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population-based cohort. J Neurol Neurosurg Psychiatry 2013;84: 1258-1264. 11.
Winder-Rhodes SE, Evans JR, Ban M, et al. Glucocerebrosidase mutations influence the natural history of Parkinson’s disease in a community-based incident cohort. Brain 2013;136:392399.
12.
Neumann J, Bras J, Deas E, et al. Glucocerebrosidase mutations in clinical and pathologically proven Parkinson’s disease. Brain 2009; 132:1783-1794.
13.
Mazzulli JR, Xu YH, Sun Y, et al. Gaucher disease glucocerebrosidase and alpha-synuclein form a bidirectional pathogenic loop in synucleinopathies. Cell 2011;146:37-52.
14.
Schondorf DC, Aureli M, McAllister FE, et al. iPSC-derived neurons from GBA1-associated Parkinson’s disease patients show autophagic defects and impaired calcium homeostasis. Nat Commun 2014;5:4028.
15.
Gegg ME, Burke D, Heales SJ, et al. Glucocerebrosidase deficiency in substantia nigra of parkinson disease brains. Ann Neurol 2012; 72:455-463.
Lower Urinary Tract Function in Dementia With Lewy Bodies (DLB)
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Dementia with Lewy bodies (DLB) is characterized by various combinations of dementia and parkinsonism, and visual hallucination and fluctuation of cognition are common.1,2 Other features supportive of the diagnosis include postural syncope.3-8 Up to now, only two urodynamic studies9,10 have been published on DLB. Sakakibara et al.9 found lower urinary tract (LUT) symptoms in all of 11 patients. Ten had urinary incontinence, and large postvoid residuals were seen in only 3. Detrusor overactivity (DO) is the major urodynamic abnormality. Abnormal motor unit potentials (MUP) of the sphincter electromyography (EMG) existed in some. Ransmayr et al.,10 in 15 DLB patients, reported similar findings without performing MUP analysis. Here we conducted an EMGcystometry study in a larger cohort of patients and analyzed the relationship between urodynamic parameters and neurological/other parameters.
Methods 1
1
Fuyuki Tateno, MD, * Ryuji Sakakibara, MD, PhD, Tsuyoshi Ogata, BSci,1 Masahiko Kishi, MD, PhD,1 Yohei Tsuyusaki, MD,1 Osamu Takahashi, BSci,2 Megumi Sugiyama, BSci2 and Akihiko Tateno, MD, PhD1 1
Neurology, Internal Medicine, Sakura Medical Center, Toho University, Sakura, Japan 2Clinical Physiology Unit, Sakura Medical Center, Toho University, Sakura, Japan
Abstract Objectives: Dementia with Lewy bodies (DLB) is the second most common degenerative cause of dementia, whereas lower urinary tract (LUT) function in DLB patients has not been fully delineated. We investigated LUT function in DLB by clinical-urodynamic observations. Methods: We examined 32 patients with DLB (23 men, 9 women; aged 59-86 [mean, 75.9] years; disease duration, 0.2-17 [3.3] years). All patients underwent an electromyography-cystometry, and 21 patients underwent the sphincter motor unit potential analysis. Results: Ninety-one percent of patients had LUT symptoms: nighttime frequency (>8 times), 84%, and urinary incontinence (>1 per week), 50%. Detrusor overactivity was revealed in 87.1%, whereas postvoid residual was minimal. Neurogenic changes were shown in 50%. Conclusion: LUT dysfunction is a common feature in DLB, attributable not only to dementia and immobility, but also to central and peripheral types of somatoC 2014 International Parkinson autonomic dysfunction. V and Movement Disorder Society Key Words: dementia with Lewy bodies, lower urinary tract dysfunction, autonomic failure, sphincter motor unit potential, Parkinson’s disease
Patients We retrospectively collected 32 patients with probable DLB3 during the past 5 years (23 men, 9 women; ages 59-86 [mean, 75.9] years; disease duration, 0.217 [3.3] years). All had cognitive impairment, and the mean score on the Mini-Mental State Examination (MMSE)11 was 21 [8-29]. Though eight patients scored over 25 in the test, their cognitive decline fluctuated, and was of a magnitude to interfere with normal social functions. The mean score on the Frontal Assessment Battery (FAB)12 was 10.8.4-17 Nineteen (59.4%) had hallucinations. All had parkinsonism, and the median score on the Hoehn-Yahr was 3 (04.5). Fifteen were tremor-dominant, and the rest were akinesia or rigidity dominant. Twenty-six patients were taking anti-parkinsonian medication, and the median daily levodopa (L-dopa; with a combination of carbidopa) requirement was 285 mg (100-600 mg). Orthostatic hypotension greater than 20 mmHg was noted in 15 of the 32 patients studied. Three males complained of erectile dysfunction. Twenty-eight had constipation.13 Eight had rapid eye movement sleep behavior disorder. No abnormalities were seen in blood tests and urinalysis. No patients had supine hypertension. None had heart failure, and their
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Correspondence to: Fuyuki Tateno, MD, Neurology Division, Department of Internal Medicine, Sakura Medical Center, Toho University, 564-1 Shimoshizu, Sakura, 285-8741 Japan, E-mail: [email protected] Relevant conflicts of interest/financial disclosures: Nothing to report. Author roles may be found in the online version of this article. Received: 5 August 2013; Revised: 18 June 2014; Accepted: 2 July 2014 Published online 30 October 2014 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/mds.25985
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echocardiographic findings were normal. We performed coefficient of variation in R-R interval in 22 patients. Eighteen of 22 patients had low coefficient of variation in R-R interval (normal, 20 mL), with a mean volume of 32 mL by an ultrasound echography. Statistics were analyzed by the Student’s unpaired t test and Mann-Whitney’s U-test.
Results LUT symptoms Eighty-four percent of patients had LUT symptoms: they were nighttime frequency (more than twice),
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84%; urinary incontinence (>1 per week), 50% (urgency type, 11; functional type due to dementia and immobility, 2; both urgency and stress type, 3; urgency and stress functional, 2); daytime frequency (>8 times), 31%; urgency, 4; and voiding difficulty, 20. None was in a state of urinary retention. In terms of LUT symptoms (particularly overactive bladder, OAB, and urinary incontinence) and neurologic symptoms (parkinsonism or dementia), LUT symptoms appeared together with or after the onset of neurological symptoms in all patients. All patients with urinary incontinence had OAB, and none had functional incontinence alone.
Urodynamic Findings and Sphincter EMG Decreased urinary flow was noted in 12 of 15 patients in whom the test was done. The 31 patients underwent EMG-cystometry, showing depressed first sensation volume at 99.9 mL (100 < normal < 300 mL) and mean bladder capacity of 198.8 mL (200 < normal < 600 mL). Detrusor overactivity was seen in 87.1%. Eight had an equivocal obstruction, and 12 had grade 3 to 6 outlet obstruction (Schafer’s nomogram); 15 had underactive (weak) detrusor (Schafer’s nomogram); no one had an acontractile detrusor; and six had detrusor-sphincter dyssynergia. The mean postvoid residual volume was 25 mL, and 6% had a postvoid residual more than 100 mL. Neurogenic changes were seen in 50% of those who underwent the MUP analysis.
Relations Between LUT Parameters and Neurologic/Other Parameters Bladder capacity was negatively related with values of the MMSE (P < 0.05) and the FAB (P < 0.05) and a recent history of hallucination (P < 0.05); first sensation volume was negatively related with the MIBG myocardial scintigraphy (P < 0.05) (Table 1).
Discussion The current study showed the frequent occurrence of LUT dysfunction in DLB as seen in 84% of patients. Parkinsonian gait disorder may lead to functional incontinence and frequent falls in DLB,19 whereas it is very uncommon in the early stage of AD.20 Nevertheless, nighttime frequency was the most common symptom (84%) in DLB. This finding suggests that urinary incontinence in DLB is not a result simply of immobility or dementia, but possibly of neurogenic detrusor dysfunction. Del-Ser et al.20 also reported that urinary incontinence usually precedes severe mental failure in DLB, and that the onset of urinary incontinence is significantly earlier in DLB than in AD. None of the DLB patients was in a state of urinary retention. Because the number of our
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TABLE 1. Relations between lower urinary tract parameters and neurologic/other parameters in DLB Lower Urinary Tract Parameters Daytime Frequency (>8 times) (%)
Motor (Hoehn Y ahr) Mild (0-2) 42.9 Moderate (3-4) 23.1 Tremor (2) 44.4 (1) 11.1 MMSE Mild (21-30) 37.5 Moderate (2.0). By MIBG scintigraphy, normal cardiac ventricular images disappear in DLB/Parkinson’s disease, indicating sympathetic denervation that is a biomarker for the diagnosis of DLB/Parkinson’s disease. *: P 5 0.05 See text.
patients is not large, we cannot simply compare the LUT function in DLB with that in PD, pure autonomic failure (PAF), MSA, or AD. However, by our previous data21-25 and by that of other researcherss,10,26-28 the severity of storage dysfunction seems to be: MSA 5 DLB > PAF 5 PD > AD (though functional incontinence caused by dementia significantly overlaps in DLB and AD), whereas that of voiding dysfunction seems to be: MSA >> DLB 5 PAF > PD > AD (Table 2). In particular, a large postvoid residual is a prominent feature in MSA, whereas it is very uncommon in Lewy body diseases and AD. In contrast, although bladder disorders are thought to occur early in Lewy body diseases,29 they rarely predate motor disorder. This is in contrast to the frequency of such findings in MSA.21,27 Electromyogram-cystometry showed DO in 87.1% of the patients studied. This is in accordance with our previous finding (71% of 7 patients)9 and Ransmayr’s finding (73% of 15 patients).10 The spino-bulbo-spinal micturition reflex is under tonic (mainly inhibitory) influences30 by the central cholinergic pathway31 and the fronto-striatal, dopamine D1-GABAergic direct pathway.32 All of these regions are known to be involved in DLB.1,2 Bladder capacity is negatively related with MMSE (P < 0.05) and FAB scores (P < 0.05) and a recent history of hallucination (P < 0.05). The results
strongly indicate that not only the basal ganglia but also cortical pathology contribute to the occurrence of DO in DLB. The occurrence of DO was reported in 40% to 78% of AD patients.25,26 Therefore, the occurrence of DO seems to be higher in DLB than in AD. Analysis of the sphincter MUPs showed neurogenic findings in 50% of the patients studied. This finding suggests the involvement of the sacral Onuf’s nucleus innervating the sphincter in DLB.17,18 Previously the Onuf’s nucleus was believed to never be involved in PD, based on pathology and EMG studies, whereas recent studies disclosed Lewy neurites and a Lewy body within the Onuf’s nucleus in PD.33 The rarity of this finding may be attributable to the fact that spinal cord tissue is rarely available in autopsy specimens. By our previous data,21-25 the prevalence of the neurogenic sphincter EMG seems to be MSA >> DLB 5 PAF >> PD > AD (Table 2). This suggests that the Onuf’s nucleus seems to be involved, along with the cerebral cortex (dementia) and the vasomotor nerves (autonomic failure), whereas it is rarely involved when pathology remains in the basal ganglia in Lewy body diseases. The first sensation volume was negatively related with the MIBG myocardial scintigraphy (P < 0.05) (cardiac noradrenergic denervation). Matsui et al.34 reported similar observation. Because stimulation of the noradrenergic beta-3 pathway
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TABLE 2. Comparison of lower urinary tract function in DLB, PAF, PD, MSA, and AD
diseases
MSA DLB PAF PD AD
LUT Symptoms
100% 91% 100% 53-70% 44%
Urinary Incontinence (Storage Dysfunction)
PVR >100ml (Voiding Dysfunction) (Mostly Peripheral)
No. of Patients
70% 8% 33% 0% 0%
245 32 6 115 24
71% 71% 33% 25-28% 33% (100% in totally dependent cases)
Ref.
Detrusor Overactivity (Mostly Central)
Neurogenic Change Of Sphincter MUPs (Somatic Denervation) (Onuf Nucleus)
Abnormal MIBG Myocardial Scintigraphy (Noradrenergic Denervation)
No. of Patients
75% 89% 67% 81% 40-78%
83% 47% 3/4 5% 0%
(0-10%) 100% (100%) (90%) (0-10%)
245 32 6 21 24
21 -
22 23 25,27,28
Ref.
21 -
22 24 10,25,26
MSA: multiple system atrophy; DLB: dementia with Lewy bodies; PAF: pure autonomic failure; PD: Parkinson’s disease; AD: alzheimer’s disease; LUT: lower urinary tract; PVR: post-void residual; MUP: motor unit potential MIBG: metaiodobenzylguanidine: ref: references.
causes relaxation of the bladder wall,30 these fibers might be involved in DLB. An approach for the care of LUT dysfunction in patients with DLB includes anti-cholinergics for OAB. However, anticholinergic side effects is of concern,35,36 as first documented in PD patients taking oxybutinin.37 Crossing the blood–brain barrier, they can act at the M1-muscarinic receptors in the brain. Drugs with less central M1-receptor selectivity and less lipophilicity might be safer.35,36 The addition of propiverine to donepezil has been shown recently to ameliorate OAB without worsening cognitive function.38 Mirabegron, a novel peripheral adrenergic beta-3 receptor agonist, is promising for ameliorating DO.39 Behavioral therapy can be used to manage functional incontinence. In conclusion, LUT dysfunction is a common feature in DLB, attributable not only to dementia and immobility, but also to central and peripheral types of somato-autonomic dysfunction.
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Sakakibara R, Hattori T, Uchiyama T, et al. Videourodynamic and sphincter motor unit potential analyses in Parkinson’s disease and
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RELN Rare Variants in Myoclonus-Dystonia Justus L. Groen, MD, PhD,1,2 Katja Ritz, MD, PhD,2 Hamid Jalalzadeh, MD,1 Sandra M.A. van der Salm, MD,1 Aldo Jongejan, PhD,3 Olaf R. Mook, PhD,4 Martin A. Haagmans, MSc,4 Aeilko H. Zwinderman, PhD,3 Mahdi M. Motazacker, PhD,4 Raoul C. Hennekam, MD, PhD,5 Frank Baas, MD, PhD2† and Marina A.J. Tijssen, MD, PhD6†*
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and Bio-Statistics, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands 4Department of Clinical Genetics, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands 5Department of Pediatrics, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands 6Department of Neurology, University of Groningen, the Netherlands
Abstract Background: Myoclonus-dystonia (M-D) is a hyperkinetic movement disorder with predominant myoclonic symptoms combined with dystonia of the upper part of the body. A proportion of M-D cases are caused by mutations in the epsilon-sarcoglycan gene. In remaining M-D patients, no genetic factor has been established, indicating genetic heterogeneity. Methods: Patients were included in a prospective clinical database and recruited from referral centers and general neurology clinics in The Netherlands. To investigate new genetic causal factors in M-D syndrome, we performed homozygosity mapping combined with exome sequencing in a three-generation M-D family and genetically screened 24 additional patients with M-D. Results: We found co-segregation of the rare missense variant Thr1904Met in the RELN gene. By additional screening of an M-D cohort, we identified cosegregation of RELN variants in two families (Thr1904Met, Ile1217Met) and identified two sporadic RELN mutation carriers (Pro1703Arg, Leu411Ile). Taken together, five of 25 SGCE-negative M-D patients carried RELN rare missense variants. Conclusion: We propose that RELN mutations contribute to the genetic heterogeneity of M-D. Reelin is a large secreted glycoprotein that plays essential roles in the cytoarchitecture of laminated brain structures and moduC 2015 lation of synaptic transmission and plasticity. V International Parkinson and Movement Disorder Society Key Words: myoclonus-dystonia, genetics, RELN
Myoclonus-Dystonia (M-D, MIM #159900) syndrome is a rare hyperkinetic movement disorder with myoclonic jerks combined with dystonia in
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*Correspondence to: Prof dr Marina AJ de Koning-Tijssen, Dept of Neurology AB 51, University of Groningen, PO Box 30.001, 9700 RB Groningen, The Netherlands, E-mail: [email protected] †
These authors contributed equally.
Funding agencies: Prinses Beatrix fund. Relevant conflicts of interest/financial disclosures: Nothing to report. Full financial disclosures and author roles may be found in the online version of this article.
1
Department of Neurology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands 2Department of Genome Analysis, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands 3Department of Clinical Epidemiology
Received: 5 August 2014; Revised: 30 September 2014; Accepted: 5 October 2014 Published online 4 February 2015 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/mds.26070
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population-based cohort. J Neurol Neurosurg Psychiatry 2013;84: 1258-1264. 11.
Winder-Rhodes SE, Evans JR, Ban M, et al. Glucocerebrosidase mutations influence the natural history of Parkinson’s disease in a community-based incident cohort. Brain 2013;136:392399.
12.
Neumann J, Bras J, Deas E, et al. Glucocerebrosidase mutations in clinical and pathologically proven Parkinson’s disease. Brain 2009; 132:1783-1794.
13.
Mazzulli JR, Xu YH, Sun Y, et al. Gaucher disease glucocerebrosidase and alpha-synuclein form a bidirectional pathogenic loop in synucleinopathies. Cell 2011;146:37-52.
14.
Schondorf DC, Aureli M, McAllister FE, et al. iPSC-derived neurons from GBA1-associated Parkinson’s disease patients show autophagic defects and impaired calcium homeostasis. Nat Commun 2014;5:4028.
15.
Gegg ME, Burke D, Heales SJ, et al. Glucocerebrosidase deficiency in substantia nigra of parkinson disease brains. Ann Neurol 2012; 72:455-463.
Lower Urinary Tract Function in Dementia With Lewy Bodies (DLB)
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Dementia with Lewy bodies (DLB) is characterized by various combinations of dementia and parkinsonism, and visual hallucination and fluctuation of cognition are common.1,2 Other features supportive of the diagnosis include postural syncope.3-8 Up to now, only two urodynamic studies9,10 have been published on DLB. Sakakibara et al.9 found lower urinary tract (LUT) symptoms in all of 11 patients. Ten had urinary incontinence, and large postvoid residuals were seen in only 3. Detrusor overactivity (DO) is the major urodynamic abnormality. Abnormal motor unit potentials (MUP) of the sphincter electromyography (EMG) existed in some. Ransmayr et al.,10 in 15 DLB patients, reported similar findings without performing MUP analysis. Here we conducted an EMGcystometry study in a larger cohort of patients and analyzed the relationship between urodynamic parameters and neurological/other parameters.
Methods 1
1
Fuyuki Tateno, MD, * Ryuji Sakakibara, MD, PhD, Tsuyoshi Ogata, BSci,1 Masahiko Kishi, MD, PhD,1 Yohei Tsuyusaki, MD,1 Osamu Takahashi, BSci,2 Megumi Sugiyama, BSci2 and Akihiko Tateno, MD, PhD1 1
Neurology, Internal Medicine, Sakura Medical Center, Toho University, Sakura, Japan 2Clinical Physiology Unit, Sakura Medical Center, Toho University, Sakura, Japan
Abstract Objectives: Dementia with Lewy bodies (DLB) is the second most common degenerative cause of dementia, whereas lower urinary tract (LUT) function in DLB patients has not been fully delineated. We investigated LUT function in DLB by clinical-urodynamic observations. Methods: We examined 32 patients with DLB (23 men, 9 women; aged 59-86 [mean, 75.9] years; disease duration, 0.2-17 [3.3] years). All patients underwent an electromyography-cystometry, and 21 patients underwent the sphincter motor unit potential analysis. Results: Ninety-one percent of patients had LUT symptoms: nighttime frequency (>8 times), 84%, and urinary incontinence (>1 per week), 50%. Detrusor overactivity was revealed in 87.1%, whereas postvoid residual was minimal. Neurogenic changes were shown in 50%. Conclusion: LUT dysfunction is a common feature in DLB, attributable not only to dementia and immobility, but also to central and peripheral types of somatoC 2014 International Parkinson autonomic dysfunction. V and Movement Disorder Society Key Words: dementia with Lewy bodies, lower urinary tract dysfunction, autonomic failure, sphincter motor unit potential, Parkinson’s disease
Patients We retrospectively collected 32 patients with probable DLB3 during the past 5 years (23 men, 9 women; ages 59-86 [mean, 75.9] years; disease duration, 0.217 [3.3] years). All had cognitive impairment, and the mean score on the Mini-Mental State Examination (MMSE)11 was 21 [8-29]. Though eight patients scored over 25 in the test, their cognitive decline fluctuated, and was of a magnitude to interfere with normal social functions. The mean score on the Frontal Assessment Battery (FAB)12 was 10.8.4-17 Nineteen (59.4%) had hallucinations. All had parkinsonism, and the median score on the Hoehn-Yahr was 3 (04.5). Fifteen were tremor-dominant, and the rest were akinesia or rigidity dominant. Twenty-six patients were taking anti-parkinsonian medication, and the median daily levodopa (L-dopa; with a combination of carbidopa) requirement was 285 mg (100-600 mg). Orthostatic hypotension greater than 20 mmHg was noted in 15 of the 32 patients studied. Three males complained of erectile dysfunction. Twenty-eight had constipation.13 Eight had rapid eye movement sleep behavior disorder. No abnormalities were seen in blood tests and urinalysis. No patients had supine hypertension. None had heart failure, and their
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Correspondence to: Fuyuki Tateno, MD, Neurology Division, Department of Internal Medicine, Sakura Medical Center, Toho University, 564-1 Shimoshizu, Sakura, 285-8741 Japan, E-mail: [email protected] Relevant conflicts of interest/financial disclosures: Nothing to report. Author roles may be found in the online version of this article. Received: 5 August 2013; Revised: 18 June 2014; Accepted: 2 July 2014 Published online 30 October 2014 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/mds.25985
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echocardiographic findings were normal. We performed coefficient of variation in R-R interval in 22 patients. Eighteen of 22 patients had low coefficient of variation in R-R interval (normal, 20 mL), with a mean volume of 32 mL by an ultrasound echography. Statistics were analyzed by the Student’s unpaired t test and Mann-Whitney’s U-test.
Results LUT symptoms Eighty-four percent of patients had LUT symptoms: they were nighttime frequency (more than twice),
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84%; urinary incontinence (>1 per week), 50% (urgency type, 11; functional type due to dementia and immobility, 2; both urgency and stress type, 3; urgency and stress functional, 2); daytime frequency (>8 times), 31%; urgency, 4; and voiding difficulty, 20. None was in a state of urinary retention. In terms of LUT symptoms (particularly overactive bladder, OAB, and urinary incontinence) and neurologic symptoms (parkinsonism or dementia), LUT symptoms appeared together with or after the onset of neurological symptoms in all patients. All patients with urinary incontinence had OAB, and none had functional incontinence alone.
Urodynamic Findings and Sphincter EMG Decreased urinary flow was noted in 12 of 15 patients in whom the test was done. The 31 patients underwent EMG-cystometry, showing depressed first sensation volume at 99.9 mL (100 < normal < 300 mL) and mean bladder capacity of 198.8 mL (200 < normal < 600 mL). Detrusor overactivity was seen in 87.1%. Eight had an equivocal obstruction, and 12 had grade 3 to 6 outlet obstruction (Schafer’s nomogram); 15 had underactive (weak) detrusor (Schafer’s nomogram); no one had an acontractile detrusor; and six had detrusor-sphincter dyssynergia. The mean postvoid residual volume was 25 mL, and 6% had a postvoid residual more than 100 mL. Neurogenic changes were seen in 50% of those who underwent the MUP analysis.
Relations Between LUT Parameters and Neurologic/Other Parameters Bladder capacity was negatively related with values of the MMSE (P < 0.05) and the FAB (P < 0.05) and a recent history of hallucination (P < 0.05); first sensation volume was negatively related with the MIBG myocardial scintigraphy (P < 0.05) (Table 1).
Discussion The current study showed the frequent occurrence of LUT dysfunction in DLB as seen in 84% of patients. Parkinsonian gait disorder may lead to functional incontinence and frequent falls in DLB,19 whereas it is very uncommon in the early stage of AD.20 Nevertheless, nighttime frequency was the most common symptom (84%) in DLB. This finding suggests that urinary incontinence in DLB is not a result simply of immobility or dementia, but possibly of neurogenic detrusor dysfunction. Del-Ser et al.20 also reported that urinary incontinence usually precedes severe mental failure in DLB, and that the onset of urinary incontinence is significantly earlier in DLB than in AD. None of the DLB patients was in a state of urinary retention. Because the number of our
U R I N A R Y
F U N C T I O N
I N
D L B
TABLE 1. Relations between lower urinary tract parameters and neurologic/other parameters in DLB Lower Urinary Tract Parameters Daytime Frequency (>8 times) (%)
Motor (Hoehn Y ahr) Mild (0-2) 42.9 Moderate (3-4) 23.1 Tremor (2) 44.4 (1) 11.1 MMSE Mild (21-30) 37.5 Moderate (2.0). By MIBG scintigraphy, normal cardiac ventricular images disappear in DLB/Parkinson’s disease, indicating sympathetic denervation that is a biomarker for the diagnosis of DLB/Parkinson’s disease. *: P 5 0.05 See text.
patients is not large, we cannot simply compare the LUT function in DLB with that in PD, pure autonomic failure (PAF), MSA, or AD. However, by our previous data21-25 and by that of other researcherss,10,26-28 the severity of storage dysfunction seems to be: MSA 5 DLB > PAF 5 PD > AD (though functional incontinence caused by dementia significantly overlaps in DLB and AD), whereas that of voiding dysfunction seems to be: MSA >> DLB 5 PAF > PD > AD (Table 2). In particular, a large postvoid residual is a prominent feature in MSA, whereas it is very uncommon in Lewy body diseases and AD. In contrast, although bladder disorders are thought to occur early in Lewy body diseases,29 they rarely predate motor disorder. This is in contrast to the frequency of such findings in MSA.21,27 Electromyogram-cystometry showed DO in 87.1% of the patients studied. This is in accordance with our previous finding (71% of 7 patients)9 and Ransmayr’s finding (73% of 15 patients).10 The spino-bulbo-spinal micturition reflex is under tonic (mainly inhibitory) influences30 by the central cholinergic pathway31 and the fronto-striatal, dopamine D1-GABAergic direct pathway.32 All of these regions are known to be involved in DLB.1,2 Bladder capacity is negatively related with MMSE (P < 0.05) and FAB scores (P < 0.05) and a recent history of hallucination (P < 0.05). The results
strongly indicate that not only the basal ganglia but also cortical pathology contribute to the occurrence of DO in DLB. The occurrence of DO was reported in 40% to 78% of AD patients.25,26 Therefore, the occurrence of DO seems to be higher in DLB than in AD. Analysis of the sphincter MUPs showed neurogenic findings in 50% of the patients studied. This finding suggests the involvement of the sacral Onuf’s nucleus innervating the sphincter in DLB.17,18 Previously the Onuf’s nucleus was believed to never be involved in PD, based on pathology and EMG studies, whereas recent studies disclosed Lewy neurites and a Lewy body within the Onuf’s nucleus in PD.33 The rarity of this finding may be attributable to the fact that spinal cord tissue is rarely available in autopsy specimens. By our previous data,21-25 the prevalence of the neurogenic sphincter EMG seems to be MSA >> DLB 5 PAF >> PD > AD (Table 2). This suggests that the Onuf’s nucleus seems to be involved, along with the cerebral cortex (dementia) and the vasomotor nerves (autonomic failure), whereas it is rarely involved when pathology remains in the basal ganglia in Lewy body diseases. The first sensation volume was negatively related with the MIBG myocardial scintigraphy (P < 0.05) (cardiac noradrenergic denervation). Matsui et al.34 reported similar observation. Because stimulation of the noradrenergic beta-3 pathway
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TABLE 2. Comparison of lower urinary tract function in DLB, PAF, PD, MSA, and AD
diseases
MSA DLB PAF PD AD
LUT Symptoms
100% 91% 100% 53-70% 44%
Urinary Incontinence (Storage Dysfunction)
PVR >100ml (Voiding Dysfunction) (Mostly Peripheral)
No. of Patients
70% 8% 33% 0% 0%
245 32 6 115 24
71% 71% 33% 25-28% 33% (100% in totally dependent cases)
Ref.
Detrusor Overactivity (Mostly Central)
Neurogenic Change Of Sphincter MUPs (Somatic Denervation) (Onuf Nucleus)
Abnormal MIBG Myocardial Scintigraphy (Noradrenergic Denervation)
No. of Patients
75% 89% 67% 81% 40-78%
83% 47% 3/4 5% 0%
(0-10%) 100% (100%) (90%) (0-10%)
245 32 6 21 24
21 -
22 23 25,27,28
Ref.
21 -
22 24 10,25,26
MSA: multiple system atrophy; DLB: dementia with Lewy bodies; PAF: pure autonomic failure; PD: Parkinson’s disease; AD: alzheimer’s disease; LUT: lower urinary tract; PVR: post-void residual; MUP: motor unit potential MIBG: metaiodobenzylguanidine: ref: references.
causes relaxation of the bladder wall,30 these fibers might be involved in DLB. An approach for the care of LUT dysfunction in patients with DLB includes anti-cholinergics for OAB. However, anticholinergic side effects is of concern,35,36 as first documented in PD patients taking oxybutinin.37 Crossing the blood–brain barrier, they can act at the M1-muscarinic receptors in the brain. Drugs with less central M1-receptor selectivity and less lipophilicity might be safer.35,36 The addition of propiverine to donepezil has been shown recently to ameliorate OAB without worsening cognitive function.38 Mirabegron, a novel peripheral adrenergic beta-3 receptor agonist, is promising for ameliorating DO.39 Behavioral therapy can be used to manage functional incontinence. In conclusion, LUT dysfunction is a common feature in DLB, attributable not only to dementia and immobility, but also to central and peripheral types of somato-autonomic dysfunction.
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RELN Rare Variants in Myoclonus-Dystonia Justus L. Groen, MD, PhD,1,2 Katja Ritz, MD, PhD,2 Hamid Jalalzadeh, MD,1 Sandra M.A. van der Salm, MD,1 Aldo Jongejan, PhD,3 Olaf R. Mook, PhD,4 Martin A. Haagmans, MSc,4 Aeilko H. Zwinderman, PhD,3 Mahdi M. Motazacker, PhD,4 Raoul C. Hennekam, MD, PhD,5 Frank Baas, MD, PhD2† and Marina A.J. Tijssen, MD, PhD6†*
I N
M Y O C L O N U S
D Y S T O N I A
and Bio-Statistics, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands 4Department of Clinical Genetics, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands 5Department of Pediatrics, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands 6Department of Neurology, University of Groningen, the Netherlands
Abstract Background: Myoclonus-dystonia (M-D) is a hyperkinetic movement disorder with predominant myoclonic symptoms combined with dystonia of the upper part of the body. A proportion of M-D cases are caused by mutations in the epsilon-sarcoglycan gene. In remaining M-D patients, no genetic factor has been established, indicating genetic heterogeneity. Methods: Patients were included in a prospective clinical database and recruited from referral centers and general neurology clinics in The Netherlands. To investigate new genetic causal factors in M-D syndrome, we performed homozygosity mapping combined with exome sequencing in a three-generation M-D family and genetically screened 24 additional patients with M-D. Results: We found co-segregation of the rare missense variant Thr1904Met in the RELN gene. By additional screening of an M-D cohort, we identified cosegregation of RELN variants in two families (Thr1904Met, Ile1217Met) and identified two sporadic RELN mutation carriers (Pro1703Arg, Leu411Ile). Taken together, five of 25 SGCE-negative M-D patients carried RELN rare missense variants. Conclusion: We propose that RELN mutations contribute to the genetic heterogeneity of M-D. Reelin is a large secreted glycoprotein that plays essential roles in the cytoarchitecture of laminated brain structures and moduC 2015 lation of synaptic transmission and plasticity. V International Parkinson and Movement Disorder Society Key Words: myoclonus-dystonia, genetics, RELN
Myoclonus-Dystonia (M-D, MIM #159900) syndrome is a rare hyperkinetic movement disorder with myoclonic jerks combined with dystonia in
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*Correspondence to: Prof dr Marina AJ de Koning-Tijssen, Dept of Neurology AB 51, University of Groningen, PO Box 30.001, 9700 RB Groningen, The Netherlands, E-mail: [email protected] †
These authors contributed equally.
Funding agencies: Prinses Beatrix fund. Relevant conflicts of interest/financial disclosures: Nothing to report. Full financial disclosures and author roles may be found in the online version of this article.
1
Department of Neurology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands 2Department of Genome Analysis, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands 3Department of Clinical Epidemiology
Received: 5 August 2014; Revised: 30 September 2014; Accepted: 5 October 2014 Published online 4 February 2015 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/mds.26070
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