M. Stöhrer, D. Castro-Diaz, E. Chartier-Kastler, G. Kramer,
A. Mattiasson, J.J. Wyndaele
Dementia (Alzheimer, Binswanger, Nasu, Pick) Guideline for timing of diagnosis and treatment Guidelines for urodynamics and uro-neurophysiology Guidelines for non-invasive conservative treatment Guidelines for minimal invasive treatment Denervation. deafferentation, neurostimulation, neuromodulation 1. AIM AND STATUS OF THESE GUIDELINES
The purpose of these clinical guidelines is to provide information on the incidence, definitions, diagnosis,therapy, and follow up observation of the condition of neurogenic lower urinary tract dysfunction (NLUTD), thatwill be useful for clinical practitioners. These guidelines reflect the current opinion of the experts in this specificpathology and thus represent a state of the art reference for all clinicians as of the date of its presentation tothe European Association of Urology.
The terminology used and the diagnostic procedures advised throughout these guidelines follow therecommendations for investigations on the lower urinary tract (LUT) as published by the InternationalContinence Society (ICS) (1-3).
Stöhrer M, Goepel M, Kondo A, Kramer G, Madersbacher H, Millard R, Rossier A, Wyndaele JJ. The standardization of terminology in neurogenic lower urinary tract dysfunction with suggestions fordiagnostic procedures, Neurourol Urodyn 1999; 18:139-158.
Abrams P, Cardozo L, Fall M, Griffiths D, Rosier P, Ulmsten U, van Kerrebroeck P, Victor A, Wein A. The standardisation of terminology of lower urinary tract function: Report from the Standardisation Sub-committee of the International Continence Society. Neurourol Urodyn 2002; 21: 167-178.
Schäfer W, Abrams P, Liao L, Mattiasson A, Pesce F, Spångberg A, Sterling AM, Zinner NR, vanKerrebroeck P. Good Urodynamic Practices: Uroflowmetry, Filling Cystometry, and Pressure-FlowStudies. Neurourol Urodyn 2002; 21: 261-274.
Risk factors and epidemiology
NLUTD may be caused by various diseases and events affecting the nervous systems controlling the LUT. Theresulting lower urinary tract dysfunction (LUTD) depends grossly on the location and the extent of theneurologic lesion (cf. 2.3.).
Overall figures on the prevalence of NLUTD in the general population are lacking, but data are available on theprevalence of the underlying conditions and the relative risk of those for the development of NLUTD.
Diabetes: This common metabolic disorder has a prevalence of about 2.5% in the American population, but thedisease may be subclinical for many years. No specific criteria exist for secondary neuropathy in this condition,but it is generally accepted that 50% of the patients will develop somatic neuropathy and 75-100% of thosewill develop NLUTD (1-2).
Alcohol abuse: This will eventually cause peripheral neuropathy, but its reported prevalence varies widely: 5-15% (3) to 64% (4). The NLUTD is probably more present in patients with liver cirrhosis and theparasympathetic system is attacked more than the sympathetic system (5). Less prevalent peripheral neuropathies:- Porphyria — bladder dilatation in up to 12% of patients (6).
- Sarcoidosis — NLUTD rare (7).
- Lumbosacral (8) zone and genital (9) herpes — NLUTD transient in most patients.
- Guillain Barré — Urinary symptoms in 30% of patients, regressive in most (10).
This may cause NLUTD (11) but no prevalence figures were found (12).
Abdominoperineal resection of rectum or uterus may cause lesions of the lower urinary tract innervation in 10-60% of patients (13,14). The extent of the resection is important: <8% after colostomy only, but 29% afterposterior resection (15). Radical prostectomy is a risk factor also (16).
Multiple sclerosis causes NLUTD in 50-90% of the patients (17-19). NLUTD is the presenting symptom in 2-12% of the patients (20).
Alzheimer, Binswanger, Nasu and Pick diseases frequently cause non-specific NLUTD (21-25).
Basal ganglia pathology (Parkinson, Huntington, Shy-Drager, etc.) Parkinson’s disease is accompanied by NLUTD in 37.9-70% (26). In the rare Shy-Drager syndrome almost allpatients have NLUTD (27).
This causes hemiplegia with remnant incontinence NLUTD in 20-50% of patients (28 - 30) with decreasingprevalence in the post-insult period (30).
These tumours can cause LUTD in 24% of the patients (31).
Spinal cord lesions can be traumatic, vascular, medical, or congenital. An incidence of 30-40 new cases permillion population is the accepted average for the USA. Most patients will develop NLUTD (32). For spina bifidaand other congenital nerve tube defects, the prevalence in the UK is 8-9 per 10,000 aged 10-69 years with thegreatest prevalence in the age group 25-29 years (33), and in the USA 1 per 1000 births (34). About 50% ofthese children will have detrusor sphincter dyssynergia (DSD) (35).
2.1.10 Disc diseaseThis is reported to cause NLUTD in 6-18% of the patients (36, 37).
Standardization of terminology
Several groups already presented guidelines for the care of patients with NLUTD for national or internationalurological community (38-41).These guidelines will evolve further as time goes by. They also contain definitionsof various important terms and procedures. The ICS NLUTD standardization report (39) is addressedspecifically at the standardization of terminology and urodynamic investigation in this patient group. Otherrelevant definitions are found in the general ICS standardization report (42).
The definitions from these references, partly adapted, and other definitions that are judged useful for the clinicalpractice in NLUTD, are listed in section 2.2.2. For specific definitions relating to the urodynamic investigationtechnique the reader is referred to the appropriate ICS report (39).
Acontractility, detrusor — see below under voiding phaseAcontractility, urethral sphincter — see below under storage phaseAutonomic dysreflexia — Increase of sympathetic reflex due to noxious stimuli with symptoms or signs of headache, hypertension, flushing face and perspiration Capacity — see below under storage phaseCatheterization, indwelling — Emptying of the bladder by a catheter that is introduced (semi-)permanently Catheterization, intermittent (IC) — Emptying of the bladder by a catheter that is removed after the procedure, mostly at regular intervals- Aseptic IC — The catheters remain sterile, the genitals are disinfected, and disinfecting lubricant is used- Clean IC — Disposable or cleansed re-usable catheters, genitals washed- Sterile IC — Complete sterile setting, including sterile gloves, forceps, gown and mask- Intermittent self-catheterization (ISC) — IC performed by the patient Compliance, detrusor — see below under storage phaseCondition — The presence of specific observations associated with characteristic symptoms or signs Diary, urinary — Record of times of micturitions and voided volumes, incontinence episodes, pad usage, and other relevant information- Frequency volume chart (FVC) — Times of micturitions and voided volumes only- Micturition time chart (MTC) — Times of micturitions only Filling rate, physiological — Below the predicted maximum: body weight [kg]/4 in ml/s (42, 43) Hesitancy — Difficulty in initiating micturition; delay in the onset of micturition after the individual is ready to Intermittency — Urine flow stops and starts on one or more occasions during voidingLeak point pressure (LPP) — see below under storage phaseLower motor neuron lesion (LMNL) — Lesion at or below the S1-S2 spinal cord level Neurogenic lower urinary tract dysfunction (NLUTD) — Lower urinary tract dysfunction secondary to confirmed Observation, specific — Observation made during specific diagnostic procedureOveractivity, bladder — see below under symptom syndromeOveractivity, detrusor — see below under storage phaseRehabilitation, LUT — Non-surgical non-pharmacological treatment for LUT dysfunctionSign — Observation by the physician including simple means (direct observation, bladder diary, pad weighing) Sphincter, urethral, non-relaxing — see below under voiding phaseSymptom — Subjective indicator of a disease or change in condition as perceived by the patient, carer, or partner that may lead to seek help from health care professionals Upper motor neuron lesion (UMNL) — Lesion above the S1-S2 spinal cord levelVoiding, balanced — In patients with NLUTD: voiding with physiologic detrusor pressure and low residual (<80 Voiding, triggered — Voiding initiated by manoeuvres to elicit reflex detrusor contraction by exteroceptive stimuliVolume, overactivity — see below under storage phase Maximum anaesthetic bladder capacity — Maximum bladder filling volume under deep general or spinalanaesthesia Increased daytime frequency — Self-explanatory; the normal frequency can be estimated at about 8times per day (44) Nocturia — Waking at night one or more times to void Urgency — The symptom of a sudden compelling desire to pass urine which is difficult to defer Urinary incontinence — Any involuntary leakage of urine. This can be specified:- Stress urinary incontinence — On effort or exertion, or on sneezing or coughing- Urge urinary incontinence — Accompanied by or immediately preceded by urgency- Mixed urinary incontinence — Associated with urgency and also exertion, effort, sneezing, or coughing- Continuous urinary incontinence Bladder sensation categorized as:- Normal — Symptom and history: Awareness of bladder filling and increasing sensation up to a strongdesire to void.
Urodynamics: First sensation of bladder filling, first desire to void, and strong desire to void at realistic bladder volumes.
- Increased — Symptom and history: An early and persistent desire to void.
Urodynamics: Any of the three urodynamic parameters mentioned under “normal” persistently at low bladder volume - Reduced — Symptom and history: Awareness of bladder filling but no definite desire to void.
Urodynamics: Diminished sensation throughout bladder filling - Absent — No sensation of bladder filling or desire to void- Non-specific — Perception of bladder filling as abdominal fullness, vegetative symptoms, or spasticity Definitions valid after urodynamic confirmation only• Cystometric capacity — Bladder volume at the end of the filling cystometry Maximum cystometric capacity — Bladder volume at strong desire to void High capacity bladder — Bladder volume at cystometric capacity far over the mean voided volume, estimated from the bladder diary, with no significant increase in detrusor pressure under non-anaesthetized condition Normal detrusor function — Little or no pressure increase during filling: no involuntary phasic Detrusor overactivity — Involuntary detrusor contractions during filling; spontaneous or provokedSubgroups:- Phasic detrusor overactivity — Characteristic phasic contraction- Terminal detrusor overactivity — A single contraction at cystometric capacity High pressure detrusor overactivity — Maximal detrusor pressure >40 cm H2O (39,45) Overactivity volume — Bladder volume at first occurrence of detrusor overactivity Detrusor overactivity incontinence — Self-explanatory Leak point pressure- Detrusor leak point pressure (DLPP) — Lowest value of detrusor pressure at which leakage is observed in the absence of abdominal strain or detrusor contraction - Abdominal leak point pressure — Lowest value of intentionally increased intravesical pressure that provokes leakage in the absence of a detrusor contraction Detrusor compliance — Relationship between change in bladder volume (∆V) and change in detrusor pressure (∆pdet): C=∆V/∆pdet [ml/cm H2O] Low detrusor compliance — C=∆V/∆pdet <20 ml/cm H2O (39) Break volume — Bladder volume after which a sudden significant decrease in detrusor compliance is Urethral sphincter acontractility — No evidence of sphincter contraction during filling, particularly at higher bladder volumes, or during abdominal pressure increase Intermittent stream (intermittency) — Stopping and starting of urine flow during micturition Hesitancy — Difficulty in initiating micturition Straining — Muscular effort to initiate, maintain, or improve urinary stream Terminal dribble — Prolonged final part of micturition when the flow has slowed to a trickle/dribble Definitions valid after urodynamic confirmation only• Normal detrusor function — Voluntarily initiated detrusor contraction that causes complete bladder Detrusor underactivity — Contraction of reduced strength and/or duration Acontractile detrusor — Absent contraction Non-relaxing urethral sphincter — Self-explanatory Detrusor sphincter dyssynergia (DSD) — Detrusor contraction concurrent with an involuntary contraction of the urethral and/or periurethral striated musculature Feeling of incomplete emptying (symptom only) Post micturition dribble - Involuntary leakage of urine shortly after finishing the micturition Pain, discomfort or pressure sensation in the lower urinary tract and genitalia that may be related to bladderfilling or voiding, may be felt after micturition, or be continuous Symptom syndrome - Combination of symptoms• Overactive bladder syndrome — Urgency with or without urge incontinence, usually with frequency andnocturia Synonyms: Urge syndrome, urgency-frequency syndromeThis syndrome is suggestive for LUTD Classification
The purpose of classification of NLUTD is to facilitate the understanding and management of NLUTD and toprovide a standardized terminology of these disease processes. The normal LUT function depends on neuralintegration at and between the peripheral, spinal cord, and central nervous systems. The gross type of NLUTDis dependent on the location and the extent of the lesion: suprapontine or pontine, suprasacral spinal cord, orsubsacral and peripheral (32,40).
The classification systems for NLUTD are based on either the neurologic substrate (type and location of the neurologic lesion), the neuro-urologic substrate (neurologic lesion and LUTD), the type of LUTD, or are strictlyfunctional. Many descriptive terms were derived from these classification systems, but they are standardized onlywithin any specific system and have little meaning outside the system and can sometimes be confusing.
A perfect classification system is not yet available. Neurologic classification systems, by nature, cannot describe the LUTD completely and vice versa. Individual variations exist in the NLUTD caused by a specificneurologic lesion. Thus for any particular patient the description of the NLUTD should be individualized.
Bors and Comarr’s (46) classic neuro-urologic classification system was deduced from clinical observations ofpatients with traumatic spinal cord injury. It specifies three elements: location of lesion, completeness of lesion,and co-ordination of LUT.
Hald and Bradley (47) reduced the number of categories in Bors and Comarr’s classification. The authors describe their system as a simple neurotopographic classification.
Burgdörfer completed Bors and Comarr’s system with information on the LUTD, broken down for detrusor, sphincter, and residual urine. This classification is published elsewhere (48).
Bradley (49) presented four control loops for the LUT. Loop I are the connections between the central nervoussystem and the pontine micturition center, loop II the intraspinal pathways between the detrusor to themicturition center (afferent) and the sacral spinal cord (efferent), loop III the sensory axons pathways from thedetrusor and the striated urethral sphincter to the sacral spinal cord, and loop IV describes the suprasacral andsegmental innervation of the periurethral striated muscles.
Lapides (50) classifies the clinical and urodynamic findings into five categories: sensory neurogenic bladder,motor paralytic bladder, autonomous neurogenic bladder, uninhibited neurogenic bladder, and reflexneurogenic bladder.
Krane and Siroky (51) present a descriptive classification of detrusor and sphincter co-ordination observed during urodynamic evaluation in patients with NLUTD, focussed on the functional interaction betweendetrusor and urethral sphincter.
Quesada et al. (52) suggested that a classification based on the functional aspects of the LUT might be morepracticable for clinical decision making.
Wein (53) provides a practical approach towards the diagnosis and therapy of LUTD by classifying against the storage and voiding functions of the LUT, and the activity of the detrusor and the urethra.
Fall et al. (54) proposed a more detailed classification of the overactive detrusor. This is included in the The ICS (42) separates the storage and voiding phases and describes the detrusor and urethral functions in each phase by specific designations (cf. 2.2.).
Madersbacher (40,55) presented a very simple classification that basically is focussed on the therapeutic consequences (fig. 2.1). It is based on the clinical concept that the important differentiation in thediagnosis exists between the situations of high and low detrusor pressure during the filling phase and urethralsphincter relaxation and non- relaxation or DSD during the voiding phase. A non-relaxed sphincter or DSD willcause high detrusor pressure during the voiding phase. This classification is the easiest one for general use inclinical diagnosis of NLUTD.
Urethral sphincter
Lesion: Spinal
Urethral sphincter
Figure 2.1. Madersbacher classification system (40) with typical neurogenic lesions The Madersbacher classification system (40) (fig. 2.1) is recommended for clinical practice.
Timing of diagnosis and treatment
Both in congenital and in acquired NLUTD, early diagnosis and treatment is essential as irreversible changesmay occur in particular in children with myelomeningocele (56-61), but also in patients with traumatic spinalcord injury (62-64), even if the related neuropathologic signs may be normal (65).
The fact must also be considered that LUTD by itself may be the presenting symptom for neurologic pathology(20,66).
Diagnosis and treatment in NLUTD should be performed as soon as possible.
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Before any functional investigation is planned, an extensive general and specific diagnosis should beperformed. Part of this diagnosis is specific for neurogenic pathology and its possible sequelae. The clinicalassessment of patients with NLUTD includes and extends that for other LUTD. The latter should consist of adetailed history, bladder diary and a physical examination. In urinary incontinence, leakage should bedemonstrated objectively.
These data are indispensable for reliable interpretation of the findings in diagnostic investigations performedsubsequently in NLUTD.
The general history should include relevant questions to neurological and congenital abnormalities, informationon the previous occurrence and frequency of urinary infections and on relevant surgery. Information must beobtained on medication with known or possible effects on the lower urinary tract (1-3). The general historyshould also include the assessment of menstrual, sexual and bowel function, and obstetric history (3).
Hereditary or familial risk factors should be recorded. Symptoms of any metabolic disorder or neurological disease that may induce neurogenic lower urinary tract dysfunction must be checked particularly.
Specific signs such as pain, infection, hematuria, fever, etc., may justify further particular diagnosis.
A list of items of particular importance is: Congenital anomalies with possible neurological impact Metabolic disorders with possible neurological impact Preceding therapy, including surgical interventions Lifestyle factors such as smoking, alcohol, or addictive drug use Urinary history: This consists of symptoms related to both the storage and the evacuation functions of thelower urinary tract. The onset and the nature of the NLUTD (acute or insidious) should be determined. Specificsymptoms and signs must be assessed in NLUTD and if appropriate be compared with the patients’ conditionbefore the neurogenic lower urinary tract dysfunction developed. The separate diagnostic fields items shouldbe diagnosed as detailed as possible (3).
• Mode and type of voiding (catheterization!) The urinary diary gives (semi-)objective information about the number of voidings, daytime and nighttimevoiding frequency, volumes voided, and incontinence and urge episodes.
Bowel history: Patients with NLUTD may suffer from a related neurogenic condition of the lower gastro-intestinal tract. The bowel history also must address symptoms related to the storage and the evacuationfunctions and specific symptoms and signs must be compared with the patients’ condition before theneurogenic dysfunction developed. Again, the diagnostic items should be detailed (3).
• Sexual history: The sexual function may also be impaired because of the neurogenic condition. The details ofthis history of course differ between men and women (3).
• Sensation in genital area and for sexual functions Neurologic history: This should concentrate on the following information.
Acquired or congenital neurologic condition Neurological symptoms (somatic and sensory), with onset, evolution, and performed therapy Spasticity or autonomic dysreflexia (lesion level above Th6) 3.2.3 GUIDELINES FOR HISTORY TAKING
An extensive general history is mandatory, concentrating on past and present symptoms and conditions for urinary, bowel, sexual, and neurologic functions, and on general conditions that might impair any of these.
Special attention should be paid to the possible existence of alarm signs, such as pain, infection, hematuria, fever, etc., that warrant further specific diagnosis.
Specific history should be taken for each of the four mentioned functions.
Physical examination
Attention should be paid to the patient’s physical and possible mental handicaps with respect to planneddiagnostic investigations. Impaired mobility, particularly in the hips, or extreme spasticity may lead to problemsin patient positioning in the urodynamics laboratory. Patients with very high neurological lesions may sufferfrom a significant drop in blood pressure when moved in a sitting or standing position. Subjective indications ofbladder filling sensations may be impossible in retarded patients.
Prostate palpation or observation of pelvic organ descensus is made.
General neurological examination: This investigates the motor and sensory functions of the body, the limbs andthe hand function. A suprapubic globe is searched for and an appreciation of the skin condition in the genitaland perineal regions is made.
Figure 3.1. Dermatomes of spinal cord levels L2-S4. Figure 3.2. Urogenital and other reflexes in lower spinal cord Specific neuro-urologic examination: This investigation is necessary in patients with NLUTD. It includes severaltests for sacral reflex activity and an evaluation of the sensation in the perineal area. Fig. 3.1 shows the differentdermatomes and fig. 3.2 the associated reflexes in this area.
Specified information should become available on:• Sensation S2-S5 on both sides of the body Volitional contraction of anal sphincter and pelvic floor A high correlation exists between the clinical neurologic findings and the NLUTD in some types of neuropathy,but less so in other types (4-9). The correspondence is low, for instance, in myelomeningocele patients (6) andin combined traumatic spinal cord lesions, but high in single-level traumatic spinal cord lesions (9).
Besides urinalysis and blood chemistry other tests are specifically indicated in patients with NLUTD. Theresults of these tests should be detailed (3).
• Free flowmetry with assessment of residual urine. Because of natural variations, multiple estimations (atleast 2-3) are necessary (3,10,11).
Quantification of urine loss by pad testing if appropriate 3.3.4 GUIDELINES FOR PHYSICAL EXAMINATION
Individual patient handicaps should be acknowledged in planning further investigations.
The neurological status should be described as completely as possible. Sensations and reflexes in the urogenital area must all be tested.
The anal sphincter and pelvic floor functions must be tested extensively.
Urinalysis, blood chemistry, imaging, free flowmetry and residual, and incontinence quantification should be performed.
Urodynamic investigation is the only method to objectify the (dys-)function of the LUT. This investigation is ofpivotal interest to describe the status of the LUT in patients with NLUTD.
In these patients, particularly when detrusor overactivity might be present, the invasive urodynamic investigation is even more provocative than in other patients. Any technical source of artefacts must becritically considered. The quality of the urodynamic recording and its interpretation must be ensured (12).
In patients at risk for autonomic dysreflexia, blood pressure assessment during the urodynamic study is In many patients with NLUTD, assessment of maximum anaesthetic bladder capacity may be useful.
The rectal ampulla should be empty of stool before the start of the investigation. Medication by drugs that influence the lower urinary tract function should be abandoned at least 48 hours before the investigation (iffeasible) or otherwise be taken into account for the interpretation of the data.
All urodynamic findings must be reported in detail and performed according to the ICS technicalrecommendations and standards (3,12,13).
Bladder diary: This semi-objective qualification of the LUT is a highly advisable diagnostic tool. For reliableinterpretation it should be recorded over at least 2-3 days (3,14). Possible pathologic findings: High voidingfrequency, very low or very high voided volumes, nocturnal voidings, urgency, incontinence.
Free uroflowmetry and assessment of residual urine: This gives a first impression of the voiding function. It ismandatory before any invasive urodynamics is planned. For reliable information it should be repeated at least2-3 times (3,10,11). Possible pathologic findings: Low flow rate, low voided volume, intermittent flow, hesitancy,residual urine.
Care must be taken in judging the results in patients who are not able to void in a normal position. Both the flow pattern and the flow rate may be modified by this inappropriate position and by any constructions todivert the flow.
Filling cystometry: The only method to quantify the filling function has limited significance as a solitaryprocedure. It is much more powerful if combined with bladder pressure measurement during micturition andeven more in video urodynamics. This investigation is necessary to document the status of the LUT functionduring the filling phase. The bladder should be empty at the start of filling. A physiological filling rate should beused with body-warm saline, as fast filling and room-temperature saline are provocative (3). Possiblepathologic findings: Detrusor overactivity, low detrusor compliance, abnormal bladder and other sensations,incontinence, incompetent or relaxing urethra. Detrusor leak point pressure: This specific investigation is important to estimate the risk for the upper urinarytract or for secondary bladder damage. When the DLPP is >40 cm H2O the upper tract is endangered (3,15).
The DLPP is a screening test only, because it gives no impression of the duration of the high pressure duringthe filling phase, which can be expected to have even more impact on the upper urinary tract (16). A high DLPPthus warrants further testing by video urodynamics to document the reflux also.
Pressure flow study: This measurement reflects the co-ordination between detrusor and urethra or pelvic floorduring the voiding phase. It is even more powerful in combination with filling cystometry and with videourodynamics. It is necessary to document the function of the lower urinary tract function during the voidingphase. Possible pathologic findings: Detrusor underactivity/acontractility, DSD, non-relaxing urethra, residualurine.
Most types of obstructions caused by NLUTD are due to DSD (17,18), non-relaxing urethra, or non- relaxing bladder neck (3,19,20). Pressure-flow analysis mostly assesses the amount of mechanical obstructioncaused by the urethra’s inherent mechanical and anatomical properties and has limited value in patients withneurogenic lower urinary tract dysfunction.
Electromyography: Registration of the activity of the external urethral sphincter, the peri-urethral striatedmusculature, the anal sphincter, or the striated pelvic floor muscles. The correct interpretation may be difficultdue to artefacts introduced by other equipment used. In the urodynamic setting useful as a gross indication ofthe patient’s ability to control the pelvic floor. Possible pathologic findings: Inadequate recruitment on specificstimuli (bladder filling, hyperreflexive contractions, onset of voiding, coughing, Valsalva, etc.).
More detailed analysis (motor unit potentials, single fibre EMG) only possible as part of a Urethral pressure measurement: This investigation has only a very limited place in NLUTD. There exists nobasic consensus on parameters indicating pathological findings (21).
Video urodynamics: This combination of filling cystometry and pressure flow study with imaging is the goldstandard for urodynamic investigation in NLUTD (3,22,23). Possible pathological findings: All as describedunder cystometry and pressure flow study, plus morphological pathology of the LUT and the upper urinarytract.
Ambulatory urodynamics: Functional investigation of the urinary tract utilizing predominantly natural filling ofthe urinary tract and reproducing normal subject activity (24).
This type of study should be considered when office urodynamics do not reproduce the patient’s symptoms and complaints. Possible pathologic findings: as under filling cystometry and pressure flow studyprovided the flow is measured also. It should be kept in mind that during this study the actual bladder volumeis unknown.
Provocative tests during urodynamics: The LUT function can be provoked by coughing, triggered voiding, oranal stretch.
Fast filling cystometry with cooled saline (the “ice water test”) is considered a discriminative test between UMNL and LMNL (25-30). Patients with UMNL will develop a detrusor contraction if the detrusormuscle is intact, patients with lower lesions will not. It gives false positive results in young children (27) andseems not fully discriminative in other patients (28,29) A positive bethanechol test (31) (detrusor contraction >25 cm H2O) was presumed to proof detrusor denervation hypersensitivity and the muscular integrity of an acontractile detrusor, but it turned out to giveequivocal results. Recently a variation of this method was reported with intravesical electromotiveadministration of the bethanechol (32). This test turned out to be both selective and predictive for successfuloral bethanechol treatment.
Specific uro-neurophysiologic tests These tests are advised as part of the neurological work-up of the patient. They comprise:• Electromyography (in a neurophysiological setting) of pelvic floor muscles, urethral sphincter and/oranal sphincter Nerve conduction studies of pudendal nerve Reflex latency measurements of bulbocavernosus and anal reflex arcs Evoked responses from clitoris or glans penis Sensory testing on bladder and urethraOther elective tests may be asked for specific conditions that became obvious during patient work-up Possible pathologic findings are dependent on the type of the test.
Urodynamic investigation is necessary to document the (dys-)function of the LUT.
The recording of a bladder diary is highly advisable.
Free uroflowmetry and assessment of residual urine is mandatory before invasive urodynamics is planned.
Video urodynamics is the gold standard for invasive urodynamics in patients with NLUTD. Should this not be available, then a filling cystometry continuing into a pressure flow study should be performed.
A physiological filling rate and body-warm saline must be used.
DLPP is an important investigation in patients with endangered upper tracts.
Specific uro-neurophysiological tests are elective procedures.
Typical manifestations of NLUTD
Typical findings in NLUTD are listed below.
Filling phase• Detrusor overactivity, spontaneous or provoked Non-relaxing bladder neckThese signs warrant further neurological evaluation, as LUTD may be the presenting symptom of REFERENCES
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The primary aims for treatment of NLUTD and their priorities are (1-5):1. Improvement of the patient’s quality of life Restoration of (parts of) the normal LUT functionFurther considerations are the patient’s disability, the cost effectiveness, the technical intricacy, and the Preservation of the upper tract function is of paramount importance (1-9). Renal failure was the main factor for mortality in the spinal cord injured patient surviving the trauma (6-9). This has lead to the golden rulein treatment of NLUTD: Assure that the detrusor pressure remains within safe limits during both the filling phaseand the voiding phase (1-5). This approach has indeed significantly reduced the mortality from urologicalcauses in this patient group (10).
The therapy of urinary incontinence is important for the social rehabilitation of the patient and thus contributes substantially to the quality of life, but is also pivotal in the prevention of urinary tract infection (UTI)(7-9). When no complete continence can be achieved, methods to attain a socially acceptable control ofincontinence can be applied.
Complex procedures that might enable a satisfactory restoration or replacement of the LUT function often may limit the patient so much that the quality of life is unacceptably impaired (1).
In patients with high detrusor pressure during the filling phase (detrusor overactivity, low detrusor compliance) or during the voiding phase (DSD, other causes of bladder outlet obstruction) the therapy is aimedprimarily at “the conversion of an active, aggressive high-pressure bladder into a passive low-pressurereservoir” despite the resulting residual urine (1).
Non-invasive conservative treatment
Incomplete bladder emptying is a serious risk factor for UTI, for developing high intravesical pressure duringthe filling phase, and for incontinence. Therefore, methods to improve the voiding process are practised inpatients with NLUTD.
Third party bladder expression (Credé): Regretfully, this method is still applied, foremost in infants and youngchildren with myelomeningocele, and sometimes in tetraplegics. The suprapubic downwards compression ofthe lower abdomen leads to an increase in the intravesical pressure, but also causes a compression of theurethra and thus a functional obstruction (11,12), that may reinforce an already existing high bladder outletresistance (13) and lead to inefficient emptying (12). Because of the high pressures that may be created duringthis procedure it is potentially hazardous for the urinary tract (14,15) and thus it is contra-indicated and its use should be discouraged unless urodynamics shows intravesical pressure to stay within the safe range (1,14-16).
Voiding by abdominal straining (Valsalva): The considerations mentioned under Credé above also hold for theValsalva manoeuvre (1,12,14,16). As most patients are unable to scale the pressure they exert on the bladderduring Valsalva, the risk of exceeding the safe range is present.
For both methods of emptying long-term complications are hardly avoidable (12,14) and the already weak pelvic floor function may be further impaired, thus exacerbating the existing incontinence (16).
Triggered reflex voiding: Stimulation of the sacral or lumbar dermatomes in patients with UMNL can elicit reflexcontraction of the detrusor (1,16). Morbidity occurs more often during the first decades of treatment (17-21).
This method may be used in patients in whom it is urodynamically safe (1, 16).
Lower urinary tract rehabilitation Behavioural modification: Prompted voiding, timed voiding (bladder training), and modification of the lifepattern in patients with NLUTD are methods to improve the incontinence situation (2,22-25).
Pelvic floor muscle exercises: This training also aims at improving the incontinence. It has proven effective instress incontinence treatment and for patients with NLUTD it is mainly used in multiple sclerosis (26).
Pelvic floor electrostimulation: To improve the effect of pelvic floor muscle exercises, or to learn the patient howto contract the pelvic floor, or to improve the patient compliance with the exercises, this may be supported byelectrostimulation (16,27-29).
Biofeedback: This method can be used for supporting the voiding pattern modification (30-33).
A medical therapy for NLUTD is not available. Most drugs used only resolve part of the problems, or areadjunct to other measures (34-40).
Detrusor overactivity: This can be treated effectively by anticholinergic substances (23,24,34-54). Theirpotentiality extends from a small reduction of detrusor overactivity to complete relaxation, depending ontherapeutic regimen and individual tolerance. Increased drug tolerance during the basically life-long necessarytherapy and the occurrence of adverse effects are topics of concern in patients with NLUTD in particular.
Generally, these patients need a higher dose then other patients with overactive detrusor (41-46) and this maylead to an early discontinuation of the therapy because of adverse events (24,41,44-46).
Oxybutynin (36-41,46-49), trospium chloride (39,41,45,50,51), and propiverine (39,43,45,52), are established medical treatments. These drugs have diverse tolerance profiles and thus another anticholinergicmay be prescribed if the patient experiences adverse effects on one. Tolteridine has been studied only inchildren with NLUTD (42). Various other drugs have been tested (16,36,38,47,48,53).
Additional treatment with desmopressin might improve the efficacy of the treatment (54-58).
Detrusor underactivity: No success had been attained with drugs for improving detrusor contractility (16,59-63),but Riedl et al. (64) have successfully applied oral bethanechol treatment in NLUTD patients with detrusoracontractility who responded positive to the electromotive intravesical bethanechol testing.
Decreasing bladder outlet resistance: Alpha-blockers have been used partly successfully for decreasing thebladder outlet resistance (16,65-70).
Increasing bladder outlet resistance: Several drugs show efficacy in the treatment of selected cases of milderstress incontinence, but there are hardly any publications in patients with NLUTD (16,71,72).
A strong contraction of the urethral sphincter and/or pelvic floor, but also anal dilatation, manipulation of thegenital region, and physical activity reflexly inhibit the micturition (16,73). Whereas the first mechanism isaffected by activation of efferent fibres, the latter ones are produced by activation of afferents (16). Electricalstimulation of the pudendal nerve afferents produces a strong inhibition of the micturition reflex and of thedetrusor contraction (74). This stimulation then might support the restoration of the balance between excitatoryand inhibitory inputs at the spinal or supraspinal level (16,75,76) and it might imply that patients withincomplete lesions will benefit (16,76,77), but patients with complete lesions will not (78).
Stimulation of the tibial nerve afferents has not been applied in patients with NLUTD.
When incontinence cannot be resolved by any of the methods described above, the detrusor pressures are inthe safe region, eventually after sphincterotomy or bladder neck incision, and furthergoing non-invasive therapyis not feasible, social continence may be achieved by collecting the urine during the incontinence (1,16).
Condom catheters with urine collection devices are a practical method for men. Otherwise incontinence padsmay offer a reliable solution. In both cases the infection risk must be closely observed (16). Because of the riskof developing high intravesical pressure, the penile clamp is absolutely contra-indicated.
The first aim of any therapy is the protection of the upper urinary tract.
The mainstay of the treatment for overactive detrusor is anticholinergic drug therapy.
Rehabilitation and neuromodulation may be effective in selected cases.
A condom catheter or pads may reduce the incontinence to a socially acceptable situation.
Any method of assisted bladder emptying should be used with the greatest caution.
Minimal invasive treatment
Intermittent self- or third party catheterization (79,80) is the gold standard for the management of NLUTD (1,16).
It is effective in patients with detrusor underactivity or acontractility (1) and in patients with detrusor overactivityif the overactivity can be successfully suppressed for instance by anticholinergic treatment (1,16,34-40).
The catheters used are made from a diversity of materials and the discussions on re-useable or disposable catheters, use of lubricants, aseptic or clean technique are still going on (1,16,81). Sterile IC, asoriginally proposed by Guttmann and Frankel (79) significantly reduces the risk of UTI and/or bacteriuria(1,16,82,83), related to clean IC introduced by Lapides et al. (80), but the cost issue may be a limiting factor(16,83). Aseptic IC is believed to be in a mid position (1,84,85). Insufficient patient education and the inherentgreater risk of UTI in patients with NLUTD are contributing factors (16,85-91).The average frequency ofcatheterizations per day is 4-6 times. Less frequent catheterization results in higher catheterization volumesand a higher risk of UTI (1,85-90). More frequent catheterization increases the risk of cross infections and othercomplications (1,85-90).
Other complications may include lower fertility in men and compromizing the urethra (16,81), although the direct relation with the IC is discussed controversely. It appears however that the prevalence of thesecomplications increases with the period that the IC has been practised and with the (temporary) use ofindwelling catheterization (89).
The prevalence of complications can be limited by adequate patient education, use of non-traumatizing techniques, and adequate precautions to prevent cross-infections (16,91).
Indwelling transurethral catheterization and, although to a lesser extent, suprapubic cystostomy are significant and early risk factors for UTI and other complications (16,21,92-102). Silicone catheters arepreferred because they are less susceptible for encrustation and because of the high incidence of latex allergyin the NLUTD population.
Intermittent catheterization is the standard treatment for patients who are unable to empty the bladder.
Patients should be well instructed on the technique and risks of IC.
The frequency of IC is 4-6 times per day.
The bladder volume must remain below 400 ml and the post-IC residual low.
Indwelling transurethral and suprapubic catheterization should be used only exceptionally, under close control and the catheter should be changed frequently. Silicone catheters are preferred and should be changed every 2-4 weeks, (coated) latex catheters need to be changed every 1-2 weeks.
For the reduction of the detrusor overactivity, anticholinergics can be applied also intravesically (103-112). Thismight reduce the adverse effects because it metabolizes differently (110) and a greater amount is sequesteredin the bladder, even more so with electromotive administration (111,112).
The vanilloids capsaicin and resiniferatoxin desensitize the C-fibers and thereby reduce the detrusor overactivity for a period of a few months until the sensation of these fibers has restored (15,113-121). Thedosage is 1-2 mMol capsaicin in 100 ml 30% alcohol or 10-100 nMol resiniferatoxin in 100 ml 10% alcohol for30 minutes. Resiniferatoxin has an about 1000-fold potency compared to capsaicin, with less pain during theinstillation, and was effective in patients refractory to capsaicin (121).
Botulinum toxin causes a long-lasting but reversible chemical denervation that lasts for about 9 months (122-126). The toxin injections are mapped over the detrusor in a dosage that depends on the preparationused. Generalized muscular weakness may be a seldom adverse effect (126).
Intravesical electrostimulation (127) enhances the sensation for bladder filling and urge to void and may restorethe volitional control of the detrusor (16,128,129). Daily stimulation sessions of 90 minutes with 10 mA pulses of2 ms duration at a frequency of 20 Hz (129,130) are used for at least one week (130). It appears that patientswith peripheral lesions are the best candidates, that the detrusor muscle must be intact, and that at least someafferent connection between the detrusor and the brain must still be present (16,129,130). Also, the positioningof the stimulating electrodes and the bladder filling apparently are important parameters (131). With theseprecautions, the results in the literature are still not unequivocal: both positive (128,130,132-136) and negative(137,138) results are reported.
Bladder neck and urethral procedures Reduction of the bladder outlet resistance is often necessary to protect the upper urinary tract. This can be achievednot only by surgical interventions (bladder neck or sphincter incision or urethral stent) but also by chemicaldenervation of the sphincter. Stress incontinence may result and can be managed by external devices (4.2.5).
Botulinum toxin sphincter injection: Detrusor sphincter dyssynergia can be treated effectively by injection withbotulinum toxin in a dosage that depends on the preparation used. The dyssynergia is abolished for a fewmonths, necessitating repeat injections. The efficacy of this treatment is high and few adverse effects havebeen recorded (139-145). Balloon dilatation: Although favourable immediate results were reported (146), no further reports were foundsince 1994. Sphincterotomy: By staged incision, the bladder outlet resistance can be reduced without completely losing theclosure function of the urethra (1,14,147). The laser technique appears to be advantageous (1,148,149).
Sphincterotomy also needs to be repeated at regular intervals in a substantial proportion of patients (150), butis efficient and without severe adverse effects (1,14,146-151). As secondary narrowing of the bladder neck mayoccur, combined bladder neck incision might be considered (1,152,153).
Bladder neck incision: This is indicated only for secondary changes at the bladder neck (fibrosis)(1,14,147,153). When the detrusor is hypertrophied and causes thickening of the bladder neck, this proceduremakes no sense (1).
Stents: The implantation of urethral stents causes the continence to be dependent on the adequate closure ofthe bladder neck only (1,5). Although the results are comparable with sphincterotomy and the stentingprocedure has a shorter surgery time and reduced hospital stay (154), the costs (1) and possible complicationsor re-interventions (154-160) are limiting factors in its use.
Increasing the bladder outlet resistance: This can improve the continence condition. Despite early positiveresults with urethral bulking agents, a relative early loss of continence is reported in patients with NLUTD(5,21,161-166).
Urethral inserts: Urethral plugs or valves for management of (female) stress incontinence have not been appliedin patients with NLUTD. The experience with active pumping urethral prosthesis for treatment of theunderactive or acontractile detrusor was disappointing (167).
Guidelines for catheterization are listed separately under 4.3.2.
Botulinum toxin injections in the detrusor are the most promising intravesical drug application for reduction of detrusor overactivity.
Intravesical electrostimulation may be of value in specific patients.
(Laser) sphincterotomy is the standard treatment for DSD or other increased bladder outlet resistance at the sphincteric area. Botulinum sphincter injections will be the first choice in patients ineligible for interventional surgery. Bladder neck incision is effective in a fibrotic bladder neck. Urethral stents still have too many complications.
Urethral bulking agents have disappointing long term effect.
Surgical treatment
Urethral and bladder neck procedures Increasing the bladder outlet resistance has the inherent risk of causing high intravesical pressure during thefilling and even more during the voiding phase. These procedures to treat the sphincteric incontinence aresuitable only when the detrusor activity is or can be controlled, when no significant reflux is present. Moreoverthey require a good condition of the urethra and bladder neck and will mostly lead to perform intermittentcatheterization after the procedure (5,168).
Urethral sling: Various materials have been used for this procedure with enduring positive results (5,168-182).
The procedure is established in women; for men the artificial sphincter is obviously the first choice (5).
Artificial urinary sphincter: This device stood the test of time in patients with NLUTD (5). It was introduced byLight and Scott (183) for this patient group and the need for revisions (184,185) have decreased significantlywith the new generations of devices (175,186-192).
Functional sphincter augmentation: By transposing the gracilis muscle to the bladder neck (193) or to theproximal urethra (194,195) the possibility exists to create a functional autologous sphincter by electricalstimulation (193,195). This would open the possibility to restore the control over the urethral closure.
Bladder neck and urethra reconstruction: The classical Young-Dees-Leadbetter (196) procedure forreconstruction of the bladder neck in children with bladder exstrophy and the Kropp urethral lengthening (197)improved by Salle (198) are established methods to restore continence provided that intermittentcatheterization is practised and/or bladder augmentation is performed (175,184,197-211).
Detrusor myectomy (auto-augmentation) The idea to enlarge a shrunken bladder by removal of lateral detrusor tissue to free the entrapped ureter in anon-functional fibrotic detrusor was put forward by Couvelaire (212). Since its clinical introduction byCartwright and Snow (213) in children and by Stöhrer (214,215) in adults, this procedure to reduce detrusoroveractivity or to improve low detrusor compliance has gained popularity because of its acceptable long-termresults, its low surgical burden, its low rate of long term adverse effects, its positive effect on the patient’squality of life, and because it does not preclude further interventions (1,5,45,213-244).
The procedure is performed extraperitoneally under general anesthesia and consists of the dissection of about 20% of the detrusor tissue around the umbilicus, leaving the mucosa intact (1,213-215). A diverticulumwill develop, but this may take 1-2 years in adults (1,213-215). The laparoscopic procedure(219,220,222,228,233), the covering of the mucosa at the detrusor defect (transperitoneal!)(217,229,232,234,238), supporting the bladder (213,216,238), or simple incision of the detrusor muscle(detrusor myotomy) (221,240-244) are proposed variations of the procedure but offer no essential advantages. Denervation, deafferentation, neurostimulation, neuromodulation Various procedures that were estimated to destroy the peripheral detrusor innervation have been abandonedbecause of poor long term results and severe complications (5). These procedures include bladder distension,cystolysis, transvaginal denervation (Ingelman-Sundberg procedure) and subtrigonal phenol injections. Sacral rhizotomy, also known as sacral deafferentation (SDAF), has achieved some success in reducing detrusor overactivity (21,245-254), but it is used nowadays mostly as an adjuvant to sacral anterior rootstimulation (255-269). Alternatives for the rhizotomy are sought in this treatment combination (270-273).
Sacral anterior root stimulation (SARS) is aimed at producing a detrusor contraction. The technique was developed by Brindley (274) and is applicable only in complete lesions above the implant location because ofits stimulation amplitude over the pain threshold. The urethral sphincter efferents are also stimulated, but as thestriated muscle relaxes faster than the smooth muscle of the detrusor, a so-called “post-stimulus voiding” willoccur. This approach has been successful in highly selected patients (255-269). By changing the stimulationparameters this method can also induce defecation or erection.
The sacral nerve stimulation or sacral neuromodulation is based on the research by Schmidt and Tanagho (275). This technique stimulates the afferents and thereby probably restores the correct balancebetween excitatory and inhibitory impulses from and to the pelvic organs at a sacral and supra-sacral level,thus reducing the detrusor overactivity (75,276). It is used either as a temporary procedure using foramenelectrodes with an external stimulator, with the expectation of perseverance of the changes after treatment, oras a chronic procedure with an implanted stimulator. In the latter case a test procedure, the percutaneousnerve evaluation (PNE), with an external stimulator is performed before the implant to judge the patient’sresponse. This procedure also has considerable success in selected patients (230,277-283).
On the basis of the successful application of these systems, future developments towards a device that may be more integrated in the body are under research (284,285).
Bladder covering by striated muscle When the bladder is covered by a (part of) striated muscle that can be stimulated electrically, or ideally couldbe contracted volitionally, an acontractile bladder could be restored to perform a voiding function. The rectusabdominis (286) and the latissimus dorsi (287) have been used successfully in patients with NLUTD.
Bladder augmentation or substitution Replacing or expanding the bladder by intestine or other passive expandable coverage will reduce the detrusorcompliance and at least reduce the pressure effect of the detrusor overactivity. The inherent complicationsassociated with these procedures include recurrent infection, stone building, perforation or diverticula, possiblemalignant changes, and for intestine metabolic abnormality, mucus production and impaired bowel function(5,288-290). As the NLUTD patient population’s age when the surgery is performed is generally much lowerthan the patients with bladder malignancy who are elected for this surgery, the possible very long termcomplications must be appraised in particular. Thus the procedures should be used with caution in NLUTDpatients, but may become necessary if all less invasive methods of treatment have failed.
Bladder augmentation, by procedures such as the clam cystoplasty, is a valid option to decrease detrusor pressure and increase bladder capacity whenever more conservative approaches have failed. Anumber of different techniques have been published. The results of the various procedures are very good andcomparable (45,226,230-232,235-237,289-292). Bladder substitution to create a low pressure reservoir may beindicated in patients with severely thick and fibrotic bladder wall. Scaffolds, probably of tissue-engineeredmaterial for bladder augmentation or substitution or alternative techniques are promising future options(236,293-300).
When no other therapy has been successful urinary diversion must be considered for the protection of theupper tract and for the patient’s quality of life (5,301).
Continent diversion: This should be the first choice for diversion. In patients for whom indwellingcatheterization or suprapubic catheterization is the only feasible treatment option the change to a continentstoma may be a better prospect (5). Some patients with limited dexterity prefer a stoma above using theurethra for catheterization (5). The continent stoma is created following various techniques. All of them howeverdo show frequent complications, including leakage or stenosis (5,302). The short term continence rates areover 80% and good protection of the upper urinary tract is achieved (5,18,301-317). For cosmetic reasons, theumbilicus is often used for the stoma site, but this may have a higher risk of stenosis (305,308,314).
Incontinent diversion: If catheterization is impossible, incontinent diversion with a urine collecting device isindicated. Fortunately, nowadays, this indication is seldom because many appropriate alternatives can beoffered (5). Ultimately it could be considered in patients who are wheelchair bound or bed-ridden withintractable and untreatable incontinence, in devastated lower urinary tracts, when the upper urinary tract isseverely compromised, and in patients who refuse other therapy (5). An ileal segment is used for the deviationin most cases (5,318-323). The rather poor long term results and the expected complications warrant apermanent follow-up (5).
Undiversion: Long-standing diversions may be successfully undiverted or an incontinent diversion changed toa continent one with the emergence of new and better techniques for control of the detrusor pressure and theincontinence (5). Also, in young patients the body image may play a role (311). The patient must be carefullycounselled and must comply meticulously with the instructions (5). Successful undiversion than can beperformed (324-326).
1.1.1. Detrusor myectomy is an acceptable option for the treatment of overactive bladder when more conservative approaches have failed. It is limited invasive and has minimal morbidity.
1.1.2. Sacral rhizotomy with SARS in complete lesions and sacral neuromodulation in incomplete lesions are effective treatments in selected patients.
1.1.3. Bladder augmentation is an acceptable option to decrease detrusor pressure whenever less invasive procedures have failed. For the treatment of a severely thick or fibrotic bladder wall a bladder substitution might be considered.
1.2.1. SARS with rhizotomy and sacral neuromodulation are effective in selected patients.
1.2.2. Restoration of a functional bladder by covering with striated muscle is still experimental.
Overactive (DSD) - refer to guidelines for minimal invasive treatment (4.3.6) 2.2.1. The placement of a urethral sling is an established procedure.
2.2.2. The artificial urinary sphincter is very effective.
2.2.3. Transposition of the gracilis muscle is still experimental.
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For general laboratory and research use onlyQuantification of Human Herpes Virus 3 (Varicella-Zoster) genomes. Introduction to Human Herpes Virus 3 (Varicella-Zoster)Herpes zoster, colloquially known as shingles, is the reactivation (from the general area of thespinal cord) of varicella zoster virus (VZV, primary infection of which leads to chickenpox),one of the Herpesviridae group, leadin

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