Current Drug Therapy, 2012, 7, 67-76 67 “Vascular Incontinence” and Normal-Pressure Hydrocephalus: Two Commonsources of Elderly Incontinence with Etiologies

Ryuji Sakakibara1,*, Jalesh Panicker2, Clare J. Fowler2, Fuyuki Tateno1, Masahiko Kishi1, Yohei Tsuyusaki1, Tomoyuki Uchiyama3 and Tatsuya Yamamoto3

1Neurology, Internal Medicine, Sakura Medical Center, Toho University, Sakura, Japan; 2Uro-Neurology, the National Hospital for Neurology & , Queen Square, London, United Kingdom; 3Neurology, Chiba University, Chiba, Japan

Abstract: This paper reviewed two common sources of elderly incontinence with brain etiologies, “vascular incontinence” (a disorder of bladder control resulting from cerebral white matter disease) and normal-pressure hydrocephalus (NPH), from a neurological point of view. Both diseases manifest with gait disturbance, , and . Urinary frequency/ urgency (overactive bladder, OAB) often precedes urinary incontinence in both diseases, and in some patients may be the initial manifestation. While NPH is less common than vascular incontinence, at approximately one-tenth the prevalence, it is important because the symptoms can be reversed by or endoscopic third . For vascular incontinence, early identification of risk factors and initiation of secondary prevention are necessary. Detrusor overactivity due to frontal hypofunction may underlie the bladder disorder in both diseases. Treatment options for urinary incontinence include anticholinergics, which do not easily penetrate the blood-brain barrier, or newer drugs that act on the adrenergic beta-3 receptor and other receptors. Keywords: Geriatric incontinence, white matter disease, normal-pressure hydrocephalus, overactive bladder, anticholinergic drug.

INTRODUCTION incontinence with brain etiologies, “vascular incontinence” (a disorder of bladder control resulting from WMD) and Urinary incontinence is a major concern in geriatric normal-pressure hydrocephalus (NPH),from a neurological populations, which has grown rapidly in recent decades. point of view. In addition, the incidence of urinary frequency/urgency (also called overactive bladder, OAB), with or without 1. Vascular Incontinence incontinence, in the general population over 40 years in age WMD and Urinary Incontinence in the Elderly is common [1-3], andincreases significantly with age. It is widely acknowledged that urinary frequency and poor There is an important body of work thathas used electron bladder control has an impact on quality of life [4] and that microscopy to examine ultrastructuraldetails of the bladder bladder dysfunction in elderly persons adds to their muscle and its innervation in the elderly, in an attempt to caretakers’ burdens and is an important factorleading to identify specific morphological features thatcorrelate with institutionalization [4]. The mechanisms of OAB and urinary detrusor overactivity (DO), detrusor hyocontractility and the incontinence in the frail elderly are multifactorial, and may disorder DHIC (detrusor hyperactivity and impaired include age-related changes in the bladder itself [4], or contractility) [9-12]. Itsfindings have provided a strong central changes innervating the bladder [5]. indication that the problem of incontinence in the frail Since 1965, the clinical triad of gait disturbance, dementia, elderly stems fromage-related changes in the bladder itself. and urinary incontinencehas been recognized in normal- pressure hydrocephalus (NPH), a brain disease that can be In contrast, arecent view has emerged that there may also treated by shunt surgeryor endoscopic third ventriculostomy be acerebral vascular component [8]. We investigated 63 [6, 7]. Similarly, a recent view has emerged that there is a subjects, 28 male and 35 female, mean age 73 years, (range cerebral vascular component in the occurrence of elderly 62-86 years) demonstrated to have varying degrees of incontinence [8]. Gait disturbance, dementia, and urinary cerebral WMD or (Fig. 1) [13]. The clinical incontinencealso occur in patients with cerebral white backgrounds of these subjects werevarious, and 19 of them matter disease (WMD), which is more common than complained of symptomsrelevant to leukoaraiosis, including normal-pressure hydrocephalus. However, OAB and urinary gaitdifficulty in seven, dysarthria in five, and amnesiain five; incontinence in both diseases have received limited none was bed-ridden. Eleven hada history of a single study. This paper reviewstwo common sources of elderly lacunar infarct, includingmild hemiparesis or hemisensory disturbance. Other subjects had tension-type , vestibular neuronitis, benign paroxysmal positionalvertigo,

*Address correspondence to this author at the Neurology, Internal Medicine, Bell’s palsy, or neurosis.Subjects with or Sakura Medical Center, Toho University, 564-1 Shimoshizu, Sakura, 285- largehemispheric lesions were excluded from thestudy.The 8741 Japan; Tel: +81-43-462-8811 ext. 2323; Fax: +81-43-487-4246; clinical symptoms included gait difficulty in 7, dysarthria in E-mail: [email protected] 5 and in 5;none was bed-ridden. Eleven had

2212-3903/12 $58.00+.00 ©2012 Bentham Science Publishers 68 Current Drug Therapy, 2012, Vol. 7, No. 1 Sakakibara et al.

Vascular incontinence and NPH

* p < 0.05 * * 100 Nocturnal 93 91 90 frequency >_ 2 80 Urge 70 incontinence 60 012 60 58 57 50

% 45

40 33 30 25 20 20 10 0 0 0 123 4 3 4 Grading of white matter lesion

* p < 0.05 * * p < 0.05 * 100 1 Gait disorder * * 90 3 Gait disorders 100 29 30 79 27 80 from slowness, 90 26 short step/ 80 25 70 festination, loss 64 22 73 20 70 60 of postural reflex Mean MMSE 64 20 60 MMSE < 24 50 47 % 42 50 MMSE < 19 45 15 40 36 36 % 40 33 30 29 10 30 27 20 16 20 8 10 5 10 10 8 0 0 00 0 0 0 0 1 234 0 1234 Grading of white matter lesion Grading of white matter lesion

Fig. (1). Cerebral white-matter changes and urinary dysfunction. (a) Schematic presentation of the grading of white-matter lesions on MRI. Grade 0, none; grade 1, punctate foci with high signal intensity in the white matter immediately at the top of the frontal horns of the ;grade 2, white-matter lesions seen elsewhere but confined to the immediate subependymal region of the ventricles; grade 3, periventricular as well as separate, discrete, deep white-matter foci of signal abnormality; andgrade 4, discrete white-matter foci that had become large and coalescent. (b) Urinary dysfunction and white-matter lesions on MRI. (c) Cognitive disorder and white-matter lesions on MRI. MMSE: mini-mental state examination. (d) Gait disorder and white-matter lesions on MRI. Cited from ref. 13. histories of single lacunar infarct, including mild hemiparesis 45%, respectively with an overall prevalence of urge urinary or hemisensory disturbance. Magnetic resonance imaging incontinence in WMD estimated at around 40%. Nocturnal (MRI)-defined WMD was graded on a scale of 0 to 4, urinary frequency was a more common and earlier feature following Brand-Zawadzki et al. [14]. Urinary function was than urinary incontinence [13]. Of particular importance was assessed by questionnaire and dysfunction was graded as the fact that OAB was not always accompanied by gait either mild, with nocturnal urinary frequency2, or severe, disorder or dementia (Grade 1, Fig. 1), so that it appeared with urge urinary incontinence. Cognitive disorder was that urinary frequency/ urgency mightbe the first clinical graded as either mild, with a mini-mental-state-examination manifestation of the observed WMD [13]. (MMSE) score of 1923, orsevere, with a score<19. Gait Until recently, WMD, variously described as white disorder was graded as either mild, with 1 feature,orsevere, matter hyperintensities, white matter change, white matter with 3 features of slowness of gait, short-step / festination ischemia, or multiple cerebral infarction of the white matter and loss of postural reflex. The prevalence of nighttime type, had been thought to be of little clinical relevance, and urinary frequency in cases of grade 1 WMD was 60%; grade regarded as an incidental phenomenon in aging. The first 2, 58%; grade 3, 93%; and grade 4, 91%, respectively, pathological description of WMDin the aged brain dates giving an overall prevalence of nighttime urinary frequency back to Durand-Fardel in1854, who named the condition of around 75%. Similarly, urge urinary incontinence in grade atrophieinterstitielle du cerveau(‘interstitial of the 1 WMD was 33%; grade 2, 25%; grade 3, 57%; and grade 4, brain’), and believed it to be asymptomatic [15]. Binswanger Vascular Incontinence and NPH Current Drug Therapy, 2012, Vol. 7, No. 1 69 in 1894 described it pathologically as Arteriosklerotische Disruption of the blood-brain barrier is likely to precipitate Hirnerkrankung/ Hirnatrophie (‘arteriosclerotic brain or worsen progression of WMD [29]. Cerebral microbleeds— atrophy’), since ‘it is very likely that the subcortical loss of small, perivascularhemorrhages—are commonly seen. Small fibers is caused by the deficiency of the blood supply vessel disease may lead to loss of autoregulation of cerebral resulting from arteriosclerosis’ [16]. In 1987, Hachinski blood supply, which results in a higher susceptibility of coined the name leukoaraiosis, which he derived from the white matter to undergo drops in blood flow during episodes Greek wordsleukos, white, and araios, rarefied, in order to of systemic hypotension [18, 19]. Recent positron emission describe the radiological images of loss of density of the tomography imaging with 18F-fluoromisonidazole showed periventricular white matter observed by CT [17]. Advances higher susceptibility to ischemia of white matter than gray in neuroimaging, particularly MRI at that time, enabled early matter in stroke cases [30, 31]. recognition of WMDcorrespondingpathologically to white matter rarefaction [18, 19]. Although there is some debate, it is known that the incidence of WMD significantly increases with Geriatric Syndromes and WMD atherosclerotic risk factors, e.g., hyperlipidemia, diabetes, obesity, metabolic syndrome, hypertension [20-22], cigarette Recent population-based MRI studies have suggested smoking, carotid plaque [32], high cardio-ankle vascular that the incidence of moderate WMD(periventricular WMD stiffness index (CAVI), and gene polymorphismof aldosterone grade > 4/9 and subcortical white matter volume > 1.5 mL) synthase [33], angiotensinogen, angiotensin II type 1 to be around 10% (7.6-24%) in the general population of persons over 55 years of age [20-22], comparable to that of receptor [34], nitric oxide synthase [34], and angiotensin- converting enzyme [35] (hypertension), methylenetetra type 2 diabetes. In those studies, WMD was graded as 0, no hydrofolatereductase gene (homocysteine metabolism) [36], white matter lesions; 1, pencil-thin periventricular lining; 2, matrix metalloproteinase-3 and -9 genes [37] (vascular smooth halo or thick lining; or 3, large confluent white remodeling), fibrinogen gene (fibrin clot formation) [38], matter lesions. The overall amount of periventricular white genes of apolipoprotein E [39] and Paraoxonase 1 [40] (lipid matter lesions was calculated by summing the scores for the three separate regions to give a total in the range 1-9 [20]. metabolism), and C-reactive protein gene () [41]. Rare but well-established genetically transmitted forms It is now recognized that WMD can developinto three of WMD also exist: one is cerebral autosomal-dominant different geriatric syndromes: arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) [42] with NOTCH3 gene mutation (endoplasmic 1) : usually mild in the Mini-Mental State reticulum dysfunction), and the other is cerebral autosomal Examination and other general cognitive functions, while recessive arteriopathy with subcortical infarcts and the Frontal Assessment Battery might be low [23]; leukoencephalopathy (CARASIL) [43] with high-temperature hallucination and delusion are rare; sometimes stepwise requirement A serine peptidase 1 (HTRA1) gene mutation deterioration24; in most advanced stages, emotional (transforming growth factor -beta dysfunction). Experimental incontinence may occur, studies have suggested that other factors contributing to 2) vascular : gait disorder or easy falls;slow, WMD include transient brain edema [44] and blood-brain short-stepped gait, often with wide-based gait, usually barrier damage [45, 46]. lacking apparent and rigidity in the hands [25]; The incidence of WMD significantly increases with age otherwise known aslower-body parkinsonismwiththe gait [20-22]. WMD slowly progresses after being identified [47, disturbance sometimesmanifesting as frontal gait apraxia; 48]; and mildly increases the rate of new-onset stroke [49] sometimes with frontal release signs (palmomental, (constituting a prodrome of future stroke). WMDisrarely snout, or grasping);in advanced stages, dysphagia and noted in subjects with transient ischemic attack (TIA), aspiration pneumonia; and whereas it is common in small vessel ischemic stroke [50, 3) following Sakakibara et al.’s paper [13] and confirmed 51]. T2*-weighted gradient-echo MRIs in subjects with by others since [26, 27],“vascular incontinence”:urinary WMD sometimes show comorbid cerebral microbleeds. frequency/ urgency with or without incontinence. At present, the etiology of cerebral microbleeds includes atherosclerosis (seen in both the basal ganglia and subcortical These three features can present in any combination; area) [52, 53] and age-related amyloid angiopathy (in the however, clinically, urinary and gait disorders are more subcortical area). Whether cerebral microbleeds alone prominent than dementia, and usually precede dementia. present with clinical symptoms remains a matter of debate Pathology of WMD [54]. Diffuse abnormalities are seen in the small deep Cause of Bladder Dysfunction in WMD perforating vessels of the hemispheric white matter, basal Detrusor overactivity (DO) is the major underlying ganglia and brain stem. These changes have been described A pathophysiology of vascular incontinence. DO is reported as “segmental arteriolar disorganisation” by Miller Fisher , in70-91% of WMD cases [13, 55], which is greaterthe and pathological changes range from lipohyalinosis to incidence following hemispheric stroke [56]. DO is a fibrinoid necrosis and disintegration of small vessels. urodynamic observation characterized by involuntary Occlusion of these vessels results in hypoperfusion and contractions during the filling phase which may be ischemia. Atherosclerosis, the predominant pathological spontaneous or provoked [57]. In our study, urodynamic finding in large vessel disease, is an uncommon finding [28]. tests were performed in 33 of the subjects, divided into 2 groupsaccording to the above criteria (grade 0, 11 elderly AFisher CM. Binswanger's : a review. J Neurol 1989; 236: 65-79. 70 Current Drug Therapy, 2012, Vol. 7, No. 1 Sakakibara et al. subjects as described above, 2 with nocturnal urinary oligodendrocyteswas marked in the frontal lobe in such frequency 2 but no urge urinary incontinence; grades patients, thus impairing not only the frontal micturition 1-4, 22 subjects, 14 male and 8 female, mean age 72 pathway, but also the frontal gait and cognitive pathways, years, 19 with nocturnal urinary frequency 2 and 12 with relevant also to vascular parkinsonism [70, 71] and dementia urge urinary incontinence) [13]. Statistical analysis was [72, 73]. performed by Student’s t test.We found that subjects with grade 1-4 WMDhadDO more commonly (82%) than Based on a recognition of the importance of WMD in the those with grade 0 WMD (9%) (p<0.05). Post-micturition elderly, Kuchel [26] analyzed the location of WMD and residuals, low compliance, detrusor-sphincter dyssynergia urinary dysfunction in 97 community-dwelling individuals and uninhibited sphincter relaxation were also more common (age 75-89 years). Baseline incontinence status and related in grade 1-4 WMD than in grade 0 WMD, though there was symptoms were evaluated using validated instruments (3IQ, no statistical significance. Urinary Incontinence Severity Index, Urogenital Distress Inventory, and Incontinence Impact Questionnaire). Regional Cerebral Control of the Bladder and How it is Affected by WMD was measured and analyzed using reference brain WMD atlases (white matterparcellation atlas [WMPA] and the The frontal cortex is now recognized as an important International Consortium on Brain Mapping [ICBM]). They higher center for micturition:damage to the prefrontal cortex, chose seven brain regions representing relevant white matter medial superior/middle frontal gyri, anterior cingulate tracts: anterior corona radiata, inferior fronto-occipital cortex, supplemental motor area and insula have been fasciculus, cingulate gyrus, cingulate hippocampal portion, shown to result in marked lower-urinary-tract dysfunction superior frontooccipital fasciculus, uncinate fasciculus, and in humans [56, 58]. These clinical observationshave been genu of the . These anterior regions are corroborated by functional neuroimaging in humans [59-61]. known to have a potential role in bladder control. The The connection between the prefrontal cortex and the anterior corona radiata contains both descending prefrontal micturition circuit is still uncertain, but it is known that the corticopontine projections and ascending thalamocortical prefrontal cortex projects fibers to the hypothalamus- (frontal/prefrontal) projections. Sixty-two (64%) of the periaqueductal gray directly. The prefrontal-striatal pathway participants were incontinent, mostly with urgency (37; may also have a role [62]. DO is considered to be 60%) and moderate tosevere symptoms (36; 58%). It was an exaggerated spinobulbospinal micturition reflex that found that the presence of WMD in the right frontal and normally promotes micturition [63]. Functional neuroimaging right inferior frontal regions predicted incontinence severity, studies have shown that the prefrontal cortex was deactivated while no significant relationship was seen with incontinence, in elderly subjects with urinary frequency/urgency as incontinence type, bother, or functional impact [26] (Fig. 2). compared with controls [64]. As regards white matter-relevant tracts, WMD that overlappedthe anterior corona radiata predicted severity and Cortical WMDlooks diffuse on MRI.However, within the degree of bother, cingulate gyrus predicted incontinence and brain, detailed pathology studies have confirmed that the severity, whereas cingulate (hippocampal portion) and frontal lobe is the most severely affected [65]. This is in line superior fronto-occipital fasciculus predicted severity. The with the facts that MRI volumetry showed frontal lobe same group reported that the volume of WMD predicted atrophy [66], where glucose [67] and N-acetyl-aspartate [68] executive function, mobility, and urinary incontinence [74]. metabolism was most severely reduced. Corresponding to this, brain perfusion was most severely reduced in the frontal Most recently, Tadic and Griffiths [27] studied 25 older lobe of subjects with WMD [69], a finding that remains to be women (age 71.5±7.5 years) with urgency incontinence. fully explained. However hypoxic-ischemic damage to Theirmean MMSE score was 29.2; none had cognitive

Vascular incortinence and NPH

A BC ACR

Cing ACR Cing ACR Cing

Cing /hippo

Cing /hippo Cing /hippo

Fig. (2). Cerebral white-matter changes and urinary dysfunction. The presence of white matter change in the right inferior frontal regions and relevant tracts (anterior corona radiata and superior fronto-occipital fasciculus) is related with incontinence, incontinence severity, and degree of bother. ACR, Anterior corona radiata; Cing, Cingulate gyrus; Cing/hippo, Cingulate hippocampal portion. Modified from ref. 26. Vascular Incontinence and NPH Current Drug Therapy, 2012, Vol. 7, No. 1 71 Vascular incontinence and NPH

6 (A) Global WMH 5 Correlations 4 3 (a) positive 2 PMC 1 0

3

2.5 Precuneus 2 1.5 (b) negative 1 0.5 0

Fig. (3). Cerebral white-matter changes and urinary dysfunction. Regional activations (e.g. medial/superior frontal gyrus adjacent to dorsal anterior cingulate gyrus, cerebellum and pontine micturition center [PMC]) have positive correlations with global white matter change (upper panel), while some regional activations (e.g. precuneus etc.) have negative correlations. Cited from ref. 27. problems. In these patients, the volume and location of the suggested; however, at present there are no large prospective WMD, specific white matter tracts, and regionalbrainactivity studies available. On the other hand, there is a risk of by functional MRI during bladderfilling and reported hemorrhagic of antiplatelet drug use when “urgency” were analyzed. As a result, brain responses to comorbid microbleeds exist [78]. Carotid endarterectomy bladder filling during self-reported “urgency” were most improved cognitive function in one study in WMD prominent in the frontal regions, including the medial/ accompanied by carotid [79]. Although edaravone, a superior frontal gyrus adjacent to the dorsal anterior free radical scavenger, has begun to be used in acute cingulate gyrus(ACG) and other areas.Regional activations ischemic stroke, its use in slowly progressive WMD awaits (e.g. the medial/superior frontal gyrus adjacent to the dorsal further study [80]. ACG) and deactivations (e.g. perigenual ACG adjacent to ventromedialprefrontal cortex) became more prominent with 2. Normal-Pressure Hydrocephalus increased global WMD (Fig. 3). Looking at the fiber tracts NPH and Urinary Incontinence in the Elderly within the white matter, e.g., anterior thalamic radiation [ATR], uncinate fasciculus [UNC], inferior fronto-occipital Normal-pressure hydrocephalus (NPH) is characterized fasciculus [IFO], inferior longitudinal fasciculus [ILF] and by a clinical presentation of gait disturbance, memory superior longitudinal fasciculus [SLF], the main effect deficit, and urinary incontinence, combined with dilated activations and deactivations were superimposed with ATR cerebral ventricles and normal (anterior, semi-horizontally projecting fibers to the medial (CSF) pressure [81]. Studies analyzingthe intracranial prefrontal cortex and perigenual ACG, and also to several hydrodynamics related to the pulse pressure, etc. B, have areasthat were deactivated; constituting55% of the global indicated that CSF pressure in NPH is not truly “normal”, WMD) and SLF (middle, semi-vertically projecting fibers to although there is an expected low threshold range. The dorsal ACG, insula, and inferior frontal gyrus; constituting clinical triad of this disorder is very much akin to those of only 8% of global WMD), respectively [27] (Fig. 3). The WMD. Therefore, before performing brain imaging, we have results indicated that the WMD, particularly the anterior to think about NPH as well as WMD. The syndrome was portion that includes ATR, are clearly related with OAB in first described by Hakim and Adams in 1965 [6, 7]. After cognitivelyintact olderwomen. five decades of investigation, the effectiveness of the diversion of CSF flow by shunt operation in treating this Treatment and Prevention of WMD syndrome is well documented [81, 82]. Recent population- Though the vascular changes may not be reversible, early based MRI studies also suggest that the incidence of NPH, or identification of risk factors and initiation of secondary asymptomaticventriculomegalywithfeaturesofidiopathicnorm prevention might arrest the disease progress. The results al-pressure hydrocephalusonMRI(AVIM), to be around 1% from studies exploring control of vascular risk factors, (0.51-2.9%) in the general population of persons over 65 hypertension [75], dyslipidemia [76] and diabetes [77] do years of age [83, 84], which is about one-tenththe prevalence not provide conclusive evidence. Falls in blood pressure may of WMD. in fact worsen gait by counteracting the high-set cerebral autoregulation [75]. The prevention of small vessel disease is BGreitz D. Radiological assessment of hydrocephalus: new theories and implications controversial. Antiplatelet medication for WMD has been for therapy. Neurosurg Rev 2004; 27: 145-165. 72 Current Drug Therapy, 2012, Vol. 7, No. 1 Sakakibara et al.

Table 1. Urodynamic Findings of Normal-Pressure Hydrocephalus

Total Number of Patients 42

Average Range

free flow voided volume 102.5 19-50 maximum flow (ml/s) 11.7 3-33 post-void residual (ml) 42.1 0-228 post-void residual>100 ml 14.3% female 3 (105-228 ml); male 3 (100-180 ml)

cystometry first sensation (ml) 134.1 0-300 bladder capacity (ml) 200.8 20-470 detrusor overactivity 95.2%

Cited from ref. [85].

We recently studied the bladder function in 42 idiopathic in 6 patients (3 women [105-228 ml], 3 men [100-180 ml]). NPH (iNPH) patients85. They were diagnosed to have In the storage phase, bladder volume at the first sensation iNPHby clinical symptoms/signs (gait, cognitive, and urinary was low(< 100 ml) in 33% of patients, normal (100-300 ml) disorders) with typical imaging features (ventricular in 67%, high(> 300 ml) in none, and the mean bladder enlargement) and normal cerebrospinal fluid pressureby a volume at the first sensation was 134 ml. In contrast, bladder spinal tap test (normal range of the opening pressure, 90-180 capacity was decreased (< 200 ml) in 57%, normal (200-600 mmH2O C). The subjects included 36 men and 6 women; ml) in 43%, and increased (> 600 ml) in none, and the mean mean age, 72 years (62-83 years). As a result, lower urinary bladder capacity was 200 ml. DO was seen in 95% of tract symptoms (LUTS) were seen in 93% of patients; these patients (Table 1). Therefore, the significant urodynamic symptoms included storage symptoms in 93% of patients abnormality that underlies bladder dysfunction in iNPH (nocturnal urinary frequency, 64%; urinary urgency (OAB), appears to be DO, which was noted in 95.2% of our 42 64%; urgency urinary incontinence, 57%; diurnal urinary patients. Previous reports of NPH have indicated results frequency, 36%) and voiding symptoms in 71% (retardation similar to our own, although the number of cases included in in initiating urination, 50%; prolongation/poor flow, 50%; these reports has been small (range, 4-12 cases) [86, 87]. The sensation of PVR, 29%; straining, 21%; and intermittency, reported frequency of DO has ranged from 63% to 100% 14%). As shown above, the majority of our patients (93%) [86, 87]. Although DO is not uncommon in general older had storage symptoms,and some had OAB without urinary populations [88, 89], the high prevalence of DO in NPH incontinence. These findings indicate that urinary urgency/ cases strongly suggests altered brain autonomic control in frequency might precede urinary incontinence in iNPH. this disorder. Therefore, for both urologists and non-urological clinicians, Cerebral Control of the Bladder and How it is Affected by it is important to think about not only vascular incontinence NPH but also NPH when we see elderly patients with OAB. Among the clinical triad of NPH,urinary incontinenceis DO in NPH patients reflects a loss of inhibition of the reported to be present in 68% (103/151), which is less micturition reflex, suggesting a primary brain autonomic common than eithergait,in 91% (138/151), ordementia, in dysfunction [90]. Recent functional neuroimaging in normal 86% (130/151) [81], and is regarded a late symptomD. volunteers has shown that the anterior cingulate, prefrontal However, as in cases of WMD, gait disturbanceand OAB cortex and insula are activated in response to bladder filling might be the early manifestations of NPH. as compared with an empty bladder [59-61]. Although NPH is a diffuse brain disease with dilated ventricles, Cause of Bladder Dysfunction in NPH hypoperfusion in the frontal lobe has been documented in We also performed urodynamics in 42 iNPH patients NPH patients using PET [91, 92], single-photon emission [85]. In the voiding phase, free flowmetry revealed that the computed tomography (SPECT) [93], and perfusion- maximum flow rate (Qmax) was low (<10 cm/s) in 40% of weighted MRI [94]. Therefore, it is possible that the frontal patients and normal (>10 cm/s) in 60%, and the mean Qmax lobe is the anatomical substrate for the development of was 11.7 ml/s. Measurement of post-void residual (PVR)by urinary incontinence in NPH. We recently studied the transurethral catheterization revealed that PVR volume was correlation between urinary incontinence and frontal elevated(>30 ml) in 43% of patients and normal (< 30 ml) in lobe function in iNPH by SPECT and statistical brain 57%, and the mean PVR volume was 42.1 ml. Among mapping [95]. Urinary symptoms were observed and [123I]- patients whose PVR was increased, PVR >100 ml was noted iodoamphetamine (IMP)-SPECT imaging was performed in 97 patients with clinico-radiologically definite iNPH. The patients included 56 men and 41 women; mean age, 74 CYuh EL, Dillon WP. Intracranial hypotension and intracranial hypertension. Neuroimaging years. The study calculated and visualized the statistical Clin N Am 2010; 20: 597-617. DMeier U, Zeilinger FS, KintzelD. Signs, symptoms and course of normal pressure difference in normalized mean tracer counts between patients hydrocephalus in comparisonwith . Acta Neurochir (Wien) 1999; 141: with urinary dysfunction of severer degrees (grade 2/4) and 1039-1048. Vascular Incontinence and NPH Current Drug Therapy, 2012, Vol. 7, No. 1 73

Vascular incortinence and NPH

RT. LAT LT. LAT RT. MED LT. MED

decrease Z 6.00 5.56 5.12

4.68 4.24 increase 3.80 3.36 2.92 2.48 2.04

urinary 0-1 vs 2-4

Fig. (4). 3D-SSP maps of differences of cerebral blood flow as measured by [123I]-labeled IMP in NPH patients with urinary grades of 0-1 and 2-4 (n=97). Upper row: decrease of tracer accumulation in the group with severe urinary dysfunction as compared to mild urinary dysfunction; lower row: increase of tracer accumulation in the group with severe urinary dysfunction. Colored areas indicate the areas of statistically significant difference (p<0.05). Cited from ref. 95. milder degrees (grade 1/4) according to the urinary return to normal, particularly in patients with good OAB/ subscales of the iNPH grading scales [85, 95]. As a result, incontinence recovery (data not shown). there was a significant decrease in tracer activity in the right- Nowadays, endoscopic third ventriculostomy(ETV) is side-dominant bilateral frontal cortex and the left inferior being increasingly acknowledged as an alternative treatment temporal gyrus in the severe urinary dysfunction group for ventriculoperitoneal/lumbar peritoneal shunt, or even as a (p<0.05) (Fig. 4 upper row). In order to minimize the effects first-line treatment, in selected patientsE. of gait and cognitive dysfunction, we performed a similar analysis amongsubjects with little or no such dysfunction, 3. Symptomatic Treatment of OAB and Urinary and obtained the same results (p<0.05) as described above. Incontinence of Brain Etiologies As shown above, there is a link between right frontal hypoperfusionand urinary dysfunction in iNPH. In addition, Urological causes are an important cause for right frontal hypoperfusion related with urinary dysfunction incontinence in the elderly. DO may occur in men with was observed in the subgroup of patients with adjusted benign prostatic enlargement; however, in 25-93% of gait or cognitive grades. The facts indicate that urinary prostatectomy cases, detrusor overactivity is reported to dysfunction might occur independently of gait or cognitive remain unchanged after surgery, the figures increase with disturbance in iNPH. age [97, 98]. Concomitant WMDs are reported in this group [99] and are likely to contribute to DO. Elderly women may In addition, there was also a significant increase in tracer present with stress incontinence, which can be differentiated activity in the bilateral posterior cingulate gyrus, left by history. pontine-mesencephalic area, etc., related with urinary dysfunction in iNPH(p<0.05) (Fig. 4 lower row). Recent Medications used to treat vascular incontinenceinclude functional PET in Parkinson’s disease with DO [96] and anticholinergic agents such as oxybutynin, propiverine, fMRI in idiopathic DO [97] showed that corticalactivation detrusitol, solifenacin,and imidafenacin [100]. Mori et al. with DO wasdecreased in the frontal pole andthe prefrontal [101] performed urodynamics in 46 dementia patients, and cortex; whereas it was higherthan in normal volunteers in the found DO in 91% of patients with WMDand 58% of supplementary motor area (SMA), whichis close to the Alzheimer’s disease patients. They conducted an open trial medial frontal and parietal gyrus as we have shown herein. with 20 mg/day of propiverine hydrochloride for 2 weeks The SMA activation associated with DO might reflect irrespective of the presence of DO, and found increased simultaneous pelvic floor contraction against the DO in order bladder capacity or lessened frequency of incontinence in to maintain urinary continence [96]. 40% of patients. Both groups responded almost equally, and patients with DO showed a more satisfactory response. Shunt Surgery of NPH on Bladder Function Treatment for urinary frequency/urgency may be particularly of benefit in subjects without marked immobility or Importantly, bladder dysfunction and frontal lobe dementia. hypoperfusion in NPH can be reversed after shunt surgery. The recovery rate of OAB and urinary incontinence in iNPH ranges around 20-80%. Among them, cerebral perfusion in the prefrontal cortex and mid-cingulate gyrus tended to ERangel-Castilla L, Barber S, Zhang YJ. The role of endoscopic third ventriculostomy in the treatment of communicating hydrocephalus. World Neurosurg.2011 Nov 7. [Epub ahead of print]. 74 Current Drug Therapy, 2012, Vol. 7, No. 1 Sakakibara et al.

The use of medications with anticholinergic side-effects how are they managed? A population-based prevalence study. BJU in the elderly is of concern, particularly when there is a risk Intl 2001; 87: 760-766. [2] Stewart WF, Van Rooyen JB, Cundiff GW, et al. Prevalence and of exacerbating cognitive impairment. Crossing the blood- burden of overactive bladder in the United States. World J Urol brain barrier (BBB), they can act at the M1-muscarinic 2003; 20: 327-336. receptors in the cerebral cortex and hippocampus, or M4- [3] Homma Y, Yamaguchi O, Hayashi K, the Members of the receptors in the basal ganglia. Factors predisposing patients Neurogenic Bladder Society Committee.An epidemiological survey to cognitive side effects include 1) central muscarinic of overactive bladder symptoms in Japan. BJU Intl 2005; 96: 1314- 1318. receptor affinity, e.g., high M1-receptor selectivity; and 2) [4] Irwin DE, Milsom I, Kopp Z, Abrams P, Cardozo L.Impact of permeability across the BBB: size, lipid solubility, fewer overactive bladder symptoms on employment, social interactions hydrogen bonds, neutral or low degree of ionization and a and emotional well-being in six European countries. BJU Intl 2005; small number of rotatable bonds [29, 102, 103]. Darifenacin 97: 96-100. [5] Resnick NM. Urinary incontinence. Lancet 1995; 346: 94-99. is an M3-selective antagonistand thus has less marked [6] Hakim S, Adams RD.The special clinical problem of symptomatic cognitive side effects while trospium, a quaternary amine, occult hydrocephalus with normal cerebrospinal pressure. J Neurol has high polarity and therefore poor permeability across the Sci 1965; 2: 307-327. BBB F,G,H. Other common anticholinergic side-effects [7] Adams RD, Fisher CM, Hakim S, Ojeman RG, Sweet are dryness of the mouth (M3) and constipation (M2,3). WH.Symptomatic occult hydrocephalus with 'normal' cerebrospinal pressure. N Eng J Med 1965; 273: 117-126. Extended-release formulations may lessen these adverse [8] Rosenberg LJ, Griffiths DJ, Resnick NM. Factors that distinguish effects [104, 105]. It has beenrecently shown that the continent from incontinent older adults with detrusor overactivity. J addition of propiverineto donepezil ameliorated OAB Urol 2005; 174: 1868-1872. without worsening cognitive function in elderly OABpatients [9] Elbadawi A, Hailemariam S, Yalla SV, Resnick NM. Structural I basis of geriatric voiding dysfunction. VII. Prospective ultrastructural/ with dementia . Mirabeglon, a noveladrenergic beta-3 urodynamic evaluation of its natural evolution. J Urol 1997; 157: receptor agonist, seems to be promising for lessening DO 1814-1822. with fewer central sideeffects [106]. [10] Elbadawi A, Yalla SV, Resnick NM. Structural basis of geriatric voiding dysfunction. III. Detrusor overactivity. J Urol 1993; 150: CONCLUSION 1668-1680. [11] Elbadawi A, Yalla SV, Resnick NM. Structural basis of geriatric This paper reviewedtwo common sources of elderly voiding dysfunction. II. Aging detrusor: normal versus impaired incontinence with brain etiologies, so-called“vascular contractility. J Urol 1993; 150: 1657-1667. incontinence” (a disorder of bladder control resulting from [12] Elbadawi A, Yalla SV, Resnick NM. Structural basis of geriatric cerebral WMD) and NPH,from a neurological point of view. voiding dysfunction. I. Methods of a prospective ultrastructural/ urodynamic study and an overview of the findings. J Urol 1993; Both diseases manifest with gait disturbance, dementia, 150: 1650-1656. and urinary incontinence. OAB often precedes urinary [13] Sakakibara R, Hattori T, Uchiyama T, Yamanishi T. Urinary incontinence in both diseases, and in some patients may function in the elderly with and without leukoaraiosis; in relation to be the initial manifestation. While NPHis less common than cognitive and gait function. J Neurol Neurosurg Psychiatry 1999; vascular incontinence, at about one-tenth the prevalence, 67: 658-660. [14] Brant-Zawadzki M, Fein G, Van Dyke C, Kiernan R, Davenport L, it is nonetheless important because the symptoms can be de Groot J. MR imaging of the aging brain; pacthy white-matter reversed by shunt surgery. For vascular incontinence, early lesions and dementia. AJNR 1985; 6: 675-682. identification of risk factors and initiation of secondary [15] Roman GC.On the history of lacunes, etatcriblé, and the white prevention are necessary. DO due to frontal hypofunction matter lesions of vascular dementia. Cerebrovasc Dis 2002; 13 (suppl 2): 1-6. may underlie the bladder disorder in both diseases. [16] Binswanger O. Die Abgrenzung der allgemeinenprogressiven Treatment options for urinary incontinence include Paralyse. BerlKlin Wochenschr 1894; 31: 1103-1105, 1137-1139, anticholinergics that do not easily penetrate the BBB, or 1180-1186. newer drugs that act on the adrenergic beta-3 receptor and [17] Hachinski VC, Potter P, Merskey H. Leukoaraiosis. Arch Neurol other receptors. 1987; 44: 21-23. [18] Fazekas F, Schmidt R, Kleinert R, Kapeller P, Roob G, Flooh E. CONFLICT OF INTEREST The spectrum of age-associated brain abnormalities: their measurement and histopathological correlates. J Neural Transm Declared none. Suppl 1998; 53: 31-39. [19] Enzinger C, Fazekas F, Ropele S, Schmidt R. Progression of ACKNOWLEDGEMENT cerebral white matter lesions — Clinical and radiological considerations. J NeurolSci 2007; 257: 5-10. Declared none. [20] de Leeuw FE, de Groot JC, Oudkerk M, et al. Hypertension and cerebral white matter lesions in a prospective cohort study. Brain REFERENCES 2002; 125: 765-772. [1] Milsom I, Abrams P, Cardozo L, Roberts RG, Thuèroff J, Wein AJ. [21] Sierra C, de La Sierra A, Mercader J, Gómez-Angelats E, How widespread are the symptoms of an overactive bladder and Urbano-Márquez A, Coca A. Silent cerebral white matter lesions in middle-aged essential hypertensive patients. J Hypertension 2002; 20: 519-524. FWagg C, Verdejo U, Molander U. Review of cognitive impairment with [22] van Dijk EJ, Breteler MMB, Schmidt R, et al. for the CASCADE antimuscarinicagents in elderly patients with overactive bladder. Int J Clin Pract 2010; Consortium. The association between blood pressure, hypertension, 64: 1279-1286. and cerebral white matter lesions cardiovascular determinants of GPagoria D, O’Connor RC, Guralnick ML. Antimuscarinicdrugs: review of the dementia study. Hypertension 2004; 44: 625-630. cognitive impactwhen used to treat overactive bladder in elderly patients. Curr Urol [23] Erkinjuntti T, Gauthier S. The concept of vascular cognitive Rep 2011; 12: 351-357. impairment. Front Neurol Neurosci 2009; 24: 79-85. HChancellor M, Boone T. Anticholinergics foroveractive bladdertherapy: central [24] Wade J, Hachinski V. Revised ischemic score for diagnosing multi- nervous system effects. CNS Neurosci Ther 2012; 18: 167-174. ISakakibara R, Ogata T, Uchiyama T, et al. How to manage overactive bladder in infarct dementia. J Clin Psychiatry1986; 47: 437-438. elderly individuals with dementia? A combined use of donepezil, a central AChE [25] Rektor I, Rektorova I, Kubova D. Vascular parkinsonism — an inhibitor, and propiverine, a peripheral muscarine receptor antagonist. J Am GeriatrSoc update. J NeurolSci 2006; 248: 185 - 191. 2009; 57: 1515-1517. Vascular Incontinence and NPH Current Drug Therapy, 2012, Vol. 7, No. 1 75

[26] Kuchel GA, Moscufo N, Guttmann CR, et al. Localization of brain [46] Pantoni L. Pathophysiology of age-related cerebral white matter white matter hyperintensities and urinary incontinence in changes. Cerebrovasc Dis 2002; 13(Suppl 2): 7-10. community-dwelling older adults. J Gerontol A BiolSci Med Sci [47] Sachdev P, Wen W, Chen X, Brodaty H. Progression of white 2009; 64: 902-909. matter hyperintensities in elderly individuals over 3 years. [27] Tadic SD, Griffiths D, Murrin A, Schaefer W, Aizenstein HJ, Neurology 2007; 68; 214-222. Resnick NM. Brain activity during bladder filling is related to [48] Enzinger C, Fazekas F, Ropele S, Schmidt R. Progression of white matter structural changes in older women with urinary cerebral white matter lesions - clinical and radiological incontinence. Neuroimage 2010; 51: 1294-1302. considerations. J Neurol Sci 2007; 257 (1-2): 5-10. [28] Mazighi M, Labreuche J, Gongora-Rivera F, Duyckaerts C, [49] Gouw AA, van der Flier WM, Fazekas F, et al. LADIS Study Hauw JJ, Amarenco JP. Autopsy prevalence of intracranial Group. Progression of white matter hyperintensities and incidence atherosclerosis in patients with fatal stroke. Stroke 2008; 39: of new lacunes over a 3-year period: the Leukoaraiosis and 1142-1147. Disability study. Stroke 2008; 39: 1414-1420. [29] Wardlaw JM. Blood-brain barrier and cerebral small vessel disease. [50] Rost NS, Fitzpatrick K, Biffi A, et al. White matter hyperintensity J NeurolSci 2010; 299: 66-71. burden and susceptibility to cerebral ischemia. Stroke 2010; 41: [30] Falcao ALE, Reutens DC, Markus R, et al. The resistance to 2807-2811. ischemia of white and gray matter after stroke.Ann Neurol 2004; [51] Rost NS, Rahman RM, Biffi A, et al. White matter hyperintensity 56: 695-701. volume is increased in small vessel stroke subtypes. Neurology [31] Lee ST, Scott AM. Hypoxia positron emission tomography 2010; 75: 1670-1677. imaging with 18F-fluoromisonidazole.SeminNucl Med 2007; 37: [52] Wardlaw JM, Lewis SC, Keir SL, Dennis MS, ShenkinS. 451-461. Cerebralmicrobleeds are associated with lacunar stroke defined [32] Patterson AJ, U-King-Im JM, Tang TY, et al.. Association between clinically and radiologically, independently of white matter lesions. white matter ischaemia and carotid plaque morphology as defined Stroke 2006; 37: 2633-2636. by high-resolution in vivo MRI. Eur J Vasc Endovasc Surg 2009; [53] Tatsumi S, Shinohara M, Yamamoto T. Direct comparison of 38: 149-154. histology of microbleeds with postmortem MR images a case [33] Verpillat P, Alpérovitch A, Cambien F, Besançon V, Desal H, report. Cerebrovasc Dis 2008; 26: 142-146. Tzourio C. Aldosterone synthase (CYP11B2) gene polymorphism [54] Werring DJ, Frazer DW, Coward LJ, et al. Cognitive dysfunction and cerebral white matter hyperintensities. Neurology 2001; 56: in patients with cerebral microbleeds on T2*-weighted gradient- 673-675. echo MRI. Brain 2004; 127: 2265-2275. [34] Henskens LH, Kroon AA, van Boxtel MP, Hofman PA, de Leeuw [55] Sakakibara R, Hattori T, Tojo M. Micturitional disturbance in PW. Associations of the angiotensin II type 1 receptor A1166C and patients with cerebrovascular dementia. Autonom Nerv Syst 1993; the endothelial NO synthase G894T gene polymorphisms with 30: 390-396. silent subcortical white matter lesions in essential hypertension. [56] Sakakibara R, Hattori T, Yasuda K, Yamanishi T. Micturitional Stroke 2005; 36: 1869-1873. disturbance after acute hemispheric stroke: analysis of the lesion [35] Purandare N, Oude Voshaar RC, Davidson Y, et al. Deletion/ site by CT and MRI. J Neurol Sci1996; 137: 47-56. insertion polymorphism of the angiotensin-converting enzyme gene [57] Abrams P, Cardozo L, Fall M, et al. Standardisation Sub- and white matter hyperintensities in dementia: A pilot study. J Am committee of the International Continence Society. The Geriatr Soc 2006; 54: 1395-1400. standardization of terminology of lower urinary tract function: [36] Kohara K, Fujisawa M, Ando F, et al. NILS-LSA Study. MTHFR report from the standardization sub-committee of the International gene polymorphism as a risk factor for silent brain infarcts and Continence Society. Neurourol Urodynam 2002; 21: 167-178. white matter lesions in the Japanese general population: The NILS- [58] Andrew J, Nathan PW. Lesions of the anterior frontal lobes LSA Study. Stroke 2003; 34: 1130-1135. and disturbances of micturition and defaecation. Brain 1964; 87, [37] Fornage M, Mosley TH, Jack CR, et al. Family-based association 233-262. study of matrix metalloproteinase-3 and -9 haplotypes with [59] DasGupta R, Kavia RB, Fowler CJ.Cerebral mechanisms and susceptibility to ischemic white matter injury. Hum Genet 2007; voiding function. BJU Int 2007; 99: 731-734. 120: 671-680. [60] Sakakibara R, Tsunoyama K, Takahashi O, et al. Real-time [38] van Oijen M, Cheung EY, Geluk CE, et al. Haplotypes of the measurement of oxyhemoglobin concentration changes in the fibrinogen gene and cerebral small vessel disease: the Rotterdam frontal micturition area: an fNIRS study. Neurourol Urodyn 2010; scanstudy. J Neurol Neurosurg Psychiatry 2008; 79: 799-803. 29: 757-764. [39] Schmidt R, Schmidt H, Fazekas F, et al. Apolipoprotein E [61] Fowler CJ, Griffiths DJ. A decade of functional brain imaging polymorphism and silent microangiopathy-related cerebral applied to bladder control. Neurourol Urodyn 2010; 29: 49-55. damage.Results of the Austrian Stroke Prevention Study. Stroke [62] Herzog J, Weiss PH, Assmus A, et al. Improved sensory gating of 1997; 28: 951-956. urinary bladder afferents in Parkinson’s disease following [40] Schmidt R, Schmidt H, Fazekas F, et al. MRI cerebral white matter subthalamic stimulation. Brain 2008; 131: 132-145. lesions and paraoxonase PON1 polymorphisms : three-year follow- [63] Fowler CJ, Griffiths D, de Groat WC. The neural control of up of the austrian stroke prevention study. Arterioscler Thromb micturition. Nat Rev Neurosci 2008; 9: 453-466. Vasc Biol 2000; 20: 1811-1816. [64] Griffiths D, Tadic SD. Bladder control, urgency, and urge [41] Reitz C, Berger K, de Maat MP, et al. CRP gene haplotypes, serum incontinence: evidence from functional brain imaging. Neurourol CRP, and cerebral small-vessel disease: the Rotterdam Scan Study Urodyn 2008; 27: 466-474. and the MEMO Study. Stroke 2007; 38: 2356-2359. [65] Hentschel F, Damian M, Krumm B, Froelich L. White matter [42] Joutel A, Corpechot C, Ducros A, et al. Notch3 mutations in lesions - age-adjusted values for cognitively healthy and demented cerebral autosomal dominant arteriopathy with subcortical infarcts subjects. Acta Neurol Scand 2007; 115: 174-180. and leukoencephalopathy (CADASIL), a mendelian condition [66] Mok V, Wong KK, Xiong Y, et al. Cortical and frontal atrophy causing stroke and vascular dementia. Ann N Y Acad Sci 1997; are associated with cognitive impairment in age-related confluent 826: 213-217. white-matter lesion. J Neurol Neurosurg Psychiatry 2011; 82: [43] Hara K, Shiga A, Fukutake T, et al. Association of HTRA1 52-57. mutations and familial ischemic cerebral small-vessel disease. N [67] Tullberg M, Fletcher E, DeCarli C, et al. White matter lesions Engl J Med 2009; 360: 1729-1739. impair frontal lobe function regardless of their location. Neurology [44] Moseley ME, Nishimura MC, Pitts LH, Bartkowski HM, James 2004; 63: 246-253. TL. Proton nuclear magnetic resonance spectroscopy of normal and [68] Schuff N, Capizzano AA, Du AT, et al. Different patterns of N- edematous brain tissue in vitro: changes in relaxation during tissue acetylaspartate loss in subcortical ischemic vascular dementia and storage. Magn Reson Imaging 1984; 2: 205-209. AD. Neurology 2003; 61: 358-364. [45] WallinA, Sjogren M, Edman A, Blennow K, Regland B. [69] Hanyu H, Shimuzu S, Tanaka Y, Takasaki M, Koizumi K, Abe K. Symptoms, vascular risk factors and blood-brain barrier function in Cerebral blood flow patterns in Binswanger's disease: a SPECT relation to CT white-matter changes in dementia. EurNeurol 2000; study using three-dimensional stereotactic surface projections. J 44: 229-235. Neurol Sci 2004; 220: 79-84. 76 Current Drug Therapy, 2012, Vol. 7, No. 1 Sakakibara et al.

[70] Baloh RW, Yue Q, Socotch TM, Jacobson KM. White matter [88] Malone-Lee JG, Wahedna I. Characterisation of detrusor contractile lesions and dysequilibrium in older people; 2.clinicopathological function in relation to old age.Br J Urol 1993; 72: 873-880. correlation. Arch Neurol 1995; 52: 975-981. [89] Resnick NM, Elbadawi A, Yalla SV. 1995. Age and the lower [71] Yamanouchi H, Nagura H.Neurological signs and frontal white urinary tract: what is normal? Neurourol Urodyn 14: 577-579. matter lesions in vascular parkinsonism. A Clinicopathol Study. [90] de Groat WC. Integrative control of the lower urinary tract: Stroke 1997; 28: 965-969. preclinical perspective.Br J Pharmacol 2006; 147: S25-S40. [72] Mok VC, Wong A, Yim P, et al. The validity and reliability of [91] Momjian S, Owler BK, Czosnyka Z, Czosnyka M, Pena A, Pickard chinese frontal assessment battery in evaluating executive JD.Pattern of white matter regional cerebral blood flow and dysfunction among Chinese patients with small subcortical infarct. autoregulation in normal pressure hydrocephalus. Brain 2004; 127: Alzheimer Dis Assoc Disord 2004; 18: 68-74. 965-972. [73] Mok VC,Wong A,Wong K, et al. Executive dysfunction and left [92] Owler BK, Momjian S, Czosnyka Z, et al. Normal pressure frontal white matter hyperintensities are correlated with neuro- hydrocephalus and cerebral blood flow: a PET study of baseline psychiatric symptoms in stroke patients with confluent white matter values. J Cereb Blood Flow Metab 2004; 24: 17-23. hyperintensities. Dement Geriatr Cogn Disord 2010; 30: 254-260. [93] Sasaki H, Ishii K, Kono A, et al. Cerebral perfusion pattern of [74] Wakefield DB, Moscufo N, Guttmann CR, et al. White matter idiopathic normal pressure hydrocephalus studied by SPECT and hyperintensities predict functional decline in voiding, mobility, and statistical brain mapping. Ann Nucl Med 2007; 21: 39-45. cognition in older adults. J Am Geriatr Soc 2010; 58: 275-281. [94] Walter C, Hertel F, Neumann E, Morsdorf M. Alteration of [75] Nagai M, Hoshide S, Kario K. Hypertension and dementia. Am J cerebral perfusion in patients with idiopathic normal pressure Hypertens 2010; 23: 116-124. hydrocephalus measured by 3D perfusion weighted magnetic [76] Duron E, Hanon O. Vascular risk factors, cognitive decline, and resonance imaging. J Neurol 2005; 252: 1465-1471. dementia. Vascular Health Risk Manag 2008: 4: 363-381. [95] Sakakibara R, Uchida Y, Ishii K, et al. The members of [77] Cukierman-Yaffe T, Gerstein HC, Williamson JD, et al. SINPHONI (Study of Idiopathic Normal Pressure Hydrocephalus ACCORDMIND Investigators.Relationship between baseline On Neurological Improvement).Correlation of right frontal glycemic control and cognitive function in individuals with type 2 hypoperfusion and urinary dysfunction in iNPH: A SPECT study. diabetes and other cardiovascular risk factors. The Action to Neurourol Urodyn 2011 Oct 28. [Epub ahead of print] Control Cardiovascular Risk in Diabetes-Memory in Diabetes [96] Kitta T, Kakizaki H, Furuno T, et al. Brain activation during (ACCORD-MIND) trial. Diabetes Care 2009; 32: 221-226. detrusor overactivity in patients with Parkinson’s disease: a [78] Gregoire SM, Jager HR, Yousry TA, Kallis C, Brown MM, positron emission tomography study. J Urol 2006; 175: 994-998. Werring DJ. Brain microbleeds as a potential risk factor for [97] Griffiths D, Derbyshire S, Stenger A, Resnick N. Brain control of antiplatelet-related intracerebralhaemorrhage: hospital-based, case- normal and overactive bladder. J Urol 2005; 174: 1862-1867. control study. J Neurol Neurosurg Psychiatry 2010; 81: 679-684. [98] Gormley EA, Griffiths DJ, McCracken PN, Harrison GM, McPhee [79] Borroni B, Tiberio G, Bonardelli S, et al. Is mild vascular cognitive MS. Effect of transurethral resection of the prostate on detrusor impairment reversible? Evidence from a study on the effect of instability and urge incontinence in elderly males. Neurourol carotid endarterectomy. Neurol Res 2004; 26: 594-597. Urodyn 1993; 12: 445-453. [80] Lapchak PA. A critical assessment of edaravone acute ischemic [99] Sakakibara R, Hamano S, Uchiyama T, Liu Z, Yamanishi T, stroke efficacy trials: is edaravone an effective neuroprotective Hattori T. Do BPH patients have neurogenic detrusor dysfunction? therapy? Expert Opin Pharmacother 2010; 11: 1753-1763. A uro-neurological assessment. Urol Int 2005; 74: 44-50. [81] Marmarou A, Black P, Bergsneider M, Klinge P, Relkin [100] Paquette A, Gou P, Tannenbaum C. Systematic review and meta- N. International NPH Consultant Group. International NPH analysis: do clinical trials testing antimuscarinic agents for Consultant Group.Guidelines for management of idiopathic normal overactive bladder adequately measure central nervous system pressure hydrocephalus: progress to date. Acta Neurochir Suppl adverse events? http://www.ncbi.nlm.nih.gov/pubmed/21718264 J 2005; 95: 237-240. Am Geriatr Soc. 2011; 59: 1332-1339. [82] Ishii K, Hashimoto M, Hayashida K, et al. A multicenter brain [101] Homma Y, Yamaguchi O. For the Imidafenacin Study Group.A perfusion SPECT study evaluating idiopathic normal-pressure randomized, double-blind, placebo- and propiverine-controlled trial hydrocephalus on neurological improvement. Dementia and of the novel antimuscarinic agent imidafenacin in Japanese patients Geriatric Cognitive Disord 2011; 32:1-10. with overactive bladder. Int J Urol 2009; 16: 499-506. [83] Hiraoka K, Meguro K, Mori E. Prevalence of idiopathic [102] Mori S, Kojima M, Sakai Y, Nakajima K. Bladder dysfunction normal-pressure hydrocephalus in the elderly population of a in dementia patients showing urinary incontinence; evaluation Japanese rural community. Neurol Med Chir (Tokyo) 2008; 48: with cystometry and treatment with propiverine hydrochloride. Jpn 197-199. J Geriat 1999; 36: 489-494. [84] Iseki C, Kawanami T, Nagasawa H, et al. Asymptomatic [103] Scheife R, Takeda M. Central nervous system safety of with features of idiopathicnormal pressure anticholinergic drugs for the treatment of overactive bladder in the hydrocephaluson MRI (AVIM) in the elderly: a prospective study elderly. Clin Ther 2005; 27: 144-153. in a Japanese population. J Neurol Sci 2009; 277: 54-57. [104] Sakakibara R, Uchiyama T, Yamanishi T, Kishi M. Dementia and [85] Sakakibara R, Kanda T, Sekido T, et al. Mechanism of bladder lower urinary dysfunction: with a reference to anticholinergic use dysfunction in idiopathic normal pressure hydrocephalus. in elderly population. Int J Urol 2008; 15: 778-788. Neurourol Urodyn 2008; 27: 507-510. [105] Chu FM, Dmochowski RR, Lama DJ, Anderson RU, Sand PK. [86] Jonas S, Brown J. Neurogenic bladder in normalpressure- Extended-release formulations of oxybutynin and tolterodine hydrocephalus. Urology 1975; 5: 44-50. exhibit similar central nervous system tolerability profiles: A [87] Ahlberg J, Noren L, Blomstrand C, Wikkelso C. Outcome of subanalysis of data from the OPERA trial. Am J Obstet Gynecol shunt operation on urinary incontinence in normal pressure 2005; 192: 1849-1855. hydrocephalus predicted by lumber puncture. J Neurol Neurosurg [106] Tyagi P, Tyagi V, Chancellor M. Mirabegron: a safety review. Psychiatry 1988; 51: 105-108. Expert Opin Drug Saf 2011; 10: 287-294.

Received: December 11, 2011 Revised: January 22, 2012 Accepted: February 23, 2012