Introduction

Multiple sclerosis (MS) is the most common autoimmune inflammatory disease that causes damage of the myelin sheath of nerves in central nervous system [1]. With a median prevalence of 80 per 100,000 in Europe and 135 per 100,000 in the USA, it is estimated that over 2.3 million individuals are living with MS worldwide [2, 3]. It is often first diagnosed between the ages of 20 and 40 and disproportionately affects more women than men [2]. While the cause of MS is unknown, a combination of genetics, immunologic factors, and environmental influences are thought to predispose individuals to the condition.

Among the various symptoms of MS—including muscle weakness, sensory and visual disturbances, fatigue, and cognitive dysfunction—neurogenic lower urinary tract dysfunction (NLUTD) contributes greatly to the morbidity of this disease. The NLUTD that can be seen in patients with MS can include storage or voiding symptoms or combinations of both. The majority of MS patients will experience neurogenic overactive bladder syndrome, a storage problem. Symptoms include increased frequency, urgency, urgency incontinence, and nocturia, which interfere with recreation, impair emotional health, and ability to perform work [4]. Patients are often greatly bothered by these symptoms leading to an overall lower quality of life. Recent advancements in the screening tools and treatment options of neurogenic overactive bladder now better address specific symptoms and may better guide management. Clinicians that are treating MS patients with NLUTD must also understand the urologic dysfunction in the context of the underlying neurologic condition including things like limitation in mobility, cognitive impairment, disease progression, etc. Though this is not the focus of the paper, clinicians should be encouraged to gain this insight.

Pathophysiology of Neurogenic Lower Urinary Tract Dysfunction

The NLUTD observed in patients with MS is a direct result of lesions in the spinal cord or brain. Generally speaking, upper motor neuron lesions, or those above the S2-S4 cord level, manifest as an overactive bladder, whereas lower motor neuron lesions, or those of the peripheral nerves to the bladder (i.e., sacral cord and conus medullaris demyelination), manifest as an acontractile bladder (some times referred to as hypotonic or areflexic bladder) [5]. In MS, cord lesions above the S2-S4 level are more common and present on Urodynamic Studies (UDS) as neurogenic detrusor overactivity or NDO [5]. NDO can occur at any volume and lead to increased bladder pressure, urgency, frequency, and urgency urinary incontinence (UI). Suprapontine lesions can lead to urgency UI by disinhibiting the micturition reflex normally maintained by descending cerebral pathways that contribute to volitional control of the lower urinary tract [6, 7]. Lastly, a combination of both upper motor neuron and peripheral lesions can lead to bladder emptying or voiding dysfunction known as detrusor-sphincter dyssynergia (DSD) [8]. The discoordination between detrusor and sphincter can lead to urinary retention, elevated post-void residual (PVR) volumes, and vesicoureteral reflux (VUR). Patients can exhibit storage and voiding dysfunction simultaneously or independently. Furthermore, as relapses and progression are a hallmark of the underlying disorder, the specific NLUTD can also change with time.

Epidemiology of Symptoms

The multifocal involvement of lesions, progression of existing lesions, and appearance of new lesions all contribute to the complexity and variety of symptoms experienced by MS patients with neurogenic lower urinary tract symptoms (NLUTS). A recent systematic review of 45 epidemiological articles reporting rates of urologic symptoms found a wide range anywhere from 6.9 to 95 % [9•]. Two large systematic reviews included in this study found the prevalence of urgency ranging from 32–86 %, frequency or urgency from 31–85 %, and incontinence from 37–72 % [10, 11]. An examination of 9702 MS patients from the North American Research Committee On Multiple Sclerosis (NARCOMS) survey found that 65 % reported at least one moderate-to-severe urinary symptom (frequency, urgency, nocturia, or leakage) [12••]. To further characterize these LUTS, a recent survey found that of the 92 % of 1047 MS patients reporting at least one LUTS, the most common was post-micturition dribble (64.9 %), urinary urgency (61.7 %), and a feeling of incomplete emptying (60.7 %) [13••]. Furthermore, 79 % experienced some type of UI. Only 311 (32 %) had seen a health care provider for these symptoms during the past year, a finding that supported previous concerns that LUTS are frequently underdiagnosed or undertreated in this population [12••, 13••].

Screening Tools for Bladder Symptoms

There are several screening tools and instruments used to evaluate patients with bladder symptoms, including commonly used tools such as the Overactive Bladder Questionnaire (OAB-Q), Kings Health Questionnaire (KHQ), and Total Health-Related Quality of Life (HRQOL). Not all are specific to screening the MS population or patients with NDO [14••]. Two new questionnaires were recently developed and validated to address this gap in order to efficiently and appropriately screen this population.

The Actionable Bladder Symptom and Screening Tool (ABSST) has been validated as a screening tool to identify MS patients with symptomatic NDO who could benefit from assessment and possibly treatment [14••]. This 17-item tool was developed with three domains—Bladder Symptoms, Coping Strategies, and Impact of Bladder Symptoms—and has demonstrated high correlation with OAB-Q and HRQOL [14••]. An 8-item short form of ABSST, which maintained the integrity of the long version, includes questions on frequency of urination, leakage, urgency, nocturia, impact on social relations, work interference, embarrassment, and an additional question directly asking if the patient would like help for their bladder problems [15]. A score of 3 or greater (from 0–8) indicated the need for further evaluation. The screening tool was developed as an easy way for neurologists or other health care professionals to quickly identify patients in clinic who may need further evaluation for bladder symptoms. Along with its ease of use in the clinical setting, the ABSST covers of multiple dimensions relevant to MS patients and, most importantly, leads to a referral when appropriate [14••, 15]. It is also conceivable that such a tool could have a role in following patients who are getting treated and determine if current treatments are adequate.

The Neurogenic Bladder Symptom Score (NBSS) is the first patient reported outcome measure designed to assess objective signs and symptoms related to neurogenic bladder dysfunction from spinal cord injury, spina bifida, and MS [16••]. Its goal is to objectively discriminate among patients with different levels of bladder symptoms rather than simply from the general population [17]. The 22 items cover three major domains—Incontinence, Storage and Voiding Symptoms, and Urinary Complications—addressing questions more relevant to neurogenic bladder populations such as those concerning urinary infections. Because bladder symptom scales may not necessarily correlate with subjective quality of life measures, two additional questions address bladder management and quality of life. Validity was demonstrated with high correlations with the American Urological Association symptom score (AUASS), International Consultation on Incontinence-Urinary Incontinence (ICIQ-UI), and SF-Qualiveen [16••]. Over time, this can be used as a tool to objectively measure changes in bladder symptoms.

Screening and identification of appropriate patients is one of the first steps in getting treatment to patients with NLUTD. Other barriers beyond identifying a need likely exist including cost, insurance, transportation, and accessibility, as well as embarrassment [18•].

Evaluation

Once appropriately identified, diagnosing bladder dysfunction requires a complete history of symptoms and physical exam. Symptoms can be grouped as storage problems (i.e., urgency, frequency, urge incontinence), voiding problems (i.e., hesitancy, incomplete emptying), or a combination of both. Voiding diaries can be helpful to try to quantify some of these symptoms and help target areas of behavior changes. Other key elements of the evaluation should include history of bowel or sexual dysfunction. A complete neurological exam should include eliciting lower extremity and perineal reflexes as well as testing for sensory or motor deficits in the lumbar and sacral regions. For patients with new bladder symptoms, urine testing and measurement of a PVR volume are both advisable. Urine testing can be accomplished via a rapid dipstick test, formal urinalysis, and/or urine culture as indicated. The urine testing may uncover hematuria or urinary tract infection (UTI) that may need to be evaluated and treated. PVR can be measured via abdominal ultrasound or catheterization and is useful for patients complaining of incomplete emptying. Several measurements with a volume of greater than 100–150 mL measured over the course of 1 to 2 weeks may require further investigation [19]. In addition, these patients may benefit from renal ultrasound to ensure that there is no upper tract sequel of the elevated post-void residual. Ultrasound also has a role in patients with recurrent urinary tract infections or known patients with impaired bladder compliance. Cystoscopy is another tool that has a role in patients with MS, for example, those with indwelling catheters. These ancillary tests should not be used indiscriminately but rather as the clinical scenario warrants.

The general goals of managing any patient with NLUTD or a neurogenic bladder are to (1) promote continence with appropriate bladder storage and emptying, (2) create a low-pressure bladder system to preserve renal function, and (3) improve quality of life for the patient [20]. Treating NLUTD due to MS is often individualized when dealing with issues related to quality of life. Therapies tend to be more dogmatic when patient’s upper tract function is at risk, though patient’s autonomy should also be addressed. Overall, the clinician needs to incorporate the patient’s risk for upper tract damage and the symptoms and degree of bother for each patient. This is all within the framework of underlying disease process and neurologic pharmacotherapy that each patient is taking.

Management of Storage Symptoms

Symptoms of frequency, urgency, urgency incontinence, and nocturia are considered the “storage symptoms” that are discussed below. These symptoms are very common and can have a profound impact on patients and possibly their care providers. A patient’s functional status, disease burden, and comorbid conditions will all factor into his/her perception and impact of the symptoms and also are considered when choosing treatment options. Impaired bladder compliance is a storage abnormality that can occur in MS, but we did not classify this as a symptom as it can occur silently. Impaired compliance occurs less commonly in the MS population (compared to other neurologic injuries such as spinal cord injury) and is not the focus of the section below. Nevertheless, it is essential to identify when suspected and manage when present.

Behavioral Modifications and Pelvic Floor Exercises

Diet and lifestyle modifications are often the first recommendations for managing symptomatic NLUTD [8]. These include weight reduction, management of constipation, smoking cessation, fluid restriction, and caffeine reduction. In a recent survey of 1047 MS patients, 71 % reported currently receiving at least one treatment modality for LUTS [13••]. The most common interventions include reduction of fluid intake (32 %) and limiting intake of caffeine and alcohol (21 %) [13••]. Fluids are typically restricted to 1–2 L per day and caffeine to 100 mg per day; however, this can vary by patient and by voiding patterns elicited through a voiding diary. Behavioral modifications include increasing the frequency of micturition, timed voiding at specific intervals, and bladder training by voiding prior to sensation of urgency.

Pelvic floor exercises, or Kegel exercises, to increase pelvic floor and urinary sphincter muscle strength has also been shown to improve bladder symptoms in the MS population. In a randomized controlled study of 30 MS patients, those engaged in regimented pelvic floor muscle therapy showed a decrease in leakage episodes by 12 % by week 9 [21]. Those that engaged in pelvic floor muscle therapy in combination with either electromyography biofeedback or neuromuscular electrical stimulation showed a statistically significant reduction in leakage episodes by 45 and 68 %, respectively, by week 9, maintaining these improvement on weeks 16 and 24 [21]. These therapies require that patients are cognitively able to participate are physically able to make it to participate and have some neural pathways that are intact. Patients with significant disability (i.e., higher Expanded Disability Status Score (EDSS)) are likely not going to benefit from these interventions.

Anticholinergics/Antimuscarinics

With regards to pharmacologic management, anticholinergic/antimuscarinic medications are often considered first to treat urgency, frequency, urgency incontinence, and nocturia. Anticholinergics/antimuscarinics decrease detrusor muscle contraction by antagonizing muscarinic receptors. Anticholinergics/antimuscarinics, such as oxybutynin, (Ditropan®, Aventis; Ditropan® XL, ALZA Corporation; Oxytrol®, Watson Pharma), tolterodine (Detrol®, Pfizer; Detrol® LA, Pfizer), trospium (Sanctura®, Odyssey Pharmaceuticals/Indevus Pharmaceuticals), and fesoterodine (Toviaz®, Schwarz Pharma AG) act by non-selectively antagonizing muscarinic receptors on smooth muscle to decrease involuntary detrusor contraction but also leads to decreased salivary production, gastrointestinal motility, and miosis [22–24]. Some anticholinergics/antimuscarinics such as darifenacin (Enablex®, Pfizer) and solifenacin (Vesicare®, Astrellas) are more selective, have a higher affinity for the M3 receptor, which plays a large role in mediating bladder contraction [23, 24].

A large meta-analysis of 16 randomized control trials addressing anticholinergic use in patients with NDO found that significantly more patients using anticholinergics reported a better cure/improvement rate than placebo at 2 weeks (63 versus 22 %) [25]. Urodynamic parameters were also significantly better including higher maximum cystometric capacity (MCC), higher mean volume at contraction, and lower maximal detrusor pressure (MDP). Dry mouth was the only adverse event significantly higher in patients on anticholinergics (32 versus 7 %). There were no significant differences in improvement rate, urodynamic parameters, or adverse events when comparing various anticholinergics to oxybutynin, or when comparing various doses of tolterodine or trospium [25]. Mode of delivery did not matter either; oral atropine versus intravesicular oxybutynin showed no significant differences, with the exception of lower dry mouth rates with intravesicular atropine [25]. Of note, this meta-analysis did not perform any subgroup analysis on patients with MS. A separate Cochrane review of 3 single center trials examining anticholinergic use in the MS patient population concluded that there was not enough evidence to support its use [26]. However, the trials included in that review were not placebo controlled.

A prospective study examining 30 MS patients with overactive bladder (OAB) found that when compared to baseline, patients treated with solifenacin 5/10 mg for 8 weeks experienced a significant improvement in median number of micturitions (−2.2 episodes/day), number of pads used (−1 pad/day), degree of urgency prior to voiding, and an increase in median volume voided (+33 mL/void) [27]. This study was again limited by the lack of a control group for comparison.

Although there is no clear-cut anticholinergic/antimuscarinic that is more effective than another, oxybutynin has historically prescribed first, followed by the addition of other medication if necessary. When selecting from these medications, tolerability, adherence, efficacy, safety, and cost are all often considered.

Desmopressin

Desmopressin, a synthetic analogue of vasopressin (also known as antidiuretic hormone (ADH) secreted from the posterior pituitary gland), has been shown to aid with nocturnal enuresis and diabetes insipidus by increasing water reabsorption in the collecting tubules of kidneys. In a recent meta-analysis of five randomized controlled trials, the use of desmopressin in MS patients with bladder symptoms has been shown to statistically lower voiding frequency in the first 6–8 h after administration or at night when compared to placebo [28]. The most common side effects experienced were related to hyponatremia and included fluid retention (0–8 %) and headache (3–4 %) [28]. This medication has good level of evidence to support use in MS, but given the potentially serious complications of hypernatremia requires a vigilant patient and practitioner to ensure that these sodium levels are monitored. This is especially important in elderly women who are at highest risk for this complication.

β3 Adrenergic Agonist

Mirabegron (Myrabetriq® Astellas Pharma) is the first available drug in this class. It is a potent agonist that targets the β3 adrenergic receptor found within urothelium and detrusor smooth muscle. Agonists of the receptor cause relaxation of the detrusor muscle during storage. The molecule has been shown to inhibit detrusor overactivity and increase bladder capacity without any increase in residual volume or decrease in micturition pressure [29]. Recently, in a randomized, placebo-controlled, double-blind study, patients with idiopathic overactive bladder (OAB) on mirabegron had a statistically significant decrease in frequency of micturition and a lower number of incontinence episodes when compared to placebo [30••]. Although there are currently no published randomized controlled trials assessing the efficacy of mirabegron in MS patients, it may prove to be an advantageous alternative to anticholinergics/antimuscarinics in this population because of a more favorable side effect profile including less cognitive effects, impairment of bladder emptying, and gastrointestinal motility. Further work is also needed in the neurogenic population to understand the clinical effect of this class of medication on bladder compliance, which can be impaired in these patients, and on those currently treated with anticholinergics/antimuscarinics.

Cannabinoids

There are over 60 different cannabinoids that can be extracted from the cannabis plant each with varying pharmacology and interaction with cannabinoid receptors [31]. Cannabinol was the first extracted cannabinoid from the plant. Delta-9-tetrahydrocannabinol (Δ9 –THC) is the major psychoactive cannabinoid. Most cannabis extract contains Δ9 –THC and cannabidiol, a non-psychoactive cannabinoid. The use of cannabis extract has been studied in MS patients for its benefits in alleviating stiffness, spasticity, tremor, pain, and bladder dysfunction. A recent subset of a multicenter, randomized controlled trial—Cannabinoids in Multiple Sclerosis, or CAMS study—of 630 MS patients with LUTS found that both cannabis extract and Δ9 –THC significantly lowered incontinence episodes by 38 and 33 %, respectively, when compared to placebo, 18 % [32]. This data supported smaller uncontrolled studies from the past, including one of 15 patients with advanced MS and refractory LUTS who experienced significant decreases in urgency, the number and volume of incontinence episodes, frequency, and nocturia using Δ9 –THC and cannabidiol [33]. Cannabinoids are currently not available for this purpose in United States.

Diuretics

Although there are no randomized controlled trials assessing efficacy of diuretics in MS patients, there is evidence to reduce nighttime frequency in men with nocturnal polyuria if given 6 h prior to bedtime [34, 19]. Electrolytes and blood pressure may need to be monitored with the use of these medications. If not comfortable with their uses, urologists can involve primary care physicians when considering diuretics.

Botulinum Toxin

Intradetrusor injection of botulinum toxin is another option of treatment when anticholinergic medications either fail to alleviate symptoms of NDO or cause intolerable side effects [5]. Botulinum neurotoxin is secreted by Clostridium botulinum, a gram-negative, spore-forming bacterium that secretes seven different serotypes (A-G) of botulinum toxin [35]. Only onabotulinumtoxinA (BOTOX ®, Allergan) has been evaluated for use in NDO. The toxin is a polypeptide consisting of a heavy and light chain that is endocytosed by the terminal bouton in the synaptic cleft. SNARE proteins in the terminal bouton necessary for the appropriate docking, fusion, and release of vesicles containing acetylcholine are cleaved by the light chain protease of the toxin. This inhibits any docking of neurotransmitter vesicles, prevents acetylcholine release into the synapse, and ultimately paralyzes the detrusor muscle [35]. Other mechanism of action may also be involved with afferent nerve signaling. The studies that are discussed below utilized a 30-injection template that spares the trigone. These injections can be done through a flexible or rigid cystoscope often utilizing just local anesthesia.

Two large multicenter, randomized, double-blind, placebo-controlled phase III trials—part of the DIGNITY (Double-blind Investigation of Purified Neurotoxin Complex In Neurogenic Detrusor Overactivity) clinical research program—have led to onabotulinumtoxinA 200 U receiving Food and Drug Association (FDA) approval for the treatment of urinary incontinence in patients with NDO from MS or spinal cord injury (SCI) [36••, 37••].

In the study by Cruz et al., 275 patients (MS; n = 154, SCI; n = 121) with greater than 14 episodes of UI per week refractory to anticholinergic medications (whether they were currently on an anticholinergic or not) were randomly assigned to three groups, OnabotulinumtoxinA 200U, 300U, or placebo. OnabotulinumtoxinA 200U significantly decreased UI episodes compared with placebo (−22 versus −13) at 6 weeks. Of those on 200U, 38 % patients were completely dry versus only 7.6 % of placebo. Furthermore, patients treated with onabotulinumtoxinA 200U had improved urodynamic parameters including statistically greater increases in MCC and greater decreases in MDP at week 6. The median duration of effect, or time until patient requested retreatment, was about 42 weeks for patients treated with either onabotulinumtoxinA dose, significantly higher than the placebo group at 13 weeks. Although there were no dose-dependent benefits observed in the 300U treatment group over 200U, of note, urinary retention was found to be significantly higher in the 300U group as these patients were more likely to have a PVR >200 cc and require clean intermittent catheterization (CIC) after treatment [36••].

Similarly, the 416 patients (MS; n = 227; SCI; n = 189) randomly assigned to three treatment groups in the Ginsberg et al. study also experienced similar outcomes. Patients treated with OnabotulinumtoxinA 200U experienced a significant decrease in UI episodes compared with placebo (−21 versus −8.8) at 6 weeks, as well as increases in MCC and decreases in MDP. These results were still significant when examining MS patients separate from SCI patients. The median duration effect for the 200U treatment group was 256 days (36.5 weeks) versus 92 days (13 weeks) for placebo [37••].

Recently, Rovner et al. combined the data from both trials (n = 691) and a similar analysis further supported all the previous findings. Upon further subgroup analysis of 241 patients (34.9 %) with low detrusor contractility (DC) at baseline (<20 mL/cmH2O), about 60 % treated with 200 or 300 U onabotulinumtoxinA did not have an involuntary detrusor contraction (IDC) at week 6 versus 13.7 % in the placebo group. For those who did have IDC, the mean MDP was significantly decreased in the 200U and 300U treatment group, −39.5 and −30.3 cmH2O, respectively, compared with placebo, −5.6 cmH2O. This finding supports the benefit of using OnabotulinumtoxinA in patients who have low baseline DC yet may experience frequent detrusor contractions, especially against bladder outlet obstruction, to reduce risk for upper tract damage [38••].

Patients in both of these trials who were refractory to anticholinergic medications either continued the anticholinergic treatment or remained off treatment during the course of the trial. A recent study that also pooled the data from these two trials demonstrated that the benefits of onabotulinumtoxinA on UI seen in both trials were independent of current anticholinergic use. In the 200U treatment group, similar decreases in episodes of UI were observed for both patients taking and not taking anticholinergics (−20.3 and −22.5, respectively). Improvements in urodynamic parameters were also independent of anticholinergic use [39].

Treatment with OnabotulinumtoxinA has also been shown to significantly improve quality of life and patient satisfaction [40]. In a double-blind, placebo-controlled study, 185 patients with NDO from MS or SCI were randomized to treatment groups of 200U, 300U, or placebo. Quality of life was assessed using the Incontinence Quality of Life (I-QOL) Questionnaire; treatment satisfaction by the Overactive Bladder-Patient Satisfaction with Treatment Questionnaire (OAB-PSTQ); and treatment goal achievement by Patient Global Assessment. Mean improvement in I-QOL total score from baseline at week 6 was significantly greater with both onabotulinumtoxinA 200 and 300 U versus placebo (+12.3 for 200 U and +14.9 for 300 U) which held up similarly at week 12. When compared to placebo, patients treated with onabotulinumtoxinA 200 or 300 U were more likely to be “somewhat” or “very” satisfied with treatment (200U 78 % and 300U 68 % versus placebo 40 %), more likely to report feeling “significant progress” toward or “complete achievement” of their primary treatment goal (200 U 63 % and 300U 62 % versus placebo 16.5 %), and more likely to report that treatment “significantly met” or “exceeded” treatment expectations when compared to placebo at both week 6 and week 12. Again, no differences between OnabotulinumtoxinA doses were appreciated [40].

Most common adverse event of OnabotulinumtoxinA treatment was urinary tract infection (UTI) [36••, 37••]. In the Cruz et al. study, there was no difference in the incidence in UTI between treatment groups among SCI patients. However, the incidence of UTI in the MS population was significantly higher in the 200U group than in placebo (31 versus 16 %) and even higher in the 300U group (35 %). MS patients made up the majority of patients not using CIC at baseline (92 % of 130 non-CIC patients). After 200U and 300U treatment, a large portion of these treatment groups (30 and 42 %, respectively) started CIC due to elevated PVR compared to placebo (12 %). The increase in rate of UTI is thought to be associated with this “de novo” use of CIC, although none of the cases were complicated UTIs. Of note, a UTI was considered an adverse event when associated with a positive urine culture; there was no distinction made between symptomatic and asymptomatic UTIs [36••].

While OnabotulinumtoxinA is clinically successful, there remains a small group of patients that show no clinical improvement after treatment. A study looking into MS patients (n = 71) found that 23 % failed to respond to OnabotulinumtoxinA injections. Of those who failed treatment, duration of disease was a predictor of failure, as both neurologic and urologic symptoms progressively worsened, suggesting that timing of initiating injection therapy may play a role in its eventual success [41].

Percutaneous Tibial Nerve Stimulation

Percutaneous tibial nerve stimulation (PTNS) (URGENT® PC, Uroplasty) therapy is a treatment option that modulates the bladder reflex pathway in those patients with idiopathic overactive bladder who are refractory to medical treatment [42]. The posterior tibial nerve, a mixed sensory-motor nerve, contains axons passing through the L4–S3 spinal roots that reach the peripheral nerves involved in sensory and motor control of the bladder. Stimulation of these nerves by a needle electrode in turn stimulates large diameter somatic afferent fibers, which evokes a central inhibition of the micturition reflex pathway in the descending pathways of the spinal cord or the brain [42]. Initial treatment consists of 12 weekly sessions for 30 min each, with additional treatments needed based on symptoms.

In a recent prospective non-placebo-controlled trial of 83 MS patients with lower urinary tract symptoms refractory to medical therapy (majority refractory to two or more anticholinergics), 74 (89 %) had a 50 % or greater improvement in symptoms after initial treatment of PTNS. The treatment benefit was sustained for 2 years with a typical maintenance regimen of 3 weeks intervals [43•]. Symptoms were measured by the patient perception of bladder condition (PPBC) questionnaire. Over time, lower urinary tract symptoms and patient treatment satisfaction improved compared to initial treatment. Furthermore, there were significant decreases in daytime frequency and nocturia, as well as significant improvements on urodynamic parameters 2 years after PTNS; MCC and threshold volume for DO were significantly increased while residual volume, MDP, and voiding pressure were all decreased [43•]. This study supports prior data on the use of PTNS in patients with MS refractory to treatment with at least two anticholinergics that found significant improvements in LUTS (most notably nocturia and daytime frequency) in 89 % of participants using KHQ after the 12-week treatment period [44]. PTNS represents a minimally invasive approach for symptomatic relief, and with the development of a transdermal approach, may eventually lead to home-based therapies [45]. This therapy relies on intact neural pathways, and more work is needed to better understand the role of this therapy and the ideal candidate.

Sacral Neuromodulation

Sacral neuromodulation (SNS) (INTERSTIM®, Medtronic) is another option for refractory overactive bladder. It also has an indication for non-obstructive urinary retention and fecal incontinence. The implantable device consists of a neurostimulator, extension cable, and lead with electrodes. The electrode is implanted into the sacral foramen of the S3 nerve root, and the neurostimulator is placed subcutaneously in the superior buttock. Various settings can be controlled externally. The mechanism of action is thought to be via stimulation of afferent nerves, which modulate CNS reflex pathways. For example, inhibiting the ascending pathway of the micturition reflex and input to the pontine micturition center can prevent reflex micturition but will not affect voluntary micturition. The use of this device in MS patients has traditionally been more limited. The device was initially not MRI compatible, and this population often has the need for such imaging. The device now has approval for brain MRI but still limits body (i.e., lower spine) MRI. The progressive nature of MS and potential evolution of the associated NLUTD has also factored into the use of this technology. The data for the MS population is somewhat limited. One retrospective case series of 25 MS patients with NLUTD, 15, or 60 %, eventually had the device implanted after a test phase and experienced symptomatic improvement by 50 % or more with regards to voiding frequency, incontinence episodes, frequency of catheterizations, and voided volumes [46]. Of note, these were patients who primarily complained of symptoms related to NDO. Selected appropriately, some patients may benefit, but more data in the MS population is needed.

Management of Voiding Symptoms

These voiding symptoms in MS include slow stream, intermittent stream, hesitancy, and straining [47]. These voiding symptoms may exist in isolation or in combination with the storage symptoms above. Here, too, the patient’s initial assessment, symptom complex, and functional status will factor into the management of voiding symptoms. Some dysfunction of voiding can be present without considerable complaint from the patient or may present primarily as storage symptoms.

Clean Intermittent Self-Catheterization and Indwelling Catheters

Clean intermittent self-catheterization, or CIC, is typically recommended for an elevated PVR (i.e., greater than 100 mL) found several times on abdominal ultrasound or catheterization when patients are having symptoms [19]. This therapy may also be utilized for patients in frank urinary retention or if they have very prolonged bladder emptying. Asymptomatic patients with elevated PVR and evidence of upper tract changes (more rare in MS) may also require CIC. CIC represents a safe and simple technique to regularly empty the bladder. This may help prevent urinary tract infections and upper tract damage. Patients may become colonized with bacteria that, if asymptomatic, do not need to be continually treated. The technique requires sterile or clean catheters of appropriate length (approximately 40 cm for males and 20 cm for females), lubrication, manual dexterity to both open the meatus and insert the catheter, and a reservoir or place to drain the urine [48]. For patients unable to perform CIC several times a day due to worsening neurologic condition, limited dexterity, mobility issues, etc., an indwelling catheter is an option for long-term draining. While some patients may initially have a urethral catheter placed, long-term uses of urethral catheters should generally be avoided. Continuous bladder drainage by way of a suprapubic is preferred. These tubes that avoid risk of urethral damage are more comfortable, easier to change, and less likely to become infected. Catheters can then be changed every few weeks. From the NARCOMS survey, it was found that 26 % used urinary catheterization (11 % currently, 15 % in the past). Of those respondents, 81 % used CIC, 43 % Foley catheterization, and 8 % suprapubic catheterization [49].

Credé’s Maneuver and Abdominal Vibration

Credé’s Maneuver involves using ones’ hands to produce downward suprapubic bladder pressure to effectively empty a neurogenic bladder. A Valsalva maneuver produces similar bladder pressure to aid in emptying. Although easy to perform, high pressures have been reported to cause hydronephrosis in 35 % and renal damage in 16 % of those using this technique for over 20 years [50]. CIC is currently the preferred method for bladder emptying.

Bladder emptying can also be achieved by the use of an external hand-held vibratory device placed on the suprapubic region during and 1 minute after voiding. A randomized controlled trial found abdominal vibration an effective method for reducing PVR in MS patients when compared to abdominal pressure alone or no treatment at all [51]. Of note, there were no significant differences in frequency or continence among treatment groups. This method is not universally acceptable, as here too elevating detrusor pressure in patients that may have a component of obstruction may eventually lead to upper tract changes.

Timed Voiding

Timed voiding is a method to regularly empty the bladder on a schedule rather than relying on an overfilled bladder as a trigger to urinate, with the aim of reducing incontinence, frequency, and urgency. This technique also relies on urge suppression to wait until the next scheduled void. If used in conjunction with a voiding diary, one can eventually aim to increase voiding intervals overtime [52].

Role of Urodynamics

Multichannel invasive urodynamic studies (UDS) clearly has a critical role in the evaluation of neurogenic patients thought to be at high risk of developing renal complications [53••]. However, with a neurologic condition like MS, the role of filling cystometrogram in preventing renal complication is less clear. This suggests that the test does not have to be used as an initial tool in the evaluation of all MS patients or as part of a routine follow-up. UDS still clearly has a role in MS as it accurately diagnoses the dysfunction that is present [54]. The most common urodynamic finding is NDO, reported in as many as 70 %, followed by DSD, in 25 %. Impaired detrusor contractility is another finding that may be diagnosed by UDS. Most patients with MS that have symptoms will present with a UDS abnormality; however, it is not always necessary to make the diagnosis. Non-invasive urodynamic tools such as Uroflow and PVR help the clinician evaluate for the need of UDS.

UDS findings and NLUTS may change overtime, yet the relationship between the two is not clear [55]. Symptomatic management and non-invasive studies may be the best starting point for many patients. Dillon et al. recommend patients with elevated PVR (>150 mL), two or more failed trials of medical therapy, obstructive symptoms, or hydronephrosis should receive an initial UDS, although other situations are at the discretion of the physician [56•].

Surgery

When possible, conservative treatment options should be exhausted prior to more invasive interventions. Some patients are refractory to conservative treatment options, and surgical intervention may be considered. Bladder augmentation can be considered for patients with small capacity or low compliance bladders. Ideal candidates for bladder augmentation are those with impaired emptying but still have the capability of performing CIC for the rest of their lives. These patients are at risk for metabolic abnormalities and stones after the procedure. After a mean of 4.4 years, it has been shown that 46 % will require intervention, although this was not specific to the MS patient population [57].

For patients with small bladder capacity, sphincter defects, or inability to perform transurethral CIC, a continent cutaneous diversion may be considered. This allows for a higher continence rate of >90 % when compared to bladder augmentation. However, when urinary diversion is considered in a patient with a progressive neurological disease, strong consideration should be given to incontinent diversion (i.e., ileal loop). This obviates the need for catheterization if disease progression limits the ability to catheterize and has a lower complication rate. It is the only choice if patients are unable to perform CIC or have chronic renal failure. Complications of diversion include ureterointestinal stenosis (2–7 %), stomal stenosis (up to 32 %), and stone formation (10 %) [58].

Conclusion

Multiple sclerosis remains one of the most common autoimmune inflammatory disorders producing complex neurogenic lower urinary tract dysfunction. The management of these patients is dependent on understanding of their neurologic disease progression, history of urologic therapies, and broad range of present urinary symptoms. Most patients will present with storage, voiding, or a combination of both storage and voiding symptoms. This will commonly be storage symptoms (i.e., frequency, urgency, and urgency incontinence) due to neurogenic detrusor overactivity. The variety of symptoms represents a spectrum of neurological lesions possible from the central nervous system that can change temporally and spatially.

The goals of managing these patients include promoting continence with appropriate bladder storage and emptying, creating a lower pressure bladder system, and improving quality of life. A crucial step in managing these patients is first identifying them. Recently developed screening tools including the ABSST and NBSS provide a new way to easily identify symptomatic MS patients who could benefit from urological evaluation. Appropriate initial evaluation includes a complete history and physical exam, with recommendations of urine testing and PVR. Urodynamics may be important for identifying the NLUTD; however, often treatment can start without a urodynamic diagnosis of NDO. Urodynamics can be used for initial evaluation if upper tract dysfunction, obstruction, or complex NLUTD is suspected.

Lifestyle modifications including fluid restriction, caffeine restriction, as well as behavioral modifications such as timed voiding and pelvic floor exercises serve as conservative measures that are initiated first. First line pharmacologic therapy includes anticholinergic/antimuscarinic medications, to treat urgency, frequency, urgency incontinence, and nocturia. Additional anticholinergics can be added if there is no improvement in symptoms. Additional agents such as desmopressin and diuretics can be added. New medications such as mirabegron (and potentially cannabinoids) may aid with improving urine storage without side effects often associated with anticholinergics/antimuscarinics (cognitive dysfunction, urinary retention), but more work is needed in the MS population. Patients refractory to medical therapy have benefited from onabotulinumtoxinA injections into the bladder. Randomized controlled trials have demonstrated improvements with urgency incontinence episodes and urodynamic parameters for onabotulinumtoxinA when compared to placebo and were independent of current use of anticholinergics. Other patients refractory to medical therapy may benefit from neuromodulation (i.e., percutaneous tibial nerve stimulation and sacral neuromodulation) targeting bladder reflex pathways. Refinement of the tools used to do this, and more compelling data will help clinicians understand which patients are ideal for these therapies.

For patients with primarily voiding symptoms, methods to empty the bladder (i.e., Credé’s maneuver, abdominal vibration, and timed voiding) have been used but clean intermittent self-catheterization remains the most recommended method as a safe and easy way to promote emptying. When this is not possible, urinary diversion with a cystotomy tube can be considered. Patients refractory to conservative approaches may benefit from complex reconstructions such as bladder augmentation or a urinary diversion.

Our repertoire of treatment options for managing NLUTD in MS patients is vast, ranging from conservative therapies to invasive surgeries. A therapeutic approach attempting to manage symptoms provides the best balance of providing a better quality of life for these patients without overuse of invasive diagnostic procedures. The future of our evaluations and treatment algorithms depends on more trials looking at the MS patient population as a distinct population among those with NLUTD.