaining 61 experienced mixed (both urge and passive) incontinence. There was no significant difference between the three subgroups in terms of patient age: mean (range) age urge group = 54 (33 –

80), mean (range) age passive group = 66 (48 – 81) years and mean (range) age mixed group = 58 (31 – 83) years, p = 0.089, one-way ANOVA. AAR and anal manometry variables (Table 3.4) were compared in the three sub-groups.

Table 3.4. Comparison of measured variables between subgroups of incontinent subjects Parameter Urge Passive Mixed p value

n=32 n=7 n=61 AAR

Opening Pressure (cm H2O) 40.9 16.4 24.1 0.003* (5.7 - 78.9) (7.0 - 52.1) (4.1 - 108) Opening Elastance (cm 1.27 0.76 0.96 2 0.013* H2O/mm ) (0.52 - 2.90) (0.41 - 1.94) (0.32 - 2 12) Closing Pressure (cm H2O) 26.8 11.4 18.4 0.009* (2.5 - 78.9) (7.0 - 34.4) (2.0 - 92.8)

Closing Elastance 1.06 0.67 0.82 2 (cmH2O/mm ) 0.019* (0.45 - 1.90) (0.36 - 3.15) (0.25 - 1.92) Hysteresis % 22.6 20.5 20.1 0.883 (-10.9 - (-10.5 - (-20.6 - 55.1) 43.8) 56.8) Squeeze Opening Pressure 55.6 18.3 35.3 (cm H2O) 0.010* (7.8 - 200) (14.6 – 200) (4.4 - 200)

Squeeze Opening Elastance 1.46 0.80 1.29 2 (cmH2O/mm ) 0.069 (0.57 - 3.44) (0.67 - 2.72) (0.55 - 2.69) Anal Manometry

MRP (cm H2O) 66 38 49 0.223 (14 - 146) (10 - 155) (8 - 295)

MSP (cm H2O) 94 62 80 0.709 (32 - 248) (14 to 245) (17 to 326)

Values are median (range). Comparison with Kruskal-Wallis Test. * = significant at 0.05 level

The resting AAR variables of Opening Pressure, Opening Elastance, Closing Pressure and Closing Elastance were all significantly different between the symptomatic sub-groups of incontinent patients, with the values of all these variables being greatest in the urge group and lowest in the passive group. No difference in Hysteresis was seen between the sub-groups. During assessment of voluntary contraction, Squeeze Opening Pressure was also significantly different between the sub-groups, but no difference was seen with Squeeze Opening Elastance. Conventional anal manometry failed to demonstrate any significant difference between the different symptomatic groups.

Comparison of AAR and anal manometry in distinguishing between incontinent women with and without evidence of an anal sphincter defect

95 of the 100 patients underwent assessment with endo-anal ultrasound (EAUS). 66 of the 95 patients (69%) had intact anal sphincters on EAUS, whereas 29 patients (31%) had a visible defect in either the external anal sphincter (EAS) or internal anal sphincter (IAS). Of these 29 patients with sphincter defects, 21 patients (72%) had isolated IAS defects, 2 patients (7%) had isolated EAS defects and 6 patients (21%) had combined internal and external sphincter defects. There was no significant difference in age between those patients with an anal sphincter defect and those with intact sphincters (mean (SD) age 54 (13) vs. 59 (13), p=0.61). Comparison of AAR and anal manometry measurements between those without an anal sphincter defect and those with a defect (in either the EAS or IAS) is presented in Table 3.5.

Table 3.5. Comparison of AAR and anal manometry in incontinent females with and without anal sphincter defects.

Variable Intact Anal Anal sphincter p value Sphincter defect

n=66 n=29

AAR Opening Pressure (cm H2O) 25.7 (6.2 - 108.0) 27.0 (4.1 - 65.0) 0.44

2 Opening Elastance (cm H2O/mm ) 1.09 (0.32 - 2.90) 0.91 (0.41 - 2.11) 0.24

Closing Pressure (cm H2O) 18.4 (5.3 - 92.8) 20.0 (2.04 – 51.9) 0.39

2 Closing Elastance (cmH2O/mm ) 0.84 (0.25 - 3.15) 0.88 (0.31 – 1.51) 0.33

Hysteresis % 17.8 (-20.6 - 55.1) 23.8 (6.2 – 56.8) 0.049*

Squeeze Opening Pressure 47.7 (4.4 - 200) 32.0 (7.8- 200) 0.078

(cm H2O) Squeeze Opening 1.37 (0.55 - 3.44) 1.27 (0.69 – 2.54) 0.47 2 Elastance(cmH2O/mm ) Anal Manometry

MRP (cm H2O) 53 (14 - 295) 53 (8 - 105) 0.41

MSP (cm H2O) 91 (17 - 300) 79 (14 - 326) 0.59

Values are median (range). Compared using Mann-Whitney U test. * = significant at 0.05 level.

The only statistically significant difference between those patients with and without an anal sphincter defect was in the AAR variable of Hysteresis, which was significantly greater in the sphincter defect group. No difference was seen in the other measured AAR variables or anal manometry. Further sub-group analysis (Appendix II) demonstrated no difference in AAR or anal manometry between patients with and without an IAS defect and between patients with and without an EAS defect.

3.5 Discussion

Anal manometry is currently the standard test of anal sphincter function. However, there is often considerable overlap between the values for normal and incontinent patients.86, 87 In view of this some physicians will base their treatment recommendations on history and examination alone. A new, more sensitive test is therefore desirable. Anal acoustic reflectometry (AAR) provides a dynamic physiological assessment of anal sphincter function. It has comparable reproducibility to anal manometry and has been shown to be a clinically reliable test with superior diagnostic accuracy than anal manometry in discriminating between continent and incontinent females.141, 142 In the present study AAR has been compared with conventional anal manometry in the assessment of women with faecal incontinence.

All the resting AAR variables except Hysteresis were found to correlate positively with the maximum resting pressure (MRP) measured manometrically. This was not surprising as both tests represent an assessment of resting anal sphincter function. Similarly, both Squeeze Opening Pressure and Squeeze Opening Elastance correlated positively with maximum squeeze pressure (MSP). Although these positive correlations may reflect the fact that both AAR and manometry are measuring a similar physiological process, there are fundamental differences between the two techniques. Anal manometry employs the use of a catheter placed within the anal canal to measure the pressure exerted on a micro-balloon at rest and during squeeze, whereas in AAR the polyurethane bag is placed within the anal canal in its collapsed form, occupying an area of only 0.4mm2 causing minimal distortion. Also, during AAR cross-sectional area measurements are taken simultaneously along the entire length of the anal canal at each pressure step. This ensures that data is recorded from the high pressure zone with more meaningful results. As the bag gradually inflates, the Opening Pressure is measured, which is the pressure at which the anal canal just starts to open. Functionally it reflects the sum of the closing forces within the anal canal that combine to resist the bag inflation. Once the Opening Pressure has been overcome and the anal canal begins to open, the Opening Elastance is calculated, reflecting the resistance of the anal canal to further distension. The Closing Pressure and Closing Elastance provide an assessment of the closing forces within the anal canal that are attempting to occlude the lumen after

68 a period of dilatation, such that would occur after defaecation. Finally, Hysteresis provides an assessment of the viscoelastic properties of the anal canal. These measurements provide a detailed insight into the physiology of the anal continence mechanism not obtainable by conventional anal manometry. It is likely, therefore, that the dynamic measurements possible with AAR are far more likely to reflect subtle alterations in the function of the anal sphincters than the static assessments provided by conventional manometry. The observations of the present study support this, and show that although the measurements obtained by AAR correlated with those obtained using conventional manometry, AAR measurements, but not conventional manometry measurements, correlated with severity of incontinence and were also able to discriminate between the patterns of faecal incontinence.

Previous studies relating the severity of faecal incontinence to manometric findings have produced inconsistent findings. A large study of 351 women noted a weak but positive correlation between MRP and faecal incontinence severity index (FISI) but no correlation with MSP.143 Conversely, other studies have failed, like ours, to confirm this.144 The relationship between current objective measurements of anal sphincter function and subjective measurements of severity remains poorly understood. The present study has shown, however, that the AAR variables of Opening Pressure, Opening Elastance, Closing Elastance and Squeeze Opening Pressure all correlated with faecal incontinence severity. Although the correlation was weak, it may suggest that AAR is more sensitive than conventional anal manometry in assessing disease severity.

Faecal incontinence can be classified according to symptoms into passive incontinence, urge incontinence or a combination of both. Patients with passive incontinence present with faecal leakage without awareness, and are generally considered to have internal anal sphincter (IAS) dysfunction.146 Patients with faecal urgency present with the inability to defer defaecation and are generally considered to have external anal sphincter (EAS) dysfunction.146 This separation is however likely to be an oversimplification. Few studies have compared the findings of anal manometry in these subgroups and, to our knowledge, this is the first to do so with AAR. Engel et al 146 divided 151 patients with faecal incontinence into passive incontinence only, urge incontinence only, or mixed incontinence. They reported a significantly lower MRP in patients with passive incontinence compared to those

69 with urge incontinence, whereas MSP was significantly lower in patients with urge incontinence compared to those with passive incontinence. A similar, larger study from the same institution more recently reported no difference in MRP between the sub-groups but lower MSP in the urge incontinence group.148 In the present study no difference in MRP was seen between the urge, passive and mixed incontinence groups, but the resting AAR variables (Opening Pressure, Opening Elastance, Closing Pressure and Closing Elastance) were all significantly different between subgroups, with the passive group having the lowest values and the urge group having the highest values. Similarly, during assessment of voluntary contraction, MSP did not differ between subgroups but a significant difference was seen in the AAR variable of Squeeze Opening Pressure.

These results suggest that AAR is more effective than anal manometry in detecting differences in anal sphincter function between symptomatic sub-groups of patients with faecal incontinence. It may be that the physiological assessment of the anal sphincter provided by AAR more accurately reflects sphincter function. All the measured variables, including MSP and Squeeze Opening Pressure were lowest in the passive incontinence group and highest in the urge incontinence group. One would expect these results for the resting variables to reflect dysfunction of the IAS, but would expect the urge incontinence group to have the lower MSP and Squeeze Opening Pressure, which predominantly measure EAS function. The explanation of urge incontinence being due to EAS dysfunction and passive incontinence being due to IAS dysfunction is, however, likely to be an oversimplification. Many factors contribute to the maintenance of continence including stool consistency, colonic motility, rectal compliance, and nerve supply therefore these findings may reflect the multi-factorial nature of faecal incontinence. It is noted, however, that when the values for the urge incontinent patients are compared with those reported in a previous study of 50 continent females from our group, using the same equipment,142 the Squeeze Opening Pressure and Maximum Squeeze Pressure (MSP) are significantly lower. This might indicate that patients with urge incontinence do have dysfunction of their EAS when compared with continent controls.

The relationship between the presence of anal sphincter defects and anal sphincter function is not clear. A large retrospective study of 330 patients with faecal incontinence reported lower MSP and MRP in patients with EAS defects but no

70 association between these variables and IAS defects.149 No difference in MSP between patients with and without sphincter defects on EAUS, but significantly lower MRP in those with defects has also been reported,143 whereas others have failed to record any difference in either MRP or MSP when patients with intact anal sphincters and those with sphincter defects have been compared.150 In the present study the only difference between those patients with and those without an anal sphincter defect was in Hysteresis, which was significantly greater in the sphincter defect group. Hysteresis represents the energy dissipated during opening and closing of the anal canal and reflects the viscoelastic properties of the anal canal.142 A defect in the sphincter muscle will lead to fibrosis and the deposition of collagen, which is known to have a higher hysteresis than muscle.142 The presence of a sphincter defect and the resulting structural abnormality may lead to less efficient anal canal opening and closing or stretch and recoil, allowing more energy to be dissipated, resulting in the higher Hysteresis seen in the sphincter defect group. No difference was found in anal manometry when patients with intact anal sphincters and patients with a visible defect on EAUS were compared and no difference was seen in the other measured AAR variables. Further sub-group analysis also demonstrated no significant difference in AAR or anal manometry between groups when the IAS and EAS were studied separately. The results from our study may reflect the indirect relationship between anal sphincter structure and function. Certainly, the presence of an anal sphincter defect does not necessarily indicate that the defect is the cause of the incontinence. Numerous studies have reported the presence of anal sphincter defects in continent patients and in post-partum asymptomatic women.77, 151 Similarly, sacral nerve stimulation (SNS) has been shown to be as effective in the treatment of faecal incontinence in patients with EAS defects as those without.152

3.6 Conclusions

This study has demonstrated that AAR correlates with symptom severity in women with faecal incontinence. Unlike anal manometry AAR can distinguish between different symptomatic subgroups of incontinence. AAR may therefore be a useful test in the assessment of women with faecal incontinence. It may help to guide

71 management in patients in whom current objective and subjective assessments are unhelpful.

Chapter 4

Anal Acoustic Reflectometry – A Novel Method

For Predicting Outcome Of Sacral Nerve

Stimulation For Faecal Incontinence

4.1 Introduction

Sacral nerve stimulation (SNS) has evolved to become an effective treatment option for a wide variety of causes of faecal incontinence (FI). Not all patients benefit from SNS, therefore a trial treatment period, percutaneous nerve evaluation (PNE), is undertaken which is almost unique in surgery. The trial period is necessary to identify those patients who are likely to have a successful result from SNS prior to the insertion of a permanent stimulator, which is costly and invasive. Most units offering SNS define a successful trial as an improvement in symptoms of at least 50% from baseline during the test phase determined from an incontinence diary. Our unit, however, has always used a level of 70% in an attempt to limit false positive results. This test period of stimulation has allowed a trial of treatment for a range of pathophysiological and morphological causes of FI, leading to an expansion of indications for SNS. Despite the clinical success and increasing experience with SNS, its mode of action remains poorly understood.

A number of authors have attempted to establish specific factors that may predict the success or failure of PNE in the treatment of FI. This information could be useful to accurately counsel and select appropriate patients prior to undertaking the procedure. In all the published reports however there is no difference between those who have a successful test and those who have an unsuccessful test in terms of prior clinical features and anorectal physiology findings, so no pre-operative predictor of successful PNE outcome is currently available.110-113 Anal Acoustic Reflectometry (AAR) has been shown to be a sensitive test of anal sphincter function. If AAR were able to confidently predict outcome from PNE, this would add to its clinical utility.

4.2 Aims

This study was designed to identify whether the outcome from PNE for faecal incontinence was related to the variables measured using AAR in an attempt to identify a potential predictor of success that might allow better patient selection. The primary aims of this study were therefore to test the following hypotheses: i) Pre-operative anal sphincter function differs between those patients having a successful response to PNE and those having an unsuccessful response. ii) Pre-operative variables determined by AAR can predict the outcome of PNE for faecal incontinence.

4.3 Methods

Patients

Data were collected prospectively from female patients with faecal incontinence undergoing PNE at our institution. Patients with anal pain or constipation were excluded from this study. Demographic data were recorded, including age at the time of PNE, type of incontinence (urge, passive, or mixed), parity, details of previous ano-rectal and gynaecological surgery and history of obstetric tears. All participants completed a pre-operative Vaizey Incontinence Score,82 giving a validated assessment of the severity of faecal incontinence. In addition to this, participants also provided a subjective assessment of their average stool consistency in the form of the Bristol Stool Scale.153 Pre-operative endoanal ultrasound (EAUS) was performed by a trained clinical scientist using a 3D endoanal ultrasound 10 MHz probe (BK Medical, Herlev, Denmark). A defect in the internal anal sphincter (IAS) was identified as a hyperechoic loss of continuity of the normal hypoechoic internal ring, and a defect of the external anal sphincter (EAS) was identified as a hypoechoic loss of continuity of the normal hyperechoic external ring.147

Protocol

AAR, followed by conventional anal manometry was performed with the patient in the left lateral position on the day of surgery, immediately prior to the PNE procedure. These techniques were identical to those previously described in the methods section (pages 52-57). All patients then underwent the PNE procedure with insertion of the temporary electrode (3065U, Medtronic, Minnesota, USA) under local anaesthesia (1% lignocaine) without sedation. Fluoroscopic guidance was not used and correct placement of the needle in the S3 foramen was confirmed by an appropriate sensory response in the peri-anal region or observation of a “bellows” contraction of the perineum and plantar flexion of the great toe. After correct positioning, the temporary electrode was connected to the external portable stimulator (Medtronic InterStimTM, model 3625, USA). The settings used during the PNE were a pulse width of 210 μs and a frequency of 14 Hz. The amplitude of stimulation could be varied from 0 – 10 V. All patients then underwent a 2 week test period of PNE, during which they had the ability to change the amplitude of

76 stimulation within the preset limits of 0 – 10 V. The test electrode was removed after 2 weeks in all patients. During the PNE test period all patients completed a daily bowel diary and a Vaizey Incontinence score at completion.82 These results were compared with pre-operative values. Collection of these data was performed by a single trained specialist nurse working at our institution with no knowledge of the AAR or manometry results. A successful test was defined as a greater than 70% reduction in the number of incontinence episodes per week and/or Vaizey incontinence score.

Statistical Analysis

A power calculation was performed using initial pilot data. These data suggested that the study would need 20 subjects in each group (successful vs. unsuccessful) to have a power of 80% at a significance level of 0.05 to detect a mean difference in

Opening Pressure of 16 cmH2O (Standard Deviation of 17 cmH2O). Categorical data were compared using the χ2 test and continuous unpaired variables were compared using the Mann-Whitney U Test. To identify any independent predictors of successful PNE outcome, variables which were significantly different or approaching significance when comparing successful and unsuccessful groups were included in a forward stepwise (Wald) multivariable logistic regression analysis. Results are reported as odds ratio (OR) and 95% confidence intervals (CI). Receiver Operator Characteristic (ROC) curves were constructed to assess sensitivity and specificity. SPSS® software version 15.0 (Armonk, New York, USA) was used for all statistical analysis.

4.4 Results

Fifty two female patients undergoing PNE for faecal incontinence were recruited to the study. Thirty two patients (62%) had a successful PNE outcome and were considered eligible for insertion of a permanent SNS device. Twenty patients (38%) had an unsuccessful response from PNE. The pre-treatment demographic data and group characteristics are presented in table 4.1.

Table 4.1 Pre-operative demographics of successful and unsuccessful groups.

Variable Successful PNE Unsuccessful PNE p value

(n=32) (n=20)

Mean Age (range) § 54 (35-76) 60 (31-83) 0.10

Parity 2 (0-5) 2 (0-4) 0.84

Vaizey Score 18 (10-23) 17 (10-24) 0.60

Bristol Stool Score 5 (2-7) 4 (1-6) 0.18

Type of incontinence: Urgea 11 3 Passiveb 2 3 0.23 Mixed 19 14

Previous anorectal surgery 8/32 3/20 0.39

Anterior sphincter repair 2 1 Postanal repair 2 Anal stretch 1 Posterior Colporrhaphy 1 Lateral sphincterotomy 1 Mucosal excision 1 2

Previous gynaecological 21/32 8/20 0.07 surgery

Hysterectomy 17 7 Anterior repair 2 1 Posterior repair 1 3 Transvaginal tape 1 1

Obstetric Perineal tears 24/32 13/20 0.44

Defect in anal sphincters on 10/29 3/17 0.22 EAUS

Values shown are median (range) unless otherwise stated. Raw data are presented for categorical variables. Comparison using Mann-Whitney U test for continuous data and χ2

78 for categorical data unless otherwise stated. § = comparison using 2 samples t test. a = inability to defer defaecation, b = faecal soiling without awareness.

There was no significant difference in age between the groups, with the mean (range) age of patients having a successful PNE outcome being 54 (35-76) years and that of the unsuccessful group being 60 (31-83) years. There were no significant differences in parity, Vaizey Incontinence Score and Bristol Stool Score between the successful and unsuccessful groups. The number of patients with a past history of ano-rectal surgery, gynaecological surgery or previous obstetric perineal tears/episiotomy was not significantly different between the groups. 46 of the 52 patients underwent assessment with endo-anal ultrasound (EAUS), 29 patients from the successful group and 17 patients from the unsuccessful group. 10 patients (34%) from the successful group had an identifiable defect in one or both of their anal spincters on EAUS, whereas 3 patients (18%) from the unsuccessful group were found to have a defect. This difference was not significant (p=0.22).

The comparison of pre-operative AAR and anal manometry measurements between those patients who had a successful PNE and those who had an unsuccessful PNE is shown in table 4.2.

Table 4.2 Comparison of AAR and manometry variables between successful and unsuccessful groups.

Variable Successful PNE Unsuccessful PNE p value (n=32) (n=20)

AAR

Opening Pressure (cm H2O) 28 (6 – 96) 17 (7 – 68) 0.01*

2 Opening Elastance (cm H2O/mm ) 0.99 (0.32 – 2.11) 0.92 (0.41 – 2.00) 0.45

Closing Pressure (cm H2O) 20 (6 – 93) 13 (3 – 62) 0.06

2 Closing Elastance (cm H2O/mm ) 1.03 (0.44 – 3.15) 0.84 (0.31 – 1.23) 0.12

Hysteresis % 20 (-21 - 66) 22 (-11 – 53) 0.70

Squeeze Opening Pressure (cm H2O) 38 (11 – 91) 25 (8 – 75) 0.08

2 Squeeze Opening Elastance (cmH2O/mm ) 1.19 (0.54 – 2.72) 1.19 (0.67 – 2.33) 0.70

Anal Manometry

MRP (cm H2O) 55 (17 – 155) 48 (10 – 131) 0.09

MSP (cm H2O) 82 (32 – 167) 78 (14 – 245) 0.34

Values shown are median (range). Comparison using Mann-Whitney U test. * = significant at 0.05 level.

Opening Pressure was significantly greater in those patients having a successful PNE outcome compared with those having an unsuccessful outcome (p=0.01). No significant difference was seen in the manometric equivalent of Maximum Resting Pressure (MRP), however it did show a trend towards being greater in the successful group. Closing Pressure and Squeeze Opening Pressure also showed a trend towards being greater in the successful PNE outcome group when compared with the unsuccessful group. There were no significant differences in the other AAR variables or Maximum Squeeze Pressure (MSP) between the successful and unsuccessful PNE groups.

To identify any possible pre-operative variable that might predict success from PNE, a multivariable logistic regression analysis was performed. All variables that were significant or approaching significance when the successful and unsuccessful groups were compared were included in a forward stepwise (Wald) selection. Age and Vaizey Incontinence score were also included. The contribution of Opening

Pressure, Closing Pressure, Squeeze Opening Pressure, Maximum Resting Pressure (MRP), age and Vaizey score were assessed. Logistic regression analysis demonstrated only Opening Pressure to be an independent predictor of success with an odds ratio of 1.084 (95% CI: 1.01 – 1.16; p=0.02).

The accuracy of a test is determined by its sensitivity and specificity. Receiver Operator Characteristic (ROC) curves can be used to select the optimal cut off value for a test and to provide an assessment of sensitivity and specificity. A ROC curve was therefore constructed for Opening Pressure (Figure 4.1).

ROC Curve

1.0

0.8

0.6 Sensitivity 0.4

0.2

0.0 0.0 0.2 0.4 0.6 0.8 1.0 1 - Specificity

Figure 4.1 ROC curve for Opening Pressure.

The predictive value of Opening Pressure can be summarised by the area under the curve (AUC), with an AUC of 1 meaning the test has perfect sensitivity and specificity. The AUC for Opening Pressure is 0.72 (95% CI: 0.57 – 0.87) demonstrating a good reliability for predicting success of PNE. From analysis of

81 this curve we can say that an Opening Pressure of greater than 18.4 cmH2O would be able to predict success from PNE with a sensitivity of 0.81 and a specificity of 0.6.

4.5 Discussion

SNS has become a highly effective and safe treatment option for selected patients with faecal incontinence. Currently, selection for insertion of a permanent sacral nerve stimulator is based on the results from the percutaneous nerve evaluation (PNE) trial period. Despite the widespread use of SNS and the evolving range of indications, little is known about patient selection and factors predictive of the outcome of PNE.110 The success of the PNE period is based on the patient’s subjective assessment of outcome. Most units define a successful test as a >50% reduction in incontinence episodes, determined by analysis of a bowel diary. Reliance upon subjective methods of assessment such as this may, however, give a false evaluation of the success of therapy.154 A number of investigators have tried to identify factors that may predict the outcome of PNE for faecal incontinence. If such factors exist, then prospective patients could be “screened” which might allow better patient selection and improved operative technique. This would have obvious economic advantages and prevent unnecessary delays in treatment. Maeda et al (2010) retrospectively reviewed data collected from 244 patients undergoing PNE between March 2001 and December 2008.110 None of the pre-operative variables, including demographic data, type of incontinence, results of ano-rectal physiology studies or endo-anal ultrasonography were reported to be of predictive value in determining the outcome of PNE.110 Only the intra-operative factors of low amplitude of sensory threshold during PNE and lead placement anterior to the sacral cortex were positive predictive factors for successful PNE outcome.110 These results are similar to those in other studies, in which no difference has been reported between patients having a successful PNE outcome and those having an unsuccessful outcome with regards to clinical features, anorectal physiology findings and presence or absence of sphincter defects on EAUS.111, 112 Other authors have reported multiple attempts at PNE screening112, 155 and abnormal anal sphincter electromyography156 to be poor prognostic factors. At present, however, there is no consistent pre-operative variable known to be of predictive value in PNE.

The current study investigated whether any differences exist between successful and unsuccessful PNE groups in terms of pre-operative variables, and if so, whether these could be used to predict the outcome. There was no significant difference in baseline demographic details between those patients with a successful PNE outcome

83 and those with an unsuccessful outcome. The mean age of the patients was lower in the successful PNE group compared with the unsuccessful PNE group, but this difference was not significant. Other studies have reported age to be of significance in determining the outcome from PNE, with younger patients more likely to have a successful outcome.111, 155 Although the current study does not support this, this finding may be due to older women having a greater progression of the pathophysiological factors causing their FI compared with younger women, making them less likely to respond positively to SNS. None of the other baseline variables were significantly different between the groups, and therefore patients should not be excluded from treatment with SNS on the basis of type of incontinence, severity of incontinence, previous anorectal or gynaecological surgery and the presence of an anal sphincter defect on endo-anal ultrasound.

In agreement with other reports, this study found no significant difference in anal manometry results between those patients with a successful PNE outcome and those with an unsuccessful outcome.111, 112, 155 Although anal manometry is currently the standard test of anal sphincter function, it does have significant limitations. As previously discussed, there is considerable overlap between the values for continent and incontinent patients.86, 87 Anal acoustic reflectometry (AAR) represents a sensitive assessment of anal sphincter function and data presented in Chapter 3 have shown, that in the assessment of women with faecal incontinence, AAR correlates with disease severity and can distinguish between different symptomatic sub-groups. In support of the data presented in Chapter 3 the current study lends further evidence to the sensitivity of AAR as a test of anal sphincter function. Opening Pressure, measured by AAR, was significantly greater in the group of incontinent women having a successful response to PNE compared with the group having an unsuccessful response. There was, however, no significant difference in the manometric equivalent of Maximum Resting Pressure (MRP) between the two groups. Opening pressure represents the pressure at which the anal canal just begins to open and functionally it reflects the ability of the anal canal to remain closed against an increasing pressure. These closing forces are generated by both active and passive elements. The combined force of both the internal anal sphincter (IAS) and external anal sphincter (EAS) represent the active elements and the surrounding connective tissues represent the passive elements. The patients with a successful

PNE outcome had a significantly greater Opening Pressure, reflecting a greater ability of the anal canal to remain closed against an increasing pressure. These findings suggest that those patients more likely to respond positively from sacral nerve stimulation are those in whom the anal sphincter complex and surrounding connective tissue are more functionally robust.

The Closing Pressure, measured by AAR, was also greater in the women having a successful response to PNE, compared with those having an unsuccessful response, the difference approaching statistical significance (p=0.06). Closing Pressure is a measure of the ability of the closing forces within the anal canal to occlude the anal canal after a period of dilatation. This difference in Closing Pressure, similar to that seen in Opening Pressure, again suggests a successful response from PNE is more likely in those patients who are able to generate greater anal closing forces.

There was no significant difference in the AAR variables of Opening and Closing Elastance between the successful and unsuccessful PNE groups. Opening Elastance represents the resistance of the anal canal to dilatation once the Opening Pressure has been overcome. Closing Elastance reflects the ability of the anal canal to close down against the polyurethane bag as it deflates. Previous anal surgery will lead to scarring and fibrosis of the anal canal which may lead to higher values of elastance. There was no significant difference in the number of patients with a history of anorectal surgery between the successful and unsuccessful PNE groups, and similarly no significant difference in Opening and Closing Elastance. This finding supports the suggestion that elastance may reflect the degree of fibrosis within the anal canal. Hysteresis was also similar in the successful and unsuccessful PNE groups. Hysteresis is the difference in area under the inflation and deflation curves expressed as a percentage and reflects the amount of energy that is dissipated during opening and closing of the anal canal. In Chapter 3, the Hysteresis was found to be greater in women with an anal sphincter defect identified on EAUS compared to those without. In Chapter 6, data are presented demonstrating a higher Hysteresis in male patients with faecal leakage compared with continent men. These male leakers also had a significantly higher incidence of previous ano-rectal surgery compared with the continent men which may account for the higher hysteresis. Indeed, surgery to the anal canal will lead to fibrosis and the deposition of collagen, which is known to have a higher hysteresis than muscle.131 Both ano-rectal surgery and anal sphincter

85 defects will cause a degree of structural abnormality which may lead to less efficient anal canal opening and closing or stretch and recoil, allowing more energy to be dissipated resulting in a higher Hysteresis. In the current study there was no difference in Hysteresis which may be accounted for by the similar proportion of patients having had ano-rectal surgery and the similar proportion having an anal sphincter defect in the successful and unsuccessful PNE groups.

The AAR variable of Squeeze Opening Pressure showed a trend towards being greater in the PNE success group compared with the unsuccessful PNE group, although this difference was not significant (p=0.08). Squeeze Opening Pressure is primarily a measure of EAS function and from these results one could surmise that those patients more likely to have a successful outcome from PNE may be those with better EAS function. This however is not reflected in the manometric equivalent of Maximum Squeeze Pressure (MSP) which was similar in both groups. During assessment of voluntary contraction with AAR the patient is asked to perform a contraction of their anal sphincters at each pressure step. This results in numerous voluntary contractions being made and may lead to EAS fatigue. The EAS has been shown to undergo fatigue and studies have demonstrated greater degrees of fatigability in incontinent subjects compared with controls.157, 158 During anal manometry the patient is asked to make only five voluntary contractions at 5,4,3,2 and 1 cm in a station pull through manner. This is unlikely to cause any degree of significant EAS fatigue. It may be therefore more appropriate to propose that patients in the successful PNE group may have a less fatigable EAS and can maintain voluntary contraction at higher pressures. The EAS is composed of predominantly slow twitch type 1 muscle fibres which make it relatively resistant to fatigue.158, 159 Moreover, Beersiek et al (1979) found changes in the histological composition of the EAS in incontinent subjects.159 There was a marked loss of muscle fibres and fibre hypertrophy and a greater amount of fibrous and fat deposition within the EAS.159 The difference in Squeeze Opening Pressure may therefore reflect differences in histological composition of the EAS between the groups leading to differences in fatigability. Further investigation involving histological examination of EAS muscle biopsies taken from patients with successful and unsuccessful PNE outcomes would be required to test this hypothesis.

The current study has shown that patients with a successful outcome from PNE have a significantly greater Opening Pressure than those with an unsuccessful outcome. Using a multivariate logistic regression model and assessing the contribution of Opening Pressure, Closing Pressure, Squeeze Opening Pressure, Maximum Resting Pressure (MRP), age and Vaizey score, this study has also shown Opening Pressure to be an independent predictor of success in PNE. A ROC curve constructed for Opening Pressure has shown it to be a highly sensitive and specific test, with a value of Opening Pressure greater than 18.4 cmH2O predicting success with a sensitivity of 0.81 and a specificity of 0.6. A patient with faecal incontinence, who has an

Opening Pressure less than 18.4 cmH2O, may be directed to an alternative treatment option, rather than a trial of SNS which is likely to fail. To our knowledge, this is the first study to demonstrate a pre-operative measure of anal sphincter function to be of predictive value in patients undergoing PNE. In view of this, AAR might be used in the future to determine who is likely to have a successful response from PNE and hence SNS. This would allow better patient selection and a more efficient management strategy.

There are possible limitations that could have affected the results of this study. During the PNE test period patients could alter the amplitude of stimulation from 0 – 10 V. This variability in stimulation could have affected the response from PNE. Outcome from PNE was assessed by comparing bowel diary results and incontinence severity during the stimulation period with similar data obtained before treatment. This type of data can be influenced by variables such as stool consistency, patient activity and behaviour patterns during the two week trial period. For example, during PNE patients might feel apprehensive about leaving the house with an external stimulator device and hence daily activity will be reduced and proximity to a toilet may reduce incontinent episodes.112 This will lead to a false positive assessment and such a patient may not benefit from permanent SNS in the long term. Despite these factors, subjective assessment using a bowel diary is the current standard technique of determining outcome from PNE. It is important to note that success from PNE does not always confer success from chronic permanent sacral nerve stimulation. Despite some studies reporting good reproducibility of the therapeutic effect seen during the PNE period108, 160, others have reported failure of therapeutic effect in 20-30% of patients with an initial successful trial period.107, 111

Further investigation is required to examine whether AAR could predict these failures.

4.6 Conclusions

AAR has been shown to be a sensitive test of anal sphincter function and is able to identify differences between those patients who have a successful PNE outcome and those who have an unsuccessful outcome. Furthermore, the AAR variable of Opening Pressure has been shown to be an independent predictor of success in PNE, which may hold value in the selection of patients for this expensive treatment option.

Chapter 5

Anal Acoustic Reflectometry In The Evaluation

Of Sacral Nerve Stimulation

5.1 Introduction

Sacral nerve stimulation (SNS) was first reported for the treatment of faecal incontinence (FI) in 1995.100 Initially it was reserved for treating patients with a functionally deficient but intact anal sphincter complex. More recently, however, the indications for SNS have expanded. It has been shown to be as effective in patients with an anal sphincter defect as those with an intact sphincter152, 161, and is now commonly used as a first line intervention when conservative measures have failed. The use of SNS for patients with idiopathic faecal incontinence was approved by the National Institute for Clinical Excellence (NICE) in 2004 and received U.S. Food and Drug Administration (FDA) approval in 2011. Despite its increasingly widespread use, the mode of action of SNS remains poorly understood. Lower bowel dysfunction is often the result of several pathophysiological processes affecting the colon and anorectum. The effect of SNS is likely to be multifactorial, providing peripheral motor stimulation to the anal sphincter complex and augmenting the sensory function of the anus, rectum and colon 162. This latter effect may explain why, paradoxically, SNS improves both faecal incontinence and chronic constipation. Studies examining the effect of SNS on anal sphincter function have shown conflicting results. Some studies have shown no change in resting anal pressure but significant increases in anal squeeze pressure after SNS 107, 108, and others have shown significant increases in both resting and squeeze pressures.109 The majority of larger studies, however, demonstrate no significant changes in anal resting or squeeze pressure.105, 106 The variation in findings is likely to reflect population heterogeneity, non-standardised methods of measurement and unreliable correlation with symptoms.

Anal acoustic reflectometry (AAR) represents a novel, dynamic assessment of anal sphincter function. Its use in the evaluation of patients undergoing SNS has not been previously reported. It is unclear whether SNS effects any changes in the variables of anal sphincter function measured by AAR.

5.2 Aims

Inconsistent changes in anal sphincter function have been reported following SNS for faecal incontinence. This study was designed to further evaluate the effect of SNS on anal sphincter function. The primary aims of this study were to test the following hypotheses: i) SNS leads to changes in anal sphincter function ii) AAR is more sensitive than conventional anal manometry in detecting changes in anal sphincter function resulting from SNS

A secondary aim of this study was to investigate whether AAR could provide an insight into the mode of action of SNS for faecal incontinence. For example, if patients with FI treated with SNS have a consistent increase in Opening Pressure, this might infer how SNS is exerting its effect.

5.3 Methods

Patients

Data were collected prospectively from female patients with faecal incontinence undergoing insertion of a permanent sacral nerve stimulator (InterStimTM II, 3058, Medtronic, Minnesota, USA) at our institution. All patients had failed to benefit from conservative treatment and had previously undergone a positive test period of percutaneous nerve evaluation (PNE). Patients with anal pain or difficult defaecation were excluded from this study. Demographic data were recorded, including age, type of incontinence (urge, passive, or mixed), parity, details of previous ano-rectal and gynaecological surgery and history of obstetric tears. All participants completed a pre-operative Manchester Health Questionnaire (MHQ), which is a FI-specific quality of life questionnaire.84 All participants also completed a pre-operative Vaizey Incontinence Score,82 giving a validated assessment of faecal incontinence severity and all completed a daily bowel diary during the two-week period prior to surgery. In addition to this, participants also provided a subjective assessment of their average stool consistency in the form of the Bristol Stool Scale.153 Pre-operative endoanal ultrasound (EAUS) was performed by a trained clinical scientist using a 3D endoanal ultrasound 10 MHz probe (BK Medical, 91

Herlev, Denmark). A defect in the internal anal sphincter (IAS) was identified as a hyperechoic loss of continuity of the normal hypoechoic internal ring, and a defect of the external anal sphincter (EAS) was identified as a hypoechoic loss of continuity of the normal hyperechoic external ring.147

Protocol

AAR, followed by conventional anal manometry was performed with the patient in the left lateral position on the day of surgery, prior to insertion of the permanent sacral nerve stimulator. These techniques were identical to those previously described in the Methods section (pages 52-57). All patients then underwent surgery under general anaesthesia with reliance upon motor responses. Correct placement of the needle in the S3 foramen was confirmed by an appropriate motor response of a “bellows” contraction of the perineum and plantar flexion of the great toe. Fluoroscopic X-ray guidance was used to confirm the position of the needle. The quadripolar electrode was then inserted and the position of the electrodes checked with fluoroscopy. A sub-cutaneous pocket for the neurostimulator was created deep to Scarpa’s fascia in the ipsilateral upper buttock. After tunnelling the permanent lead to the subcutaneous pocket, it was attached to the neurostimulator and implanted in the pocket. The wounds were closed and programming of the neurostimulator performed the following morning on the ward prior to discharge by a single trained specialist nurse. Stimulation settings were set at a pulse width of 210 μs and a frequency of 14 Hz. Optimum response from SNS was achieved by regular assessment by a specialist nurse. Patients were then reviewed at follow up 3 – 12 months after the procedure. At this time patients were asked whether they subjectively felt there had been improvement in their symptoms and repeat bowel diary and Vaizey Incontinence Score analysis were performed. These data were recorded by a trained specialist nurse who had no knowledge of the AAR or anal manometry results. After this initial assessment both AAR and anal manometry were repeated in the same manner as previously described. Assessment at 3 – 12 months post-operatively was chosen as this allowed enough time to optimise the stimulation parameters, enough time for any affect on anal sphincter function to take place and the number lost to follow up would still be limited.

Statistical Analysis

Continuous paired variables were compared using the Wilcoxon Signed Ranks Test. SPSS® software version 15.0 (Armonk, New York, USA) was used for all statistical analysis.

5.4 Results

Twenty five female patients undergoing insertion of a permanent sacral nerve stimulator for treatment of faecal incontinence were recruited to the study. The mean (range) age of the patients was 56 years (36-79 years) and the median (range) Vaizey Score was 17 (10-22). Nine patients suffered with urge incontinence only, 2 patients had passive incontinence only and 14 patients had both urge and passive faecal incontinence. The basic demographic data and patient characteristics are presented in Table 5.1 below.

Table 5.1 Demographics of female patients undergoing permanent SNS

Variable Patients undergoing permanent SNS

(n=25)

Mean Age (range) 56 (36-79)

Parity 2 (0-5)

Vaizey Score 17 (10-22)

Bristol Stool Score 4 (2-6)

Type of incontinence Urgea 9 Passiveb 2 Mixed 14 Previous anorectal surgery 6

Anterior sphincter repair 5 Peri-anal abscess 1 Previous gynaecological surgery 11

Hysterectomy 7 Transvaginal tape 2 Anterior Repair 2 Obstetric perineal tears/episiotomy 16

Defect in anal sphincter on EAUS 6

Values shown are median (range) unless otherwise stated. Raw data presented for categorical variables. a = inability to defer defaecation, b = faecal soiling without awareness.

Twenty one patients (84%) were followed up post-operatively with repeat assessment of anal sphincter function with AAR and anal manometry. Median (range) follow-up was 7 months (3-19 months). Of the 4 patients in whom no follow up data were available, 2 declined further investigation of anal sphincter function and 2 were lost to follow-up. Faecal incontinence severity (Vaizey), bowel diary analysis (incontinence episodes/week) and quality of life (MHQ) at the time of follow-up were compared with baseline values before SNS and are presented in Table 5.2.

Table 5.2 Comparison of effect of SNS at follow-up compared with baseline

Baseline At follow-up p value Median 7 (3-19) (n=21) months (n=21) Vaizey Incontinence Score 17 (10-22) 9 (3-19) <0.001 * Bristol Stool Score 4 (2-6) 4 (2-6) 0.99 Incontinent episodes/week 9 (0-28) 0 (0-16) 0.009* Manchester Health Questionnaire 635 (459-875) 390 (68-678) 0.001* Values shown are median (range). Comparison using Wilcoxon Signed Ranks Test. * = significant at 0.05 level.

There was a significant improvement in Vaizey Score at follow-up, with the median score improving from 17 to 9 (p<0.001). There was also a significant reduction in the number of incontinent episodes/week (p=0.009) and a significant reduction in the MHQ score (p=0.001). Twenty of these 21 patients (95%) reported a subjective benefit from SNS at the time of follow-up. In the one patient who had no benefit from SNS, the Vaizey Score increased from 17 to 19 and the number of incontinent episodes/week increased from 11 to 16. No cause for the failure was found. Of note is that the pre-operative AAR variable of Opening Pressure in this patient was 18.96 cmH2O which is very close to the cut-off of 18.4 cmH2O, values greater than which were shown to be of positive predictive value in PNE in Chapter 4. Nineteen of the remaining 20 patients who reported a subjective benefit from SNS had an Opening

Pressure >18.4 cmH2O and one had an Opening Pressure of 14 cmH2O. The scatter plot below (Figure 5.1) demonstrates the spread of pre-operative Opening Pressures in relation to the cut off value of 18.4 cmH2O.

Figure 5.1 Range of pre-operative Opening Pressure

60 0 2 40 cmH

Permanent SNS failure

20 Opening Pressure = 18.4 cmH2O

Opening Pressure

Only one patient, who had a successful result from SNS, had a pre-operative

Opening Pressure of <18.4 cmH2O. The remaining nineteen patients with a successful SNS outcome at follow up had an Opening Presssure >18.4 cmH2O.

The paired comparison of the variables of anal sphincter function (AAR and anal manometry) at follow up with baseline is presented in Table 5.3. At the time of follow-up assessment all patients had their stimulators switched on.

Table 5.3 Comparison of AAR and manometry variables before and after permanent SNS.

Variables Pre-permanent Post-permanent p SNS SNS value

(n=21) (n=21)

AT REST

Opening Pressure (cm H2O) 32 (14 – 76) 32 (14 – 76) 0.39

2 Opening Elastance (cm H2O/mm ) 1.10 (0.41 – 3.19) 0.97 (0.34 – 3.15) 0.13

Closing Pressure (cm H2O) 25 (9 – 69) 26 (11 – 67) 0.77

2 Closing Elastance (cm H2O/mm ) 1.06 (0.49 – 3.75) 0.93 (0.20 – 2.16) 0.60

Hysteresis (%) 19 (5 - 55) 21 (5 – 35) 0.74

MRP (cm H2O) 59 (28 – 123) 65 (33 – 114) 0.29

DURING SQUEEZE

Squeeze Opening Pressure (cm H2O) 48 (17 – 138) 47 (15 – 176) 0.88

2 Squeeze Opening Elastance (cmH2O/mm ) 1.19 (0.55 – 2.78) 0.91 (0.29 – 2.10) 0.03*

MSP (cm H2O) 85 (34 – 140) 93 (45 – 241) 0.09

Values shown are median (range). Comparison using Wilcoxon Signed Ranks Test. * = significant at 0.05 level.

SNS had no effect on the resting assessment of anal sphincter function. No significant differences were found in any of the resting AAR variables, nor the manometric MRP. During assessment of voluntary contraction, SNS had no significant effect on the AAR variable of Squeeze Opening Pressure or on the manometric equivalent of MSP. There was, however, a significant reduction in Squeeze Opening Elastance.

5.5 Discussion

The mechanism of action of sacral nerve stimulation (SNS) remains unclear, and consequently it is difficult to predict the type of patient who will benefit most. Studies investigating the effect of SNS on anal sphincter function have reported inconsistent findings. Melenhorst et al (2007) prospectively examined 100 patients undergoing permanent SNS.107 They demonstrated significantly higher anal squeeze pressures at 6, 12 and 24 months post-operatively but no change in anal resting pressure.107 This is in agreement with other studies which also report higher squeeze pressures, but unchanged resting pressures with SNS.108, 163 Other studies, however, have reported significantly increased anal resting and squeeze pressures with SNS.109, 164, 165 These relatively small studies prompted investigators to hypothesise that SNS works by augmenting anal sphincter function. Larger studies, however, have reported contrasting results, demonstrating no change in anal resting or squeeze pressure after permanent SNS.105, 106, 166 These studies, together with more recent work demonstrating SNS to be effective in patients with anal sphincter defects,152, 161 suggest that its mode of action is more complex.

The current study presents follow up data, including anal sphincter assessment with AAR, in 21 patients undergoing permanent SNS, with a median follow-up of 7 months. Subjective benefit from SNS was reported by 20 of the 21 patients, all of whom had an improvement in the Vaizey Incontinence Score and number of incontinent episodes per week. There was no change in the anal manometry variables of MRP or MSP at follow-up and this is in agreement with other reports.105, 106, 166 SNS also appeared to have no significant effect on the resting AAR variables. These variables assess the anal sphincter’s response to stretch, as previously discussed, and reflect IAS function, EAS function and the properties of the connective tissues in and around the anal canal. SNS therefore appears not to have a significant effect on the closing forces within the anal canal or on the resistance of the anal canal to stretch. Similarly, during the assessment of voluntary contraction, there was no change in the Squeeze Opening Pressure at follow-up. There was, however, a significant reduction in the Squeeze Opening Elastance with SNS. During the AAR assessment of voluntary contraction the patient is asked to “squeeze” their anal sphincter at each pressure level until such a pressure is reached that a voluntary contraction makes no difference to the cross-sectional area of the

98 polyurethane bag. An opening curve is therefore constructed, similar to the resting opening curve, from which the Squeeze Opening Elastance is calculated. It is therefore likely to reflect EAS function. This finding of reduced Squeeze Opening Elastance was unexpected and suggests that the resistance of the anal canal to opening during voluntary contraction was less with SNS. This result should be interpreted with caution as study numbers are low and no other change in EAS function (MSP or Squeeze Opening Pressure) was demonstrated.

In Chapter 4, results suggested that a positive outcome from PNE could be predicted by the AAR variable of Opening Pressure. It was shown, using ROC curve analysis, that an Opening Pressure of greater than 18.4 cmH2O could predict success from PNE with a sensitivity of 0.81 and a specificity of 0.6. It is interesting to note that of the 20 patients who benefited from permanent SNS, 19 patients had a pre-operative

Opening Pressure greater than 18.4 cmH2O. In addition, the patient who reported no benefit from SNS, had a pre-operative Opening Pressure of 18.96 cmH2O. This study therefore, supports the results presented in Chapter 4, which suggest that AAR may be a clinically useful test in the selection of suitable patients for SNS.

This study produced results which corroborate the findings of much of the work in this field. SNS did not produce a significant change in anal sphincter function despite clinical improvement, and therefore the hypotheses proposed in the aims can be rejected. This study supports the view that the mechanism of action of SNS is unlikely to be solely due to peripheral motor stimulation to the anal sphincter. It is the view of many that SNS also effects changes in rectal sensation, changes in colonic and rectal motor activity and changes in brain activity. During SNS, both efferent and afferent nerve fibres are stimulated. Many studies examining rectal sensation have reported increased rectal sensitivity with SNS.108, 164, 167 Others, however, have shown no change in rectal sensitivity with SNS107, and some have shown reduced sensitivity.168 The effect of SNS on rectal sensation is therefore unclear and further neurophysiological research is required. There is a growing appreciation for the effect of SNS on the higher cortical control of continence and ano-rectal function. Sheldon et al (2005) demonstrated a decrease in cortico-anal excitability after two weeks of SNS in patients with FI, who symptomatically improved without changes in anal resting or squeeze pressures.169 These central inhibitory changes in the anal motor cortex were postulated to be secondary to

99 reduced sphincter attention in response to symptom improvement. Whatever the explanation, the study demonstrated dynamic brain changes in response to SNS, which may play a role in the maintenance of continence. Other studies have also demonstrated changes in brain activity with SNS. In women with urinary retention, SNS has been shown to restore mid-brain activity to normal and decrease cortical activity.170 It is likely that SNS for faecal incontinence induces similar changes in brain activity.

To date no consensus exists as to the exact mechanism of action of SNS. It is likely to have a multi-modal effect on anal motor and rectal sensory function, together with modulation of higher cortical centres involved in descending control of ano-rectal function. The current study did not demonstrate any clinically significant findings but was limited by patient numbers. Time to follow up was also impossible to keep constant and therefore differences in length of stimulation could have altered the results. Another limitation to the study is the inevitable variability in the permanent SNS electrode position, which may lead to heterogeneous responses between patients. Further research, particularly in the investigation of the afferent pathways and central effects of SNS, is necessary to gain a greater understanding of this complex intervention.

5.6 Conclusions

This study has demonstrated no significant effect of SNS on anal sphincter function measured by anal manometry or AAR. The complex processes by which SNS exerts its effect are still unclear and further investigation is necessary to determine which patients are likely to benefit the most.

100

Chapter 6

Anal Acoustic Reflectometry In The Evaluation

Of Male Patients With Faecal Leakage

101

6.1 Introduction

Faecal incontinence (FI) has been reported to affect 15% of the general population over 50 years of age.73 Although it has been suggested that the prevalence of FI is similar between men and women, there have been very few studies addressing FI in men.72, 74 A distinct clinical sub-group of male patients with faecal incontinence is seen in specialist clinics and has been described in the literature. These men typically complain of faecal leakage particularly in the hours following defaecation, without the usual symptoms of incontinence throughout the rest of the day. Sentovich et al (1995) defined faecal leakage as “the loss of small amounts of liquid stool or solid smears of stool, resulting in minor staining of underclothes”.116 The prevalence of this pattern of incontinence is currently unclear. A recent study by Qureshi et al (2011) found that 33 of 43 male patients referred to a UK teaching hospital from 2006-2008 complaining of incontinence met the definition of faecal leakage.171 Ano-rectal physiology studies are frequently normal and indeed Qureshi et al (2011) found normal anal sphincter pressures in their cohort of leakers.171 Titi et al (2007) also found no significant difference in anal sphincter pressures between male leakers and normal controls, and also reported that most had structurally normal sphincters on EAUS.119 The pathophysiology of male faecal leakage therefore currently remains unknown. It is consequently difficult to provide clear guidance on appropriate therapy. It is unclear whether the dynamic physiological assessment of anal sphincter function provided by anal acoustic reflectometry (AAR) might be more sensitive than the current standard of anal manometry in the identification of the underlying pathophysiological processes involved in male patients with faecal leakage.

102

6.2 Aims i) The primary aims of this study were to test the following hypotheses:

• Males with faecal leakage have a measurable difference in anal sphincter function compared with continent males. • AAR is more sensitive than conventional anal manometry in detecting a difference in anal sphincter function in males with faecal leakage. ii) Male patients with faecal leakage typically complain of symptoms following defaecation. The process of defaecation and the resulting anal canal dilatation may therefore be crucial to the underlying pathophysiological process. The secondary aim of this study was therefore to assess whether anal canal dilatation results in a measurable difference in anal sphincter function.

6.3 Methods

Male patients with faecal leakage, who met the definition proposed by Sentovich et al (1995),116 were recruited from the specialist pelvic floor clinic. Men with other types of anal incontinence, such as those with involuntary loss of flatus or urge incontinence were excluded from the study. Continent males were recruited from elective operating lists. Data were collected prospectively. General demographic data were collected, including details of any previous ano-rectal surgery. All participants completed the Vaizey Incontinence Score82 giving a validated assessment of faecal incontinence severity. In addition to this participants also provided a subjective assessment of their stool consistency in the form of the Bristol Stool Scale.153 All participants were age-matched to within 2 years, with the exception of one pair who were age-matched to within 9 years. Age-matching was carried out with no knowledge of the test results, and on no basis other than the age of the patient. All participants underwent measurement with AAR followed by anal manometry in the left lateral position. AAR and manometry were performed as detailed in the Methods section on pages 52-57. After initial assessment was complete a period of anal canal dilatation was performed. A 27mm proctoscope (Seward Thackray) was inserted into the anal canal and held in place for 10 seconds. The patient was then asked to bear down, expelling the proctoscope. A further 10

103 second gap was left and both AAR and anal manometry were then repeated as previously described. This protocol was identical in every patient. A 27mm proctoscope was used and held in position for 10 seconds as it was felt that this most accurately represented the average stool diameter and time taken for defaecation.

Endoanal ultrasound (EAUS) was performed by a trained clinical scientist using a 3D endoanal ultrasound 10 MHz probe (BK Medical, Herlev, Denmark) in 13 of the male leakers. A defect in the internal anal sphincter (IAS) was identified as a hyperechoic loss of continuity of the normal hypoechoic internal ring, and a defect of the external anal sphincter (EAS) was identified as a hypoechoic loss of continuity of the normal hyperechoic external ring.147

Statistical Analysis

A power calculation was performed using initial pilot data. These data suggested that the study would need 17 subjects in each group (leaker vs. continent control) to have a power of 80% at a significance level of 0.05 to detect a mean difference in

Closing Pressure of 20 cmH2O (Standard Deviation of 20 cmH2O). Categorical data were compared using the χ2 test, continuous unpaired variables were compared using the Mann-Whitney U Test and paired variables (before and after proctoscopy) compared with the Wilcoxon Signed Ranks Test. SPSS® software version 15.0 (Armonk, New York, USA) was used for all statistical analysis.

104

6.4 Results

Thirty subjects were recruited to this study. Fifteen male leakers were compared with fifteen age-matched controls. The demographic data and group characteristics are presented in table 6.1.

Table 6.1 Demographics of continent males and males with faecal leakage.

Variable Continent Males Male Leakers p value

(n=15) (n=15)

Mean Age (years) 55.6 55.5

Vaizey Score (median) 0 12

Bristol Stool Score 4 4 0.68 (median)

Previous anorectal 1/15 10/15 <0.0001 § surgery

Haemorrhoidectomy 3 Mucosal Excision 5 Fistula 1 Anal stretch 1 Peri-anal abscess 1

Defect on EAUS N/A 8/13

IAS Defect 8

EAS Defect 0

Comparison using Mann-Whitney U Test unless otherwise stated. § = comparison using χ2 test

The mean age of the continent males was 55.6 years (range 36-80 years) and the mean age of the male leakers was 55.5 years (range 27–80 years). The median Vaizey Incontinence Score for continent males was 0 (range 0-6) whereas the median score for male leakers was 12 (range 4-18). There was no difference in the reported consistency of stool measured using the Bristol Stool Scale153, with continent males reporting a median score of 4 (range 3-5) and male leakers also reporting a median score of 4 (range 3-6).

105

There was a significant difference between the groups with the male leakers having a higher incidence of previous anorectal surgery (p<0.0001). None of the continent males underwent endo-anal ultrasound (EAUS). 13 of the 15 men with faecal leakage underwent EAUS. Of these 13 men, 8 (62%) had an internal anal sphincter (IAS) defect.

The variables measured by both AAR and anal manometry for the two groups are presented in table 6.2.

Table 6.2 Comparison of measured variables in age-matched continent males and male leakers.

Variables Continent Males Male leakers p value (n=15) (n=15)

AT REST

Opening Pressure (cm H2O) 65 (41 – 93) 42 (12 – 85) 0.003*

2 Opening Elastance (cm H2O/mm ) 1.30 (0.76 – 2.45) 1.00 (0.47 – 2.94) 0.206

Closing Pressure (cm H2O) 64 (32 – 76) 30 (8 – 82) 0.001*

2 Closing Elastance (cm H2O/mm ) 1.12 (0.61 – 2.72) 0.90 (0.45 – 2.65) 0.11

Hysteresis (%) 13 (-45 - 29) 21 (5 – 47) 0.026*

MRP (cm H2O) 106 (31 – 127) 85 (38 – 177) 0.213

DURING SQUEEZE

Squeeze Opening Pressure (cm H2O) 175 (98 – 201) 201 (74 – 201) 0.983

2 Squeeze Opening Elastance (cmH2O/mm ) 1.76 (0.80 – 2.78) 1.17 (0.13 – 2.02) 0.101

MSP (cm H2O) 231 (100 – 455) 288 (121 – 451) 0.662

Values shown are medians (range). Comparison using Mann-Whitney U test. * = significant at 0.05 level.

During the resting assessment all the measured parameters were lower in the male leakers with both Opening Pressure (p=0.003) and Closing Pressure (p=0.001) being significantly lower. Hysteresis was significantly greater in the male leaker group (p=0.026). No significant difference was seen in the manometric MRP.

106

During the assessment of voluntary contraction with AAR, six of the continent subjects and eight of the men with faecal leakage, were able to squeeze their anal sphincter when prompted, to completely collapse the polyurethane bag, from fully distended at a pressure of 200 cmH2O. This is the current maximum pressure measurable with the AAR equipment therefore the exact Squeeze Opening Pressure and Elastance for these patients was impossible to determine. These subjects were recorded as having a Squeeze Opening Pressure of 201 cmH2O, but the Squeeze Opening Elastance could not be estimated. During squeeze assessment there was no significant difference in both the variables measured with AAR and anal manometry between the groups.

Nine male patients with faecal leakage were assessed both before and after proctoscopy as described in the Methods section. Five of these men were able to squeeze their anal sphincter to completely collapse the polyurethane bag at a pressure of 200 cmH2O and therefore the Squeeze Opening Elastance could not be estimated. Six continent men were assessed both before and after proctoscopy and three of these men had sufficiently strong voluntary anal contraction to render measurement of Squeeze Opening Elastance impossible. The comparison of variables measured with AAR and anal manometry before and after proctoscopy in the male leakers and in the continent males are presented in table 6.3 and table 6.4 respectively.

107

Male Leakers:

Table 6.3 Comparison of AAR and manometry variables before and after proctoscopy in the male leakers.

Variables Before Proctoscopy After Proctoscopy p value

(n=9) (n=9)

AT REST

Opening Pressure (cm H2O) 41 (12 – 85) 33 (15 – 80) 0.31

2 Opening Elastance (cm H2O/mm ) 1.00 (0.63 – 2.94) 0.94 (0.66 – 1.43) 0.11

Closing Pressure (cm H2O) 23 (8 – 82) 20 (11 – 75) 0.52

2 Closing Elastance (cm H2O/mm ) 0.74 (0.49 – 2.65) 0.77 (0.35 – 1.32) 0.18

Hysteresis % 27 (5 - 47) 13 (1 – 48) 0.86

MRP (cm H2O) 83 (38 – 177) 49 (37 – 86) 0.04*

DURING SQUEEZE

Squeeze Opening Pressure (cm H2O) 201 (79 – 201) 201 (83 – 201) 0.29

Squeeze Opening Elastance 1.24 (0.13 –2.02) 1.35 (0.07 – 3.73) + 2 ~ (cmH2O/mm )

MSP (cm H2O) 282 (121 – 422) 197 (164 – 373) 0.07

Values shown are medians (range). Comparison using Wilcoxon Signed Ranks Test. ~ n=4, + = analysis not performed due to small numbers with squeeze opening elastance data. * = significant at 0.05 level.

108

Continent Males:

Table 6.4 Comparison of AAR and manometry variables before and after proctoscopy in the continent males.

Variables Before Proctoscopy After Proctoscopy p value

(n=6) (n=6)

AT REST

Opening Pressure (cm H2O) 37 (20 – 45) 40 (25 – 55) 0.08

2 Opening Elastance (cm H2O/mm ) 0.89 (0.40 – 1.56) 0.66 (0.40 – 1.22) 0.69

Closing Pressure (cm H2O) 29 (18 – 63) 38 (21 – 48) 0.89

2 Closing Elastance (cm H2O/mm ) 0.98 (0.40 – 2.72) 0.53 (0.35 – 1.35) 0.25

Hysteresis % 13 (-45 - 22) 15 (-2 – 21) 0.60

MRP (cm H2O) 101 (50 – 122) 77 (56 – 110) 0.50

DURING SQUEEZE

Squeeze Opening Pressure (cm H2O) 172 (109 – 201) 142 (109 – 201) 0.11

Squeeze Opening Elastance 1.61 (1.02 – 1.76) 0.62 (0.55 – 1.74) + 2 ~ (cmH2O/mm )

MSP (cm H2O) 282 (179 – 518) 201 (179 – 603) 0.69

Values shown are medians (range). Comparison using Wilcoxon Signed Ranks Test. ~ n=3, + = analysis not performed due to small numbers with squeeze opening elastance data.

In the male leakers, there were no significant differences in the variables measured with AAR before and after anal canal dilatation with proctoscopy. However, there was a significant reduction in the manometry variable of MRP (p=0.04) following proctoscopy. In the continent men anal canal dilatation with proctoscopy had no significant effect on the variables measured with AAR or conventional anal manometry.

109

6.5 Discussion

There are few reports in the literature regarding male patients with faecal leakage. In a retrospective review, Sentovich et al (1995) compared the anorectal physiology findings of 14 male leakers with 11 faecally incontinent males and 20 continent male controls.116 He defined faecal incontinence as the involuntary loss of gas, liquid or solid stool, and leakage as the loss of small amounts of liquid stool or solid smears of stool resulting in minor staining of the underclothes. The leakers were found to have significantly lower anal resting and squeeze pressures than the continent males but higher pressures than incontinent males. The resting anal sphincter length was also found to be significantly longer in leakers compared with normal and incontinent men. The authors proposed that in leakers the longer anal sphincter generating only intermediate pressures allows stool to become trapped in the anal canal only to leak thereafter.116 In a similar study, Parellada et al (1998) also found significantly longer anal sphincters in men with leakage compared with continent men, but conversely significantly higher resting anal pressures.117 More recent studies by Titi et al (2007) and Qureshi et al (2011) have found no difference in anorectal physiology, including anal sphincter length, between male leakers and continent men.119, 171 Both these authors agree however, that male faecal leakage appears to be a distinct clinical entity. No consistent pathophysiological abnormality has been identified in studies so far.

The present study of male faecal leakage is the first to include assessment with anal acoustic reflectometry to our knowledge. All male leakers met the definition of leakage as proposed by Sentovich et al.116 The stool consistency was similar between the groups as assessed using the Bristol Stool Scale.153 There were no significant differences in maximum resting pressure or maximum squeeze pressure between the groups and this is in contrast to Sentovich and Parellada but is in agreement with Titi and Qureshi.116, 117, 119, 171 The internal anal sphincter (IAS) is thought to be responsible for 60-85% of anal canal resting pressure, with tonic external anal sphincter (EAS) activity and the venous anal cushions making up the remaining 15-40%.34, 35, 39 Eight male leakers were found to have an IAS defect on EAUS, but despite this there was no evidence of significantly lower anal resting pressure in this group. Clearly the IAS defects seen on EAUS did not translate into a

110 functional abnormality detectible by conventional anal manometry. This study supports those of Titi, Qureshi and Parellada in that the pathophysiology of male leakage cannot be assumed to be due to lower anal canal resting pressures. All of the twelve male leakers who had undergone EAUS were found to have an intact EAS and indeed this was reflected in the maximum squeeze pressure and squeeze opening pressure. The leakers had similar median maximum squeeze pressure and squeeze opening pressure compared with the continent males (p=0.662 and p=0.983 respectively). This was to be expected as male leakers, by definition, do not complain of urgency or urge incontinence.

Anal acoustic reflectometry (AAR) represents a dynamic assessment of anal sphincter function as opposed to the static anal manometry measurements of resting pressure and squeeze pressure. During AAR the sphincter complex is assessed during stretch and relaxation as the polyurethane bag is inflated and deflated. The male leakers were found to have a significantly lower Opening Pressure and Closing Pressure compared with the continent men (p=0.003 and p=0.001 respectively). The Opening Pressure represents the pressure at which the anal canal just begins to open during bag inflation. Functionally it represents the ability of the anal canal to resist dilatation and is a measure of the forces keeping the anal closed. These forces are generated by active elements, namely the IAS and EAS, and by passive forces, namely the surrounding connective tissues. Whereas the MRP reflects the resting tone within the IAS and EAS, the Opening Pressure reflects the active resistance of the anal canal to opening. When analysing the opening AAR curve of pressure vs. cross-sectional area, shown in figure 4.1, it appears that the anal canal resists opening up to a critical pressure, at which it then opens (shown in Figure 6.1, section A).

111

A B

Figure 6.1 Area vs. Pressure graph showing opening and closing traces, demonstrating the acoustic parameters. Section A = Active resistance to anal canal opening. Section B = Passive dilatation once the Opening Pressure has been overcome.

The ability of the anal canal to remain closed against an opening force was reduced in the leakers, reflected by the lower Opening Pressure. This could be due to poorer IAS and EAS function, however, as there were no significant differences in maximum resting pressure (MRP), maximum squeeze pressure (MSP) or Squeeze Opening Pressure between leakers and continent males in this study, this is uncertain. It may be that a local contractile reflex is stimulated by the stepwise bag inflation within the anal canal. The forces keeping the anal canal closed against the increasing pressure are likely to be a result of the resting tone of the anal sphincter muscles together with this reflex contractile activity. Once the Opening Pressure is reached, the anal canal then begins to open (shown in Figure 6.1, section B), suggesting that this active reflex contraction is overcome. Male leakers may

112 therefore have a disturbance in the neural reflex activity within the anal canal resulting in lower opening pressures.

The Closing Pressure was also found to be significantly lower in male leakers. The Closing Pressure represents the pressure at which the tonic and active contractile forces of the IAS and EAS are able to occlude the anal canal after a period of dilatation. The forces involved with closing the anal canal after it has opened are likely to be similar to those responsible for the Opening Pressure. As the Closing Pressure is reduced in male leakers the ability of these closing forces to occlude the anal canal, after a period of dilatation such that may occur during defaecation, may be impaired.

Male leakers typically complain of leakage in the hours following defaecation. In contrast to theories proposed by Sentovich116 and Parellada117, our hypothesis is that in male leakers the ability of the anal canal to return to its closed form after defaecation is impaired as shown by the reduced Closing Pressure. This, together with the impaired resistance to dilatation resulting in lower Opening Pressures, results in leakage of stool.

Although the Opening and Closing Elastance showed a trend towards being lower in the male leakers compared with the continent males, there was no significant difference between the groups. The Opening Elastance, calculated as the gradient of the opening curve, represents the resistance of the anal canal to dilatation once the Opening Pressure has been overcome. While the pressure required to open the anal canal was less in the male leakers, once the anal canal started to open there was no difference in the resistance of the anal canal to dilatation in response to increasing pressure. If the Opening Pressure represents the level at which the closing forces generated by the IAS and EAS are overcome, then the Elastance may reflect the passive elements within the anal canal. The connective tissues of the anal canal may be responsible for this resistance to dilatation once the Opening Pressure has been reached and hence this study suggests that no difference exists in the connective tissue components between male leakers and continent men. This is in agreement with Mitchell et al (2012) who found no difference in Opening Elastance between incontinent and continent females.142 The current study also demonstrated no significant difference in Closing Elastance between the groups. The Closing

113

Elastance represents the ability of the anal canal to close down against a reducing pressure and again may reflect the passive recoil of connective tissue elements within the anal canal. Once the Closing Pressure is reached the active elements are then able to close the anal canal, and as already discussed, this pressure is significantly lower in the men with faecal leakage. Further study is required to determine exactly the contribution of the IAS, EAS and connective tissues to the different variables measured with AAR. Simultaneous EMG of the IAS and EAS during AAR would be required to demonstrate whether muscle activity does indeed decrease after the Opening Pressure is reached. The contribution of the connective tissues in and around the anal canal to the AAR variables of Opening and Closing Elastance could be investigated by studying patients with anal stenosis and comparing them to patients with a known connective tissue disorder such as Ehlers- Danlos Syndrome. If Elastance relates to the nature of the connective tissues one would expect to see higher values in the patients with anal stenosis compared with those with connective tissue disease.

The Hysteresis was significantly greater in the male leakers. Hysteresis represents the energy dissipated during opening and closing of the anal canal and reflects the viscoelastic properties of the anal canal. In previous work by Mitchell (2010), the Hysteresis was also found to be significantly greater in incontinent females when compared with an age-matched group of continent females.133, 142 He proposed that this may reflect differences in the histological composition of the sphincter complex. In this study 10 of the 15 male leakers had a history of previous anorectal surgery, compared with 1 of the continent males (p<0.0001). The inevitable scarring may result in less efficient anal canal opening and closing or stretch and recoil, allowing more energy to be dissipated, resulting in a higher hysteresis. Indeed, surgery to the anal canal will lead to fibrosis and the deposition of collagen, which is known to have a higher hysteresis than muscle.131

This study has shown that male faecal leakage is associated with an identifiable abnormality in anal sphincter function. This abnormality is characterised by a significant reduction in the AAR variables of Opening Pressure and Closing Pressure. This altered anal canal physiology may be associated with previous anorectal surgery, which produces an abnormality that is below the threshold for detection by conventional methods of assessment. Indeed, this study has shown that

114 no difference exists between the groups when assessed with anal manometry, but that AAR is sensitive enough to detect this alteration. AAR may have potential advantages over conventional anal manometry in the routine assessment of this distinct clinical sub-group of male patients with faecal incontinence. In cases where a definite abnormality in anal sphincter function is demonstrated, patients will feel reassured and management options may be guided by the AAR results. AAR may also help in evaluating the effect of surgery and assessing any resulting changes in anal sphincter function.

AAR represents a dynamic assessment as it measures anal sphincter function during stretch and recoil, essentially mimicking defaecation. In this research setting AAR was always performed first, before anal manometry and before any digital examination of the anal canal. This technique was employed to prevent any potential effect anal canal dilatation may have on the AAR parameters. However, to further test our theory of male leakage, AAR and anal manometry were performed before and after a period of more significant anal canal dilatation, such as would occur during defaecation. This was achieved using a proctoscope (Seward Thackray) inserted into the anal canal for a defined period of time, after which the subject was asked to bear down expelling the instrument. Nine male leakers and six continent males were assessed in this manner. In the continent men anal canal dilatation produced no change in the anal sphincter function measured by AAR or anal manometry. However, in the men with faecal leakage, a significant reduction in MRP was seen following anal canal dilatation. No significant reduction was seen in the resting AAR variables. Although numbers are low, this finding adds weight to the theory that the process of defaecation is key to the pathophysiology of faecal leakage in these men, as most only complain of symptoms in the hours following defaecation. The effect of dilating the anal canal did not appear to affect the AAR variables. This may have been because the AAR variables themselves are measured during stretch and recoil of the anal canal, and as AAR is a dynamic assessment, the elements that contribute to the variables may not be affected by recent dilatation. If the reduction in MRP immediately following anal canal dilatation is translated clinically, such that a similar phenomenon occurs in the male leakers following defaecation, then this lower anal canal tone may lead to leakage of stool. This reduction in MRP following anal canal dilatation, together with the lower baseline

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Opening and Closing Pressures in male leakers may explain the post defaecatory leakage.

Limitations to this study include the low numbers of subjects recruited. The initial power calculation determined that the study would need 17 subjects in each group to have 80% power. Despite not reaching this number, statistically significant differences were found and a post hoc power calculation found the study to be appropriately powered. Robust conclusions can therefore be drawn with confidence. It is also important to note that in this study, 8 of the male leakers had a demonstrable IAS defect on EAUS. Although this did not result in a difference in MRP between the groups, further investigation is necessary to compare male leakers without a sphincter defect to a control group of continent males. In addition to this, the effect of ano-rectal surgery needs to be clarified. With greater numbers, sub- group comparison could be performed, comparing male leakers with no previous ano-rectal surgery to an age matched group of continent men with no previous anorectal surgery. Further investigation into the effect of anal canal dilatation is also required. A larger proctoscope with a longer period of dilatation may have produced different results. In this study however, the process of defaecation was felt to be most accurately represented by the protocol used. Similarly, a longer rest period after anal canal dilatation may have yielded different results and further investigation is warranted.

6.6 Conclusions

Overall this study has provided an insight into the pathophysiological processes involved in male patients with faecal leakage. Anal acoustic reflectometry has allowed a dynamic physiological assessment of anal sphincter function allowing a new theory of faecal leakage to be proposed. Furthermore, in contrast to anal manometry, AAR appears to be sensitive to discriminate male leakers from continent males. An identifiable abnormality has been detected using AAR, which may help the physician in the assessment of these men and may provide some assistance in guiding management.

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Chapter 7

Anal Acoustic Reflectometry In The Evaluation

Of Anal Sphincter Function During General

Anaesthesia And Neuromuscular Blockade

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7.1 Introduction

Resting pressure within the anal canal is generated by the tonic activity of the internal and external anal sphincters together with the expansion of the anal venous cushions. The exact contribution made by each of the anal sphincters to resting pressure is difficult to measure in view of the concentric anatomy. It is thought, however, that the IAS makes up 60-85% of resting anal pressure, with the remaining 15-40% being attributable to the EAS and anal cushions.34, 35, 39 These estimates are based on studies using conventional anal manometry.

The variables measured by anal acoustic reflectometry (AAR) provide an alternative insight into anal sphincter physiology compared with conventional anal manometry. The response of the anal canal to stretch and relaxation is demonstrated by the AAR opening and closing curves. The individual components to the curve are composed of contributions from IAS activity, EAS activity and the surrounding connective tissues. However, it is unclear exactly what contributions the IAS, EAS and perianal connective tissues make in the determination of the AAR variables, and conversely it is also unclear exactly what elements of the anal sphincter mechanism are being assessed with the AAR variables. The EAS is a voluntary striated muscle and can therefore be selectively paralysed with the use of intravenous neuromuscular blocking agents, leaving the IAS to function normally. By inhibiting the action of the EAS, its contribution to the resting parameters of anal sphincter function can be assessed. An estimation of IAS and connective tissue contributions can also be made. Results presented in Chapter 3 suggest that AAR is a more sensitive assessment of anal sphincter function in patients with faecal incontinence compared with anal manometry. The contribution of the IAS and EAS to resting anal sphincter function may therefore be more accurately assessed with AAR.

118

7.2 Aims

This study was designed to determine the relative contributions of the EAS and IAS to anal tone by using AAR to study anal sphincter function during general anaesthesia with and without neuromuscular blockade. The aims of the study were therefore to test the following hypotheses: i) General anaesthesia leads to a significant reduction in resting anal sphincter function. ii) Paralysis of the EAS leads to a significant reduction in resting anal sphincter function.

7.3 Methods

Male subjects with no previous history of anorectal pathology or peri-anal surgery were recruited to the study. As this study was an investigation of normal anal sphincter physiology, female subjects were excluded in view of the associated variability of childbirth trauma to the perineum and anal sphincter mechanism. Male patients over 18 years of age, with no symptoms of faecal incontinence (FI) or difficult defaecation, were recruited from elective operating lists at University Hospital South Manchester. Demographic data were recorded, including age, type of surgery being undertaken, details of previous abdominal surgery, and details of bowel habit. All participants completed a pre-operative Vaizey Incontinence Score.82 In addition to this, participants also provided a subjective assessment of their average stool consistency in the form of the Bristol Stool Scale.153 All participants underwent measurement with AAR, followed by anal manometry in the left lateral position, as detailed in the Methods section on pages 52-57. Measurement was performed pre-operatively, with the patient fully conscious without any pre-anaesthetic medication, on the day prior to surgery or on the day of surgery itself. AAR and anal manometry were then repeated in the operating theatre, with the patient in the left lateral position on the operating table, under general anaesthesia (GA) without neuromuscular blockade. After this assessment was complete, the tests were then repeated again after complete muscle paralysis with a competitive neuromuscular blocking agent. These agents will paralyse the EAS, a voluntary striated muscle, leaving the smooth muscle of the IAS intact. These steps 119 were taken to allow separate analysis of the effect of general anaesthesia and then neuromuscular blockade on anal sphincter function. Muscle paralysis was achieved using intravenous atracurium (Hameln Pharmaceuticals, UK) at a dose of 0.6mg/kg, in all cases. Complete muscle paralysis was confirmed by the anaesthetist prior to measurement with the use of a MicroStimulator DB (Viamed, Yorkshire, UK) which assessed the function of the facial nerve.

In a separate cohort of male patients, two repeat measurements with AAR and manometry were performed under GA alone, without the addition of a neuromuscular blocking agent. This cohort were studied to ensure that the change in the AAR and manometry variables that were demonstrated with neuromuscular blockade were due to the blockade itself, and not an effect of GA over time.

All anaesthetic medication given was recorded, including the type and end-tidal saturation of volatile gas used. In addition, the time of induction, the time of initial measurement of the patient under GA with AAR and anal manometry and the time of the repeat measurement were noted.

Statistical Analysis

Continuous unpaired data were compared using the Independent Samples t Test. Continuous paired data were compared using Friedman’s Test, with Dunn’s multiple comparison test used to analyse individual differences between subsets. SPSS® software version 15.0 (Armonk, New York, USA) and GraphPad Prism 4 (La Jolla, California, USA) were used for statistical analysis.

120

7.4 Results

Twenty five continent male subjects were recruited to the study. The mean (range) age of the subjects was 66.8 years (29 – 85 years). No subject had previously had any form of ano-rectal surgery and the median Vaizey Incontinence Score was 0 (range 0-2). The median Bristol Stool Score was 3 (range 2-5). Fifteen of these subjects underwent surgery that necessitated neuromuscular blockade. These patients were assessed with AAR and anal manometry. Consecutive measurements were taken from individual patients while conscious, while under GA alone and then under GA with the addition of a neuromuscular blocking agent. Ten subjects underwent GA without the use of a neuromuscular blocking agent. These subjects were measured consecutively while conscious, and then twice during GA alone, to control for the potential longer term effect of GA on anal sphincter tone. The type of surgery that was undertaken is presented in Table 7.1.

Table 7.1 Type of surgery undertaken

Type of Surgery Number of patients Surgery requiring neuromuscular blockade Laparoscopic sigmoid colectomy 3 Laparoscopic right hemicolectomy 4 Open right hemicolectomy 2 Laparoscopic inguinal hernia repair 4 Laparoscopic cholecystectomy 1 Excision of pilonidal sinus 1 Surgery requiring GA without neuromuscular blockade Inguinal hernia repair 9 Femoral hernia repair 1

In all patients, 1.5mg/kg of propofol (Braun, Germany) was used as the induction agent and sevoflurane or desflurane in oxygen and air was used to maintain anaesthesia. Atracurium (Hameln Pharmaceuticals, UK) was used as the neuromuscular blocking agent in all cases (0.6mg/kg).

121

The comparison of the variables of anal sphincter function measured in 15 men while conscious, while under GA and while under GA with neuromuscular blockade are presented in Figure 7.1 overleaf.

122

Opening Pressure Opening Elastance

* *

70 2.0 60

2 1.5 50 O 2 40

O/mm 1.0 2

cmH 30

20 cmH 0.5 10 0 0.0 Conscious GA GA + NMB Conscious GA GA + NMB Measurement Measurement

Closing Pressure Closing Elastance

* 3.0 60

50 2.5 2 2.0

O 40 2

30 O/mm 1.5 2 cmH 20 1.0 cmH 10 0.5

0 0.0 Conscious GA GA + NMB Conscious GA GA + NMB Measurement Measurement

Maximum Resting Pressure (MRP) Hysteresis * 50 140

40 120 100 30 O

2 80 % 20 60 cmH 40 10 20 0 0 Conscious GA GA + NMB Conscious GA GA + NMB Measurement Measurement

Figure 7.1. Line plots demonstrating trends in measured variables. * = significant at 0.05 level. GA = general anaesthesia, NMB = neuromuscular blockade.

123

There was a significant reduction in Opening Pressure, Closing Pressure and Maximum Resting Pressure (MRP) when measured in patients under general anaesthesia compared to pre-operative conscious measurements. There was then a significant increase in Opening Pressure when patients were subsequently measured after intravenous administration of a neuromuscular blocking agent and confirmation of voluntary muscle paralysis. Closing Pressure and MRP showed a similar trend, however this was not significant. Opening Elastance, Closing Elastance and Hysteresis did not significantly change when measured in patients fully conscious, under GA and under GA with neuromuscular blockade.

The comparison of the variables of anal sphincter function measured in the 10 men while conscious and twice repeated under GA alone are presented in Figure 7.2.

124

Opening Pressure Opening Elastance

* * 60 1.25 50

2 1.00 40 O 2 0.75 30 O/mm 2 cmH 20 0.50 cmH 10 0.25

0 0.00 Conscious GA (1st) GA (2nd) Conscious GA (1st) GA (2nd) Measurement Measurement

Closing Pressure Closing Elastance

* 60 1.50 50 1.25 40 2

O 1.00 2 30 O/mm

2 0.75 cmH 20 0.50 cmH 10 0.25

0 0.00 Conscious GA (1st) GA (2nd) Conscious GA (1st) GA (2nd) Measurement Measurement

Hysteresis Maximum Resting Pressure (MRP)

* 50 120

40 100 80

30 O 2

% 60 20 cmH 40

10 20

0 0 Conscious GA (1st) GA (2nd) Conscious GA (1st) GA (2nd) Measurement Measurement

Figure 7.2 Line plots demonstrating trends in measured variables. * = significant at 0.05 level. GA = general anaesthesia.

125

There was a significant reduction in Opening Pressure, Closing Pressure and Maximum Resting Pressure (MRP) when measured in patients under general anaesthesia compared to pre-operative conscious measurements. There was no significant change in these variables when AAR and manometry were repeated again under GA. Opening Elastance, Closing Elastance and Hysteresis did not significantly change when measured in patients under GA compared to pre-operative conscious measurements, however Opening Elastance did significantly increase when measured under GA for the second time.

The timing of measurements were recorded in both groups of patients. The time delay from induction of anaesthesia to the first and second measurements with AAR is presented in Table 7.2 below.

Table 7.2 Comparison of measurement timings between protocol subsets

GA + neuromuscular GA alone group p value blockade group Time from induction 15.6 (7 - 23) 13.1 (4 - 34) 0.36 to 1st measurement (minutes) Time from induction 28.5 (16 - 41) 23.7 (14 - 41) 0.15 to 2nd measurement (minutes) Time from 1st 12.8 (8 - 18) 10.6 (7 – 19) 0.08 measurement to 2nd measurement (minutes) Values presented are mean (range). Comparison using Independent Samples T test.

The mean time from induction to the first assessment under GA was not significantly different between those patients having GA and neuromuscular blockade and those patients having GA alone (p=0.36). The mean time from induction to the second assessment was also not significantly different between the groups (p=0.15) and neither was the time interval between measurements (p=0.08).

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7.5 Discussion

Fifteen patients in this study underwent surgery requiring neuromuscular blockade. Voluntary striated muscle paralysis was achieved by giving an intravenous dose of a competitive neuromuscular blocking agent. These drugs compete with acetylcholine for the motor end plate receptor, resulting in end plate depolarisations that are below the threshold to cause muscle action potentials. Anal canal pressure at rest is the result of a combination of IAS tone, EAS tone and the expansion of the anal venous cushions. The EAS is a voluntary striated muscle, and therefore will be completely paralysed by the intravenous neuromuscular blocking agent. Under such conditions its contribution to the maintenance of anal canal closure at rest should therefore be negligible. The results reported in this study were surprising. After general anaesthesia a significant drop in Opening Pressure, Closing Pressure and Maximum Resting Pressure (MRP) was seen. After the administration of an intravenous neuromuscular blocking agent, however, a significant increase in Opening Pressure was demonstrated. An increase, that was approaching statistical significance, was also seen in Closing Pressure and MRP. In ten patients assessed twice under GA alone these changes were not replicated.

Duthie and Watts (1965), using conventional anal manometric techniques, studied the resting pressure in the anal canal of twenty subjects before anaesthesia, during light general anaesthesia and during general anaesthesia with muscle relaxant.34 They reported a significant reduction in mean anal canal resting pressure under general anaesthesia when compared with readings taken when conscious. A significant reduction was also seen with general anaesthesia and muscle paralysis when compared with conscious readings, but the pressure in the anal canal was very similar under GA with and without muscle paralysis. They concluded that the EAS does not contribute to the anal canal pressure at rest and only plays a part when a bolus is present within the anal canal.34 The present study found similar results when measuring anal canal Maximum Resting Pressure (MRP). A significant reduction in MRP was seen in patients after GA. There was, however, no significant difference between MRP during GA and during GA with neuromuscular blockade, which is in agreement with Duthie and Watts. In the present study, the median MRP in fact increased after muscle paralysis, although this was not significant. This is

127 surprising as one would expect MRP to drop further after the onset of muscle paralysis.

Frenckner and Euler (1975) studied ten normal subjects before and after bilateral pudendal nerve block.35 The striated EAS is supplied by the pudendal nerve and the authors confirmed EAS paralysis by recording the EAS EMG activity. No EMG activity was seen in five patients after pudendal nerve block, and in the remaining five, only single motor units were detected. The authors stated that the anal resting pressure after pudendal nerve block could be attributed to the IAS alone, whereas before the block it was attributed to both the IAS and EAS.35 They found that after bilateral pudendal nerve block the maximal anal pressure reduced from a mean of 64 mmHg to 54 mmHg, concluding that the smooth IAS muscle contributed approximately 85% of the anal pressure at rest.35 Lestar et al (1989) studied 21 patients before and during general anaesthesia with neuromuscular blockade.39 Unlike the present study they did not distinguish between the effect of general anaesthesia alone and neuromuscular blockade. The authors considered the difference between resting anal pressure recorded before and during anaesthesia with neuromuscular blockade to represent the contribution of the EAS.39 They reported a 30% reduction in anal resting pressure during anaesthesia with neuromuscular blockade when compared with conscious measurements, and concluded that at rest 55% of the anal basal pressure could be attributed to IAS activity, 30% to the tonic activity of the striated EAS and the remaining 15% to expansion of the haemorrhoidal plexuses.39

The present study differs to that of Frenckner’s and Lestar’s in that anal sphincter function has been studied before GA, during GA and during GA with neuromuscular blockade. All patients underwent induction of anaesthesia with intravenous propofol and maintainance of anaesthesia with either sevoflurane or desflurane. Propofol causes central nervous depression but also causes a reduction in skeletal muscle tone.172, 173 There is also evidence that propofol has an inhibitory effect on gastro- intestinal smooth muscle. Lee et al (1999) prepared strips of healthy descending colon smooth muscle taken from resection specimens.174 These strips were mounted in an organ bath and the contractile activity was measured during stimulation with acetylcholine in cumulative doses, with and without different concentrations of propofol. Propofol was reported to significantly reduce acetylcholine-induced

128 contraction and spontaneous contraction of the colonic smooth muscle.174 It is likely, therefore, to have a similar effect on the IAS which is a continuation of the rectal smooth muscle. The inhaled volatile gases used in this study to maintain anaesthesia also cause skeletal muscle relaxation by depressing neuromuscular function.172, 173 The pharmacological effects of these anaesthetic agents are likely to account for the reduction in MRP seen under GA.

In the current study a significant decrease in Opening and Closing Pressure under general anaesthesia was also seen. Opening Pressure represents the pressure at which the anal canal just begins to open. Functionally it represents the sum of the closing forces in and around the anal canal that are resisting bag inflation. Initially, as the pressure within the polyurethane bag increases, the high pressure zone of the anal canal resists opening and the bag remains collapsed with a very small cross- sectional area. These closing forces can only resist the increasing pressure within the anal canal up to a certain point, at which the anal canal then begins to open. Previous work by Mitchell (2010) has shown that this Opening Pressure is significantly lower in faecally incontinent females when compared with an age-matched group of continent females.133 The higher the Opening Pressure the more powerful the resistance to anal canal opening. The forces contributing to Opening Pressure are largely the tonic activity within the IAS and EAS which play the greatest role in keeping the anal canal closed at rest.39 The surrounding connective tissues will also contribute. It is our hypothesis, however, that it is the active elements, i.e. the IAS and EAS that are largely responsible for the Opening Pressure. From the shape of the Opening AAR curve we do not see a gradual increase in cross-sectional area as the pressure within the polyurethane bag is increased. Instead, we observe the anal canal completely resist opening until the critical opening pressure is reached, after which the anal canal opens up rapidly. The tonic activity within the IAS and EAS appears to be overcome and “switch off” when the Opening Pressure is reached allowing the anal canal to then open. It is likely therefore that there is a local contractile reflex within the anal sphincter apparatus that is triggered by the stepwise bag inflation and subsequent stretch. Indeed muscle spindle stretch receptors have been found in the EAS of the human and cat.59, 61 The muscle contraction resulting from this reflex is then overcome once the Opening Pressure is reached. Studies of feline EAS have found that the EMG impulse from the EAS at rest increased when

129 the sphincter was stretched.59 Evidence exists to support EAS resting tone being reliant on a spinal reflex arc. Patients with tabes dorsalis, a condition in which sensory afferent pathways are blocked, show no EMG activity in the EAS at rest, but normal activity on voluntary contraction.64 This suggests resting EAS tone is reliant on intact afferent pathways. Patients with complete spinal cord transection above the 3rd lumbar segment have also been found to have normal resting EMG activity in the EAS, confirming the theory of a spinal reflex arc being responsible for the resting EAS activity.64 A similar spinal reflex controlling IAS tone is also likely to exist. Indeed, Frenckner (1975) studied 8 male patients with traumatic transverse spinal cord lesions and compared anal physiology results with those of 8 healthy male controls.53 They reported similar resting anal pressures in the patients and controls. As the resting pressure in the anal canal is reported to be predominantly due to IAS function, they concluded that resting IAS tone is independent of higher cerebral connections and again is reliant upon a spinal reflex arc.53

The Closing Pressure measured in our study represents the pressure at which the anal canal just closes after dilatation. It assesses the ability of closing forces in the anal canal to occlude the anal canal again after a period of dilatation. Again these closing forces, similar to Opening Pressure, represent the tonic and active contractions within the IAS and EAS with the associated regulatory mechanisms. Similar to MRP, induction and maintenance of general anaesthesia resulted in a significant reduction in Opening and Closing Pressure. This is likely to be an effect of the anaesthetic agents discussed above. Although no exact estimate can be made, the large and significant effect of GA suggests the importance of EAS muscle tone, as well as IAS muscle tone, on resting anal sphincter function.

After the intravenous neuromuscular blocking agent was given a significant increase in Opening Pressure was demonstrated. There was also an increase in Closing Pressure and MRP, although this was not significant. These findings were unexpected. In this clinical state the EAS is completely paralysed and therefore the Opening Pressure is predominantly a measure of IAS function. In this study therefore, a marked increase in IAS function was observed when the EAS was paralysed. This finding is in contrast to Duthie and Watts (1965) who found no significant difference between anal resting pressure under GA alone and GA with neuromuscular blockade.34 Resting IAS tone is modulated by autonomic and enteric

130 neural stimulation. The sympathetic innervation to the IAS derives from the hypogastric plexuses, and the parasympathetic innervation from the 1st, 2nd and 3rd sacral segments via the pelvic plexus.52 Frenckner and Ihre (1976) compared anal resting pressures in patients having a high spinal anaesthetic (T6-T12) with those having a low spinal anaesthetic (L5-S1).30 A high spinal anaesthetic inhibits autonomic and somatic nerve supply to the sphincter complex, whereas a low spinal anaesthetic inhibits parasympathetic and somatic supply leaving the sympathetic nerve supply intact. They found a significantly greater reduction in anal resting pressure with high spinal anaesthesia (32 mmHg) compared with low spinal anaesthesia (11 mmHg), and concluded that at rest there is a tonic excitatory sympathetic drive to IAS.30 Further support for a sympathetic excitatory effect on IAS tone came from Carlstedt and colleagues (1988).31, 175 In both animal and human models they have demonstrated that electrical stimulation of the sympathetic hypogastric nerves elicits IAS contraction.31, 175 This excitatory effect is likely to be 176 mediated via α1-adrenoceptors. However, Lubowski et al (1987) demonstrated IAS relaxation in response to sympathetic stimulation.37 They suggested that this effect was mediated through inhibitory β adrenergic fibres and indeed other studies have shown β receptor stimulation to have an inhibitory effect on IAS tone.52 The precise action of the parasympathetic and enteric nervous systems on the IAS remains poorly understood.

The enteric nervous system, part of the autonomic nervous system, comprises the internal and external submucous plexuses, the myenteric plexus and the subserosal plexus.52 Within the enteric nervous system exist complex local reflex pathways, such as the recto-anal inhibitory reflex, and numerous neurotransmitters have now been identified. Stimulation of inhibitory non-adrenergic non-cholinergic enteric neurones (NANC) causes IAS relaxation.52 Nitric oxide (NO) has been identified as the predominant inhibitory neurotransmitter of NANC transmission in the human IAS causing relaxation and reduction of IAS tone.38 Acetylcholine relaxes the IAS by stimulating NO synthesis.52 177 NO donors have become the mainstay of treatment for anal fissures.

IAS contraction or tone is regulated by changes in cytosolic calcium (Ca2+) levels, which in turn is regulated by the autonomic and enteric neural influences discussed above. IAS contraction is dependent on an increase in cellular Ca2+, which can be

131 produced by direct influx of Ca2+ through membrane channels, or by stimulation of 2+ α1-adrenoceptors resulting in the release of Ca from the sarcoplasmic reticulum. 2+ Antagonists to membrane Ca channels or α1-adrenoceptors cause IAS relaxation.

Relaxation is also caused by stimulation of β2-adrenoceptors which serves to drive Ca2+ back into the sarcoplasmic reticulum. However the main relaxant effect comes from the stimulation of NO containing NANC enteric neurones which, via cyclic guanosine-3’5’-monophosphate (cGMP) decrease cytosolic Ca2+. As mentioned before acetylcholine promotes NO synthesis and therefore stimulation of muscarinic nerves cause IAS smooth muscle relaxation through the release of acetycholine.52

The exact mechanism by which neuromuscular blockade appeared to cause an increase in IAS tone and therefore an increase in Opening Pressure is unknown. The agents used in this study were non-depolarising or competitive neuromuscular blockers. These drugs compete with acetylcholine for the acetylcholine receptor. As discussed, acetylcholine promotes NO synthesis. If its effects are blocked, NO synthesis may be inhibited which may in turn lead to increased IAS tone. There are no reports of this direct effect of non-depolarising neuromuscular blockade in the literature but this mechanism may explain the increase in Opening Pressure. To test this hypothesis further one could biopsy the IAS before and after neuromuscular blockade in patients undergoing abdomino-perineal excision of the rectum, where trauma to the IAS is inconsequential. NO induction could then be measured to identify whether there was any direct effect of the neuromuscular blocking agent.

Another explanation for these findings could be that a spinal or enteric reflex mechanism exists that serves to increase IAS tone. Once the EAS is paralysed this reflex is triggered to increase IAS tone, thereby compensating for the reduction in resting pressure, with the resultant effect of increasing Opening Pressure.

When patients were measured twice under GA alone there was no significant change in Opening Pressure, Closing Pressure or MRP. The timing of the measurements was not different between the GA alone and GA plus neuromuscular blockade groups. It is unlikely, therefore, that the change in Opening Pressure observed with neuromuscular blockade was related to the inhibitory effect of GA declining over time. An initial aim of this study was to assess the contribution of the EAS to both MRP and the resting AAR variables. The results of this study make any estimation

132 of EAS contribution inaccurate because GA alone appeared to have a profound effect on resting anal sphincter function and neuromuscular blockade and paralysis of the EAS appeared to augment IAS function. These findings also lead us to question the validity of previous studies. Results reported by Duthie and Watts and Lestar et al may now need to be re-interpreted in light of the current findings, and the widely held view that the EAS contributes 15-30% towards resting anal tone may in fact be incorrect.34, 39 Further research is needed to investigate the contribution of the EAS to resting anal sphincter function and the contribution it makes to the resting AAR variables. A study to investigate the effect of bilateral pudendal nerve block, using local anaesthetic, on resting anal sphincter function is currently being planned. This study will avoid the confounding factor of GA.

Neither general anaesthesia nor neuromuscular blockade appeared to have any significant effect on Opening or Closing Elastance. This supports the hypothesis discussed in Chapter 6 that elastance may be a measure of the properties of the perianal connective tissue. Connective tissues are not under the influence of nervous control or from higher cortical centres. They would, therefore, not be affected by GA or neuromuscular blockade, which is reflected by the similar Opening and Closing Elastance in the study subsets. When 10 men were studied repeatedly under GA alone, the Opening Elastance was significantly greater at the 2nd measurement. This finding should be interpreted with caution as study numbers are low and no similar change was seen in Closing Elastance.

Hysteresis, was not affected by general anaesthesia or neuromuscular blockade. Hysteresis represents the energy dissipated during opening and closing of the anal canal, or during stretch and recoil of the structures in and around the anal canal. The amount of energy dissipated will reflect the structure of the anal sphincter musculature as well as the peri-anal connective tissues. However, the Hysteresis is expressed as a percentage and represents the difference in area between the inflation and deflation curves, and therefore any effect of GA or neuromuscular blockade on muscle function will not cause a significant change to the percentage loss of energy. This is reflected by the similar values of Hysteresis found in patients measured while conscious, under GA and under GA with neuromuscular blockade.

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The main limitation to this study was the variability of the anaesthetic regimens used. The doses of propofol and atracurium are weight dependent and therefore were kept constant from case to case, however the concentration of volatile gas used varied. Depth of anaesthesia may have been an influencing factor in the measured variables. End tidal saturation of the volatile gas used to maintain anaesthesia provides an estimate of the depth of anaesthesia, however there is no accurate method of measurement. Consequently it was impossible to keep constant and therefore may have been a source of bias. The methods used in this study, however, ensured that for every case, the measurement technique and timing was identical and, in addition, the data recorded were paired and therefore external confounding factors were limited. Another potential limitation to the study was that paralysis of the EAS following intravenous administration of the neuromuscular blocking agent was not confirmed by performing EMG of the EAS. Testing of the facial nerve was used as a surrogate marker of complete muscle paralysis which is routine for surgical cases, and measurement was not commenced until confirmation of facial nerve paralysis by the anaesthetist. Despite this, however, we cannot be sure that the EAS was completely paralysed.

7.6 Conclusions

The significant reduction in resting anal sphincter function seen after general anaesthesia in this study has highlighted the importance of skeletal muscle tone and higher cortical control as regulatory factors. The unexpected increase in Opening Pressure following neuromuscular blockade requires further clarification, but suggests the presence of complex neuropharmacological and reflex mechanisms involved in maintaining resting anal sphincter tone and anal continence.

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Chapter 8

Overall Conclusions and Future Work

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Anal acoustic reflectometry has been adapted from urethral reflectometry, and has been shown to be a reproducible and clinically reliable technique. It provides an alternative physiological assessment of anal canal function to conventional anal manometry, and its use can be applied to further our understanding of anal sphincter physiology, to the investigative work up of a patient with faecal incontinence and to the evaluation of treatment outcomes.

In the assessment of women with faecal incontinence, AAR measurements, but not anal manometry measurements, were shown to correlate with the severity of incontinence and were also able to discriminate between the patterns of faecal incontinence. AAR provides the investigator with a more sensitive assessment of anal sphincter function in patients with faecal incontinence than that of anal manometry. AAR may help to guide management in patients in whom current objective and subjective assessments are unhelpful. Further work is needed to clarify the relationship between anal sphincter function and the structural integrity of the sphincters.

Sacral nerve stimulation (SNS) is an established treatment option for faecal incontinence but is not effective in all patients. Selection of patients for SNS is based on a test period of stimulation, percutaneous nerve evaluation (PNE). A successful PNE outcome is assessed by comparison of bowel diaries and symptom severity questionnaires, which lack objectivity and are subject to bias. The identification of a reproducible and objective parameter that could predict a patient’s response to PNE and ultimately SNS would be a valuable development. In Chapter 4, the AAR variable of Opening Pressure, but not the manometric equivalent of MRP was shown to be significantly greater in patients having a successful outcome from PNE. Opening Pressure was also shown to be an independent predictor of success. AAR may therefore allow better patient selection and improve cost effectiveness of SNS in patients with FI. Although promising, it should be noted that success from PNE does not necessarily confer success from chronic permanent SNS. It has been reported that the therapeutic effect of SNS fails in 20-30% of patients despite an initial successful PNE period.107, 111 Further research is planned to investigate whether AAR can predict these failures. If AAR can predict success not only from PNE, but also long term success from permanent SNS, it may be an invaluable method of screening patients with obvious economic advantages. Long term follow

136 up of patients undergoing SNS for faecal incontinence in whom pre-operative AAR has been performed is required.

The mode of action of SNS remains poorly understood. Data presented in Chapter 5 suggest that SNS does not produce a significant change in anal sphincter function. This finding corroborates much of the work in the field and suggests that SNS exerts its affect by mechanisms other than only peripheral motor stimulation to the anal sphincter.

Male patients with faecal leakage are a distinct clinical subgroup in whom the pathophysiology remains unclear. Unlike anal manometry, AAR was able to demonstrate a measurable difference in anal sphincter function in male leakers when compared with continent controls. Both the Opening Pressure and Closing Pressure were significantly lower in male leakers when compared to continent controls, which suggests that the closure mechanism of the anal canal following defaecation is impaired in these men allowing the leakage of stool. This leakage may be associated with previous ano-rectal surgery and further work is needed to clarify this relationship. Further investigation is planned to study patients with faecal leakage who have no history of ano-rectal surgery and to compare their AAR results with those of continent controls. The time constraints of the current research period prohibited this sub-group comparison as the number of male patients presenting to the out-patient clinic who met the definition of leakage was low.

The variables of anal sphincter function measured by AAR are different to those of anal manometry and no existing studies have reported which components of the anal sphincter mechanism are being measured by each of the AAR variables. The study presented in Chapter 7 aimed to determine the relative contribution of the EAS and IAS to resting anal sphincter function by using AAR to investigate male subjects while conscious, while under general anaesthesia and while under general anaesthesia with neuromuscular blockade. A significant reduction in Opening Pressure, Closing Pressure and MRP was observed with general anaesthesia. After EAS paralysis a significant increase in Opening Pressure was observed and a similar trend was seen in Closing Pressure and MRP. This suggests the presence of complex regulatory mechanisms involved in maintaining resting anal sphincter tone. Further research is planned to investigate the contribution of the EAS and IAS to resting anal

137 sphincter function. A study comparing the effect of bilateral pudendal nerve block on resting anal sphincter function will aid our understanding of the contribution the EAS to the resting AAR variables.

AAR is a promising new technique with numerous applications. The AAR variables of Opening Pressure and Closing Pressure appear to provide a more sensitive assessment of resting anal sphincter function than the manometric equivalent of MRP. Opening and Closing Pressure, which measure the closing forces within the anal canal, may be of value in assessing patients with faecal incontinence resulting from anorectal procedures such as haemorrhoidectomy and lateral sphincterotomy which may disrupt the anal closing mechanism. The AAR variables of Opening and Closing Elastance which are thought to reflect the properties of the peri-anal connective tissues may be of value in assessing patients following anal irradiation and in those patients with anal stenosis. Further studies with AAR could examine the effect of, and outcome from, various therapeutic procedures to the anorectum. The use of anal bulking agents, topical preparations for anal fissure and botulinum toxin injection could all be evaluated with AAR. As the number of treatment options for faecal incontinence expands, an investigative test that accurately reflects sphincter function is desirable to determine aetiology and guide management. AAR may represent a significant advance in the assessment of anal sphincter function.

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Appendices

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Appendix I Opening (cmH2O) Pressure prtr1Oeao Difference Operator2 Operator 1 tDvDfeec 1.1469257 St Dev Difference Mean Difference 76 82 -0.58 48.26 47.68 63 63 -0.02 16.36 16.34 67 59 0.83 15.95 16.78 28 58 -2.98 45.81 42.83 58 55 0.35 15.54 15.89 97 84 1.29 38.45 39.74 13 21 -0.80 62.17 61.37 34 35 -0.16 53.58 53.42 81 82 -0.14 48.26 48.12 57 68 -1.05 36.81 35.76 66 72 -0.58 37.22 36.64 50 54-0.37 45.4 45.03 70 76 -0.54 37.63 37.09 01 92 0.92 39.26 40.18 01 13 -1.13 41.31 40.18 75 84 -0.92 38.45 37.53 .657 1.33 5.73 7.06 374.21.98 41.72 43.7 . .4-1.24 6.54 5.3 -0.20 Opening Elastance (cmH2O/mm2) prtr1Oeao Difference Operator2 Operator 1 .428 -0.14 0.14 2.88 1.98 2.74 2.12 .405 0.09 0.55 0.64 .107 -0.03 0.74 0.71 .3171.13 1.7 2.83 .604 -0.03 0.49 0.46 .416 0.1 1.64 1.74 .716 0.09 1.68 1.77 .915 0.06 1.53 1.59 .509 0.17 0.98 1.15 .110 0.12 1.09 1.21 .122 -0.04 2.25 2.21 .306 0.3 0.63 0.93 .3260.23 2.6 2.83 .424 0.05 2.49 2.54 .505 -0.07 0.52 0.45 .111 0.22 1.19 1.41 .512 -0.18 1.23 1.05 . .90.21 1.49 1.7 0.2748301 0.13 Closing Pressure (cmH2O)Closing Pressure prtr1Oeao Difference Operator2 Operator 1 82 04 -2.2 40.49 38.29 50 51 -0.12 15.13 15.01 50 39 1.1 13.91 15.01 84 29 -4.53 42.94 38.41 07 11 -0.35 51.12 50.77 41 45 -0.43 44.58 44.15 70 72 -0.13 37.22 37.09 38 49 -1.11 24.95 23.84 24 16 0.74 21.68 22.42 79 641.57 36.4 37.97 73 74-0.03 27.4 27.37 73 82 -0.85 28.22 27.37 57 55 0.18 35.58 35.76 79 68 1.16 36.81 37.97 57 64-0.64 36.4 35.76 573.80.12 35.58 35.7 061.4-0.44 11.04 10.6 .261 0.49 6.13 6.62 .124 -0.24 2.45 2.21 1.3427769 -0.30 Closing Elastance (cmH2O/mm Elastance Closing prtr1Oeao Difference Operator 2 Operator 1 .1170.11 1.7 1.81 .803 0.07 0.31 0.38 .504 -0.1 0.45 0.35 .210 0.5 1.02 1.52 .105 -0.02 0.53 0.51 .915 0.08 1.51 1.59 .813 0.09 1.39 1.48 .615 0.01 1.55 1.56 .408 0.18 0.86 1.04 1.17 .215 -0.15 1.57 1.42 .402 -0.03 0.27 0.24 .515 0.04 1.51 1.55 .216 0.08 1.64 1.72 .404 -0.01 0.45 0.44 .210 -0.02 1.04 1.02 .908 0.15 0.84 0.99 . .4-0.04 1.74 1.7 . .1-0.01 0.61 0.6 0.17 1 0.1385873 2 ) 0.06 ytrss( ) Hysteresis (% prtr1Oeao Difference Operator 2 Operator 1 72 62 0.96 16.25 17.21 70 58 1.23 15.82 17.05 35 28 0.73 12.83 13.56 73 78 -0.42 17.81 17.39 91 14 7.72 11.47 19.19 78 38 4.02 23.86 27.88 62 65 -0.35 16.57 16.22 99 960.38 19.6 19.98 00 990.15 29.9 30.05 37 74 -3.71 37.46 33.75 96 18 -2.21 21.84 19.63 11 31 -2.05 23.16 21.11 14 09 0.56 30.91 31.47 19 96 2.3 29.64 31.94 25 33 9.21 43.35 52.56 68 51 1.64 15.17 16.81 721.30.37 16.83 17.2 611.5-0.25 16.35 16.1 .71.4-1.97 10.14 8.17 3.1762595 0.96

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Appendix II

Incontinent women with a defect involving the IAS alone were compared with incontinent women with intact anal sphincters on EAUS. The results are shown in the table below.

Variable Defect of IAS Intact Sphincters p (n=21) (n=66) value

REST Opening Pressure (cm H2O) 25 (4 - 65) 26 (6 - 108) 0.367

2 Opening Elastance (cm H2O/mm ) 0.99 (0.41 - 2.11) 1.09 (0.32 - 2.90) 0.372

Closing Pressure (cm H2O) 20 (2 - 52) 18 (5 - 93) 0.342

2 Closing Elastance (cmH2O/mm ) 0.91 (0.31 - 1.23) 0.84 (0.25 - 3.15) 0.442

Hysteresis % 24 (6 - 57) 18 (-21 - 55) 0.054

MRP (cm H2O) 53 (8 - 105) 53 (14 - 295) 0.422

SQUEEZE Squeeze Opening Pressure (cm 35 (8 - 200) 48 (4 - 200) 0.144

H2O) Squeeze Opening Elastance 1.26 (0.69 - 2.54) 1.37 (0.55 - 3.44) 0.377 2 (cmH2O/mm )

MSP (cm H2O) 77 (14 - 326) 91 (17 - 300) 0.734

Comparison of incontinent females with a defect of the IAS alone with those with intact sphincters. Values are median (range). Comparison using Mann-Whitney U test.

151

Incontinent women with a defect involving the EAS were compared with incontinent women with intact anal sphincters on EAUS. The results are shown in the table below.

Variable Defect of EAS Intact sphincters p (n=8) (n=66) value

REST Opening Pressure (cm H2O) 33 (8 - 63) 26 (6 - 108) 0.938

Opening Elastance (cm 0.85 (0.59 - 1.90) 1.09 (0.32 - 2.90) 0.338 2 H2O/mm )

Closing Pressure (cm H2O) 25 (4 - 49) 18 (5 - 93) 0.860

2 Closing Elastance (cmH2O/mm ) 0.80 (0.49 - 1.51) 0.84 (0.25 - 3.15) 0.458

Hysteresis % 20 (12 - 41) 18 (-21 - 55) 0.397

MRP (cm H2O) 54 (20 - 104) 53 (14 - 295) 0.710

SQUEEZE Squeeze Opening Pressure 30 (8 - 77) 48 (4 - 200) 0.216

(cm H2O) Squeeze Opening 1.44 (0.71 - 2.15) 1.37 (0.55 - 3.44) 0.978 2 Elastance(cmH2O/mm )

MSP (cm H2O) 81 (32 - 133) 91 (17 - 300) 0.568

Comparison of incontinent females with an EAS defect with those with intact anal sphincters. Values are median (ranges). Comparison using Mann Whitney U test.

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