REVIEWS

Management of neurogenic bladder

in patients with multiple sclerosis
Véronique Phé1,2, Emmanuel Chartier–Kastler1 and Jalesh N. Panicker2
Abstract | Lower urinary tract (LUT) dysfunction is common in patients with multiple sclerosis and is
a major negative influence on the quality of life of these patients. The most commonly reported
symptoms are those of the storage phase, of which detrusor overactivity is the most frequently
reported urodynamic abnormality. The clinical evaluation of patients’ LUT symptoms should include
a bladder diary, uroflowmetry followed by measurement of post-void residual urine volume,
urinalysis, ultrasonography, assessment of renal function, quality-of‑life assessments and sometimes
urodynamic investigations and/or cystoscopy. The management of these patients requires a
multidisciplinary approach. Intermittent self-catheterization is the preferred option for management
of incomplete bladder emptying and urinary retention. Antimuscarinics are the first-line treatment
for patients with storage symptoms. If antimuscarinics are ineffective, or poorly tolerated, a range of
other approaches, such as intradetrusor botulinum toxin A injections, tibial nerve stimulation and
sacral neuromodulation are available, with varying levels of evidence in patients with multiple
sclerosis. Surgical procedures should be performed only after careful selection of patients. Stress
urinary incontinence owing to sphincter deficiency remains a therapeutic challenge, and is only
managed surgically if conservative measures have failed. Multiple sclerosis has a progressive course,
therefore, patients’ LUT symptoms require regular, long-term follow‑up monitoring.

1
Pitié-Salpêtrière Academic
Hospital, Department of
Urology, Assistance-Publique-
Hôpitaux, 47–83 boulevard
de l’hôpital, 75651 Paris
Cedex 13, France.
2
Department of Uro-
Neurology, The National
Hospital for Neurology
and Neurosurgery and
UCL Institute of Neurology,
33 Queen Square,
London WC1N 3BG, UK.
Correspondence to V.P.
veronique.phe@aphp.fr
doi:10.1038/nrurol.2016.53
Published online 31 Mar 2016
Multiple sclerosis is the commonest progressive neuro­
logical disorder in young people, with a mean age at
onset of 30 years, and a prevalence of 108 cases per
100,000 people in Europe1. Multiple sclerosis has a
progressive course, of which four major subtypes have
been identified. A relapse–remitting course is most
commonly reported, in 85% of patients with multiple
sclerosis. Nearly 50% of these individuals develop a
progressive course (described as secondary progres­
sion) over a median time period of 11 years2. Less com­
monly, patients might have a primary progressive course,
charac­terized by progressive symptoms from the onset of
disease, or have a progressive, relapsing course. Chronic
autoimmune T‑cell-mediated inflammation of the
central nervous system (CNS), resulting in disruption
of myelin sheaths, is the pathological hallmark of this
disorder (FIG. 1). Relapse–remitting multiple sclerosis is
characterized by the appearance of new and active focal
inflammatory demyelinating lesions in the white matter,
whereas progressive multiple sclerosis is characterized
by diffuse injury of normal-appearing white matter,
­cortical demyelination and axonal loss3,4.
Owing in part to spinal cord involvement, the inevi­
table progression of multiple sclerosis symptoms leads
to increased disability and a decline in mobility. The
Expanded Disability Status Scale (EDSS) is a useful tool
to guide the measurement of progression of neurologi­
cal disability and includes an assessment of pyramidal,
cerebellar, brainstem, sensory, bowel, bladder, visual and
cerebral functions5. Disease-modifying treatments are
currently available to prevent progression in patients
with relapse–remitting multiple sclerosis. Until the past
decade only IFN‑β and glatiramer were available. Now,
newer molecules have become available such as natali­
zumab, as well as oral medications such as fingolimod6.
These treatments prevent relapses and the possible accu­
mulation of neurological disability, however, uncertainty
remains as to whether or not these treatments delay
progression of non-motor manifestations such as lower
urinary tract (LUT) dysfunction.
LUT symptoms are reported by >80% of patients
with multiple sclerosis. Symptoms might occur during
the early stages of the neurological disease and some­
times might be reported at initial presentation7. Clinical
evidence suggests that LUT symptoms most often result
from spinal cord lesions and, indeed, a correlation exists
between LUT symptoms and the degree of pyramidal
symptoms observed in the lower limbs8,9. However,
LUT symptoms might also result from cognitive prob­
lems (memory loss, amotivation, apraxia and language

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Key points Considering the widespread distribution of lesions

throughout the CNS in patients with multiple sclerosis,
• Lower urinary tract (LUT) symptoms are common in patients with multiple sclerosis; the establishing a precise correlation between neurological
exact symptoms vary in type and severity, and can evolve with progression of the disease lesions and LUT dysfunction is often difficult; how­
• The management of LUT dysfunction in these patients requires a consensual approach, ever, the prevalence of LUT dysfunction increases with
with cooperation between different medical professionals, and should take into longer disease duration and greater physical disability22.
consideration possible progression of the disease Furthermore, the presence of LUT symptoms might
• Intermittent self-catheterization is essential for the management of patients with be overlooked in the clinical management of patients
voiding symptoms, but might also have a role in management of those with with multiple sclerosis. Indeed, results of a survey con­
storage symptoms
ducted by the North American Research Committee
• Intradetrusor botulinum toxin A injections are a highly effective and minimally invasive On Multiple Sclerosis, published in 2010, revealed that
treatment of storage dysfunctions
only 43% of patients with the disease with moderate to
• Surgical options include augmentation cystoplasty, cutaneous continent diversion and severe overactive bladder symptoms had their symptoms
ileal conduit surgery, and should be performed only after careful selection of patients
­evaluated by a urologist22.
• Multiple sclerosis has a progressive course and, therefore, patients with multiple
sclerosis who also have LUT symptoms require regular long-term follow‑up monitoring
Urodynamic presentation
Urodynamic investigations enable precise evaluation
of the functional pathophysiology of patients’ specific
dysfunction), additional localized causes (bladder out­ LUT dysfunction and of the risk factors for urinary
let obstruction, urinary tract infection or stress incon­ tract damage in patients with multiple sclerosis, thus
tinence), functional incontinence (reduced mobility helping clinicians to plan the optimal management
or general debilitation) or medications (such as opioid of LUT symptoms. Detrusor overactivity is the most
analgesics or tricyclic antidepressants). LUT symptoms, frequently reported urodynamic abnormality, with a
like cognitive symptoms, also progressively worsen, and prevalence of 34–91%8,14–18,23. Detrusor underactivity
become more difficult to manage with increasing dis­ is reported in ≤37%, and low bladder compliance in
ability. Furthermore, LUT symptoms negatively influ­ 2–10% of patients with multiple sclerosis14,18,23. Detrusor
ence patients’ quality of life. Data from several studies activity can also be normal in 3–34% of patients with
have shown that, in terms of patients’ overall quality of multiple sclerosis reporting LUT symptoms14,18,23. The
life, urinary incontinence is considered to be one of the reported prevalence of detrusor–sphincter dyssyner­
worst aspects of living with this disease10,11. In a self-­ gia (DSD) in these patients ranges from 5–60%14–18,23
selected group of patients with multiple sclerosis who and this vari­ation probably reflects the patient group
responded to a questionnaire, 70% of patients consid­ studied and/or technical difficulties in detecting abnor­
ered the disruptive effect of LUT symptoms on their mal detrusor–sphincter contraction. With a median
life as ‘high’ or ‘moderate’ (REF. 11). Several therapeutic prevalence of 35%, DSD becomes more common if
options are currently available to treat LUT symptoms in patients’ symptoms are monitored over a longer period
patients with multiple sclerosis. The aim of this Review of time24. Urodynamic abnormalities also often coexist:
is to describe the diagnosis and management of LUT DSD can be combined with either detrusor overactiv­
­dysfunction in patients with multiple sclerosis. ity in 43–80% of patients or with detrusor underactivity
in 5–9%, resulting in incomplete bladder emptying24.
Presentation of LUT dysfunction However, urodynamic abnormalities can also be identi­
Clinical presentation fied in patients who are asymptomatic15. Urodynamic
Over 80% of patients with multiple sclerosis report the abnormalities can also change with time in any given
incidence of LUT symptoms. This figure can vary, how­ patient with the evolution of the disease. Following a
ever, according to the severity of the neurological dis­ urodynamic study of 22 patients, with a mean follow‑up
ability of patients in the study cohort12,13. LUT symptoms duration of 42 months, investigators reported that 12
generally appear after a mean of 6 years of evolution of of these 22 patients, whose symptoms were assessed
the neurological disease13 and might be reported as a using repeated cystomano­metric tests, had changes
presenting complaint in 10% of patients. Patients with in their bladder capacity, contractility, pressure or
multiple sclerosis can present with a wide range of LUT detrusor compliance during the follow‑up period25.
symptoms. Of these, symptoms of the storage phase Only those with DSD, which was observed in 13
(overactive bladder symptoms) are the most frequently of the patients, had ­stable urological symptoms ­during
reported. Indeed, increased urinary urgency is observed the follow‑up period25.
in 38–99% of patients with multiple sclerosis, increased No evidence exists that a patient’s age or type of
urinary frequency in 26–82% and urge incontinence multiple sclerosis (remittent or progressive) has any
in 27–66%8,14–18. Stress urinary incontinence (SUI) is influence on their urodynamic presentation. However,
also frequently reported with a prevalence of 56%, and a patient’s gender might independently influence uro­
patients often report mixed urinary incontinence19. By dynamic presentation, with a significant increase in
contrast, symptoms of the voiding phase are less fre­ the maximum amplitude of uninhibited detrusor con­
quent, with a prevalence of 6–49%8,17,18. Symptoms of tractions, of the detrusor leak-point pressure (defined
both the storage and voiding phases can coexist in 50% as the lowest detrusor pressure at which urine leakage
of patients20,21. occurs in the absence of either a detrusor contraction

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a Inflammatory neuronal damage b Non-inflammatory neuronal damage

Oligodendrocyte
Microglia

Pro-inflammatory and
cytotoxic molecules Neuronal connectivity
Macrophage
Activated
microglia
Damage

CD4+ B cell Retrograde Anterograde

CD8+ T cell degeneration Wallerian
T cell degeneration

Degeneration

Pycnotic nuclei
Anterograde Wallerian Neuronal dying back Retrograde Anterograde
degeneration degeneration Wallerian
degeneration

Figure 1 | Mechanisms of neuronal injury and degeneration in patients with multiple sclerosis. a | Proinflammatory
and cytotoxic molecules released by inflammatory cells within subarachnoid or intracortical immune Nature Reviews
infiltrates, | Urology
as well as
cell contact-dependent mechanisms of T-cell mediated damage, might lead to microglia and/or macrophage activation
and oligodendrocyte injury. This process can directly or indirectly lead to death of the neuronal cell body and nuclei
(lower panel). Such cell death leads to morphological alterations, such as the characteristic pycnotic nuclei, shrinkage of
dendrites and axonal degeneration in the cerebral cortex. This could in turn lead to dysfunction of the downstream
neuronal network via anterograde trans-synaptic (Wallerian) degeneration. b | Undisturbed neuronal connectivity, and its
related functions, could be impaired by retrograde degeneration propagating backwards in cortical neurons whose axons
have been damaged in white matter lesions or along white matter tracts such as the corticospinal tract. This white matter
tract damage can lead to microglial activation and retrograde neuronal cell death. Reproduced with permission obtained
from Nature Publishing Group © Calabrese, M. et al. Nat. Rev. Neurosci. 16, 147–158 (2015).

or increased abdominal pressure) and of the maximum
detrusor pressure in men compared with women14. The
preva­lence of DSD increases with the duration of mul­
tiple sclerosis. Thus, DSD is present in 13% of patients
after 48 months of evolution of multiple sclerosis, in
15% of patients between 48 months and 109 months,
and in 48% of patients 109 months after diagnosis20.
The correlation between detrusor overactivity and a
higher EDSS score or pyramidal damage seems prob­
able14,26 and a correlation between DSD and pyramidal
damage or the degree of disability has also been sug­
gested8,14,20. However, no correlation between detrusor
underactivity and ­neurological symptoms has, thus far,
been reported15.
Pathophysiology of LUT dysfunction
In the pathophysiology of multiple sclerosis, lesions
of the CNS result in a characteristic pattern of LUT
dysfunction according to the specific location of these
lesions. Whereas subcortical white-matter lesions
result in detru­s or overactivity, lesions of the spinal
cord result in the combined occurrence of detrusor
overactivity and DSD (FIG. 2). However, considering the
multitude of lesions that characterize this condition,
establishing the relative contributions of individual
lesions to LUT dysfunction is often not possible. In gen­
eral, lesions that are more caudally placed have a greater
effect on LUT dysfunction and LUT dysfunction arises
most often following spinal cord involvement. In a few
­studies, investigators have attempted to evaluate the
association between the site of the lesion and the spe­
cific LUT dysfunction. Indeed, the presence of DSD has
been reported to be indicative of cervical spinal cord
lesions, and detrusor hyporeflexia to be indicative of a
pontine lesion23.
Complications of LUT dysfunction
Urological complications are less frequently reported
in patients with multiple sclerosis compared with those
with other neurological disorders, such as traumatic
spinal cord injury or spina bifida, but they are certainly
not rare14,20. Potential urological complications include
pyelo­nephritis (9% of patients), upper tract dilata­
tion (8%), bladder stones (5%), kidney stones (5%),

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vesicoureteral reflux (5%), renal failure (2–3%) and
bladder cancer (0.29%), although this risk increases (to
5.7%) in regular catheter users16,27–30. Hence, urological
complications are probably the most common cause
of hospitalization in patients with multiple sclerosis14.
In an epidemiological study, the risk of renal failure in
patients with multiple sclerosis was found to be equiv­
alent to the risk reported in the general population20,31.
Identified risk factors for complications included detru­
sor over­activity, elevated intravesical pressure, the pres­
ence of an indwelling catheter and the duration of the
neurological disease20,32.
Clinical investigations
The evaluation of patients with multiple sclerosis report­
ing LUT symptoms should include use of a bladder diary,
uroflowmetry followed by measurement of post-void
residual volumes, urinalysis, ultrasonography, assess­
ment of renal function and sometimes a uro­dynamic
study and /or cystoscopy. An assessment of a patient’s
­quality of life is an integral part of the evaluation20.
Bladder diary
The International Continence Society (ICS) recom­
mends the use of a bladder diary in the clinical assess­
ment of patients with LUT symptoms. The bladder
diary is an extension of history taking and provides a
prospective, real-time assessment of LUT symptoms,
fluid intake and baseline LUT symptoms before man­
agement, and also helps to evaluate the outcomes of any
treatment33 (FIG. 3).
Assessment of quality of life
Many questionnaires are available to assess
LUT-symptom-related quality of life. However only
Qualiveen® (MAPI research trust, Lyon, France)34 is
validated for evaluation of the quality of life of patients
with neurological disease and is recommended by the
European Association of Urology (EAU)35. This ques­
tionnaire comprises 30 items and covers bother (nine
items), constraints (eight items), fears (eight items) and
feelings (five items). Each item is scored from 0–4. Each
of the four scales are scored from 0–100, with lower
scores indicating a better quality of life (meaning fewer
limitations, fears, constraints or negative feelings) and
higher scores indicating a worse quality of life. The
Qualiveen® questionnaire is currently translated into
six different languages.
Urinalysis
Findings from urinalysis help to provide evidence of
any urinary tract infections and urinalysis should be
performed in all patients during their initial evaluation
or, subsequently, when reporting the occurrence of new
symptoms. Negative urinalysis findings (for example,
revealing a lack of leukocyte esterases and/or nitrites)
are useful in excluding the possibility that symptoms are
caused by infections as this test has a high negative pre­
dictive value (>98%). However, the positive predictive
value is low (around 50%)36. Thus, when an infection
is suspected, midstream or catheter urine specimens
should be sent for microbiological culture. For patients
who perform intermittent self-catheterization (ISC) or

Suprapontine lesion Over-

• History: predominantly storage symptoms active
• Ultrasound: insignificant PVR urine volume
• Urodynamics: detrusor overactivity
Normo-active

Spinal (infrapontine-suprasacral) lesion Over-

• History: both storage and voiding symptoms active
• Ultrasound: PVR urine volume usually raised
• Urodynamics: detrusor overactivity, detrusor-sphincter dyssynergia
Overactive

Under- Under-
Sacral/infrasacral lesion active active
• History: predominantly voiding symptoms
• Ultrasound: PVR urine volume raised
• Urodynamics: hypocontractile or acontractile detrusor
Normo-active Underactive

Figure 2 | Patterns of lower urinary tract dysfunction following neurological disease. The pattern of lower urinary
Nature Reviews | Urology
tract dysfunction following neurological disease is determined by the site and nature of the lesion. The blue box denotes
the region above the pons and that in green denotes the sacral cord and infrasacral region. Figures on the right show the
expected dysfunctional states of the detrusor–sphincter system. PVR, post-void residual. Reproduced with permission
obtained from Elsevier © Panicker, J. et al. Lancet Neurol. 14, 720–732 (2015).

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The management pf patients with multiple sclerosis and LUT symptoms treatment or if the patient has had recurrent urinary
tract infections, measurement of the post-void residual
Assessment
volume should be repeated.
• History • Urinalysis/culture
• General assessment, quality • Urinary tract imaging,
of life, expectations from measures of renal function Urodynamics
treatment • Measuring post-void Urodynamic techniques, including uroflowmetry and
• Bladder diary residual volume
• Physical examination • Urodynamics filling cystometry, with or without additional synchro­
nous fluoroscopic screening (videourodynamics), are
all useful methods of examining LUT function, ena­
Storage symptoms bling evaluations of the pressure–volume relationship
Detrusor overactivity during non-physiological filling of the bladder and
during voiding.
The need to perform a urodynamic investigation in all

Disability
Increased post-void Normal post-void
residual volume residual volume patients with multiple sclerosis during initial assessment
is currently under debate, as the risk of damage to the
upper urinary tract is considered to be lower in patients
Learn ISC Treatment options with multiple sclerosis compared with that of those with
other neurological disorders, such as spinal-­cord injury
or spina bifida20,31,40,41. Guidelines published by The UK
Behavioural therapies National Institute for Health and Care Excellence (NICE)
and a Turkish consensus statement provide guidance on
the management of patients with urinary incontinence
Antimuscarinics owing to neurological disease; both guidelines recom­
mend not to offer uro­dynamic investigations (such as fill­
Tibial nerve stimulation Intradetrusor
ing cystometry and/or pressure–­flow studies) routinely
sacral neuromodulation? BoNT-A injections to patients with neurological disease who are known to
have a low risk of renal complications (for example, most
patients with multiple sclerosis)40,42. By contrast, the
Yes International Francophone Neuro-Urological Expert
ISC possible? Study Group (GENULF) recommends using urodynam­
No ics in the initial diagnosis of patients20. The inclusion of
urodynamics in the routine assessment of patients with
Augmentation Incontinent urinary diversion– Indwelling urethral/ multiple sclerosis is, therefore, determined by the avail­
cystoplasty option in selected patients suprapubic catheter
able local guidance; however, urodynamic investigations
Figure 3 | Algorithm for the management of storage symptoms in patients with are generally recommended in patients with risk factors
Natureof
multiple sclerosis. Maintaining quality of life, including preservation Reviews | Urology
renal function predisposing to upper urinary tract damage such as in
is the primary aim of management of these symptoms. At initial presentation, the most those with concomitant SUI, in those whose symptoms
conservative approaches should be considered the primary treatments of storage have failed to respond to first-line treatment or if surgical
symptoms; although, as patients’ disease progresses, more invasive management treatment is being considered9,43.
approaches might be required. BoNT-A, botulinum neurotoxin A; ISC, intermittent self
catherization; LUT, lower urinary tract. Assessment of renal function
Creatinine clearance, calculated based upon analysis of a
24‑hour urine sample, is a more accurate method of esti­
have an indwelling catheter, findings of microbiologi­ mating kidney function than serum creatinine level or
cal urinalysis will almost invariably be positive owing the estimated glomerular filtration rate44.
to chronic bacteriuria. Thus, periodically sending urine
samples for culture should be discouraged in the absence Other investigations
of fresh neurological or urological symptoms37–39. Other investigations, such as cystoscopy or retrograde
ureterocystography might be required and the need
Ultrasonography for these should be assessed on a case‑by‑case basis.
Findings of renal ultrasonography in patients with Cystoscopy might be indicated in individuals with recur­
multiple sclerosis can be entirely normal but can also rent urinary tract infections to investigate the presence of
sometimes reveal the presence of hydronephrosis and/or stones or diverticulae, or if risk factors for bladder c­ ancer
stones, both of which require a specific management are present20. Retrograde cystography is performed to
plan. Measurements of the post-void residual volume assess any vesicoureteral reflux, although, this might also
form part of the initial assessment, and this is measured be identified using videourodynamics45.
either using ultrasonography, or alternatively using a
single in–out catheterization, followed by measurement Management
of the subsequent volume of urine. Furthermore, if the The management of LUT symptoms in patients
clinician has reason to suspect a patient has developed with multiple sclerosis requires a multidisciplinary
incomplete bladder emptying owing to the effects of a approach involving the input of urologists, neurologists,

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rehabili­tation physicians, continence advisers and the
various stakeholder groups that represent patients35.
In patients with multiple sclerosis, the overall, long-term
aims of management are to protect the upper urinary
tract, to achieve continence and to improve the patient’s
overall quality of life. The management strategy has to
take both the neurological disability and the patient’s
living environment into consideration. Furthermore,
considerations should be given to urinary and bowel
functions together if both systems are affected, as both
symptoms and treatments of one system might also influ­
ence the other43. In patients presenting with both storage
and voiding LUT symptoms, the management strategy
should combine the treatments available for storage
symptoms and the treatments for voiding symptoms.
were randomly allocated to one of two groups. Group
one, in which patients received pelvic floor muscle train­
ing, electromyography biofeedback and placebo neuro­
muscular electrical stimulation (n = 37), and group two,
in which patients received pelvic floor muscle training,
electromyography biofeedback and active neuro­muscular
electrical stimulation (n = 37). After 9 weeks of treatment,
the mean number of incontinence episodes observed in
group two was significantly greater than that observed
in group one (by 85% versus 47% of baseline levels,
respectively; P = 0.0028)49. However, despite these encour­
aging results, concomitant treatment with antimuscarinics
was maintained in the majority of studies in this area54.
Consequently the exact effects of isolated use of physical
treatments cannot be accurately assessed.

Management of storage symptoms Medical treatment

General measures and physical treatments
A fluid intake of 1.5–2 l per day is recommended in the
general population and, although not specifically recom­
mended, this level of intake should also apply to patients
with multiple sclerosis. Furthermore a reduction in caf­
feine intake below 100 mg per day has been shown to
reduce symptoms of the storage phase46.
Physical therapy can be effective for the treatment of
LUT symptoms in patients with multiple sclerosis with
mild disability 47–51. In our own clinical experience of such
an approach, bladder retraining involves the patient vol­
untarily ‘holding on’, or refraining from voiding with a
fairly full bladder for increasingly longer periods of time,
often as part of an incremental programme supervised
by specialist continence advisers or physiotherapists. Of
course, these interventions can only be expected to be
effective in patients with intact neural control of their pel­
vic floor muscles; therefore, an assessment of a patient’s
control of their pelvic floor muscles should be made
before initiating treatment. Such interventions are often
difficult to initiate in patients with cognitive impairments.
Regular pelvic floor exercises can enhance the inhibitory
effect of pelvic floor contractions on the detrusor52.
A prospective trial was conducted to investigate the
effects of pelvic floor rehabilitation as a treatment of
­detrusor overactivity in 30 female patients with multiple
sclerosis53. In 25 of these 30 patients, the strength of the
pelvic floor was significantly improved after one month
of regular exercises (P <0.001). A significant increase in
mean functional bladder capacity, as read from patients’
voiding charts, was also observed (from 173.8 +/– 53.9
to 208.5 +/– 57.6 cm3; P = 0.005). Furthermore, the mean
urinary frequency decreased significantly (from 12.7 +/–
3.6 to 9.1 +/– 2.6 voids per day; P <0.01) as did the mean
number of daily episodes of incontinence (from 2.8 +/–
1.3 to 1.5 +/– 1.5 episodes per day; P <0.01)49. Moreover,
combining active neuromuscular electrical stimulation
with pelvic floor muscle training and electromyography
(EMG) biofeedback can result in a substantial reduction
in the severity of LUT symptoms53.
Further evidence for the combination of pelvic floor
exercises with neuromuscular electrical stimulation is pro­
vided by a randomized controlled trial: 74 patients with
multiple sclerosis who presented with LUT dysfunction
Antimuscarinics
Antimuscarinics and/or intermittent self catheterization
(ISC) are the cornerstone of LUT symptom management
in patients with early-stage multiple sclerosis55. The use
of antimuscarinics results in a decreased sensation of uri­
nary urgency, an improvement in continence, an increase
in bladder capacity, a significant reduction of maximum
detrusor pressure and a significant improvement in qual­
ity of life of patients with a variety of neuro­logical dis­
eases56–58. In patients with multiple sclero­sis, the evidence
base supporting the clinical use of antimusca­rinics is
limited. Not all currently available antimuscarinics have
been systematically investigated in patients with multi­
ple sclerosis and their use is often based upon inferences
of efficacy from data from other patient groups58. The
efficacy, tolerability and safety of anticholinergic drugs
among patients with multiple sclerosis was assessed in
a Cochrane review published in 2009 (REF. 59). However,
this review included data from only three single-­centre
randomized crossover trials that were either placebo-­
controlled or designed to compare the effects of two
or more treatments57,60,62. In the Cochrane review59, the
authors did not find sufficient evidence to prove any sig­
nificant benefit of antimuscarinics in patients with mul­
tiple sclerosis. The authors also noted a high incidence of
adverse effects (such as dry mouth or constipation) with
more than one in five trial participants having to with­
draw from antimuscarinic treatment59. Findings of sys­
tematic reviews do not support the superiority of any one
drug over another. However, the most clinically relevant
differences between antimuscarinics are in the adverse
event profile. For example, tolterodine, when used at self-­
selected doses, is comparable with oxybutynin in terms
of increasing patients’ bladder capacities and improving
continence, but with less dry mouth62. The intravesical
administration of atropine is an interesting approach that
has been reported to be as effective as oral oxybutinin,
with fewer adverse effects57. However, the limited avail­
ability of atropine and the necessity to visit the clinic for
each instillation is a major inconvenience, which restricts
the use of this approach.
Cognitive impairment is reported in patients with
multiple sclerosis, especially as the disease advances,
and the choice of antimuscarinic should, therefore, be

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guided by the potential risk of adverse effects on the
CNS. Medications such as trospium chloride are, rela­
tive to oxybutynin, tolterodine and solifenacin, less likely
to cross the blood–brain barrier and might be a medica­
tion to consider in patients with advanced-stage multiple
sclerosis. Darifenacin, a selective antagonist of the M3
receptor, which is not known to be involved in cogni­
tion, provides an alternative to trospium41. However,
studies supporting the use of darifenacin specifically
in patients with multiple sclerosis are currently lacking.
Combinations of regular doses of two different anti­
muscarinics have been shown to be effective and well
­tolerated in a few patients63.
In conclusion, antimuscarinics remain widely pre­
scribed agents despite the availability of only limited
evidence of their efficacy or effectiveness in patients
with multiple sclerosis. Use of these agents can improve
symptoms of the storage phase and patients’ quality of
life. However, patients must be informed of the poten­
tial long-term adverse effects, including the risk of an
increased post-void residual volume, which then might
require ISC.
Desmopressin
Treatment with the synthetic antidiuretic hormone des­
mopressin, used orally or intranasally at different doses
(from 10–100 μg), has been shown to reduce night time
urinary frequency in patients with multiple sclerosis64–71.
Some of these data are from randomized-controlled
trials, and some from other studies. These investiga­
tions64–71 generally included only small numbers of
patients with multiple sclerosis and had short (<6‑week)
durations of both treatment and follow‑up monitoring.
If taken during the day, similar doses of desmopressin
to those used at night can also provide relief from LUT
symptoms for up to 6 hours without rebound nocturia72.
Moreover, the use of desmopressin is associated with res­
toration of sleep patterns and substantial improvements
in LUT symptoms, as determined using the International
Consultation on Incontinence Questionnaire–
Overactive Bladder questionnaire72. However, hypo­
natraemia is a serious adverse effect of desmopressin,
and serum sodium levels should be checked before the
drug is administered to establish a baseline level, and
at day 3 and day 7 after commencing daily administra­
tion72. Thus, desmopressin is not recommended for use
more than once daily, and should be used with caution
in elderly patients (defined as those >65 years of age).
Other adverse effects of desmopressin include headaches
(3.2–18.7%), nausea (3.2–10.5%), fluid retention (36.8%)
and rhinitis and/or epistaxis (3.2–10.5%)64–71.
Cannabinoids
Some evidence exists supporting the use of cannabinoids
in the management of LUT symptoms in patients with
multiple sclerosis. The rationale for cannabinoid use in
the control of LUT symptoms stems from the established
expression of cannabinoid receptors of both subtypes
(CB1 and CB2) in the urothelium and afferent nerves
of the human bladder, similar to those of several other
experimental animals73. In a large, placebo-­controlled
trial with a cohort of 647 patients with multiple scler­
o­s is, oral administration of a cannabis extract or
Δ9‑tetrahydrocannabinol (Δ9‑THC) reduced the fre­
quency of urge incontinence episodes (by 38%, 33% and
18%, respectively; P = 0.05 and 0.039 for comparisons of
cannabis extract or Δ9‑THC with placebo, respectively)
and pad weight (mean reduction of 44.7 ml, 43.2 ml and
43.9 ml for cannabis extract, Δ9‑THC or a combination
of treatments, respectively, versus a mean increase of
8.3 ml for placebo; combined mean difference versus
placebo of 52.1 ml, 95% CI 13.4–90.9 ml; P = 0.001)74.
In a small open-label trial including 21 patients with
advanced-stage multiple sclerosis, the safety, tolerability,
dose range and efficacy of two whole-plant extracts of
cannabis sativa was evaluated. Patients received extracts
containing Δ9‑THC and cannabidiol (CBD; 2.5 mg of
each per spray) for 8 weeks followed by Δ9‑THC only
(2.5 mg THC per spray) for a further 8 weeks, and then
entered into a long-term extension phase. Urinary
urgency, the number and volume of incontinence epi­
sodes, urinary frequency and the number of episodes
of nocturia all decreased significantly following treat­
ment (P <0.05). However, daily total volume voided,
catheterized, and urinary incontinence pad weights
also decreased significantly in patients who received
both extracts75.
Data from a multicentre, double-blind, placebo-­
controlled trial evaluating the efficacy of sublingual
Sativex® (GW pharmaceuticals, Cambridge, UK),
which is an endocannabinoid modulator consisting of
THC and cannabidiol, in a 1:1 ratio, in patients with
advanced-stage multiple sclerosis demonstrated some
improvements in the frequency of episodes of urinary
incontinence, daytime urinary frequency and nocturia76.
However, no significant differences in the frequency of
episodes of urinary incontinence was observed between
patients who received Sativex® and those who received
placebo after 8 weeks of treatment, despite this being the
primary endpoint of the study76. A license was granted in
2010 for the use of Sativex® to treat spasticity in patients
with multiple sclerosis in the UK; although, this license
does not apply to the treatment of LUT symptoms.
Intravesical treatments
Onabotulinum toxin A (BoNT‑A), which is commer­
cially available as BOTOX® (Allergan, Irvine, California,
USA) has been licensed since 2012 in several countries
for use in patients with treatment-refractory neurogenic
detrusor overactivity owing to multiple sclerosis or spi­
nal cord injury. BoNT‑A is the only type of botulinum
toxin to be evaluated for the management of any LUT
dysfunction in large, multicentre, randomized controlled
trials77–80. However, the use of abobotulinum toxin A,
which is commercially available as Dysport® (Ipsen,
Paris, France) as a treatment of neurogenic detrusor
overactivity but not other forms of LUT dysfunction, is
also supported by a high level of evidence81.
BoNT‑A has several putative mechanisms of action;
in addition to inhibiting the release of vesicular neuro­
transmitters from parasympathetic nerve terminals
of the detrusor smooth muscle, this toxin is also

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likely to inhibit the release of transmitters involved in
afferent signalling pathways in the bladder mucosa82.
Intradetrusor injections of BoNT‑A are highly effective
in reducing the incidence of urinary incontinence, in
improving patients’ urodynamic parameters and, there­
fore, their quality of life77–79,83. Two doses of BoNT‑A,
200 units versus 300 units, have been tested in two
double-blind, placebo-controlled randomized trials
with cohorts of patients with neurogenic detrusor over­
activity owing to either multiple sclerosis or spinal cord
injury78,79. Data from both studies did not reveal any
significant differences in efficacy between doses; how­
ever, the need to initiate ISC after injections was higher
in those receiving 300‑unit injections than in those
receiving 200‑unit injections or placebo (12%, 30% and
42%79 and 10%, 35% and 42%79 of patients not already
using ISC required ISC after receiving placebo, 200‑unit
or 300‑unit injections, respectively). The effects of
BoNT‑A injections usually last for 6–9 months, there­
fore, repeated injections are often necessary. All patients
with multiple sclerosis should have been taught, or
agreed to learn to do ISC before being treated with
BoNT‑A injections as 88% of patients need to perform
de novo ISC83. However, the need for ISC did not affect
quality of life outcomes83.
Mehnert et al.84 investigated the effects of 100‑unit
injections of BoNT‑A in 12 patients with multiple scler­
osis and overactive bladder symptoms. Follow‑up ­visits
were planned 6–7 and 12–14 weeks after injections.
Investigators found that 6–7 weeks following the injec­
tion, maximum bladder capacity increased significantly
(P = 0.034), and maximum detrusor pressure (P = 0.004),
daytime urinary frequency (P = 0.004), urinary urgency
(P = 0.008) and pad use (P = 0.011) all decreased sig­
nificantly. Furthermore, daytime urinary frequency
(P = 0.002), night time urinary frequency (P = 0.005),
urinary urgency (P = 0.013) and pad use (P = 0.02) all
decreased significantly 12–14 weeks following injec­
tions. Post-void residual volume significantly increased
in these patients following 100‑unit BoNT‑A injections,
and reached 222 ml initially but decreased progressively
for 12 weeks post-treatment; overall, three patients
needed to perform de novo ISC84. Further studies, with
larger populations and longer follow‑up durations are
required to investigate the benefits of a lower dose of
BoNT‑A in patients with multiple sclerosis who are not
willing or able to self-catheterize. An alternative option
for patients who cannot reach the urethra to perform
ISC is to control LUT symptoms using intradetrusor
BoNT‑A injections and create a continent urinary diver­
sion using a catheterizable channel (Mitrofanoff, Monti
or Casale’s principles)85. In our own clinical experience,
BoNT‑A injections do have to be repeated following sur­
gery, although generally, the patient can still perform ISC
using this continent stoma.
Furthermore, the use of BoNT‑A injections has also
been shown to decrease the incidence of symptomatic
urinary tract infections. This effect seems to be related
to improvement in urodynamic parameters, reflecting
improved reservoir capacity at low bladder pressures86.
Finally, evidence exists, from a series of three patients
with end-stage multiple sclerosis, that intradetrusor
injections of BoNT‑A might provide some benefit to
patients with an indwelling urethral catheter who report
urine leakage owing to catheter bypassing87.
Neuromodulation
Stimulation of the tibial nerve or sacral nerve root S3
has proven to be successful in managing overactive
bladder symptoms. The exact mechanisms of action of
this approach remain uncertain but are thought to be
a result of modulation of spinal pelvic reflexes through
­activation of inhibitory interneurons88.
Tibial nerve stimulation. Tibial nerve stimulation can
be administered either using a needle to deliver electri­
cal stimulation (the percutaneous approach) or using
an electrode patch (the transcutaneous approach).
The transcutaneous method has the advantage that it
can be easily used at home, either by the patient or by
their carer, in comparison to the percutaneous method,
which requires the insertion of a needle close to the tibial
nerve by a health-care professional. Percutaneous tib­
ial nerve stimulation has been shown to be effective in
managing storage symptoms and improving urodynamic
parameters in patients with multiple sclerosis89–91. Initial
percutaneous stimulation is usually delivered during
30‑min, weekly sessions, over a period of 10–12 weeks,
and generally followed in responders by a period of
maintenance therapy, of which the optimal characteris­
tics are poorly defined. This therapy is safe, the patients’
reported subjective and objective cure rates are between
60–80%, patients’ treatment satisfaction is generally high
(70%) and their overall quality of life is usually improved
substantially89,91–94. Data from a study of 19 patients with
multiple sclerosis who received weekly, 30‑min percu­
taneous stimulation of the tibial nerve for 12 weeks
revealed a significant improvement in urodynamic
parameters, including maximum cystomanometric
capacity (increased from 199.7 to 266.8 ml; P < 0.001),
maximum detrusor pressure at maximum cystoman­
ometric capacity (decrease from 48.8 to 35.8 cm H2O;
P = 0.001), maximum flow rate (increased from 11.6
to 13.2 ml; P = 0.003) and post-void residual v­ olume
(decreased from 82.9 to 48 ml; P = 0.006)95.
The efficacy of transcutaneous tibial nerve stimula­
tion has been proven in a multicentre study of a cohort
of 70 patients with multiple sclerosis and symptoms of
overactive bladder96. All patients received transcutan­
eous tibial nerve stimulation for 20 minutes per day, for
a period of 3 months. Clinical improvement in symp­
toms was observed in 82.6% and 83.3% of the patients
on day 30 and day 90, respectively, with significant
improvements in urinary urgency, frequency, patients’
self-reported symptoms, continence and quality of life
observed between day 0 and day 90 of the study (P <0.05
for all changes)96. The initial acute cystometric response
(defined as a >30% increase in cystometric capacity
and/or reflex volume) to the first session of transcu­
taneous stimulation was positive in 51.2% of patients,
without any notable correlations with longer-term clini­
cal effectiveness of the treatments96. Further studies are

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required in order to assess the long-term effects of per­
cutaneous neuromodulation and to better understand
the need for ‘top up’ to maintain these effects.
The safety of tibial nerve stimulation is particularly
useful to patients who are disabled, who might be more
susceptible to the deleterious adverse effects of anti­
muscarinics than those with a lower level of disability.
In our own clinical experience, in such populations, the
use of tibial nerve stimulation as the first-line treatment
can be considered appropriate; although, this sugges­
tion is not supported by any published evidence, thus
far. The advantage, to the clinicians, of the percutan­
eous approach over the transcutaneous method is that
patients’ symptoms can be monitored on a weekly basis
by the health-care team. However, patients might con­
sider a weekly visit to be a constraint, especially if they
are disabled. Use of the transcutaneous method has
the advantage that patients can benefit from receiv­
ing the treatment at home, but without the possibility
of checking if the stimulation they are receiving is opti­
mally conducted. By contrast, the lack of any proven
ameliorative effects on increased detrusor pressures
might be a limitation of the percutan­eous approach in
patients with severe neurogenic detrusor overactivity
and high detrusor pressures, which increase the risk of
damage to the upper urinary tract.
Sacral neuromodulation. Sacral nerve stimulation is a
minimally invasive treatment that can be used to treat
patients with treatment-refractory LUT symptoms
owing to a range of different underlying neurological
diseases97. Similar to other forms of neuromodulation,
the exact underlying neurophysiological mechanisms of
action are complex and currently not fully understood.
Neuromodulation might exert its effect through acti­
vation of afferent pathways that modulate the activity
of other neural pathways within the spinal cord and
higher centres98. Results of a study, published in 2000,
show that urodynamic parameters improve from base­
line to 6 months post-implantation, including maximum
bladder capacity (from 244 ml to 377 ml), volume at first
uninhibited contraction (from 214 ml to 340 ml) and the
average number of voids per day (from 16.1 voids to 8.2
voids)97. The findings of a meta-analysis published in
2010 indicate that sacral neuromodulation might be
effective (in terms of reduced incontinence and fewer
voids per day) and safe in patients with neurogenic LUT
dysfunctions99. Elsewhere, in a retrospective case series
of 33 patients with neurogenic LUT dysfunctions, 31
reported satisfaction with their treatment100. However,
the course of the underlying neurological disorder has
been shown to adversely influence the ability to derive
long-term benefits from sacral neuromodulation101,102.
As a result, some authors have proposed that sacral
neuro­modulation should be used in patients with mul­
tiple sclerosis of a relapse–remitting course, who have
not had a relapse for at least 2 years101. The incidence
of complications after sacral neuromodulation seems
not to be significantly different from that of the general
population of patients with LUT dysfunctions with no
established neurogenic aetiology103. In a study enrolling
62 patients with a neurological condition (among them
13 had multiple sclerosis) receiving sacral neuromodu­
lation therapy, the reported revision and explantation
rates were 10.4% and 12.5% respectively. Complications
included wound seroma (0.8%), wound infection (4.1%),
back pain (0.8%), leg pain (1.2%), implantable perma­
nent generator site pain (8.2%), a sensation of shock
upon stimulation (0.8%), lead breakage (2.5%), lead
migration (0.8%) and device malfunction (3.3%)101.
Published data are available from other studies in this
area, however, these studies included only small num­
bers of patients with multiple sclerosis and are highly
heterogeneous102–106: most of the series were retrospective
and data from patients with multiple sclerosis were gen­
erally not analysed separately from data from patients
with other neurological conditions. Currently, no data
from randomized controlled trials are available in this
area, and the types of patients who are most suitable for
sacral neuromodulation is also largely unknown.
Surgery
Surgical treatments of LUT dysfunction in patients with
multiple sclerosis are appropriate in certain situations:
when conservative therapies have failed; when ISC
through the urethra is not possible; or in patients with
serious complications such as sepsis, urethral or perineal
fistulae, renal failure or severe urinary incontinence.
Augmentation cystoplasty. In highly-motivated patients
where ISC can be achieved in the long term, but whose
LUT symptoms are refractory to more-conservative
treatments, augmentation cystoplasty is recommended.
The goal of an augmentation cystoplasty procedure,
which involves surgically enlarging the bladder, is to
restore a low-pressure and compliant reservoir and, thus,
achieve urinary continence. This procedure is often per­
formed using a segment of detubularized ileon to aug­
ment the urinary bladder. Zachoval et al.107 reported the
outcomes of augmentation ileocystoplasty performed in
nine patients with multiple sclerosis, of whom eight had
­detrusor hyperreflexia that was refractory to conserva­
tive treatment and one had renal insufficiency. With
a follow‑up duration of 6–19 months, investigators
recorded an increase in the maximum mean detrusor
capacity from 105 to 797 ml and a decrease in the maxi­
mum detrusor pressure from 53 cm H2O to 30 cm H2O.
A substantial improvement in LUT symptoms was
observed in all patients and the quality-of‑life score, as
assessed using a questionnaire with a 0–6 scale (0 indi­
cating excellent quality of life, six indicating unbear­
able), improved from a mean of five to 0.7 (REF. 107).
Importantly, the patient who had renal insufficiency
had a decrease in serum creatinine from 286 μmol/l to
150 μmol/l, suggesting that this surgery had a renopro­
tective effect in this patient108. Elsewhere, in more var­
ied but larger patient cohorts, the rates of continence
(78% for patients with neuropathic bladders and 93%
for those with detrusor instability) 3 years after augmen­
tation are high, as are the patient satisfaction rates108,109.
Therefore, augmentation ileocystoplasty is an effective
surgical approach for patients with multiple sclerosis

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who also have treatment-refractory neurogenic blad­
der, provided that patients are able to self-catheterize,
and this approach can improve patients’ LUT-specific
quality of life.
Augmentation cystoplasty is currently feasible using a
robot-assisted laparoscopic approach110; although, com­
parative studies are needed to confirm the results and the
reduced morbidities observed following use of this pro­
cedure in comparison with those obtained with the open
approach. Augmentation cystoplasty procedures can also
be performed concomitantly with a cutaneous continent
urinary diversion in circumstances where the patient is
unable to perform ISC through the urethra. For cosmetic
reasons, the umbilicus is often used as the stoma site in
these patients. The short-term continence rates achieved
with augmentation cystoplasty in combination with a
continent urinary diversion are >80% and good protec­
tion of the upper urinary tract is usually achieved111–113.
An improvement in quality of life, as assessed using the
Qualiveen® questionnaire, has also been reported114;
furthermore, the reported rates of continence (86%), as
well as satisfaction with both functional and aesthetic
outcomes (88% and 92%, respectively) are high after a
mean follow‑up duration of 21.6 months114. However,
all of these patients have a high risk of complications,
including stomal leakage or stenosis. Regular clinician
visits to monitor patients’ adherence and continence
status are, therefore, required.
Non-continent urinary diversion. Despite the availabil­
ity of procedures to create a catheterizable outlet, some
patients remain unable or unwilling to perform ISC.
Quadriplegia, limited dexterity and/or devastating cog­
nitive impairment are the main causes of this inability.
In order to restore a low-pressure reservoir without the
use of an indwelling urethral, or suprapubic catheter
and to improve quality of life, a noncontinent cutan­
eous diversion using an ileal conduit and a urine collect­
ing device can be performed115. Ultimately, use of such
an approach could be considered in patients who are
wheelchair-­bound or bedridden (including in those with
skin ulcers), with intractable and/or untreatable incon­
tinence, in patients with devastating LUT symptoms,
when the upper urinary tract is severely c­ ompromised
or in patients who refuse other therapies.
A cystectomy is usually performed as a first-line
approach to prevent pyocystitis. Much of the data on
the outcomes of patients who underwent ileal conduit
surgery are from patients who underwent this pro­cedure
after pelvic cancer surgery. Regarding patients with
neuro­logical diseases, some studies have provided data
on the outcomes of ileal conduit surgery among patients
with multiple sclerosis. In a retrospective study, investi­
gators reported the functional outcomes of ileal conduit
procedures performed in a population of 53 patients
with multiple sclerosis with neurogenic bladder116.
Despite the fact that ileal conduit surgery was found to
be associated with substantial perioperative morbidi­
ties, including blood loss requiring transfusion (n = 17),
pneumonia (n = 3), pyelonephritis (n = 3), pelvic abscess
(n = 1), wall abscess (n = 2), septicaemia (n = 1) and
haemorrhagic shock (n = 2), the surgical procedure did
significantly improve the mean overall Qualiveen® score
(from 2.1 before surgery to 1.16 after surgery; P = 0.02).
The investi­gators found that the postoperative morbid­
ity rate was 18.2%. Interestingly, limitations (1.64 ± 1.38
before surgery versus 0.60 ± 0.69 after surgery; P = 0.005),
constraints (2.91 ± 1.01 before surgery versus 2.07 ± 0.93
after surgery; P = 0.16) and specific urinary impact index
(1.86 ± 0.96 before surgery versus 1.25 ± 0.71 after sur­
gery; P = 0.024) subscores of the Qualiveen® were sig­
nificantly improved at 6 months after surgery116. In a
prospective study, authors reported the quality-of‑life
outcomes of 44 patients with multiple sclerosis who
underwent laparoscopic ileal conduit surgery to treat
their LUT dysfunction117. The authors found that the
postoperative morbidity rate was 18.2%. Minor (Clavien
grade ≤2) and major (Clavien grade ≥3) complications
occurred in 13.6% and 6.8% of patients, respectively.
Noted complications included asymptomatic ureteroileal
stenosis (n = 6) and pyelonephritis (n = 3).
Management of SUI
SUI owing to sphincter deficiency that does not respond
to behavioural modifications requires a specialised man­
agement approach. Social continence, where symptoms
are controlled to the extent that patients’ quality of life
is largely unaffected, can be achieved by collecting urine
during incontinence episodes using pads, for example.
In our own clinical experience, condom catheters with
urine collection devices are also a practical method for
managing SUI in men as these tend to result in fewer
hygiene issues, and are more affordable than pads. Use
of a penile clamp is contraindicated in patients with
detrusor overactivity or low bladder compliance owing
to the risk of developing high intravesical pressures36.
Neurogenic SUI remains a therapeutic challenge: cur­
rently, no nonsurgical treatments for this condition exist,
and the armamentarium for management comprises
midsuburethral synthetic slings, fascial slings, artificial
urinary sphincters, periurethral bulking agents and ure­
thral closure116. No published data on neurogenic SUI
specifically in patients with multiple sclerosis currently
exist. Therefore, selection of the most appropriate treat­
ment should be made on a case‑by‑case basis, consider­
ing the patient’s ability to perform ISC and the extent of
any cognitive impairment.
Management of voiding symptoms
Intermittent catheterization
ISC is the preferred method for the treatment of incom­
plete bladder emptying or urinary retention in patients
with neurogenic bladder35. This approach to manage­
ment of incomplete bladder emptying was originally
described by Lapides and colleagues118, in 1971, in a
woman with multiple sclerosis. ISC has to be initi­
ated in patients whose incomplete bladder emptying
is reflected by the presence of a high residual volume.
This high residual volume is generally accepted to be
>100 ml, however the exact volume depends upon the
characteristics of the individual patient. Actually, no
evidence-­based cut off post-void residual value exists for

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the recommendation to start clean intermittent catheter­
ization in patients with multiple-sclerosis-related LUT
dysfunction41. The average frequency of catheterization
per day is 4–6 times, as bladder volume at catheteriza­
tion should ideally, as a rule, not exceed 400–500 ml119.
ISC is rarely necessary in the early stages of multiple
sclerosis but becomes increasingly likely to be needed
as a patient’s mobility deteriorates. The introduction of
self-catheterization can be challenging in patients with
multiple sclerosis, therefore, training and support from
the health-care team is required. The ability of patients
with multiple sclerosis to learn ISC might be influenced
by the extent of symptoms, as indicated by the EDSS; by
contrast, cognitive decline seems not to limit a patient’s
ability to learn ISC120. When having to perform ISC,
patients with multiple sclerosis might face several bar­
riers: patient-related factors include physical disabilities
and psychological factors, and external factors include
access to public toilets. These factors have to be indi­
vidually addressed121. Use of ISC decreases the risk of
urinary tract infections and upper urinary tract dam­
age, promotes urinary continence and, in some studies,
has been demonstrated to improve patients’ quality of
life32,122–125. For patients with multiple sclerosis who also
have severe limb spasticity and poor mobility, a willing
carer can be taught to catheterize the patient.
Some patients are unable to reach their urethra,
which is necessary in order to self-catheterize, owing to
limited hand dexterity or other physical limitations, such
as obesity. For such patients, a continent catheterizable
tube is created using various surgical techniques, includ­
ing the appendix (Mitrofanoff ’s principle) or a portion
of small intestine (Yang-Monti and Casale’s principles)85.
Data from a study of a small cohort of patients with
multiple sclerosis reveal that use of α‑adrenoceptor antag­
onists reduces post-void residual volumes126; although,
the experience in clinical practice indicates that many
patients fail to derive any consistent benefits from this
approach. However, symptoms of poor voiding owing to
outflow obstruction might be caused by prostate enlarge­
ment in men, or a pelvic-organ prolapse in women. The
possible presence of one of these two conditions should
be assessed during initial clinical examination.
Long-term indwelling catheterization
For patients with a substantially increased post-void
residual volume who are unwilling or unable to con­
duct ISC, or who have incontinence that is refractory
to treatment, a long-term indwelling transurethral or
suprapubic catheter is often used to ensure that the
bladder empties and to provide urinary continence.
However, long-term indwelling catheter use “should be
avoided when possible” (REF. 35) because this might lead
to a range of complications including recurrent urinary
tract infections, catheter blockages, catheter bypass­
ing, urethral destruction, bladder stones and bladder
­cancer127–131. Despite these possible complications, how­
ever, long-term catheterization does not substantially
alter a patient’s quality of life132. A suprapubic catheter
is recommended over a transurethral catheter for long-
term use9,42; however, the potential for complications
should be discussed with the patient and alternatives
should be presented; this is a grade A recommendation
provided by the EAU35.
Management of DSD
Urethral sphincterotomy. The main objectives of the
treatment of DSD are to improve voiding function, to
decrease voiding pressures and to avoid the need for
indwelling catheters. However, the possibility of using
a condom catheter and the existence of efficient blad­
der contractions are a prerequisite. Moreover, long-
term follow‑up monitoring is absolutely necessary,
owing to the risk of reflex voiding, leading to a rise in
intravesical pressure, which could potentially damage
the upper urinary tract. Urethral sphincterotomy, a
procedure designed to weaken the contractions of the
urethral sphincter, can be conducted using one of sev­
eral different techniques, including laser and electrode
endoscopic sphincterotomy133, sphincteric stent prosthe­
sis133 and dilatation using a balloon. Regardless of the
technique used, sphincterotomy should only be focused
on the striated sphincter. The effectiveness of sphincter­
otomy has been demonstrated in a prospective study of
patients with DSD owing to spinal cord injury: 83.7%
of patients had a decrease in voiding pressure, subjective
autonomic dysreflexia was resolved in 93.2% of patients
and febrile urinary tract infections disappeared in 76.7%
of patients134.
BoNT‑A. A few published reports exist from studies
designed to investigate the outcomes of intraurethral
injections of BoNT‑A for the treatment of DSD. In a
multicentre, randomized double-blind study, investi­
gators evaluated the efficacy and safety of 100‑unit
injections of BoNT‑A into the striated sphincter as a
treatment of DSD in 86 patients with multiple scler­
osis135. The authors administered the treatment as a
single transperineal injection using striated sphincter
electro­myography: the coaxial needle was inserted on the
median line 2 cm above the anal margin in men, or in the
upper external or internal quarter, above the urethral
meatus in women, thus enabling the striated sphincter
to be localized135. The injection was delivered after first
having verified that the needle was not inserted into a
blood vessel. Compared with placebo, BoNT‑A injec­
tions significantly increased the voided volume (by 54%;
P = 0.02) and reduced both the premicturition and maxi­
mal detrusor pressures (by 29% and 21%, respectively;
both P = 0.02). By contrast, BoNT‑A injections had no
significant effect upon post-void residual v­ olumes and
both treatments were equally well tolerated135.
Following a randomized-controlled double-blind
study designed to compare the efficacy and tolerability
of transperineal injections of BoNT‑A versus those of
lidocaine, including three patients with multiple scler­
osis in a cohort of 13 patients, investigators reported
that post-void residual volume was significantly
decreased (by 141.4 ml 7 days after treatment; P <0.03);
DSD and patient satisfaction were both improved
in the BoNT‑A but not in the lidocaine group136. In
another report, investigators described similar results

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in a prospective nonrandomized study with a cohort
of 21 patients, eight of whom had multiple sclerosis137;
however, data from patients with multiple sclerosis
were not analysed separately in this study. Moreover, in
both studies136,137, contrary to the study by Gallien and
colleagues135, electro­myography was not used to locate
the striated sphincter. Results from studies with small
patient cohorts, which have a high risk of bias relative
to those with larger cohorts, have revealed evidence of
limited quality, suggesting that intraurethral BoNT‑A
injections given as a treatment of functional blad­
der outlet obstruction in adults with neurogenic bladder
dysfunction improve certain urodynamic param­eters
30  days after treatment; these parameters include
higher voided urine volumes and lower premaximal
and maximal detrusor pressures, as summarized in a
meta-analysis138. In conclusion, only limited evidence
is available to support the use of intraurethral BoNT‑A
injections in the treatment of DSD in patients with mul­
tiple sclerosis. Moreover, the need for reinjections is a
major drawback138.
Follow‑up monitoring
Patients with multiple sclerosis should have their symp­
toms reviewed regularly as both the type and severity
of LUT dysfunction can change with neurological pro­
gression9,20,40. Recommendations exist for long-term
urological follow‑up monitoring, taking into account
the presence of specific risk factors: duration of multi­
ple sclerosis >15 years, presence of an indwelling cath­
eter, ample uninhibited detrusor contractions, high
detrusor pressure or DSD9,20,40. For patients who are
risk-free according to these criteria, a systematic annual
evaluation is advocated, including use of a 3‑day bladder
diary and uroflowmetry with measurement of the post-
void residual volume. The International Francophone
Neurourological Expert Study Group20 recommends a
urodynamic investigation every 3 years, whereas the UK
consensus on the management of the bladder in multiple
sclerosis recommends urodynamic investigations only in
the event of second-line or intravesical treatment being
required, or when a patient is considered to be at risk of
damage to the upper urinary tract9.
For patients who are deemed to have a higher risk of
rapid worsening of LUT symptoms, the annual evalu­
ation should be more complete, and should include ultra­
sonography of the urinary tract, measurement of renal
creatinine clearance and a quality-of‑life assessment.
The urodynamic follow‑up should be systematic. The
specific choice of investigations should be determined
in ­discussions among an expert m­ ultidisciplinary team.
Conclusions
LUT symptoms are common in patients with multiple
sclerosis and can negatively affect patients’ quality of
life. During the early stages of LUT dysfunction, anti­
muscarinic medications and ISC are the first-line treat­
ments. Treatment pathways are now available that offer
guidance on selecting the most appropriate manage­
ment strategy. Patients should be assessed and m­ anaged
by health-care professionals with a suitable level of
experience, who can offer at least one of the number
of effective treatment options. Long-term moni­toring of
patients with multiple sclerosis is essential as the type
and severity of LUT dysfunction can change with
­neurological progression.

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Acknowledgements
V.P. acknowledges support from the European Urological
Scholarship Programme
Author contributions
All authors researched data for this article, and made a sig-
nificant contribution to discussions of content. V.P. wrote the
manuscript, and all authors reviewed and/or edited
the ­manuscript prior to submission.
Competing interest statement
E.C.K. has acted as a consultant of Allergan, Astellas,
Axonics, Coloplast, Medtronic and and, and has received
honoraria from Allergan, Astellas, Coloplast, Medtronic and
Pfizer. V.P. and J.P. declare no competing interests.
Review criteria
A literature research was performed using searches of the
Medline database with the following keywords alone or in
combination: “multiple sclerosis”, “neurogenic bladder”,
“prevalence”, “epidemiology”, “intermittent” catheterization”,
“antimuscarinics”, “desmopressin”, “botulinum toxin A”, “can-
nabinoids”, “tibial nerve stimulation”, “sacral neuromodula-
tion”, “augmentation cystoplasty”, “continent urinary
diversion”, “ileal conduit” and “sphincterotomy”. Relevant
articles that reported the prevalence of LUT symptoms
among patients with multiple sclerosis or the outcomes of the
management of LUT symptoms among patients with multiple
sclerosis specifically were identified. The studies were limited
to full-text articles that were published in English and in
French until the 1st of May 2015. Case reports were excluded.

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