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Journal of Parkinson’s Disease xx (20xx) x–xx DOI 10.3233/JPD-140434 IOS Press
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Pan-American Consortium of Multiple System Atrophy (PANMSA). A Pan-American multicentre cohort study of Multiple System Atrophy
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a Department
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of Movement Disorders, Instituto Neurociencias de Buenos Aires, INEBA, Buenos Aires, Argentina Nacional de Neurolog´ıa y Neurocirug´ıa, M´exico City, Mexico c Instituto Nacional de Ciencias Neurol´ ogicas, Lima, Per´u d CETRAM, Facultad de Ciencias M´ edicas, Universidad de Santiagode Chile, Santiago de Chile, Chile e Cl´ınica Las Condes, Santiago de Chile, Chile f Clinical Research Services and Support (OCRSS) University of Louisville, KY, USA g Department of Neurology, Sanatorio de la Trinidad Mitre, Buenos Aires, Argentina h Servicio Neurolog´ıa, Hospital Torn´ u, Ciudad Aut´onoma de Buenos Aires, Argentina i UC San Diego Movement Disorder Center, La Jolla, CA, USA b Instituto
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Emilia Gattoa,g,∗ , Mayela Rodr´ıguez-Violanteb , Carlos Consentinoc , Pedro Chana-Cuevasd , Marcelo Mirandae , Ellin Gallinf , Jose L. Etcheverrya , Yesenia Nu˜nezc , Virginia Parisig , Gabriel Persig , Celeste Vecchia , Ana Sanguinettia , Alejandro Allevah , Juliana Aparcanac , Luis Torresc and Irene Litvani
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Keywords: Parkinsonism, multiple system atrophy, MSA, synucleinopathies, Latin America
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Abstract. Background: Multiple system atrophy (MSA) is an adult-onset and rapidly progressive, neurodegenerative condition that presents with autonomic dysfunction, parkinsonism, cerebellar ataxia and corticospinal deficits. Clinical, demographic and epidemiological data from different regions have provided valuable information concerning the natural history of MSA. There are no published data of Multiple System Atrophy (MSA) in Latin American countries. Objective: To describe clinical and epidemiological data of patients with “possible” MSA from seven referral movement disorders centers from Argentina, Chile, Mexico, Peru and United States. Methods: We conducted a retrospective, observational, cross-sectional Pan-American multicentre cohort study of MSA. Results: The sample was composed of 82 females and 77 men with the diagnosis of “possible” MSA with a mean age at onset of 65 ± 10 years. 67.29% of the individuals had a MSA-P variant with a mean age at onset of 61.47 ± 10.28 years, whereas the mean age at onset in the MSA-C patients was 57.44 ± 10.58 years. Interestingly, MSA-Cwas more prevalent in Non-Caucasian (50Mestizo and 2 Asian patients) than Caucasians (51.92% vs. 20.79%, p = 0.0001). Dysautonomic symptoms were present in 95.6% of the patients, parkinsonism in 85.5%, pyramidal signs in 25.8% and depression in 48.4% of the patients. Conclusions: Our epidemiological and clinical data appears to be similar to other Western international series, however, of note, the MSA-C phenotype was predominant in Non-Caucasians, more specifically the Mestizo population. This observation opens a new path to explore. Larger prospective epidemiologic studies in Latin America may provide valuable information concerning MSA in the region.
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∗ Correspondence
to: Emilia Mabel Gatto MD, Juramento 1155 Buenos Aires, CP 1428, Argentina. Tel.: +54 11 4785 30 97; E-mail:
[email protected]. 3◦ A.
ISSN 1877-7171/14/$27.50 © 2014 – IOS Press and the authors. All rights reserved
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Data analysis
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(Argentina, Chile, Mexico, Peru and the United States) participated in the present study. The clinical diagnosis of MSA was made on the basis of the current consensus criteria for the disease (revised criteria for clinical diagnosis of MSA, 2008) and ancillary neuroimaging [4]. Any other causes of Parkinsonism or secondary causes of MSA-C were excluded including vascular lesions, immunemediated, metabolic, infectious or the more frequent hereditary spinocerebellar ataxia, SCA, type 1, 2,3, and Friedreich ataxia). All consecutive patients with a diagnosis of clinical “possible” MSA between 2001 to 2013 were included after they signed an informed consent. Epidemiological and demographic data were collected including gender, age, ancestry and place of residence (urban or rural). Disease-specific information included family history, age at symptom onset, disease duration since symptom-onset, clinical manifestations (motor and non-motor symptoms) and treatment. When available, magnetic resonance imaging (MRI) was analyzed and the presence of atrophy, crux cerebrii and putaminal hyperintensity, were recorded. An extensive neurological examination was performed by a board certified neurologist with expertise in movement disorders. Cognitive dysfunction was assessed with the Mini Mental Status Examination (MMSE) test, with a cutoff ≤ 24. When available, assessment of depression was recorded. Since each of these centers used different scales to evaluate these patients, we could not include the data from any formal MSA scale.
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Multiple system atrophy (MSA) is an adult-onset, progressive neurodegenerative disease characterized by varying combination of parkinsonism, cerebellar ataxia, corticospinal tract dysfunction and non-motor symptoms including autonomic failure, sleep disorders and respiratory manifestations [1, 2]. Neuropathological findings consist of degeneration in multiple brain areas including substantianigra, striatum, cerebellum, pontine nuclei, and spinal cord with distinctive aggregates of ␣-synuclein, primarily in oligodendroglia [2]. The first consensus criteria for clinical diagnosis of MSA was published in 1998 and revised in 2008 (sensitivity of 41%) [3, 4]. Depending on the predominant motor presentation, two clinical MSA phenotypes can be distinguished: MSA-P with predominant parkinsonism and striatonigral system involvement and MSA-C dominated by cerebellar ataxia and olivopontocerebellar pathway involvement [2, 5]. Prevalence rates range from 1.9 to 4.4/100,000 and the incidence has been estimated as 3/100,000 per year in the population older than 50 years [6]. Over the past years, large series from different international networks from Europe, Japan, China and North America have provided relevant insight into the epidemiology and natural history of MSA and confirmed the predominance of the MSAParkinsonism (MSA-P) phenotype in Europe and the MSA-Cerebellar (MSA-C) phenotype in Japan [1, 5, 7, 8]. Although, the causes of regional differences remain poorly understood, genetic predisposition and exposure to environmental toxins have been suggested as the most likely hypothesis [9–11]. To our best knowledge, no epidemiological and demographic data has been reported from Latin-America, a region with a great mixture of populations and cultures. Studies in different ethnic groups are required to improve our knowledge about theMSA phenotypic expression as well as the genetics and environmental factors that could contribute to the MSA pathogenesis [9, 11]. Herein we describe the clinical and demographic characteristics of subjects diagnosed with possible MSA from 7 referral centers in North America and Latin America (Pan-American Multiple System Atrophy-Study Group-PANMSA).
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INTRODUCTION
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E. Gatto et al. / Multiple System Atrophy, Panamerican Consortium
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Demographic data was reported in percentages, mean and standard deviation. Frequencies of symptoms were compared using Chi² or Fisher’s exact test. T-test or non-parametric tests (Mann–Whitney U test) were used when appropriate (p < 0.05). All tests were two sided, and significance level was set at P < 0.05. Statistical analyses were performed using SPSS 15.0 (SPSS Inc).
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RESULTS
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Patient characteristics
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We conducted a retrospective, observational, crosssectional study. A total of seven centers from the PANMSA Consortium across five different countries
A total of 159 patients (82 females and 77 males) were included in this study. The mean age at disease onset was 65.6 ± 10.2 years. The overall prevalence
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Frequency of symptoms are shown in Fig. 1. Autonomic symptoms were present in 95.6% (n = 152) of patients, 94% of those with MSA-C and 97.2% of those with MSA-P. Urinary symptoms were present in 78% (n = 124) followed by orthostatic hypotension in 70.4% (n = 112). Only 5.7% (n = 9) of patients reported urinary incontinence. Erectile dysfunction was reported in 41.5% (n = 32) of the male patients.
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Clinical autonomic features
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since symptom onset: MSA-P = 5.5 ± 3.14 vs. MSAC = 5.45 ± 3 years; p = 0.93.
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of MSA-P was 67.3 % (107 individuals) while MSAC was reported in 31.44% (50 individuals), in two cases this information was missing. A significant difference was observed in the mean age at onset between MSA-P and C variants (MSA-P: 61.47 ± 10.3 years vs. 57.44 ± 10.2 years; p = 0.02). Fifty two patients reported Non-Caucasian ancestry; 50 of them were Mestizo (non-white of mixed European and Amerindian descent) and 2 reported Asian ancestry. MSA-C variant was identified in 51.92% (n = 27) of Non-Caucasian patients and in 20.8% of Caucasian individuals (p = 0.0001). There were no betweengroup differences in the estimated disease duration
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Fig. 1. Clinical presentation of MSA. A: Autonomic dysfunction. B: Parkinsonism signs and symptoms. C: Miscellaneous symptoms. Ref: Fig.1A incontinence = Faecal Incontinence; Fig.1 C RBD = REM Behavior Disorders, RLS = Restless Legs.
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Fig. 2. Magnetic resonance imaging findings in the patients with Multiple System Atrophy.
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All MSA-C patients exhibited some degree of ataxia; falls were reported in 64.5% of them and brain MRI showed cerebellar atrophy in 63.8% of patients with cerebellar variant, while in MSA-P, only 29.7% showed cerebellar atrophy. Nystagmus was not included in view of the high number of missing data.
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Parkinsonism was observed in 85.5% of all cases, moreover 74.0% of patients classified as MSACshowed parkinsonian symptoms. Bradykinesia was associated to rigidity in 85.5% (n = 136) of the patients, postural instability in 79.2% (n = 126), postural and resting tremor was observed in 20.1% (n = 32) and 32.1% (n = 51) of the cases,.
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Survival analysis
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Treatment response
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Depression was reported in 48.4% (n = 77), dementia in 15.7% (n = 25), visual hallucinations in 10% (n = 16), insomnia in 36.5% (n = 58) and excessive daytime sleepiness in 22.6% (n = 36). Rapid eye movement sleep behavior disorder (RBD) was present in 22.6% (n = 36) of the patients. Other findings included disproportionate anterocollis in 5% (n = 8), camptocormia in 12.6% (n = 20), dysphonia in 49.1% (n = 78), dysarthria in 44.7% (n = 71) and dysphagia in 50.3% (n = 80).
A total of 89.7% (n = 141) of patients were on levodopa therapy. Levodopa response was defined as ≥ 30% of motor improvement reported by the patient or physician. The response to levodopa was partial (≤30% improvement in motor scales) in 34%(n = 48), 42.5% (n = 60) of the patients had minimal response or were unresponsive. Only 23.4% (n = 33) of patients showed a good levodopa response.
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Magnetic resonance imaging Brain MRI was available in only 94 patients (59%). The frequency of classical brain MRI signs (hyperintensity rim in dorsolateral putamen, “Cross Hot Bun sign” in the pons, pons and cerebellar atrophic changes are shown in Fig. 2.
Survival could be determined in only 17 patients with an estimated mean disease survival of 5.3 ± 2.5 years (range 1–10 years). DISCUSSION Hereby we describe the clinical and demographic characteristics of the first series of patients with “possible” MSA from seven referral centers located in North America (Mexico and United States) and South America (Argentina, Chile and Peru). We found that the MSA phenotypical expression varied among the different ethnic groups suggesting that genetic factors may influence its clinical presentation [11]. Recent genetic studies performed in different populations from Japan and different European Countries contribute to support this hypothesis and highlight the relevance of extensive studies conducted in other populations around the world [1, 5, 7, 9]. To the best of our best knowledge, the present study constitutes the first to analyze a Latin-American population. Although in the present series we observed a great population mixture, there was a higher prevalence of MSA-P in Caucasians individuals. Conversely, MSA-C predominated in Non-Caucasian patients, over 96 % of who was “Mestizo”. In this regard, the population from Peru and Mexico has the higher “Mestizo” ethnic composition of the region(≥47% and ≥ 60% of their populations, respectively) [14]. There is also a large presence of
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ACKNOWLEDGMENTS
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We thank the patients and their families for their participation. [12]
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FINANCIAL DISCLOSURE/CONFLICT OF INTEREST Authors have nothing to disclose related to the manuscript.
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Wenning GK, Geser F, Krismer F, Seppi K, Duerr S, Boesch S, K¨ollensperger M, Goebel G, Pfeiffer KP, Barone P, Pellecchia MT, Quinn NP, Koukouni V, Fowler CJ, Schrag A, Mathias CJ, Giladi N, Gurevich T, Dupont E, Ostergaard K, Nilsson CF,Widner H, Oertel W, Eggert KM, Albanese A, del Sorbo F, Tolosa E, Cardozo A,Deuschl G, Hellriegel H, Klockgether T, Dodel R, Sampaio C, Coelho M, Djaldetti R, Melamed E, Gasser T, Kamm C, Meco G, Colosimo C, Rascol O, Meissner WG, Tison F, Poewe W & European Multiple System Atrophy Study Group (2013) The natural history of multiple system atrophy: A prospective European cohort. Lancet Neurol, 12, 264-274. Kuzdas-Wood D, Stefanova N, Jellinger KA, Seppi K, Schlossmacher MG, PoeweW, & Wenning GK (2014) Towards translational therapies for multiple system atrophy. Prog Neurobiol, 118C, 19-35. Gilman S, Low PA, Quinn N, Albanese A, Ben-Shlomo Y, Fowler CJ, Kaufmann H, Klockgether T, Lang AE, Lantos PL, Litvan I, Mathias CJ, Oliver E, Robertson D, Schatz I, & Wenning GK (1999) Consensus statement on the diagnosis of multiple system atrophy. J Neurol Sci, 163 94-98. Gilman S, Wenning GK, Low PA, Brooks DJ, Mathias CJ, Trojanowski JQ, Wood NW, Colosimo C, D¨urr A, Fowler CJ, Kaufmann H, Klockgether T, Lees A, Poewe W, Quinn N, Revesz T, Robertson D, Sandroni P, Seppi K, & Vidailhet M (2008) Second consensus statement on the diagnosis of multiple system atrophy. Neurology, 71, 670-676. Yabe I, Soma H, Takei A, Fujiki N, Yanagihara T, & Sasaki H (2006) MSA-C is the predominant clinical phenotype of MSA in Japan: Analysis of 142 patients with probable MSA. J Neurol Sci, 249 115-121. Wenning GK, & Stefanova N (2009) Recent developments in multiple system atrophy. J Neurol, 256, 1791-1808. Gilman S, May SJ, Shults CW, Tanner CM, Kukull W, Lee VM, Masliah E, Low P, Sandroni P, Trojanowski JQ, Ozelius L, Foroud T & North American Multiple System Atrophy Study Group (2005) The north American multiple system atrophy study group. J Neural Transm, 112, 1687-1694. Guo XY, Cao B, Lei F, Huang L, Chen K, Song W, Zhao B, Tang X, & Shang H (2013) Clinical and polysomnographic features of patients with multiple system atrophy in Southwest China. Sleep Breath, 17, 1301-1307. Multiple-System Atrophy Research Collaboration (2013) Mutations in COQ2 in familial and sporadic multiple-system atrophy. N Engl J Med, 369, 233-244. Lee ST, Chu K, Jung KH, Ban JJ, Im WS, Jo HY, Park JH, Lim JY, Shin JW, MoonJ, Lee SK, Kim M, & Roh JK (2014) Altered expression of miR-202 in cerebellum of multiplesystem atrophy. Mol Neurobiol [Epub ahead of print] PubMed PMID: 24981430. Ozawa T, Revesz T, Paviour D, Lees AJ, Quinn N, Tada M, Kakita A, Onodera O, Wakabayashi K, Takahashi H, Nishizawa M, & Holton JL (2012) Difference in MSA phenotype distribution between populations: Genetics or environment? J Parkinsons Dis, 2, 7-18. Stankovic I, Krismer F, Jesic A, Antonini A, Benke T, Brown RG, Burn DJ,Holton JL, Kaufmann H, Kostic VS, Ling H, Meissner WG, Poewe W, Semnic M, Seppi K, Takeda A, Weintraub D, & Wenning GK; Movement Disorders Society MSA (MODIMSA) Study Group (2014) Cognitive impairment in multiple system atrophy: A position statement by the neuropsychology task force of the MDS multiple system atrophy (MODIMSA) study group. MovDisord, 29, 857-867.
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REFERENCES
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Asian Peruvians, who are one of the largest Japanese and Chinese descendent populations in Latin America. This ethnic composition could provide a reliable hypothesis to explain the MSA-C predominance in this population. However larger studies that include genetic studies are needed to support this hypothesis. Our findings in regards to the frequency of motor, autonomic, sleep, behavioral and cognitive disturbances, as well as treatment response are similar to previous studies conducted in Western populations [1, 2, 7]. Nevertheless, we identified an unexpected high frequency of visual hallucinations, which could be related to high doses of dopaminergic medication but merits a more thorough study since hallucinations are not a feature of MSA[15]. The present study has some limitations including: 1) a retrospective design, which may be subject to bias; 2) the lack of use of validated scales for the clinical evaluation of these patients and 3) the lack of neuropathological confirmation from the patients who died and lack of autonomic functioning testing, positron emission tomography (PET) or single-photon emission computed tomography (SPECT) imaging in the rest of the patients. In this regard, most of these testing are not readily available in most of Latin American countries. Nevertheless, the strength of this study is the fact that MSA data from Latin America are scarce or null and the analysis of this series represents the first attempt to explore the demographics and epidemiological characteristics of MSA patients in this particular region. Moreover, the finding of a predominance of MSA-C in the “Mestizo”population supports the importance of conducting a larger epidemiologic study that would include the evaluation of genetic, epigenetic and environmental risk factors to better understand the etiopathogenesis of this disease in this region. These epidemiological data will contribute to improve the medical care of patients living in this region.
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