Nocturia in Patients With Multiple Sclerosis

Management Review

Management Review Nocturia in Patients With Multiple Sclerosis Benoit Peyronnet, MD,1,2 Lauren B. Krupp, MD,3 W. Stuart Reynolds, MD, MPH,4 Xavier Gamé, MD, PhD,5 Gérard Amarenco, MD,6 Jean-Nicolas Cornu, MD, PhD,8 Lana Zhovtis Ryerson, MD,3 Carrie Lyn Sammarco, DrNP, FNP-C, MSCN,3 Jonathan E. Howard, MD,3 Robert W. Charlson, MD,3 Roger R. Dmochowski, MD,4 Benjamin M. Brucker, MD2 1Department of Urology, University of Rennes, Rennes, France; 2Department of Urology, New York University, New York, NY; 3Department of Neurology, New York University, New York, NY; 4Department of Urology, Vanderbilt University Medical Center, Nashville, TN; 5Department of Urology, University of Toulouse, Toulouse, France; 6Department of Neurourology, Tenon Hospital, Paris, France; 7Department of Neurology, University of Rennes, Rennes, France; 8Department of Urology, University of Rouen, Rouen, France The prevalence of nocturia in patients with multiple sclerosis (MS) is high, ranging from 20.9% to 48.8% in this population. Its underlying pathophysiology is complex and different from the non-neurogenic population. In the MS population, the pathophysiology may involve neurogenic lower urinary tract dysfunction (NLUTD) such as detrusor overactivity (NDO), detrusor-sphincter dyssynergia, or detrusor underactivity resulting in reduced bladder capacity. Nocturnal polyuria is also a significant contributor to the pathogenesis of nocturia in MS patients and may be the result of specific mechanisms such as nocturnal hypertension through autonomic cardiovascular dysfunction or lack of diurnal variation of antidiuretic hormone production (ADH) due to demyelinating lesions of the spinal cord. Nocturia might be particularly burdensome in MS patients by contributing to fatigue, a common and highly debilitating symptom in this population. There is likely a complex and multidirectional relationship between nocturia, other sleep disorders, and fatigue in the MS population that has yet to be explored. The assessment of nocturia in MS should rely upon a thorough history and physical examination. Urinalysis should be done to rule out urinary tract infection, a frequency-volume chart might help elucidating the underlying mechanisms, and post-void residual volume may be of interest to screen for urinary retention that could be asymptomatic in MS patients. Other tests such as urodynamics or polysomnography are indicated in selected patients. The treatment should be tailored to the underlying cause. The first steps involve behavioral interventions and treatment of cofactors. When possible, the predominant mechanism should be addressed first. In case of predominant NDO, antimuscarinics and beta-3 agonists should be offered as a first-line treatment and intradetrusor injections of botulinum toxin as a second-line treatment. In cases of incomplete bladder emptying, Vol. 21 No. 2/3 • 2019 • Reviews in Urology • 63 Nocturia in Patients With Multiple Sclerosis continued clean-intermittent self-catheterization is often used as part of multiple other interventions. In cases of nocturnal polyuria, desmopressin may be offered, inclusive of use of newer formulations (desmopressin acetate nasal spray, desmopressin orally disintegrated tablet) in countries where they are approved. [Rev Urol. 2019;21(2/3):63–73] ® © 2019 MedReviews , LLC KEY WORDS Nocturia • Nocturnal polyuria • Desmopressin • Voiding diary • Multiple sclerosis • Fatigue M ultiple 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 people in Europe and 135 per 100,000 people in the United States, it is estimated that over 2.3 million individuals are living with MS worldwide.2,3 Neurogenic lower urinary tract dysfunction (NLUTD) is common in MS patients, resulting in lower urinary tract symptoms (LUTS) in up to 95% of the MS population.4 Among the multitude of LUTS experienced by MS patients, nocturia is often stressed as one of the most common and bothersome, associated with sleep disturbance and deprivation, low vitality, poor emotional health, and an overall reduced quality of life.5 This article reviews the evidence regarding nocturia pathophysiology, epidemiology, and management in the MS population. Definition and Epidemiology of Nocturia According to the International Continence Society (ICS), nocturia is defined as the complaint that the individual wakes at night 1 or more times to void.6 However, several studies have demonstrated that a single nocturia episode has only marginal impact on patients’ quality of life.7 Hence, the threshold of $2 voids per night is the most widely accepted to define clinically meaningful nocturia, that is, nocturia associated with significant negative outcomes for health and well-being.7-9 In the non-neurogenic population, the prevalence of nocturia has been demonstrated to increase with age. When using $2 voids per night as a definition, nocturia was found to affect 2% to 18% of adults age 20 to 39 years, and up to 59% of men and 62% of women 64 • Vol. 21 No. 2/3 • 2019 • Reviews in Urology older than 70 years.9-10 Overactive bladder (OAB) symptoms are observed in over 90% of patients with MS.11-12 Although the epidemiology of OAB symptoms in MS patients has been well studied,11-12 data on the prevalence of nocturia in this specific population are relatively scarce. However, the available data suggest nocturia is highly prevalent in the MS population, observed in 20.9% to over 48.8% of patients of mean age 39.3 to 52.5 years.13-16 In the large North American Research Committee on Multiple Sclerosis (NARCOMS) registry, nocturia was found to be the most common OAB symptoms in MS patients, reported as being moderately to greatly bothersome by 48.8% of the 9702 patients evaluated.13-14 Pathophysiology of Nocturia in MS Patients Nocturia had long been regarded predominantly as a male symptom caused by benign prostatic hyperplasia (BPH) contributing to prostatism.17-18 However, the similar prevalence of nocturia among men and women has since been demonstrated and the pathophysiological contributions of kidney and bladder dysfunctions and numerous non-urological comorbidities (eg, sleep apnea, endocrine dysfunction, cardiovascular disease, etc) to the symptom of nocturia has been increasingly recognized.10 It is now well established that three different pathophysiological mechanisms may be involved in the genesis of nocturia: reduced bladder capacity, global polyuria, and nocturnal polyuria.8,19 There is a wide spectrum of underlying causes to these three mechanisms, and the causative factors involved in the MS population differ from those observed in the non-neurogenic population. The pathophysiological mechanisms of nocturia, and potential unique underlying causes in MS are summarized in Table 1. Nocturia in Patients With Multiple Sclerosis TABLE 1 Pathophysiological Mechanisms of Nocturia and Potential Unique Mechanisms in Multiple Sclerosis Versus Non-neurogenic Patients Reduced Bladder Capacity Global Polyuria Nocturnal Polyuria Potential Underlying Mechanisms Potential Underlying Mechanisms Potential Underlying Mechanisms MS Patients NDO DSD DU Non-neurogenic Patients OAB BPH MS Patients Non-neurogenic Patients Diabetes insipidus Diabetes insipidus (hypothalamus Poorly controlled lesion induced) diabetes mellitus Primary polydipPolydypsia sia (cognitive Iatrogenic dysfunction) MS Patients SCI-related nocturnal hypertension SCI-related lack of diurnal variation of ADH production Daytime lower-limb venous pooling due to neurological impairment Obstructive sleep apnea Non-neurogenic Patients Night-time fluid intake Obstructive sleep apnea Edematous state Lack of diurnal variation of ADH secretion Mixed ADH, antidiuretic hormone; BPH, benign prostatic hyperplasia; DSD, detrusor sphincter dyssynergia; DU, detrusor underactivity; MS, multiple sclerosis; NDO, neurogenic detrusor overactivity; OAB, overactive bladder. Reduced Bladder Capacity The underlying causes of reduced bladder capacity in MS patients include unique etiologies that differ from those observed in the non-neurogenic population, which commonly include only OAB or BPH.9,19 As MS can generate demyelinating lesions anywhere in the central nervous system (CNS), there are a large variety of neurogenic lower urinary tract dysfunctions (NLUTD) that can be associated with MS.11-12,20 Typically, lesions in the subcortical white matter, brainstem, and spinal cord are associated with neurogenic detrusor overactivity (DO), which is reported in over 90% after 10 years of MS course.11,21 Lesions of the reticulospinal tracts usually result in detrusor-sphincter dyssynergia (DSD) that has been reported in up to 35% of MS patients overall.20-21 Finally, lesions at the conus medullaris can cause detrusor underactivity (DU), which have been observed in up to 25% of MS patients.20-21 NLUTD are not mutually exclusive and often coexist.11-12,20-21 Because neurogenic DO (NDO) and neurogenic voiding dysfunction (DU and DSD) are the most probable causes of reduced bladder capacity in MS patients, the treatment algorithm for this population differs significantly from nonneurogenic patients, where reduced bladder capacity is identified as one of the determinants of nocturia. 40 mL/kg body weight.10,19 In the non-neurogenic population, global polyuria often results from behavioral polydipsia, poorly controlled diabetes mellitus (with dehydration prompting high fluid intake), or side effects of medications such as diuretics, selective serotonin reuptake inhibitors, calcium channel blockers, tetracycline, and lithium.19 In addition to these causes, MS patients may have cognitive changes contributing to behavioral polydipsia. Diabetes insipidus is a rare cause of global polyuria that should be considered in MS patients with hypothalamic involvement. Global Polyuria Global polyuria, also called 24-hour polyuria, is defined as a 24-hour urinary output exceeding Nocturnal Polyuria Nocturnal polyuria is defined by the ICS as a nocturnal polyuria index (NPI): nocturnal urine volume Vol. 21 No. 2/3 • 2019 • Reviews in Urology • 65 Nocturia in Patients With Multiple Sclerosis continued (including the first morning void)/24hour urine volume of more than 20% in young patients and 33% in elderly patients.6 In non-neurogenic patients, nocturnal polyuria usually results from impaired circadian rhythm of antidiuretic hormone (ADH) secretion, excessive nocturnal fluid intake, diuretics intake at night, increased levels of atrial natriuretic peptide (ANP) due to obstructive sleep apnea or congestive heart failure, or edematous state with thirdspace fluid sequestration from supine positioning at night leading to interstitial fluid redistribution into the intravascular compartment and thus leading to additional water load on the kidney and increased urine production.19,24 As the prevalence of most of these mechanisms increase with age, several studies have demonstrated that, in nonneurogenic populations, nocturnal polyuria assumes greater importance in older nocturic patients whereas reduced bladder capacity appears to play a greater role in younger patients.25 Despite MS patients being younger than other typical nocturic populations, the role of nocturnal polyuria might be of greater importance in MS versus same-aged non-neurogenic patients with nocturia. For example, MS patients have a high prevalence of obstructive sleep apnea, a well-established cause of nocturnal polyuria through increased level of ANP.29 Furthermore, MS patients may have unique pathophysiology contributing to the nocturnal polyuria. For example, patients with spinal cord injury have been shown to have nocturnal hypertension as a result of changes in the spinal cord vasomotor pathways and autonomic cardiovascular dysfunction. This elevated nocturnal blood pressure favors increased salt clearance at night.26 We could theorize that MS patients with significant burden of disease in the spinal cord may then have nocturnal polyuria through similar mechanism. Lack of diurnal variation of ADH production is another mechanism of nocturnal polyuria due to a spinal cord lesion and that could also contribute to nocturia in MS patients.27-28 It is assumed to be related to impaired sympathetic control of cardiovascular homeostasis in postural changes.27-28 Other causes of nocturnal polyuria in spinal cord–injured patients that may also play a role in MS patients could be a decrease of vascular tone due to impaired autonomic function and lack of the skeletal muscle pump. This may result in lower limb venous pooling while upright and returning circulating volume while recumbent overnight and thus increasing renal perfusion pressures.26-28 Although work with the spinal cord–injured population provides a pathophysiological basis, these mechanisms still need investigation in the MS population. These possible mechanisms of nocturnal polyuria in MS patients are presented in Figure 1. Fatigue, Nocturia, and Other Sleep Disorders in MS Patients According to the 1998 Multiple Sclerosis Council for Clinical Practice Guidelines, fatigue is defined as a subjective lack of physical and/or mental energy that is perceived by the individual or caregiver to interfere with usual and desired activities.30 This is an extremely prevalent symptom in the MS population, affecting over 80% of patients.31 Fatigue has also been proven highly burdensome and to negatively impact MS Lack of diurnal variation of ADH production driven by spinal cord lesions Daytime lower limb venous pooling due to neurological impairment Nocturnal polyuria in MS patients Obstructive sleep apnea Nocturnal hypertension due to autonomic cardiovascular dysfunction Figure 1. Postulated mechanisms of nocturnal polyuria in patients with multiple sclerosis. ADH, antidiuretic hormone; MS, multiple sclerosis. 66 • Vol. 21 No. 2/3 • 2019 • Reviews in Urology Nocturia in Patients With Multiple Sclerosis patients’ quality of life.32 Although the pathophysiology of fatigue in MS patients is still uncertain, there is a consensus that fatigue pathogenesis is multifactorial in nature.32-33 MS-related fatigue is usually conceptualized as either primary (intrinsic to the MS disease process) or secondary to chronic illness factors, such as medication, depression, or poor sleep.32-33 MS patients have a higher frequency of sleep disorders as compared with the general population, including obstructive sleep apnea, narcolepsy, rapid-eye movement sleep behavior disorder, periodic limb movements of sleep, and restless leg syndrome.32-34 Sleep disorders have thus been increasingly recognized as significant contributors to MS-related fatigue and, according to the recent management algorithm, should always been looked for and considered when treating fatigue in MS patients.33-34 With a prevalence of 20% to 48.8%, nocturia is one of the most common sleep disorders in MS patients.13-16,35 However, although the impact of other sleep disorders on fatigue has been extensively studied in the MS population, to our knowledge no study has examined the relationship between nocturia and fatigue in MS.34 However, one may assume that nocturia, as other sleep disorders, may significantly contribute to the pathogenesis of MS-related fatigue and that screening for and treating nocturia may improve the outcomes of the comprehensive management of fatigue in MS patients. Interestingly, it has been recently postulated that sleep deprivation, by affecting the circadian fluctuations of physiologic function such as hemodynamics (through natriuresis and dopaminergic dysregulations), may increase nighttime urine production, adding to the complexity of the relationship between sleep disorders and nocturia.36 As several studies suggest that fatigue may not only be a consequence but also a cause of sleep disorders, there is likely a complex and multidirectional relationship between nocturia, sleep disorders, and fatigue in the MS population (Figure 2). Further studies examining the extent to which the urge to urinate may be a consequence, rather than a cause, of nocturnal awakenings will be necessary to improve our understanding of the complex relationship between these entities. Assessment of Nocturia in Multiple Sclerosis Patients As in the general population, the assessment of nocturia in MS patients should be comprehensive, aiming to explore the multiple possible underlying mechanisms in order to tailor treatment. It begins with a thorough history, especially asking about daytime LUTS, which may suggest reduced bladder capacity as an underlying mechanism (in contrast, isolated nocturia would indicate nocturnal polyuria might be predominant).4-5,9,37 The use of questionnaires such as the International Prostate Symptoms Score (IPSS), overactive bladder symptoms score (OABSS), or Qualiveen may help documenting LUTS, even though the first two have not been validated specifically in the MS population.4-5,9,37 Patients should also be asked about fluid intake and comorbid conditions with special emphasis on those known to contribute to nocturia (eg, congestive heart disease, venous insufficiency, etc).9,37 Screening for symptoms of obstructive sleep apnea, including using tools such as the Epworth Sleepiness Scale, may be particularly relevant in MS patients owing to its high prevalence in this population.32,35 The existence of other sleep disorders (eg, restless leg syndrome, periodic limb movements of sleep, etc) should also be determined. On physical examination, attention should be given to the presence of peripheral edema, bladder distention, and obesity as clues to the underlying etiology. Sleep disorders Nocturia Fatigue Figure 2. The complex and multidirectional relationship between nocturia, sleep disorders, and fatigue in multiple sclerosis patients. Vol. 21 No. 2/3 • 2019 • Reviews in Urology • 67 Nocturia in Patients With Multiple Sclerosis continued Concomitant conditions possibly contributing to the occurrence of nocturia, such as pelvic organ prolapse or enlarged prostate (on digital rectal examination), should be sought.9 On clinical evaluation, attention should also be paid to the patients’ neurological status as it has been proven to strongly correlate with the presence and severity of NLUTD in MS patients and may be another clue to mechanisms underpinning nocturia.4,12,21 Mobility could contribute specifically by causing functional nocturnal incontinence by hampering autonomous access to the bathroom. The evaluation should also strive to evaluate the impact of nocturia, notably on patients’ quality of life and fatigue. To that purpose, the Impact of Night-Time Urination (INTU) questionnaire, a dedicated patient-reported outcome measure has recently been developed and validated (in men and women but not specific to MS patients), might be of interest.38 One may also evaluate the presence and severity of fatigue using validated questionnaires such as the Fatigue Severity Scale (FSS).39 Completion of a frequency-volume chart (FVC) is unanimously recommended by all scientific societies to elucidate the underlying pathophysiological mechanisms of nocturia.8,25,37 However, the impact of FVC on nocturia treatment outcomes has never been proven.40 The prevalence of nocturnal polyuria is very high10 and one may assume that some clinical factors may predict the involvement of nocturnal polyuria (the amount of urine voided at night as estimated by the patient, etc). However, the predictive value of these clinical parameters has never been evaluated and FVC remains the gold standard in the assessment of patients with nocturia. Urinalysis is recommended to rule out urinary tract infections and diabetes.8,25,37 An assessment of post-void residual volume (PVR) might also be of interest to rule out voiding dysfunction, which may not always be symptomatic in MS patients.4-5,12,21 Polysomnography should be considered in case of clinical suspicion of obstructive sleep apnea syndrome. If NLUTD is suspected based on the initial work-up, urodynamics may be considered to identify DU, DSD, and NDO. Brain MRI might be considered if diabetes insipidus is diagnosed to rule out demyelinating lesions in the hypothalamus. All these elements and tests of possible interest in the evaluation of nocturia in MS patients are summarized in Table 2. Treatment A simplified algorithm of therapeutic management of nocturia in MS patients is presented in Figure 3. Physicians should strive to tailor the treatment to the underlying cause of nocturia. Behavioral Interventions Regardless of the underlying mechanism, behavioral interventions are the first steps in managing nocturia. Simple measures such as education about the normal physiology of the bladder and behavioral interventions have been shown to improve nocturnal voids.9,37 Dietary modifications, with limitation of nighttime fluid intake, voiding before going to bed, and avoidance of TABLE 2 Assessment of Nocturia in Patients With Multiple Sclerosis History Lower urinary tract symptoms Fluid intake Comorbid conditions (congestive heart disease, venous insufficiency) Symptoms of obstructive sleep apnea (Epworth Sleepiness Scale) Other sleep disorders Impact of nocturia Physical examination Edematous state Palpable bladder/ bladder distension Obesity Pelvic organ prolapse Benign prostatic hyperplasia Neurological status Other tests Frequency volume chart Urinalysis Post-void residual volume Urodynamics Polysomnography Elements put forward in this table are only suggestions of possible tools that may help evaluating nocturia in these patients. However, evaluation of each individual MS patient with nocturia should be individualized and guided by clinical judgements. 68 • Vol. 21 No. 2/3 • 2019 • Reviews in Urology Nocturia in Patients With Multiple Sclerosis next therapeutic step. However, like OAB medications, the effect of botulinum toxin injections on nocturia has not been specifically investigated in the randomized controlled trials that have led to its approval in NDO.45-46 Of note, after a recent placebo controlled randomized trial, onabotulinum toxin A can now be offered to non-catheterizing MS patients at the lower dose of 100 U.47 MS patients with bothersome nocturia Behavioral interventions Treatment of cofactors Failed? Treat predominant mechanism first Reduced bladder capacity Nocturnal polyuria Voiding dysfunction? Yes - Alpha-blockers - Clean-intermittent catheterization Desmopressin* No - Antimuscarinics/ Beta3 agonists - Intradetrusor injections of botulinum toxin Global polyuria - Decrease 24h fluid intake - Refer to endocrinologist if diabetes mellitus or insipidus is diagnosed or suspected Figure 3. Treatment algorithm of nocturia in multiple sclerosis (MS) patients. caffeine, alcohol, and tea, should also be implemented before any pharmacological treatment is considered.9,24,37 Adherence and persistence of these methods in this population are largely unknown. In patients with increased nocturnal urine output, addressing specific factors such as leg edema (leg elevation in the early evening, use of compressive stocking), more systemic edematous state (altering the timing of diuretic medication administration if appropriate), or obstructive sleep apnea syndrome (continuous positive airway pressure) may also be beneficial. Treatment of NDO In nocturic MS patients with predominantly reduced bladder capacity (vs nocturnal polyuria and global polyuria) and no complaint of voiding dysfunction (nor high PVR), the underlying cause of nocturia is likely to be NDO. Antimuscarinics and/or beta-3 agonists are the first line treatment options in these scenarios, paralleling idiopathic OAB care pathways.41 However, no data have been reported so far regarding the impact of these pharmacological treatments on the specific symptom of nocturia. Of note, among all OAB medications currently available, randomized controlled trials have been published only for oxybutynin, solifenacin, and mirabegron.42-44 If nocturia persists, intradetrusor injections of onabotulinum toxin A is the Treatment of Voiding Dysfunction In nocturic MS patients with predominantly reduced bladder capacity (vs nocturnal polyuria and global polyuria) complaining of voiding symptoms, and diagnosed with high PVR, voiding dysfunction is likely to be the major underlying etiology of nocturia. Alpha-blockers could be offered as a first-line treatment, but cleanintermittent self-catheterization is often regarded as the gold-standard management in these situations, especially in case of high PVR.4-5,12,21 Similar to NDO treatments, the impact of alpha-blockers or self-catheterization on nocturia has not specifically been studied. Desmopressin Desmopressin, a synthetic analog of vasopressin, is usually regarded as the therapeutic option of choice to treat nocturia due to nocturnal polyuria, with several clinical trials demonstrating that it results in reduced nocturnal urine output and nocturnal voids.48 Nine studies have aimed to assess the role of desmopressin in MS patients with nocturia, including seven small randomized controlled trials.49-58 The main findings of these studies are summarized in Table 3. They reported an efficacy that parallels that reported in the general population with a mean reduction of number of nocturic Vol. 21 No. 2/3 • 2019 • Reviews in Urology • 69 Year 1983 1990 1994 1995 Study Hilton P et al50 Kinnv AC et al51 70 • Vol. 21 No. 2/3 • 2019 • Reviews in Urology Eckford SD et al52 Eckford SD et al53 United Kingdom United Kingdom Sweden United Kingdom Country 8 Desmopressin 50 μg/day 8 Desmopressin 20 μg/day 8 8 Placebo Desmopressin 40 μg/day 31 31 Placebo Desmopressin 20 μg/day 13 13 Placebo Desmopressin 16 16 Placebo Desmopressin 20 μg/day Number of Patients Groups Male/Female 46 46 46 46 NR NR 48 48 NR NR 0/8 0/8 0/8 0/8 11/22 11/22 4/9 4/9 0/16 0/16 NR NR NR NR 1.8 1.8 NR NR 2.5 2.5 Number of Nocturia Episodes at Baseline Randomized Controlled Trials Mean Age (y) Main Characteristics and Findings of Studies on Desmopressin in MS Patients TABLE 3 NR NR NR NR 20.5 20.1 NR NR 21.3 20.5 Mean Reduction in Number of Nocturia Episodes per Night 0 0 0 0 2 (6.5%) 0 0 0 0 0 Hyponatremia (%) 0 0 0 0 2 (6.5%) 2 (6.5%) 0 0 1 (10%) 1 (10%) Nausea/ Headaches (%) Nocturia in Patients With Multiple Sclerosis continued Greece United Kingdom United Kingdom USA Sweden 10 10 Desmopressin 20 μg/day Desmopressin 20 μg/day 16 Desmopressin 22 22 placebo Desmopressin 20 μg/day 17 Desmopressin 10 μg/day 17 Placebo 22 22 Placebo Desmopressin 20 μg/day LE, level of evidence; NR, not reported; NA, not applicable. 2008 Zahariou A et al58 1998 Hoverd PA et al56 1999 1996 Valiquette G et al55 Tubridy N et al57 1996 Fredrikson S54 43.5 43.5 47.5 43 43 48.9 48.9 51 51 0/10 0/10 3/16 Case Series 10/16 10/16 3/14 3/14 7/19 7/19 2.3 2.3 NR NR NR 2.3 2.3 NR NR 21.4 20.7 21.4 NR NR 21.2 20.3 NR NR 0 0 0 1 (4.5%) NR 4 (23.5%) NR 0 0 1 (10%) 1 (10%) 4 (21.1%) 2 (9.1%) NR 1 (5.9%) NR 0 0 Nocturia in Patients With Multiple Sclerosis Vol. 21 No. 2/3 • 2019 • Reviews in Urology • 71 Nocturia in Patients With Multiple Sclerosis continued episodes per night ranging from 0.48 to 1.4.49-58 However, these studies raised safety concerns, with up to 24% of patients developing hyponatremia,49 resulting in a marginal use of desmopressin in the MS population. Other significant drawbacks of existing literature on desmopressin in MS patients are the lack of patient-reported outcomes and quality of life measures.49-58 Two newer formulations of desmopressin have recently been approved for nocturia in the United States [desmopressin acetate nasal spray (Noctiva , Serenity Pharmaceuticals, Milford, PA) and in Europe/Canada/Australia [desmopressin orally disintegrated tablet (Nocdurna , Ferring Pharmaceuticals, Saint Prex, Switzerland)].59 These approvals were significant milestones by being the first labeled drug for nocturia (United States) and by making desmopressin also available to elderly patients (age .65 years), a large patient population who previously had limited treatment options as the approval for desmopressin sublingual wafer (Minirin Melt , Ferring Pharmaceuticals) had an upper age limitation of 65 years.59 Nocdurna is a desmopressin orally disintegrated tablets in gender-specific doses, tailored specifically for men (50 mcg) and women ® ® ® (25 mcg) that has been approved in Canada, Australia, and Europe based on the publication of two phase 3 randomized controlled trials conducted in men and in women, respectively.59 Nocdurna has recently been approved by the FDA and is expected to be commercially available in United States shortly. Noctiva is a desmopressin acetate nasal spray (AV002) that has recently been FDA approved as a very low-dose desmopressin formulation.60 Noctiva has been designed and engineered to achieve consistent, rapid, low blood concentrations by adding cyclopentadecanolide, an excipient that enhances the bioavailability of the drug. Additionally, it is administered by nasal spray that is designed to allow for even and rapid absorption in the nasal turbinates. These developments allow for the lowest therapeutic dose of antiduretic to be administered, but limits the antidiuretic effect to the hours of sleep, thereby minimizing the risk of hyponatremia.60 AV002 has been evaluated in two large randomized placebo-controlled trials, evidencing a better safety profile compared with previous desmopressin formulations in the general population.61 AV002 might especially be of interest in MS patients owing to its safety profile. Further studies are needed to elucidate the outcomes of these newer formulations of desmopressin specifically in the MS population. Conclusions Nocturia is highly prevalent in MS patients. The pathophysiology of nocturia in MS population may be unique and more complex as compared with the general population and needs further evaluation. Nocturia may contribute to fatigue, one of the most burdensome symptoms of MS. Owing to the complexity of nocturia in MS patients, a comprehensive assessment aiming to identify underlying etiologies is paramount in order to tailor the therapeutic approach and increase the chance of treatments’ success. The recently approved pharmacological treatments targeting nocturnal polyuria might be of interest in the MS population, although more studies in this population are required to demonstrate safety, efficacy, and potential for qualityof-life improvement. Drs. Dmochowski and Brucker were consultants for Serenity Pharmaceuticals until January 2019. The other authors have nothing to disclose. References 1. 2. Compston A, Coles A. Multiple sclerosis. Lancet. 2002;359:1221-1231. Rubin SM. Management of multiple sclerosis: an overview. Dis Mon. 2013;59:253-260. Main Points • Nocturia is highly prevalent in multiple sclerosis (MS) patients, and the pathophysiology of nocturia in this population may be unique and more complex as compared with the general population. • Nocturia may contribute to fatigue, one of the most burdensome symptoms of MS. • Owing to the complexity of nocturia in MS patients, a comprehensive assessment aiming to identify underlying etiologies is paramount in order to tailor the therapeutic approach and increase the chance of treatments’ success. • The recently approved pharmacological treatments based on desmopressin targeting nocturnal polyuria might be of interest in the MS population, although more studies in this population are required to demonstrate safety, efficacy, and potential for quality-of-life improvement. 72 • Vol. 21 No. 2/3 • 2019 • Reviews in Urology Nocturia in Patients With Multiple Sclerosis 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. World Health Organization. Atlas: Multiple Sclerosis Resources in the World 2008. Geneva, Switzerland: World Health Organization; 2008. https://www.who. int/mental_health/neurology/Atlas_MS_WEB.pdf. Accessed April 22, 2019. Aharony SM, Lam O, Corcos J. Evaluation of lower urinary tract symptoms in multiple sclerosis patients: review of the literature and current guidelines. Can Urol Assoc J. 2017;11:61-64. Panicker JN, Fowler CJ, Kessler TM. Lower urinary tract dysfunction in the neurological patient: clinical assessment and management. Lancet Neurol. 2015;14:720-732. van Kerrebroeck P, Abrams P, Chaikin D, et al. The standardisation of terminology in nocturia: report from the Standardisation Sub-committee of the International Continence Society. Neurourol Urodyn. 2002;21:179-183. Tikkinen KA, Johnson 2nd TM, Tammela TL, et al. Nocturia frequency, bother, and quality of life: how often is too often? A population-based study in Finland. Eur Urol. 2010;57:488-496. Everaert K, Hervé F, Bower W, et al. How can we develop a more clinically useful and robust algorithm for diagnosing and treating nocturia? ICI-RS 2017. Neurourol Urodyn. 2018;37(suppl 4):S46-S59. Kowalik CG, Cohn JA, Delpe S, et al. Nocturia: evaluation and current management strategies. Rev Urol. 2018;20:1-6. Bosch JL, Weiss JP. The prevalence and causes of nocturia. J Urol. 2013;189(1 suppl):S86-S92. de Sèze M, Gamé X. Multiple sclerosis and pelviperineology: urinary and sexual dysfunctions and pregnancy. Prog Urol. 2014;24:483-494. Sadiq A, Brucker BM. Management of neurogenic lower urinary tract dysfunction in multiple sclerosis patients. Curr Urol Rep. 2015;16:44. Marrie R, Cutter G, Tyry T, et al. Disparities in the management of multiple sclerosis-related bladder symptoms. Neurology. 2007;68:1971-1978. Mahajan ST, Patel PB, Marrie RA. Under treatment of overactive bladder symptoms in patients with multiple sclerosis: an ancillary analysis of the NARCOMS Patient Registry. J Urol. 2010;183:1432-1437. Khalaf KM, Coyne KS, Globe DR, et al. Lower urinary tract symptom prevalence and management among patients with multiple sclerosis. Int J MS Care. 2015;17:14-25. Akkoç Y, Ersöz M, Yüceyar N, et al. Overactive bladder symptoms in patients with multiple sclerosis: frequency, severity, diagnosis, and treatment. J Spinal Cord Med. 2016;39:229-233. Abrams P. New words for old: lower urinary tract symptoms for “prostatism”. BMJ. 1994;308:929-930. Abrams P. Nocturia: escaping the “prostate-centric” approach. J Urol. 2011;185:781-782. Van Kerrebroeck P, Andersson KE. Terminology, epidemiology, etiology, and pathophysiology of nocturia. Neurourol Urodyn. 2014;33(suppl 1):S2-S5. Panicker JN, Fowler CJ. Lower urinary tract dysfunction in patients with multiple sclerosis. Handb Clin Neurol. 2015;130:371-381. de Sèze M, Ruffion A, Denys P, et al; GENULF. The neurogenic bladder in multiple sclerosis: review of the literature and proposal of management guidelines. Mult Scler. 2007;13:915-928. Thouvenot E, Schmidt C, Héroum C, et al. Diabetes insipidus as a first manifestation in multiple sclerosis. Neurology. 2011;76:1939-1944. Woolley J, Douglas VC, Cree BA. Neuromyelitis optica, psychiatric symptoms and primary polydipsia: a case report. Gen Hosp Psychiatry. 2010;32:648.e5-e8. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42. Dani H, Esdaille A, Weiss JP. Nocturia: aetiology and treatment in adults. Nat Rev Urol. 2016;13:573-583. Weiss JP, Bosch JL, Drake M, et al. Nocturia Think Tank: focus on nocturnal polyuria: ICI-RS 2011. Neurourol Urodyn. 2012;31:330-339. Goh MY, Millard MS, Wong ECK, et al. Comparison of diurnal blood pressure and urine production between people with and without chronic spinal cord injury. Spinal Cord. 2018;56:847-855. Kilinç S, Akman MN, Levendoglu F, Ozker R. Diurnal variation of antidiuretic hormone and urinary output in spinal cord injury. Spinal Cord. 1999;37: 332-335. Szollar S, North J, Chung J. Antidiuretic hormone levels and polyuria in spinal cord injury. A preliminary report. Paraplegia. 1995;33:94-97. Hensen HA, Krishnan AV, Eckert DJ. Sleep-disordered breathing in people with multiple sclerosis: prevalence, pathophysiological mechanisms, and disease consequences. Front Neurol. 2018;8:740. Multiple Sclerosis Council for Clinical Practice Guidelines, ed. Fatigue and Multiple Sclerosis: EvidenceBased Management Strategies For Fatigue In Multiple Sclerosis. Washington, DC: Paralyzed Veterans Association of America; 1998. Minden SL, Frankel D, Hadden L, et al. The Sonya Slifka Longitudinal Multiple Sclerosis Study: methods and sample characteristics. Mult Scler. 2006;12:24-38. Krupp LB, Serafin DJ, Christodoulou C. Multiple sclerosis-associated fatigue. Expert Rev Neurother. 2010;10:1437-1447. Veauthier C, Hasselmann H, Gold SM, Paul F. The Berlin Treatment Algorithm: recommendations for tailored innovative therapeutic strategies for multiple sclerosis-related fatigue. EPMA J. 2016;7:25. Veauthier C, Paul F. Sleep disorders in multiple sclerosis and their relationship to fatigue. Sleep Med. 2014;15:5-14. Marrie RA, Reider N, Cohen J, et al. A systematic review of the incidence and prevalence of sleep disorders and seizure disorders in multiple sclerosis. Mult Scler. 2015;21:342-349. Denys MA, Cherian J, Rahnama’i MS, et al. ICI-RS 2015—Is a better understanding of sleep the key in managing nocturia? Neurourol Urodyn. 2018;37:2048-2052. Oelke M, De Wachter S, Drake MJ, et al. A practical approach to the management of nocturia. Int J Clin Pract. 2017;71(11). Bennett JB, Gillard KK, Banderas B, et aL. Development of a new patient-reported outcome (PRO) measure on the Impact of Nighttime Urination (INTU) in patients with nocturia-Psychometric validation. Neurourol Urodyn. 2018;37:1678-1685. Krupp LB, LaRocca NG, Muir-Nash J, Steinberg AD. The fatigue severity scale. Application to patients with multiple sclerosis and systemic lupus erythematosus. Arch Neurol. 1989;46:1121-1123. Drangsholt S, Ruiz MJA, Peyronnet B, et al. Diagnosis and management of nocturia in current clinical practice: who are nocturia patients, and how do we treat them? World J Urol. 2018 Oct 4. doi: 10.1007/s00345018-2511-4. Gormley EA, Lightner DJ, Faraday M, et al Diagnosis and treatment of overactive bladder (non-neurogenic) in adults: AUA/SUFU guideline amendment. J Urol. 2015;193:1572-1580. Amarenco G, Sutory M, Zachoval R, et al. Solifenacin is effective and well tolerated in patients with neurogenic detrusor overactivity: results from the double-blind, randomized, active- and placebo-controlled SONIC urodynamic study. Neurourol Urodyn. 2017;36:414-421. 43. 44. 45. 46. 47. 48. 49. 50. 51. 52. 53. 54. 55. 56. 57. 58. 59. 60. 61. Nicholas RS, Friede T, Hollis S, Young CA. Anticholinergics for urinary symptoms in multiple sclerosis. Cochrane Database Syst Rev. 2009:CD004193. Krhut J, Borovička V, Bílková K, et al. Efficacy and safety of mirabegron for the treatment of neurogenic detrusor overactivity-Prospective, randomized, double-blind, placebo-controlled study. Neurourol Urodyn. 2018;37:2226-2233. Cruz F, Herschorn S, Aliotta P, et al Efficacy and safety of onabotulinumtoxinA in patients with urinary incontinence due to neurogenic detrusor overactivity: a randomised, double-blind, placebo-controlled trial. Eur Urol. 2011;60:742-750. Ginsberg D, Gousse A, Keppenne V, et al. Phase 3 efficacy and tolerability study of onabotulinumtoxinA for urinary incontinence from neurogenic detrusor overactivity. J Urol. 2012;187:2131-2139. Tullman M, Chartier-Kastler E, Kohan A, et al. Lowdose onabotulinumtoxinA improves urinary symptoms in noncatheterizing patients with MS. Neurology. 2018;91:e657-e665. Ebell MH, Radke T, Gardner J. A systematic review of the efficacy and safety of desmopressin for nocturia in adults. J Urol. 2014;192:829-835. Phé V, Schneider M, Peyronnet B, et al. Desmopressin for treating nocturia in patients with multiple sclerosis: a systematic review. A report from the Neuro-Urology Promotion Committee of the International Continence Society (ICS). NeuroUrol Urodyn. 2019;38:563-571. Hilton P, Hertogs K, Stanton SL. The use of desmopressin (DDAVP) for nocturia in women with multiple sclerosis. J Neurol Neurosurg Psychiatry. 1983;46:854-855. Kinn AC, Larsson PO. Desmopressin: a new principle for symptomatic treatment of urgency and incontinence in patients with multiple sclerosis. Scand J Urol Nephrol. 1990;24:109-112. Eckford SD, Swami KS, Jackson SR, Abrams PH. Desmopressin in the treatment of nocturia and enuresis in patients with multiple sclerosis. Br J Urol. 1994;74:733-735. Eckford SD, Carter PG, Jackson SR, et al. An open, inpatient incremental safety and efficacy study of desmopressin in women with multiple sclerosis and nocturia. Br J Urol. 1995;76:459-463. Fredrikson S. Nasal spray desmopressin treatment of bladder dysfunction in patients with multiple sclerosis. Acta Neurol Scand. 1996;94:31-34. Valiquette G, Herbert J, Maede-D’Alisera P. Desmopressin in the management of nocturia in patients with multiple sclerosis. A double-blind, crossover trial. Arch Neurol. 1996;53:1270-1275. Hoverd PA, Fowler CJ. Desmopressin in the treatment of daytime urinary frequency in patients with multiple sclerosis. J Neurol Neurosurg Psychiatry. 1998;65:778-780. Tubridy N, Addison R, Schon F. Long term use of desmopressin for urinary symptoms in multiple sclerosis. Mult Scler. 1999;5:416-417. Zahariou A, Karamouti M, Karagiannis G, Papaioannou P Maximal bladder capacity is a positive predictor of response to desmopressin treatment in patients with MS and nocturia. Int Urol Nephrol. 2008;40:65-69. Peyronnet B, Brucker BM, Michel MC. Lower urinary tract symptoms: what’s new in medical treatment? Eur Urol Focus. 2018;4:17-24. Cohn JA, Kowalik CG, Reynolds WS, et al. Desmopressin acetate nasal spray for adults with nocturia. Expert Rev Clin Pharmacol. 2017;10:1281-1293. Kaminetsky J, Fein S, Dmochowski R, et al. Efficacy and safety of SER120 nasal spray in nocturia patients pooled analysis of 2 randomized, double-blind, placebocontrolled phase 3 trials. J Urol. 2018;200:604-611. Vol. 21 No. 2/3 • 2019 • Reviews in Urology • 73