Committee I

Committee II

Neuro-Urology

Prof. M. Sherif Mourad (Chair), Professor of Urology, Ain Shams University, Cairo

Dr. Wally I. Mahfouzz, Assistant Professor of Urology, Alexandria University

Dr. Kareem M. Taha, Lecturer of Urology, Zagazig University

Dr. Ahmed S. Ghonaimy, Assistant Lecturer of Urology, Menoufia University

Contents
II.1 List of Abbreviations
  • ANLUTD - Adult Neurogenic Lower Urinary Tract Dysfunction
  • AUDS - Ambulatory Urodynamics
  • AUA - American Urological Association
  • AUS - Artificial urinary sphincter
  • AD - Autonomic Dysreflexia
  • BPO - Benign Prostatic Obstruction
  • BP - Blood Pressure
  • BM - Bowel Management
  • BCR - Bulbocavernosus Reflex
  • CVS - Cerebrovascular Stroke
  • DLPP - Detrusor Leak Point Pressure
  • DSD - Detrusor Sphincter Dyssynergia
  • DUA - Detrusor Underactivity
  • DM - Diabetes Mellitus
  • DRE - Digital Rectal Examination
  • DMSA - Dimercaptosuccinic acid
  • ED - Erectile Dysfunction
  • EAU - European Association of Urology
  • FDA - Food and Drug Administration
  • FVC-BD - Frequency-Volume Chart Bladder Diary
  • GFR - Glomerular Filtration Rate
  • IPD - Idiopathic Parkinson’s Disease
  • ICI - International Consultation on Incontinence
  • ICS - International Continence Society
  • IPSS - International Prostate Symptom Score
  • LUT - Lower Urinary Tract
  • LUTS - Lower Urinary Tract Symptoms
  • MAG3 - Mercaptoacetyltriglicine
  • MESA - Microsurgical Epididymal Sperm Aspiration
  • MS - Multiple Sclerosis
  • MSA - Multiple System Atrophy
  • NB - Neurogenic Bladder
  • NBSS - Neurogenic Bladder Symptom Score
  • NLUTD - Neurogenic Lower Urinary Tract Disease
  • OAB - Overactive Bladder
  • PS - Parkinsonian Syndrome
  • PDE5Is - Phosphodiesterase Type 5 Inhibitors
  • PMC - Pontine Micturition Center
  • RCTs - Randomized Controlled Trials
  • SB - Spina Bifida
  • SCI - Spinal Cord Injury
  • TESE - Testicular Sperm Extraction
  • TENS - Transcutaneous Electrical Nerve Stimulation
  • TURP - Transurethral Resection Of The Prostate
  • UUT - Upper Urinary Tract
  • UPP - Urethral Pressure Profile
  • EMG - Urethral Sphincter Electromyography
  • UI - Urinary Incontinence
  • UTI - Urinary Tract Infection
  • VUR - Vesico-Ureteral Reflux
  • VUDS - Video-Urodynamics
  • VCUG - Voiding Cystourethrogram

II.2 Abstract.

II.2.1 Objectives.
The Urologic Egyptian Guidelines on Neuro-Urology aim to help and guide clinical practitioners to have knowledge of the incidence, standard definitions, diagnosis, therapy, and follow-up of NLUTD. This document integrates recent international guidelines with local experts’ opinions based on Egyptian healthcare and socioeconomic circumstances.

II.2.2 Methods.
Databases searched included Medline, Cochrane Libraries, EAU guidelines, ICS recommendations, 6th ICI recommendations, AUA and NICE guidelines, from January 2018 and September 2020.

Review of several meta analyses, leading institutional protocols and relevant Egyptian publications were taken into consideration. All statements were graded according to strength of recommendation. Each statement was given a strength rating (strong or weak).

II.2.3 Results.
These guidelines represent the best clinical evidence-based medicine available. These guidelines are not solely based upon the level of evidence of the international publications but also include expertise of the treating doctor and expectations of every patient.

II.2.4 Conclusions.
Early diagnosis of NLUTD is fundamental before deciding any plan of management. Accordingly, tailoring and individualizing the plan of management follows, which ensures the best practice of clinical care offered to these patients. The role of these guidelines is to offer expert advice on how to manage these patients.

II.3 Introduction.
The lower urinary tract (LUT) is under the regulation of the nervous system, which acts at many levels; the cerebral cortex, pontine micturition center (PMC) and lastly the sacral spinal center. These centers relay their signals to the peripheral nerves in the pelvis to reach the end organs (bladder and sphincter). The two main functions of the LUT are the storage and voiding of urine.

Neurological diseases are vast, and they may have adverse consequences on the urinary system. The extent and site of the neurological insult will determine the type of neurogenic lower urinary tract disease (NLUTD).

The worst complication of NLUTD is upper urinary tract (UUT) deterioration, which is the leading cause of mortality in this subset of patients. UUT deterioration is more with spinal cord injury (SCI) and spina bifida (SB) patients. It is very crucial to stratify NLUTD patients into high and low risk groups, in order to individualize the plan of management and prevent further deterioration and complications. Therefore, early diagnosis, treatment and follow-up of these patients is crucial.

II.3.1 Aims and Objectives.
The Urologic Egyptian Guidelines on Neuro-Urology aim to help and guide clinical practitioners to have knowledge of the incidence, standard definitions, diagnosis, therapy, and follow-up of NLUTD. This document integrates recent international guidelines with local experts’ opinions based on Egyptian healthcare and socioeconomic circumstances. It also reflects the opinions of experts in Neuro-Urology and represent state-of-the art references for all clinicians, as of the publication date.

The terminology used and the diagnostic procedures mentioned in this chapter follow the recommendations published by the International Continence Society (ICS).

These guidelines represent the best clinical evidence-based medicine available. These guidelines are not solely based upon the level of evidence of the international publications but also include expertise of the treating doctor and expectations of every patient. Every patient is a unique case by himself and the treating urologist should take an advice from the guidelines which may not be, in some situations, perfectly satisfying all the findings in a particular patient. Therefore, the guidelines should not be a final legal document but should help during investigation of a particular case.

II.3.2 Methodology.
The committee members were selected according to their expertise in the field of Neuro-urology. The committee members are all functional urologists from four different Egyptian Universities; Ain Shams, Alexandria, Zagazig and Menoufia Universities. All members have no conflict of interest.

Databases searched included Medline, Cochrane Libraries, European Association of Urology (EAU) guidelines, ICS recommendations, 6th International consultation on incontinence (ICI) recommendations, American Urological Association (AUA) and NICE guidelines, in the period from January 2018 and September 2020.

Review of several meta analyses, leading institutional protocols and relevant Egyptian publications were also taken into consideration. All statements were graded according to strength of recommendation. Each statement was given a strength rating (strong or weak).

II.4 Neurogenic bladder (NB)
II.4.1 Definition.
The term “neurogenic bladder” describes lower urinary tract dysfunction that has occurred likely as a result of a neurological injury or disease (1) which may be in the central, autonomic or peripheral nervous systems.

The International Continence Society (ICS) defines “Adult neurogenic lower urinary tract dysfunction" (ANLUTD) as abnormal or difficult function of the bladder, urethra (and/ or prostate in men) in mature individuals in the context of clinically confirmed relevant neurologic disorder (2).

II.4.2 Causes, epidemiology and prevalence of Neuro-Urological Disorders.
These disorders are classified according to Panicker et al. into: (3).

II.4.2.1 Suprapontine and pontine lesions.
These patients suffer from storage symptoms, with neurogenic detrusor overactivity (NDO) due to loss of the inhibitory action of the pontine micturition center (PMC).

II.4.2.1.1 Cerebrovascular stroke (CVS):

57-83% of neuro-urological symptoms appear after 1 month of CVS and 71-80% show spontaneous recovery at 6 months (4). Persistence of urinary incontinence (UI) correlates with poor prognosis (5).

II.4.2.1.2 Dementias:

A group of diseases that occur in 6.4% of adults over 65 years old including Alzheimer’s disease (60–80%), Vascular disease (10–20%) and other diseases (10%) such as Lewy bodies, normal pressure hydrocephalus, fronto-temporal degeneration and Creutzfeldt-Jakob disease. Urinary incontinence incidence is 3 times more frequent than in non-demented patients (6, 7).

II.4.2.1.3 Parkinsonian syndrome (PS):

It includes idiopathic Parkinson’s disease (IPD) (75-80%), Non-IPD (18%) such as "Multiple system atrophy (MSA), progressive supranuclear palsy and secondary Parkinson’s (2%)". PS represents second most prevalent neurodegenerative disease after Alzheimer’s disease. Most of these patients present with nocturia (78%) and overactive bladder (OAB) (36–93%) (8). Patients with lower urinary tract symptoms (LUTS) at presentation fair worse disease progression (9).

II.4.2.1.4 MSA:

It is the most frequent non-IPD PS. Autonomic failure (postural hypotension and urinary dysfunction) is essential for diagnosis (10). OAB symptoms manifest early and detrusor underactivity (DUA) appears with disease progression (11). Impaired detrusor contractility with postvoid residual (PVR) > 150 mL is the urodynamic finding distinguishing MSA from IPD (12-14).

II.4.2.1.5 Traumatic brain injury:

Usually presents with 44% storage dysfunction, 38% voiding dysfunction and 60% have urodynamic abnormalities (15).

II.4.2.1.6 Cerebral palsy:

Its incidence is 3.1-3.6/1,000 in children aged 8 yrs. Urinary incontinence is the most frequent symptom (20–94%) and NDO is present in 9–97% (16).

II.4.2.1.7 Normal pressure hydrocephalus:

Presence of the classic triad of gait, cognitive disturbance and UI, which affects 98-100% of patients (17).

II.4.2.2 Spinal (Infrapontine and suprasacral) lesions.
These patients present with both storage (NDO) and voiding symptoms {NDO and detrusor sphincter dyssynergia (DSD)}

II.4.2.2.1 Spinal cord injury (SCI):

Prevalence of traumatic SCI in developed countries ranges from 280 to 906/million. Early after injury, it manifests with depressed spinal reflexes below the level of injury and areflexic acontractile bladder (spinal shock) which lasts for a variable amount of time (from days to months). Nearly 95% of cases present with NDO and DSD but DUA occurs in about 33% according to site of injury (18, 19).

II.4.2.2.2 Spina bifida (SB):

Lumbar and lumbosacral forms are the most common. Bladder function is impaired in up to 96% and half of patients are incontinent (20).

II.4.2.2.3 Multiple sclerosis (MS):

Incidence is about 9.6/100,000/year and is more common in women. 10% of patients present with LUTS at disease onset, while 75% of patients will develop LUTS after 10 years. NDO occurs in 86%, DSD in 35% and DUA in about 25% of cases (21, 22).

II.4.2.2.4 Other causes: (spinal cord tumors, infections/para-infectious "transverse myelitis" and lesion following spinal anesthesia or spine surgery):

They present with storage and voiding symptoms, depending on lesion’s level (23).

II.4.2.3 Sacral and infrasacral lesions.
These patients present with voiding symptoms (detrusor acontractility)

II.4.2.3.1 Lumbar spine, degenerative diseases, disk prolapse, spinal canal stenosis and spinal tumours:

Disc prolapse is the most common lesion and is more common in females above 45 years. DUA is the most common finding (up to 83%) (18, 24).

II.4.2.3.2 Iatrogenic pelvic nerve lesions:

(as in cases of radical pelvic surgeries). Voiding symptoms are more common than storage symptoms (25).

II.4.2.3.3 Peripheral neuropathy:

It is caused by diabetes mellitus (DM) (most common), alcohol abuse, genital herpes and Guillain Barré syndrome. They present initially with OAB symptoms then DUA at later phase (such as diabetic cystopathy) (26).

II.5 Classifications.
The current classification systems serve as a frame work, since it is not possible to map all lesions and its consequences in every patient in a single classification (27). Most of these systems are of no use today such as: Lapides (1970), Bors and Comarr (1971), Wein functional classification (1981), Hald and Bradley classification (1982), Krane and Siroky urodynamic classification (1984) and ICS system by Abrams et. al 2002 (28).

More recently, three classification systems were described according to pattern of clinical urological and urodynamic manifestations and aimed to predict site of neurologic affection. These systems are:

II.5.1 Madersbacher system:
It presented eight main types of lower urinary tract dysfunction (27)

II.5.2 The system described by Panicker et al.:
It is a very simple system that can be used for every day practice (3)

II.5.3 SALE classification
(Stratify by Anatomic Location and Etiology) that has seven categories based on the anatomic level of neurologic dysfunction. It also includes bowel dysfunction aspects and should describe a patient suffering from neurogenic bladder and simultaneously inform the most appropriate treatment, follow-up regime and long-term prognosis (29).

II.6 Diagnosis.
II.6.1 History.
It includes onset, course and duration of various neurological, urinary, sexual and bowel manifestations.

Urologic history should include the following:
  • LUT assessment using validated questionnaires like International prostate symptom score (IPSS), the Qualiveen questionnaire for MS patients (30, 31), the Quality life index-SCI (32), the Neurogenic Bladder Symptom Score (NBSS) (33, 34) and Incontinence-Quality of Life (I-QoL) questionnaire (35). It is worth mentioning that no evidence was found for which validated questionnaires are the most appropriate for use (36).
  • Exclusion of warning symptoms such as fever, loin pain, hematuria and dysuria which may be suggestive of urinary tract infection (UTI) (37), because patients with SCI usually find it difficult to report UTI-related symptoms accurately (38, 39).
  • A three-day frequency-volume chart bladder diary (FVC-BD) is important in diagnosis (40); however, there is inadequate evidence or recommendations on its utility in neuro-urologic patients. It is recommended to be used before urodynamics (UDS) as it may help to ensure and evaluate whether the cystometry, especially cystometric capacity, is representative of the patient's typical situation (41).

Sexual history is crucial in NB patients. Men may have neurogenic erectile dysfunction (ED) and/or ejaculatory problems. Women may complain of dyspareunia, vaginal dryness, vaginal hyperaesthesia, arousal and/or orgasmic dysfunction (42).

Bowel history includes defecation desire, pattern and frequency along with rectal sensation and presence or absence of fecal incontinence or constipation. The QoL scoring tool related to Bowel Management (QoL-BM) can be used to assess bowel dysfunction in MS and SCI patients (43).

Present history of neurological and non-neurological diseases is important. Family history of neurological and urological diseases should be taken to exclude congenital, genetic and familial diseases. Moreover, history of pelvic or urological operations along with nature and time of brain or spinal trauma, if present, should not be missed in assessment. Lastly, special lifestyle habits such as smoking, alcohol intake and recreational drugs use should be evaluated (38, 39, 42, 44).

Autonomic dysreflexia (AD) is a sudden and exaggerated autonomic response to various noxious stimuli in patients with SCI or spinal dysfunction at or above level of T6. It is crucial to take into consideration the noxious stimuli which may elicit AD such as bladder or bowel distension, catheterization, cystoscopic manipulation, sexual intercourse, infected toe and pressure sores. AD manifests with an increase in systolic blood pressure more than 20 mmHg from baseline and can lead to fatal complications if not discovered and treated promptly (45, 46).

II.6.2 Examination.
Vitals of the patient especially blood pressure are essential because patients with NB may suffer from either persistent or postural hypotension and/or episodes of uncontrolled hypertension (47). General neurological examination especially for gait, motor power, sensations, mental health and spasticity should be done in the primary evaluation of these patients (48).

Complete neuro-urological status should be described. The patient should lie in lithotomy position to have access to the lower sacral segments S3, S4 and S5. Pain (pin-prick), touch and pressure sensations and reflexes in the urogenital area must be tested (Figure 3) (3).

Most commonly tested reflexes in the lower spinal cord are the cremasteric reflex (L1-L2), the knee reflex (L2-L4), the ankle reflex (L5-S2), bulbocavernosus reflex (BCR) (S2-S4) and anal reflex (S4-S5) (49). BCR and anal reflex are by far the most important reflexes (50, 51). In suprasacral SCI, a negative BCR indicates a defect in the sacral reflex arc either on the afferent or efferent sides of the pudendal nerve or in the spinal cord segments L5-S5. In contrast to other reflex activity, BCR returns within a few hours after SCI. Anal reflex usually parallels the findings of the BCR (52).

Digital rectal examination (DRE) is a crucial step in examination. It should focus on the configuration of the anus (normal or patulous), the anal sphincter tone (normal, spastic, flaccid), rectal prolapse, stool impaction (if present) and prostate examination in males. Preserved ability for voluntary contraction and relaxation of the external anal sphincter is a good prognostic sign to achieve continence with bladder retraining programs. Finally, vaginal examination in females with assessment of pelvic organ prolapse should not be missed (49).

II.6.3 Investigations.
Urine analysis is indicated in the presence of symptoms or signs of UTI such as fever, urinary incontinence, leakage around catheter, spasticity, malaise, lethargy, cloudy urine, malodorous urine, back pain, bladder pain, dysuria and AD (54). Moreover, it can be used to assess response to antibiotic treatment (55).

Urine culture is done in case of significant pyuria. A cut off of 103 cfu/ml is the minimum level of detection. Moreover, a cutoff 105 cfu/ml with the absence of symptoms is compatible with a UTI. It is important to recognize that this cutoff is only a guideline recommendation and any colony count in a catheterized patient may potentially represent significant bacteriuria and should be interpreted along with the patients’ clinical picture (40, 56).

Cystoscopy, either flexible or rigid, may be indicated in cases of recurrent UTI, abnormal imaging or recurrent catheter blockage which may be due to either bladder calculi or significant proteinaceous debris (57).

Patients with NB have a higher risk of developing renal failure (58). Cystatin-C based glomerular filtration rate (GFR) is more accurate than serum creatinine estimated GFR because body composition is usually disturbed with decreased muscle mass (59-61).

Ultrasound is fundamental in NB patients in the initial assessment and during follow up for diagnosis of UUT dilatation and scarring, PVR and morphological abnormalities of the LUT (e.g. diverticulae, increased bladder wall thickness, presence of intravesical prostatic protrusion in men) as well (62, 63).

PVR measurement using a catheter or what is called ‘‘in–out catheterization’’ can be used, but it is more irritating to the patient and carries increased UTI risk (64).

Voiding cystourethrogram (VCUG) is recommended in certain neuro-urological patients to assess the bladder capacity, detect vesico-ureteral reflux (VUR) if present and estimate PVR. Dimercaptosuccinic acid (DMSA) or mercaptoacetyltriglicine (MAG3) renal scan can be used for renal functions’ assessment in patients with risk factors of upper urinary tract (UUT) deterioration (65).

Uroflowmetry should be used in primary assessment of LUTS, whenever feasible, before any invasive UDS in patients who can void (66). It should be repeated at least two to three times, and patients should void volumes greater than 150 ml for proper interpretation of results (3, 67). It gives information about flow rate, flow pattern, flow time and voided volume.

UDS is the gold standard tool to evaluate LUT function in NB patients, especially when there is evidence or history of SCI (3, 68). Liquid‐filled catheters and external transducers with the reference level of the upper edge of the symphysis pubis are recommended by the ICS (41, 69). Moreover, the rectal ampulla should be empty of stool before the start of the investigation (70).

Continuous careful observation and assessment of collected signals along with in detail reporting of all findings according to the ICS technical recommendations and standards should be ensured. Moreover, FVC-BD, uroflowmetry and PVR results are recommended prior to invasive UDS. Also, patients should be actively engaged in the test (53, 66).

The fluid type and temperature, filling method and rate, catheter sizes, pressure recording technique, and patient position should all be patient tailored (41). In NB patients, body-warm saline using 6 Fr. double lumen urodynamic urethral or suprapubic catheter with filling rate starting at 10 ml/min is recommended. If there is no rise in the Pdet, this can be increased to 20 ml/min. However, if Pdet begins to rise, then filling should be stopped for 5-10 min until the pressure has settled, and then restarted at 10 ml/min (71). ICS also recommends that all UDS tests are performed in the patient's preferred or most usual position: comfortably seated and/ or standing, if physically possible (41). However, many NB patients will not be able to stand or even sit, so these patients have to lie down throughout filling and voiding. This is likely to give appropriate information (37).

In patients at risk of AD, it is advisable to measure blood pressure (BP) during test because catheterization and bladder filling may be a noxious stimulus to the bladder (72, 73). Prophylactic antibiotics reduce the risk of bacteriuria, but not of UTI after UDS (74). Thus, prophylactic antibiotics are not recommended before UDS testing (75). However, urinalysis for screening for infection or hematuria should be ordered before the test (76).

Filling cystometry has limited role as a solitary procedure. It is much more effective if combined with voiding phase or with video-urodynamics (VUDS). The bladder should be empty at the start of filling (37).

High Pdet during UDS is a risk factor for UUT deterioration (77, 78). Cut‐off values of Pdet are controversial (79, 80). It usually ranges from 40-75 cmH2O in most studies (65). Detrusor leak point pressure (DLPP) has low sensitivity regarding prediction of UUT deterioration (79, 81).

McGuire et al. found that cut‐off value of Pdet in patients with low bladder compliance secondary to myelomenigocele (MMC) is 40 cmH2O. There is some evidence that a bladder capacity < 200 mL and detrusor pressures over 75 cmH2O are independent risk factors for UUT damage in patients with SCI (65).

Urethral pressure profile (UPP) has a very limited role in neuro-urological disorders. There is no consensus on parameters indicating pathological findings in NB patients (82).

VUDS is the gold standard test for diagnosis of NLUTD. However, the physiological nature of VUDS is often questioned because of the use of radiological contrast (which has a different density than urine) and being instilled at a lower temperature. Furthermore, the bladder is retrogradely filled, often at a rate higher than physiological filling rates. The patient is placed in an artificial environment, which may also affect lower urinary tract dynamics (83).

Ambulatory urodynamics (AUDS) may theoretically be a more physiological test to evaluate LUT function as the bladder is filled through normal diuresis and it can be performed in the patient’s own environment. Moreover, it can be conducted for a longer period of time allowing the patient to perform normal activities. However, the procedure is time-consuming, technically challenging and not widely available, making it more prone to artefacts (83).

Urethral sphincter electromyography (EMG) has a role in diagnosis of DSD in NLUTD but needs more studies to be popularized. The most common used electrodes are surface perineal electrodes (ICS standard), needle electrodes, vaginal or anal electrodes (41).

Table II:1 Recommendations for investigations of NB

Recommendations

Strength rating
1. Take extensive general history focusing on past and present symptoms, with special emphasis on four main domains: urinary, sexual, bowel and neurological functions Strong
2. Quality of life assessment should be completed with validated QoL questionnaires for neuro-urological patients Strong
3. Drug, family, past and present history of neurologic and non-neurologic diseases along with history of external and iatrogenic trauma should be properly taken from patients with NLUTD Strong
4.Special attention should be paid to warning signs such as fever, hematuria, dysuria, leaking around catheter and autonomic dysreflexia, which could alter/change diagnosis and thus affect the current management Strong
5. Perineal and genital examination should be performed, including motor and sensory assessment beside specific lumbosacral reflexes Strong
6. The anal sphincter activity and pelvic floor muscles should be tested Strong
7. Urine analysis should be performed in the initial evaluation of NLUTD. It has a role in exclusion of UTI in NB patients. It also can be used for following up after antibiotic treatment Strong
8. Assessment of renal functions is essential in diagnosis and follow-up. GFR can be best measured by Cystatin-C based GFR Strong
9. Renal ultrasound should be done in all NB patients to assess UUT functions in primary assessment of NLUTD Strong
10. Bladder ultrasound with PVR measurement is mandatory in the primary evaluation of NLUTD patients Strong
11. VCUG is recommended in certain neuro-urological patients to assess the bladder capacity, detect VUR if present and estimate PVR Weak
12. Perform uroflowmetry in NLUTD patients who can void Strong
13. Perform a urodynamic investigation to detect and specify LUTD, use same session repeat measurement Strong
14. Body-warm saline using 6 Fr. double lumen urodynamic urethral catheter with filling rate starting at 10 ml/min is recommended. If there is no rise in the Pdet, this can be increased to 20 ml/min Strong
15. Prophylactic antibiotics reduce the risk of bacteriuria, but not of UTI after UDS. It is not recommended before UDS testing Strong
16. Use VUDS in neuro-urological patients. if not, pressure-flow study should be used instead with VCUG when indicated Strong
17. EMG, with surface perineal electrodes, could be used if DSD is suspected in NB patients Weak
II.7 Treatment of NLUTD.
The main goals of management for NLUTD are satisfaction and avoidance of adverse outcomes which includes (84, 85):
  • Protecting upper urinary tract from sustained high filling and voiding pressures (i.e., >40 cmH2O).
  • Achieving regular bladder emptying, avoiding stasis and bladder over distension and minimizing PVR to less than 100mls (ideally <50mls).
  • Preventing and treating complications such as UTIs, stones, strictures and AD
  • Achievement (or maintenance) of urinary continence (Social goal).
  • Restoration of LUT function (Adequate storage and emptying at low intravesical pressure).
  • Improvement of the patient’s QoL.

Other factors should be considered when choosing therapy such as: disease prognosis (progressive or malignant), patient’s disability, patient’s compliance with treatments, desire to remain catheter free, desire to avoid surgery, sexual activity and possible complications (86).

Treatment should always begin with the simplest, most reversible form(s) of therapy, and then proceed to the complex one (86). The main goal in the management plan in patients with high Pdet during the filling phase (DO, low bladder compliance) is conversion of an overactive, high-pressure bladder into a low-pressure reservoir despite the increased PVR. Reduction of Pdet contributes to urinary continence, and consequently to social rehabilitation and QoL. It is also pivotal in preventing UTIs. However, it should be noted that complete continence cannot always be obtained.

Some specific situations require particular attention in NLUTD (87):

  • AD: Various triggers of episodes of AD are recognized, including iatrogenic urological procedures. Routine blood pressure monitoring during investigation or invasive therapy is therefore appropriate.
  • Allergy to latex needs appropriate preventive and therapeutic arrangements to be in place in case of anaphylactic reaction.

Lines of treatment are divided into the following:
  • Non-invasive treatment (conservative treatment)
  • Minimally invasive
  • Surgical treatment

II.7.1 Non-invasive treatment (Conservative treatment).
II.7.1.1 Assisted bladder emptying (Credé manoeuvre, Valsalva manoeuvre and triggered reflex voiding).
In males with tetraplegia and insufficient hand dexterity to perform CIC, drainage by reflex voiding with triggering manoeuvres such as suprapubic tapping, stroking inner thigh and use of an external urinary collection device is possible.

These methods could be used in cases of incomplete bladder emptying, but they carry dangerous risk factors for UTI, high intravesical pressure and incontinence (53, 88). Such manoeuvres result in an increase in Pdet which is deleterious to the upper tract, therefore they could be recommended only for patients whose situation has proven to be urodynamically safe and stable, with absent or surgically reduced outlet resistance (85).

II.7.1.2 Containments.
External appliances that can be used for urine collection during incontinence include pads, condom catheters and penile clamps. Condom catheters with urine collection devices are practical in men (85). The penile clamp is absolutely contraindicated in case of NDO or low bladder compliance because of the risk of developing high intravesical pressure and pressure sores/necrosis in cases of altered/absent sensations.

II.7.1.3 Pelvic floor muscle training.
It is an option to be considered for people with NLUTD due to MS or other neurological conditions where the potential to voluntarily contract the pelvic floor is preserved. A variety of techniques that might improve the outcomes of pelvic floor muscle training have been described; these include electrical stimulation of the pelvic floor and biofeedback system (89).

II.7.1.4 Bladder rehabilitation.
Aims to re-establish bladder function in neuro-urological patients. Electrical stimulation aims at stimulation of the pudendal nerve afferents, thus inhibiting the micturition reflex and detrusor contraction (90). Tibial nerve stimulation and transcutaneous electrical nerve stimulation (TENS) might be effective and safe for treating NLUTD, but more well-designed randomized controlled trials are required to reach definitive conclusions (91-93).

II.7.1.5 Drug treatment.
To protect urinary tract and improve long-term outcomes, especially in patients with a suprasacral SCI or MS, a combination of different therapies (e.g. CIC and anti-muscarinic drugs) is advised (94-97).

II.7.1.5.1 Anti-muscarinic drugs.

Are the first-line for treating NDO, increasing bladder capacity and reducing NDO incontinence episodes, by the inhibition of parasympathetic pathways (85, 98-104). Higher doses or a combination of anti-muscarinic agents may be an option to maximize outcomes in neurological patients (1, 99, 100, 105-107), but may result in higher incidence of adverse events.

Anti-muscarinic agents used are: Oxybutynin (85, 99), trospium chloride (103), tolterodine (108) and propiverine (103). They are well-established, effective and well tolerated treatments even in long-term use (102, 103, 109, 110). Darifenacin (111, 112) and solifenacin (113) have been evaluated in NDO secondary to SCI, MS and PD (103, 111, 113), with results similar to other anti-muscarinic drugs. All these drugs are grade A recommendation.

Side effects include dry mouth, blurred vision, cognitive effects, dry eyes and constipation (114). Monitoring PVR in people who are not using intermittent or indwelling catheterization after starting anti-muscarinic treatment is essential (89).

II.7.1.5.2 Beta-3-adrenergic receptor agonists (Mirabegron).

Its role in neuro-urological patients is still unclear. In MS and SCI patients, with very short follow up, mirabegron has not demonstrated any significant effect on urodynamic parameters (detrusor pressure or cystometric capacity) despite the reported improvement in LUTS (115, 116). A standard dosage of 50 mg has been found effective without affecting the cognitive function in patients with PD (117). Combination therapy of mirabegron and desmopressin in MS patients has shown promising results (118).

II.7.1.5.3 Phosphodiesterase type 5 inhibitors.

Male MS patients using daily tadalafil of 5mg to treat neurogenic ED (119) reported an improvement in their OAB symptoms.

II.7.1.5.4 Para-sympathomimetics (Pyridostigmine and bethanecol chloride).

Cholinergic drugs, have been considered to enhance detrusor contractility and promote bladder emptying (120). However, their use in NLUTD hasn’t been proven beneficial, and their use in NLUTD should not be offered.

II.7.1.5.5 Alpha-blockers.

They seem to be effective for decreasing bladder outlet resistance, PVR and AD (121-123) e.g. tamsulosin, naftopidil and silodosin. However, 6th International consultation on incontinence (ICI) (2016) suggested off -label use of α blockers in patients with DSD.

II.7.2 Minimally invasive treatment.
II.7.2.1 Catheterization.
Intermittent catheterization is the standard treatment for patients who cannot empty their bladders (85). Whether sterile or clean IC, it is not established yet if the strategy used would affect the incidence of UTI, other complications or not (124).

Factors responsible for contamination are inadequate patient education and the inherently high risk of UTI in neuro-urological patients (85, 125-129). The average catheterization times is four to six times per day and the catheter size most often used is between 12-16 Fr. Bladder volume should not exceed 400-500 mL at catheterization time.

Indwelling transurethral catheterization and suprapubic cystostomy are associated with wide range of complications as well as an enhanced risk for UTI (85, 130-135), therefore both procedures should be avoided, when possible.

Female patients with tetraplegia, due to greater difficulty with CIC and lack of a satisfactory external collecting device, generally use either a suprapubic or an indwelling urethral catheter due to difficulty in performing CIC. In addition, in males with tetraplegia, where there are concerns about long-term complications that may be associated with high intravesical pressures from unbalanced reflex voiding, suprapubic catheters are being recommended (136).

Foley catheters should not be used because of the high incidence of latex allergy in the neuro-urological patient population, therefore silicone catheters are preferred as they are less susceptible to encrustations (137).

II.7.2.2 Intravesical instillation.
Anti-muscarinics can also be installed intravesically to reduce NDO if the oral route cannot be tolerated (138-141). A significant reduction in adverse events was observed for intravesical administration of oxybutynine compared to oral administration (142).

II.7.2.3 Botulinum toxin injections in the bladder.
Botulinum toxin A causes reversible chemical denervation lasting for about nine months (143, 144). It has been proven effective in patients with neuro-urological disorders due to MS, SCI and PD in multiple randomized controlled trials (RCTs) and meta-analyses (145-147).

Neuro-urological patients with an indwelling catheter and concomitant bladder pain and/or catheter bypass leakage could benefit from botulinum toxin injections. The recommended dose is 200-300 IU injected in the detrusor muscle, in 30 sites in the bladder, with exclusion of the trigone, for theoretical prevention of VUR.

It is a valid food and drug administration (FDA-approved) option for patients with spinal cord diseases (SCI and MS) (89). In patients with maximal filling detrusor pressure of > 40 cmH2O, it is necessary to perform UDS to monitor bladder pressure after its injection (148). Repeated injections are possible even after initial low response rates without loss of efficacy (143, 149-152). The clinical efficacy of botulinum toxin A injection in patients with low morbidity after failure of augmentation enterocystoplasty has been shown (153).

The most frequent side effects are UTIs, haematuria and urinary retention that may necessitate (154) CIC especially in MS patients. However, a lower dose of botulinum toxin A (100 U) may reduce the rate of CIC in those patients (155).

II.7.2.4 Bladder neck and urethral procedures.
II.7.2.4.1 Procedures to reduce of the bladder outlet resistance.

They aim at protection of the UUT. This can be achieved by chemical denervation of the sphincter using Botulinum Toxin A (100 IU injected in four spots 3, 6,9,12 o’clock in the external sphincter) in cases of DSD (repeat injection is needed), or by surgical interventions (bladder neck or sphincter incision) which is indicated only for secondary changes (fibrosis) at the bladder neck. Sphincterotomy is irreversible and should be limited to men who are able to wear a condom catheter. The incision is at the twelve o’clock with cold knife or neodymium: YAG laser, and it needs to be repeated at regular intervals (156, 157).

Prosthetic sphincterotomy using a urethral endoprosthesis (or stent) is an alternative but is associated with significant complications. Men who wish to have children should be warned of the risk of ejaculatory duct obstruction (87).

II.7.2.4.2 Procedures to increase bladder outlet resistance.

These procedures are reserved for those with sphincteric UI to improve the continence status. Despite early positive results with urethral bulking agents, a relative early loss of continence is reported in patients with neuro-urological disorders (85, 158, 159).

II.7.3 Surgical treatment.
UDS should be offered before performing surgical treatments for NLUTD (89).

II.7.3.1 Bladder neck and urethral procedures.
These procedures can be divided into those that increase outlet resistance for neuro urological patients with sphincteric UI and those procedures that decrease outlet resistance for patients with outlet obstruction.

II.7.3.1.1 Procedures to increase outlet resistance.

There is high risk of increased intravesical pressure, so it is suitable only when the detrusor activity can be controlled and when no significant reflux is present. A simultaneous bladder augmentation and CIC may be needed (85).

II.7.3.1.1.1 Urethral sling.

The procedure is well established in women who can catheterise themselves (85, 160-163). The pubovaginal sling is considered the procedure of choice in this subgroup of patients, but recent reports suggest that both the transobturator (TOT) and the retropubic (TVT) approaches may also be considered but with a higher incidence of de novo urgency (164, 165). In men, both autologous and synthetic slings could be used (166-170).

II.7.3.1.1.2 Artificial urinary sphincter (AUS).

AUS insertion is a viable option, with acceptable long-term outcomes, but with higher complication and re-operation rates in neuro-urological patients; therefore, patients must be informed regarding the success rates as well as the complications that may occur following the procedure (171, 172). It is mainly reserved for males, however, could be used in female patients, but the cuff has to be inserted around the bladder neck.

II.7.3.1.1.3 Functional sphincter augmentation.

It entails transposing the gracilis muscle to the bladder neck (173) or proximal urethra (174), with the possible creation of a functional autologous sphincter by electrical stimulation (173-175).

II.7.3.1.1.4 Bladder neck and urethra reconstruction.

The classical Young-Dees-Leadbetter procedure (176) for bladder neck reconstruction is an option to restore continence, provided that CIC is practiced and/or bladder augmentation is performed (85, 177).

II.7.3.1.2 Procedures to decrease anatomic outlet resistance.

II.7.3.1.2.1 Transurethral resection of the prostate (TURP).

Benign prostatic obstruction (BPO) is a common cause for bladder outflow obstruction in middle age and elderly men, and is often a contributory factor for NLUTD in PD. It was widely believed for several years that men with PD should not undergo prostate surgery because of the high risk of incontinence (178). There is some evidence to support TURP in patients with PD. In a study on 23 patients with PD, TURP was successful in up to 70 %. The risk of de novo urinary incontinence after surgery was reported as minimal (179).

II.7.3.1.2.2 Bladder neck incision/ resection.

It is done between the 3 or 9 o’clock position or full circle, and is indicated in those with high PVR and when a prominent obstruction of the sclerotic fibrotic ring in the bladder neck is identified during cystoscopy (180).

II.7.3.2 Bladder covering by striated muscle.
Bladder contractility can be restored again by covering acontractile bladder with striated muscle that can be stimulated electrically or can be contracted voluntarily. Latissimus dorsi (181) and rectus abdominis (182) have been used successfully in patients with neuro-urological symptoms (183, 184).

II.7.3.3 Bladder augmentation.
Replacing or expanding the bladder by intestine improves bladder compliance and reduces NDO (185, 186). It should be considered for:
  • People with non-progressive neurological disorders
  • Those with complications of impaired bladder storage (hydronephrosis, refractory NDO, hypo compliance or incontinence)
  • Only after thorough clinical and urodynamic assessment and discussion with the patient and/or their family members and care givers about treatments to improve bladder storage (89).

Cautious use of such procedure is needed because of long-term complications that include bladder perforation (1.9%), mucus production (12.5%), metabolic abnormalities (3.35%), bowel dysfunction (15%), and urolithiasis (10%) (187). So, life-long follow-up should be offered to these patients.

Augmenting a bladder usually impairs its intrinsic ability to empty to completion, and CIC is usually needed (89). Patients performing CIC with augmentation cystoplasty had better urinary function and satisfaction with their urinary symptoms compared to patients performing CIC with or without botulinum toxin treatment (188).

Auto-augmentation (detrusor myectomy): This has been described with the adjunct of overlaying omentum or of a demucosalised intestinal patch in order to support the exposed bladder mucosa. The advantages include low surgical burden, low rate of long-term adverse effects, better patient QoL, and it does not interfere with further interventions (84, 85, 189-192). However, it showed sub-optimal results in the long-term follow-up.

II.7.3.4 Urinary diversion.
Must be considered for the protection of the UUT when no other therapy is successful (85).

Continent diversion: It should be the first choice for urinary diversion for those with limited dexterity. Umbilicus is often used for the stoma site (193-197). It is an effective treatment option in neuro-urological patients unable to perform CIC through the urethra.

Incontinent diversion: It is the last resort for patients with neurogenic bladder using ileal segment. It is considered in the event of a motor handicap with intractable incontinence and cannot catheterise themselves, in patients with LUT destruction, when the UUT is severely compromised, and in patients who refuse other therapies (85).

II.8 Management of UTIs in neuro-urological patients.
Patients with NLUTD are at increased risk of UTI as a result of a variety of factors which include incomplete bladder emptying, high storage and voiding bladder pressures, VUR and the use of catheters (198).

The goal of reducing both the frequency and severity of UTIs can be achieved in some patients by general measures such as increasing fluid intake and attention to hygiene in relation to urinary tract management. Investigations may demonstrate treatable causes for repeated UTIs such as the presence of urinary tract stones or incomplete bladder emptying (89).

Asymptomatic bacteriuria in patients with neuro-urological disorders should not be treated as it results in significantly more resistant bacterial strains without improving the outcome (199). There is no consensus in the literature about the duration of treatment of symptomatic UTI as it depends on the severity of the UTI and the involvement of kidneys and the prostate. Generally, a five to seven-day course of antibiotic treatment is advised, which can be extended up to fourteen days according to the extent of the infection (199). The choice of antibiotic therapy should be based on culture and sensitivity.

Recurrent UTI in patients with neuro-urological disorders may indicate suboptimal management of the underlying functional problem, e.g. high bladder pressure during storage and voiding, incomplete voiding or bladder stones.

In a meta-analysis, the use of hydrophilic catheters was associated with a lower rate of UTI (54). Bladder irrigation has not been proven effective (200). Low-dose, long-term, antibiotic prophylaxis can reduce UTI frequency, but increases bacterial resistance and is therefore not recommended (200).

There is currently no preventive measure for recurrent UTI in patients with neuro-urological disorders that can be recommended without limitations. Prophylaxis in patients with neuro-urological disorders is important to pursue, but since there are no data favoring one approach over another, prophylaxis is essentially a trial and error approach.

II.9 Management of sexual dysfunction and infertility in patients with NLUTD.
II.9.1 Erectile dysfunction.
II.9.1.1 Phosphodiesterase type 5 inhibitors (PDE5Is).
They are recommended as first-line treatment in neurogenic ED (201, 202). In SCI patients, all currently available PDE5Is (tadalafil, vardenafil and sildenafil) improved retrograde ejaculation and improved erectile function and satisfaction on IIEF-15.

Long-term therapy for ED is necessary in most neuro-urological patients and due to this, some have a low compliance rate or stop therapy because of side effects (203), most commonly headache and flushing (202). It may induce relevant hypotension in patients with quadriplegia/high-level paraplegia and MSA (203). Many patients with SCI use on-demand nitrates for the treatment of AD, so they must be counselled that PDE5Is are contraindicated when using nitrate medication.

II.9.1.2 Mechanical devices.
Mechanical devices (vacuum tumescence devices and penile rings) an effective but are less popular (204-208). They should be used cautiously due to risks of penile necrosis from lost sensations.

II.9.1.3 Intracavernous injections and intraurethral application.
May be offered to those patients who are not responding to oral drugs. Intracavernous injections (alprostadil, papaverine and phentolamine) are effective in SCI, MS, and DM (209-215). Complications include pain, priapism and corpora cavernosa fibrosis.

Intracavernous vasoactive drug injection is the first-line therapeutic option in patients taking nitrate medications, as well as those with concerns about drug interactions with PDE5Is, or in whom PDE5Is are ineffective.

II.9.1.4 Penile prostheses.
Penile prostheses may be considered for treatment of neurogenic ED when all conservative treatments have failed. Serious complications, including infection and prosthesis perforation, may occur in about 10% of patients, depending on implant type (216-218).

II.9.2 Male fertility.
ED, ejaculation disorders, impaired sperm quality or various combinations of these disorders may deteriorate fertility in neuro urological patients. Other factors contributing to neurogenic infertility are pelvic and retroperitoneal surgery, diabetes mellitus, MS and SCI (219).

Retrograde ejaculation may be reversed by sympathomimetic agents contracting the bladder neck. These drugs include imipramine, ephedrine and pseudoephedrine (219). Semen harvesting from the urine may be considered if antegrade ejaculation is not achieved (220).

Prostatic massage is safe and easy to use for obtaining semen in men with lesions above T10 (221). In several patients, vibro-stimulation or trans rectal electro ejaculation are needed for sperm retrieval (219, 222, 223). In men with SCI, especially at or above T6, AD might occur during sexual activity and ejaculation (224, 225).

Surgical procedures, such as, microsurgical epididymal sperm aspiration (MESA) or testicular sperm extraction (TESE), may be used if vibro-stimulation and electro-ejaculation are not successful (226, 227).

II.9.3 Female sexuality.
The greatest physical barrier to sexual activity is UI. After SCI, about 65-80% of women continue to be sexually active, but to a much lesser extent than before the injury, and about 25% report a decreased satisfaction with their sexual life (228-231). Reflex lubrication and orgasm are more prevalent in women with SCI who have preserved the sacral reflex arc (S2-S5). In SCI women with a complete lesion of the sacral reflex, arousal and orgasm may be evoked through stimulation of other erogenous zones above the level of lesions (232-234). Problems with positioning and spasticity affect mainly quadriplegic patients (228, 235-237).

II.9.4 Female fertility.
There are limited numbers of studies on female fertility in neurological patients, therefore clinical management should be individualised to optimise both the mother’s reproductive outcomes and medical condition.

Women with SCI are more likely to suffer complications during pregnancy, labour and delivery compared to able-bodied women. Regarding anaesthesia, epidural anaesthesia is chosen for most patients with AD during labour and delivery (238, 239).

II.10 Follow-up of NLUTD.
Patients with NLUTD are known to be at high risk of suffering from urinary tract symptoms and complications. For some conditions, such as SB and SCI, there is a risk of silent renal deterioration due to the development of hydronephrosis or the formation of renal stones. Furthermore, some patients with NLUTD will have progressive neurological conditions which will be expected to have an increasing adverse impact on LUT function. The effect of ageing on a damaged LUT will often be greater than its effect on the normally innervated LUT (89). For all these reasons, there is an argument to be made for offering patients with NLUTD long-term monitoring of their urinary tract.

The time interval between initial investigations and control diagnostics should not exceed one to two years. In high-risk neuro-urological patients, this interval should be much shorter.

It should be in the form of:
  • Urinalysis should be performed only in symptomatic patients (240).
  • Lifelong ultrasonography of the UUT at regular intervals in high-risk patients (those with SCI or SB and those with adverse features on UDS such as impaired bladder compliance, DSD or VUR); about once every six months (3, 240).
  • Physical examination and urine laboratory should take place every year (3, 240).
  • UDS should be performed as a diagnostic baseline, and repeated during follow-up, more frequently in high-risk patients (SB and SCI) (3, 241). It is recommended yearly in this high-risk group, otherwise could be done every two years.
  • Specialized, investigation should be warranted for any significant clinical change (e.g. DMSA scan), However, there is a lack of high level evidence (242).
  • Increased prevalence of muscle invasive bladder cancer in NLUTD patients necessitates long-term follow-up (243). The exact frequency of cystoscopy with or without cytology remains unknown.
  • Adolescent patients with neurological pathology are at risk of being lost to follow-up during the transition to adulthood (244).

Table II:2 Recommendations for treatment of NB

Recommendations

Strength rating
1. Do not recommend assisted bladder emptying techniques (Crede, Valsalva or triggered reflex voiding) as they are hazardous to the upper tract EXCEPT in patients with absent or surgically removed outlet resistance Strong
2. Do not offer penile clamps as they are absolutely contraindicated in cases of NDO or low bladder compliance because of the risk of developing high intravesical pressure and pressure sores/necrosis in cases of altered/absent sensations Strong
3. Prescribe anticholinergics as the first-line medical therapy for NDO Strong
4. Offer combination therapy of antimuscarinics and Beta 3 agonists to maximise outcomes for NDO Strong
5. Monitor PVR in people who are not using intermittent or indwelling catheterisation after starting anticholinergics Strong
6. Prescribe α-blockers to decrease bladder outlet resistance in NLUTD, putting into consideration their off -label in patients with DSD Strong
7. Do not offer cholinergics for underactive detrusor due to NLUTD Strong
8. Use CIC as a standard treatment for patients who are unable to empty their bladder Strong
9. The average catheterisation times is four to six times per day Strong
10. The catheter size most often used is between 12-16 Fr Strong
11. Bladder volume should not exceed 400-500 mL at catheterisation time Strong
12. Do not use Foley catheters because of the high incidence of latex allergy in the neuro-urological patient population. Use silicone catheters instead Weak
13. Avoid indwelling transurethral and suprapubic catheterisation whenever possible Strong
14. Use intradetrusor botulinum toxin injection to reduce NDO when antimuscarinic therapy fails Strong
15. The recommended dose of botulinum toxin is 200 IU, intradetrusor injection, in 30 sites in the bladder, with exclusion of the trigone, for theoretical prevention of VUR Strong
16. Offer bladder neck incision in a fibrotic sclerotic bladder neck Strong
17. Offer botulinum toxin A 100 IU intrasphincteric in cases of DSD Weak
18. Offer pubovaginal sling as the procedure of choice in neuro-urological females with decreased outlet resistance who can do self-catheterization Strong
19. Both TOT and the TVT may also be offered to neuro-urological females with decreased outlet resistance, but with a higher incidence of de novo urgency Weak
20. Insert an AUS in male patients with neurogenic stress urinary incontinence (SUI) Strong
21. Offer bladder augmentation as an alternative to treat refractory NDO and/or impaired bladder compliance Strong
22. Consider urinary diversion when no other therapy is successful for NDO and/or impaired bladder compliance Strong
23. Do not perform screening for asymptomatic bacteriuria nor treat it in NLUTD patients Strong
24. Avoid the prescription of long-term antibiotics for recurrent UTIs Strong
25. When changing catheters in patients with a long-term indwelling urinary catheter, do not offer antibiotic prophylaxis routinely Strong
26. Consider antibiotic prophylaxis for patients who have a history of symptomatic UTI after catheter change or experience trauma during catheterization Strong
27. Prescribe oral PDE5I as first-line medical treatment in neurogenic ED Strong
28. Perform intracavernous injections of vasoactive drugs as second-line medical treatment in neurogenic ED Strong
29. Reserve penile prostheses for selected patients when all other treatments have failed Strong
30. Perform vibrostimulation and transrectal electroejaculation for sperm retrieval in men with SCI Strong
31. Do not offer medical therapy for the treatment of neurogenic sexual dysfunction in women Strong
32. Assess the upper urinary tract every six months in high-risk patients by ultrasonography Strong
33. Perform a physical examination and urine laboratory every year in high-risk patients Strong
34. Perform UDS as a mandatory baseline diagnostic intervention. It is recommended yearly in high-risk group, otherwise could be done every two years Strong
II.11 Conclusions.
Early diagnosis of NLUTD is fundamental before deciding any plan of management. Extensive history taking, thorough examination together with laboratory, radiological and urodynamic investigations should be done in every NLUTD patient. Accordingly, tailoring and individualizing the plan of management follows, which ensures the best practice of clinical care offered to these patients. The role of these guidelines is to offer you expert advice on how to manage these patients.
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