1. health and fitness
2. disease
3. incontinence

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