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Gender distribution of patients with Parkinson’s disease treated with subthalamic deep brain stimulation; a review of the 2000–2009 literature
Parkinsonism and Related Disorders 17 (2011) 146e149
Contents lists available at ScienceDirect
Parkinsonism and Related Disorders journal homepage: www.elsevier.com/locate/parkreldis
Review
Gender distribution of patients with Parkinson’s disease treated with subthalamic deep brain stimulation; a review of the 2000e2009 literatureq Gun-Marie Hariz a, b, *, Takeshi Nakajima c, d, Patricia Limousin c, Tom Foltynie c, Ludvic Zrinzo c, Marjan Jahanshahi c, Katarina Hamberg e a
Department of Community Medicine and Rehabilitation, Occupational Therapy, University of Umeå, Sweden Department of Clinical Neuroscience, University of Umeå, Sweden UCL Institute of Neurology, Queen Square, London, UK d Department of Neurosurgery, Tokyo Women’s Medical University, Tokyo, Japan e Department of Public Health and Clinical Medicine, Family Medicine, University of Umeå, Sweden b c
a r t i c l e i n f o
a b s t r a c t
Article history: Received 29 August 2010 Received in revised form 30 November 2010 Accepted 2 December 2010
Purpose: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) has been the mainstream surgical procedure for advanced Parkinson’s disease (PD) during the last decade. Reports from a few individual centres have hinted that women who receive STN DBS are under-represented. We aimed to evaluate the gender distribution of patients with PD who had received STN DBS during the last ten years, and to discuss the findings in relation to studies on gender prevalence of PD. Methods: A search of the PubMed database of clinical papers in English language related to STN DBS between 2000 and 2009 was conducted. Care was taken to minimize redundancies in reporting of published patients. The proportion of men and women were expressed in total and according to pre-defined geographic regions. Results: One hundred and thirty five papers were eligible for review. The gender of the patients was specified in 119 papers on a total of 3880 patients, of which 63% were men. According to geographic origin of publications, the percentage of men with STN DBS was 68% in North America, 62% in Europe, 69% in Australia and 50% in Asia. Conclusions: The proportion of male patients who undergo STN DBS seems to exceed the reported male/ female ratio of patients with PD. Ó 2010 Elsevier Ltd. All rights reserved.
Keywords: Parkinson’s disease Subthalamic nucleus Deep brain stimulation Gender Sex
Contents 1. 2. 3. 4.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .147 Materials and methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .147 Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .147 Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .147 4.1. Specifying gender in DBS publications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148 4.2. Gender distribution of STN DBS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148 4.3. Gender prevalence of PD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148 4.4. Possible reasons for male preponderance among STN DBS patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148 4.5. Weaknesses and pitfalls of this study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148 Financial disclosures/conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148 Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149
q The review of this paper was entirely handled by the Co-Editor-in-Chief, Z.K. Wszolek. * Correspondence to: Department of Community Medicine and Rehabilitation, Section of Occupational Therapy, Umeå University, 901 87 Umeå, Sweden. Tel.: þ46 70 3644366; fax: þ46 90 786 9267. E-mail address: [email protected] (G.-M. Hariz). 1353-8020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.parkreldis.2010.12.002
G.-M. Hariz et al. / Parkinsonism and Related Disorders 17 (2011) 146e149
147
Table 2 Distribution of women and men with Parkinson’s disease treated with STN DBS in the three multicenteremultinational studies.
1. Introduction Parkinson’s disease (PD) is common in both women and men [1]. Some prevalence studies indicated that PD affects men more than women [2,3,4,5,6], while others found equal distribution of the disease among the sexes [7,8,9,10,11,12]. Over the last decade, deep brain stimulation (DBS) of the subthalamic nucleus (STN) has become the mainstream surgical procedure for patients with advanced PD. According to estimates, more than 30 000 patients worldwide had been treated with STN DBS for PD by mid-2000 [13]. There are only two studies in the literature about the gender distribution of patients undergoing any surgery for PD. In 2000 Hariz et al. reported that 65% of published patients worldwide who had surgery between 1985 and 1999 were men [14]. In 2003, Eskandar et al. reported that in the United States 67% of patients who had surgery between 1996 and 2000 were men [15]. Both these studies took into account all surgical procedures for PD, including stereotactic lesions (thalamotomy, pallidotomy) as well as DBS in various brain targets. Setiawan and coworkers from Calgary, Canada, reported in 2006 a survey of patient referrals to DBS for movement disorders at their centre and noticed that women were under-represented [16]. Recently, Pavon et al. highlighted the shortcomings of the literature and the paucity of studies addressing gender issues in STN DBS [17]. In order to evaluate the gender distribution of patients with PD who had received STN DBS, we review the literature of the last ten years, and we discuss the findings in relation to the gender prevalence of PD.
Total of three multicentre studies No of centres included in trial* No of countries included in trial* Total no of reported patients No (%) of male patients No (%) of female patients
DBS for PD Study Group (ref. 18)
Vesper et al. (ref. 19)
Deuschl et al. (ref. 13)
39
18
17
10
13
9
12
2
285
96
111
a
78b
173 (60.7)
60 (62.5)
63 (56.8)
50 (64.1)
112 (39.3)
36 (37.5)
48 (43.2)
28 (35.9)
*Some of the centres/countries were involved in more than one study. a Two patients had DBS in GPi and 5 in Vim thalamus. b Two patients were randomised to STN DBS but did not undergo surgery.
purpose of the present study, these papers were analysed separately from the other papers. All papers were scrutinized with respect to the following criteria: number of patients operated on, whether gender of patients was reported, and the ratio of women and men when available. The findings were considered on a worldwide scale, as well as according to the following geographical areas: a) North America; b) Europe; c) Australia; and d) Asia. 3. Results
2. Materials and methods The PubMed database was searched using the key words “subthalamic nucleus” and “deep brain stimulation” and “Parkinson’s disease”, for articles published in the English language between January 2000 and December 2009. Papers reporting patient data and including three patients or more were retrieved and reviewed. Purely technical notes and review articles were not considered. However, papers reporting studies on patients with STN DBS related to physiology, imaging, psychology, and other subjects were included. Papers reporting a mixture of surgical procedures for PDeother than STN DBSewere only retained for the present analysis if the paper provided details on the sex distribution of patients within each surgical procedure. In cases of multiple papers published from the same institution, we considered only the paper with the largest number of patients to avoid duplicate inclusion of the same patients, as long as it was published within the specified decade. Papers were grouped according to institution and country of origin. Single centre studies with authors from different institutional affiliations were arbitrarily grouped according to the institutional affiliation of the senior author. Multinational, multicentre publications were also considered; however, for the specific
The PubMed search provided a total of 975 papers dealing with STN DBS and published during 2000e2009. Of these, 505 papers were eligible for review. Upon further examination of these papers, there remained 135 publications that fitted the methods criteria of the present study. Table 1 shows the total number of patients included and the percentage of males and females on a worldwide scale and according to geographic origin of publications. In the 3880 published patients in whom gender was reported, 37% were women and 63% men. These proportions of men and women were approximately similar in all world regions represented, except in publications from Asia where STN DBS showed almost equal distribution between women and men. Table 2 shows results from the three multinational multicentre studies [13,18,19] on a total of 285 patients, 39.3% of whom were women. 4. Discussion Our survey of the English language literature on STN DBS published between 2000 and 2009 revealed that, on a global scale, women represented roughly 37% of the operated patients. Europe and North America accounted for 88% of published papers including 89% of reported patients. While women constituted 38%
Table 1 Distribution of women and men with subthalamic nucleus (STN) deep brain stimulation (DBS) for Parkinson’s disease, in publications worldwide and in specific parts of the world.
No of papers (%) No of papers (%) in which gender was specified Total no (%) of reported patients No (%) of patients with gender reported No (%) of men No (%) of women
Worldwide
North America
Europe
Australia
Asia
135 119 (88.1) 4700 3880 (82.6) 2445 (63.0) 1435 (37.0)
43 37 1461 1082 735 347
76 68 2736 2432 1513 919
4 3 135 77 53 24
12 11 368 289 144 145
(31.9) (86.0) (31.1) (74.1) (67.9) (32.1)
(56.3) (89.5) (58.2) (88.9) (62.2) (37.8)
(3.0) (75.0) (2.9) (57.0) (68.8) (31.2)
(8.9) (91.7) (7.8) (78.5) (49.8) (50.2)
148
G.-M. Hariz et al. / Parkinsonism and Related Disorders 17 (2011) 146e149
of European patients and 32% of North American patients, the proportion of women in the Asian studies was close to 50%. 4.1. Specifying gender in DBS publications Our study showed that gender of patients who had DBS of the STN was specified in 88% of the papers (Table 1). According to a meta-analysis on adverse events of DBS by Appleby et al, including 546 papers dealing with DBS for any indication and in any brain target, published between 1996 and 2005, gender was specified in 51% of the papers [20]. In a meta-analysis by KleinereFisman et al. on outcomes of STN DBS [21], five of the 34 reviewed publications did not specify the gender of patients. Since there may be differences between men and women in symptom profile of advanced PD [22], such as the observation that women more than men exhibit dyskinesias [23,24,25], as well as differences in effects and side effects of surgery [23,26,27], it is important to specify the sex of operated patients in clinical publications. 4.2. Gender distribution of STN DBS Comparison of the gender distribution of STN DBS in the present study with that of PD patients undergoing DBS between 1985 and 1999 in any brain target, i.e. pallidum, thalamus or STN [14], revealed a small increase in the percentage of female patients from 34% ten years ago to 37% in this study. In 2003, Eskandar et al. reported that among the 573 patients who underwent DBS in the US between 1996 and 2000, 70% were male [15]. Kenney et al. from Houston [28] evaluated 5290 patients with PD, of whom 60.6% were male. From this population, 182 patients were selected to receive DBS, and among these patients 73.1% were men. The authors concluded: “Like other authors, we found that more male patients were treated with DBS in our centre, and the proportion of male patients exceeded the usual male/female predominance of PD” [28]. These figures are close to those we found in our review concerning gender distribution of STN DBS in North American publications (Table 1). KleinereFisman et al. reported 63.8% male patients in their meta-analysis of outcomes of STN DBS studies published between 1993 and 2004, with a total of 921 patients [21]. Hamani et al. [29] also found a 63% male preponderance in 38 studies from 34 centres in 13 countries. These figures are similar to our findings when taking into account all STN DBS publications regardless of geographical origin (Table 1). In order to avoid duplication of patients’ inclusions in this survey of the literature, the gender distribution of patients in the three multinational multicentre studies was reported separately (Table 2). Here, the percentage of females in a total of 285 patients ranged from 37.5% to 43%. Hence, the results of our survey call into question whether the distribution of STN DBS in women and men mirrors the gender distribution of PD itself [28]. 4.3. Gender prevalence of PD Clear evidence of any gender preponderance in prevalence of PD is lacking [6,8,11]. The prevalence of PD in the general population varies according to applied methodology, diagnostic criteria, age distribution and case finding strategy [30,31]. Some authors reported a male predominance [2,3,4,5,6], while others found no difference of PD prevalence between women and men, [7,8,9,10,11,12]. Further, some studies found a higher prevalence of PD in women [32,33]. Methodologies using door-to-door surveys are generally considered the most accurate methods or “the gold standard” [34] when determining prevalence. In the European collaborative study using door-to-door surveys, de Rijk et al. found no differences in prevalence of PD between men and women [7,8].
A systematic review of prevalence and incidence of PD in Asia [31] revealed that the prevalence of PD was slightly lower in Asia compared to western countries and epidemiological studies from Japan [33,35,36], as well as from Taiwan [37] found a preponderance of PD in women. Publications on STN DBS from Asian countries accounted, however, only for 8% of the reported patients worldwide, and here the distribution of women and men was equal (Table 1). 4.4. Possible reasons for male preponderance among STN DBS patients The observation that in the western world the proportion of male patients who receive STN DBS exceeds “the usual male/female predominance of PD” [28], eassuming that such predominance existse has no simple answer. Eskandar et al, in their review of surgery for PD in the US, stated that surgically treated patients were more likely to be male, Caucasian, and to have higher incomes, perhaps reflecting biases on the part of the medical caregivers, the patients, or their interactions [15]. Seitawan et al. from Canada acknowledged that women were under-represented in those referred for surgery, and they advocated education of both physicians and patients, as well as different strategies to approach females with regard to surgery, in order to allow more patients to benefit from this treatment [16]. Pavon et al. in their “call for improved clinical studies and for comparative effectiveness research” [17] suggested studies on gender differences in PD presentation and symptoms and more specifically on medical decision-making processes that may explain gender-based referral biases for surgery. In a wider perspective, some authors have discussed discrepancies between women and men in access to secondary or tertiary health care that may be due to barriers at the referral, diagnosis or treatment stage of health care provision [34,38,39,40]. In the case of STN DBS for PD, further studies need to investigate issues such as: does the neurosurgeon or the neurologist unconsciously favour selection of men for surgery? Could it be that men with PD require surgery more often than women? Are women more concerned with the potential complications of surgery, while men are higher risk takers? Do women cope better than men with the symptoms of the disease? These are some of the issues that deserve further evaluation other than by mere review of the literature. 4.5. Weaknesses and pitfalls of this study In this survey of the literature, only papers published in the English language were considered, and published patients are likely to represent only a tiny part of all operated patients worldwide. More importantly, despite our efforts to ascertain accuracy in compilation of numbers of published patients, we cannot exclude that some patients were accounted for twice or more, especially from centres with prolific publication outputs. Notwithstanding these aspects, it appears that fewer women than men receive STN DBS than what would be expected from the gender distribution of PD found in community-based studies. Financial disclosures/conflict of interest Gun-Marie Hariz: Nothing to declare, Takeshi Nakajima: Nothing to declare, Patricia Limousin: Nothing to declare. Tom Foltynie receives research support from the Cure Parkinson’s Trust, Parkinson’s UK, and the Brain Research Trust. He has received honoraria for speaking at academic meetings sponsored by Teva Lundbeck, GSK, Solvay, Orion & UCB Pharma. Ludvic Zrinzo: Nothing to declare, Marjan Jahanshahi: Nothing to declare. Katarina Hamberg: Nothing to declare.
G.-M. Hariz et al. / Parkinsonism and Related Disorders 17 (2011) 146e149
Acknowledgements The authors thank Marwan Hariz for critical review of the manuscript. Gun-Marie Hariz and Katarina Hamberg are supported by a grant from The Swedish Research Council. The Unit of Functional Neurosurgery at the UCL Institute of Neurology is supported by the UK Parkinson Appeal. References [1] Marsden CD. Parkinson’s disease. J Neurol Neurosurg Psychiatr 1994;57:672e81. [2] Benito-León J, Bermejo-Pareja F, Rodríguez J, Molina JA, Gabriel R, Morales JM. Neurological disorders in central Spain (NEDICES) study group. Prevalence of PD and other types of Parkinsonism in three elderly populations of central Spain. Mov Disord 2003;18:267e74. [3] Clavería LE, Duarte J, Sevillano MD, Pérez-Sempere A, Cabezas C, Rodríguez F, et al. Prevalence of Parkinson’s disease in Cantalejo, Spain: a door-to-door survey. Mov Disord 2002;17:242e9. [4] Fall PA, Axelson O, Fredriksson M, Hansson G, Lindvall B, Olsson JE, et al. Agestandardized incidence and prevalence of Parkinson’s disease in a Swedish community. J Clin Epidemiol 1996;49:637e41. [5] Mayeux R, Denaro J, Hemenegildo N, Marder K, Tang MX, Cote LJ, et al. A population-based investigation of Parkinson’s disease with and without dementia. Relationship to age and gender. Arch Neurol 1992;49:492e7. [6] Román GC, Zhang ZX, Ellenberg JH. The Neuroepidemiology of Parkinson’s disease. In: Ellenberg JH, Koller WC, Langston JW, editors. Etiology of Parkinson’s disease. New York: Marcel Dekker; 1995. p. 203e43. [7] de Rijk MC, Breteler MMB, Graveland GA, Ott A, Grobbee DE, van der Meché FGA, et al. Prevalence of Parkinson’s disease in the elderly: the Rotterdam Study. Neurology 1995;45:2143e6. [8] de Rijk MC, Tzourio C, Breteler MMB, Dartigues JF, Amaducci L, Lopez-Pousa S, et al. For the EUROPARKINSON study Group. Prevalence of Parkinsonism and Parkinson’s disease in Europe: the EUROPARKINSON collaborative study. European community concerted action on the epidemiology of Parkinson’s disease. J Neurol Neurosurg Psychiatr 1997;62:10e5. [9] Tison F, Dartigues JF, Dubes L, Zuber M, Alperovitch A, Henry P. Prevalence of Parkinson’s disease in the elderly: a population study in Gironde, France. Acta Neurol Scand 1994;90:111e5. [10] Morgante L, Rocca WA, Di Rosa AE, De Domenico P, Grigoletto F, Meneghini F, et al. Prevalence of Parkinson’s disease and other types of parkinsonism: a door-to-door survey in three Sicilian municipalities. The Sicilian NeuroEpidemiologic Study (SNES) Group. Neurology 1992;42:1901e7. [11] Tanner CM. Epidemiology of Parkinson’s disease. Neurol Clin 1992;10:317e29. [12] Ellenberg JH. Early life and demographic factors predisposing to Parkinson’s disease. In: Ellenberg JH, Koller WC, Langston JW, editors. Etiology of Parkinson’s disease. New York: Marcel Dekker Inc; 1995. p. 277e94. [13] Deuschl G, Schade-Brittinger C, Krack P, Volkmann J, Schäfer H, Bötzel K, et al. German Parkinson Study Group, Neurostimulation Section. A randomized trial of deep-brain stimulation for Parkinson’s disease. N Engl J Med 2006;355:896e908. [14] Hariz GM, Hariz MI. Gender distribution in surgery for Parkinson’s disease. Parkinsonism Relat Disord 2000;6:155e7. [15] Eskandar EN, Flaherty A, Cosgrove GR, Shinobu LA, Baker 2nd FG. Surgery for Parkinson disease in the United States, 1996 to 2000: practice patterns, shortterm outcomes, and hospital charges in a nationwide sample. J Neurosurg 2003;99:863e71. [16] Setiawan M, Kraft S, Doig K, Hunka K, Haffenden A, Trew M, et al. Referrals for movement disorder surgery: under-representation of females and reasons for refusal. Can J Neurol Sci 2006;33:53e7. [17] Pavon JM, Whitson HE, Okun MS. Parkinson’s disease in women: a call for improved clinical studies and for comparative effectiveness research. Maturitas 2010;65:352e8.
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Contents lists available at ScienceDirect
Parkinsonism and Related Disorders journal homepage: www.elsevier.com/locate/parkreldis
Review
Gender distribution of patients with Parkinson’s disease treated with subthalamic deep brain stimulation; a review of the 2000e2009 literatureq Gun-Marie Hariz a, b, *, Takeshi Nakajima c, d, Patricia Limousin c, Tom Foltynie c, Ludvic Zrinzo c, Marjan Jahanshahi c, Katarina Hamberg e a
Department of Community Medicine and Rehabilitation, Occupational Therapy, University of Umeå, Sweden Department of Clinical Neuroscience, University of Umeå, Sweden UCL Institute of Neurology, Queen Square, London, UK d Department of Neurosurgery, Tokyo Women’s Medical University, Tokyo, Japan e Department of Public Health and Clinical Medicine, Family Medicine, University of Umeå, Sweden b c
a r t i c l e i n f o
a b s t r a c t
Article history: Received 29 August 2010 Received in revised form 30 November 2010 Accepted 2 December 2010
Purpose: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) has been the mainstream surgical procedure for advanced Parkinson’s disease (PD) during the last decade. Reports from a few individual centres have hinted that women who receive STN DBS are under-represented. We aimed to evaluate the gender distribution of patients with PD who had received STN DBS during the last ten years, and to discuss the findings in relation to studies on gender prevalence of PD. Methods: A search of the PubMed database of clinical papers in English language related to STN DBS between 2000 and 2009 was conducted. Care was taken to minimize redundancies in reporting of published patients. The proportion of men and women were expressed in total and according to pre-defined geographic regions. Results: One hundred and thirty five papers were eligible for review. The gender of the patients was specified in 119 papers on a total of 3880 patients, of which 63% were men. According to geographic origin of publications, the percentage of men with STN DBS was 68% in North America, 62% in Europe, 69% in Australia and 50% in Asia. Conclusions: The proportion of male patients who undergo STN DBS seems to exceed the reported male/ female ratio of patients with PD. Ó 2010 Elsevier Ltd. All rights reserved.
Keywords: Parkinson’s disease Subthalamic nucleus Deep brain stimulation Gender Sex
Contents 1. 2. 3. 4.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .147 Materials and methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .147 Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .147 Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .147 4.1. Specifying gender in DBS publications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148 4.2. Gender distribution of STN DBS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148 4.3. Gender prevalence of PD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148 4.4. Possible reasons for male preponderance among STN DBS patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148 4.5. Weaknesses and pitfalls of this study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148 Financial disclosures/conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148 Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149
q The review of this paper was entirely handled by the Co-Editor-in-Chief, Z.K. Wszolek. * Correspondence to: Department of Community Medicine and Rehabilitation, Section of Occupational Therapy, Umeå University, 901 87 Umeå, Sweden. Tel.: þ46 70 3644366; fax: þ46 90 786 9267. E-mail address: [email protected] (G.-M. Hariz). 1353-8020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.parkreldis.2010.12.002
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Table 2 Distribution of women and men with Parkinson’s disease treated with STN DBS in the three multicenteremultinational studies.
1. Introduction Parkinson’s disease (PD) is common in both women and men [1]. Some prevalence studies indicated that PD affects men more than women [2,3,4,5,6], while others found equal distribution of the disease among the sexes [7,8,9,10,11,12]. Over the last decade, deep brain stimulation (DBS) of the subthalamic nucleus (STN) has become the mainstream surgical procedure for patients with advanced PD. According to estimates, more than 30 000 patients worldwide had been treated with STN DBS for PD by mid-2000 [13]. There are only two studies in the literature about the gender distribution of patients undergoing any surgery for PD. In 2000 Hariz et al. reported that 65% of published patients worldwide who had surgery between 1985 and 1999 were men [14]. In 2003, Eskandar et al. reported that in the United States 67% of patients who had surgery between 1996 and 2000 were men [15]. Both these studies took into account all surgical procedures for PD, including stereotactic lesions (thalamotomy, pallidotomy) as well as DBS in various brain targets. Setiawan and coworkers from Calgary, Canada, reported in 2006 a survey of patient referrals to DBS for movement disorders at their centre and noticed that women were under-represented [16]. Recently, Pavon et al. highlighted the shortcomings of the literature and the paucity of studies addressing gender issues in STN DBS [17]. In order to evaluate the gender distribution of patients with PD who had received STN DBS, we review the literature of the last ten years, and we discuss the findings in relation to the gender prevalence of PD.
Total of three multicentre studies No of centres included in trial* No of countries included in trial* Total no of reported patients No (%) of male patients No (%) of female patients
DBS for PD Study Group (ref. 18)
Vesper et al. (ref. 19)
Deuschl et al. (ref. 13)
39
18
17
10
13
9
12
2
285
96
111
a
78b
173 (60.7)
60 (62.5)
63 (56.8)
50 (64.1)
112 (39.3)
36 (37.5)
48 (43.2)
28 (35.9)
*Some of the centres/countries were involved in more than one study. a Two patients had DBS in GPi and 5 in Vim thalamus. b Two patients were randomised to STN DBS but did not undergo surgery.
purpose of the present study, these papers were analysed separately from the other papers. All papers were scrutinized with respect to the following criteria: number of patients operated on, whether gender of patients was reported, and the ratio of women and men when available. The findings were considered on a worldwide scale, as well as according to the following geographical areas: a) North America; b) Europe; c) Australia; and d) Asia. 3. Results
2. Materials and methods The PubMed database was searched using the key words “subthalamic nucleus” and “deep brain stimulation” and “Parkinson’s disease”, for articles published in the English language between January 2000 and December 2009. Papers reporting patient data and including three patients or more were retrieved and reviewed. Purely technical notes and review articles were not considered. However, papers reporting studies on patients with STN DBS related to physiology, imaging, psychology, and other subjects were included. Papers reporting a mixture of surgical procedures for PDeother than STN DBSewere only retained for the present analysis if the paper provided details on the sex distribution of patients within each surgical procedure. In cases of multiple papers published from the same institution, we considered only the paper with the largest number of patients to avoid duplicate inclusion of the same patients, as long as it was published within the specified decade. Papers were grouped according to institution and country of origin. Single centre studies with authors from different institutional affiliations were arbitrarily grouped according to the institutional affiliation of the senior author. Multinational, multicentre publications were also considered; however, for the specific
The PubMed search provided a total of 975 papers dealing with STN DBS and published during 2000e2009. Of these, 505 papers were eligible for review. Upon further examination of these papers, there remained 135 publications that fitted the methods criteria of the present study. Table 1 shows the total number of patients included and the percentage of males and females on a worldwide scale and according to geographic origin of publications. In the 3880 published patients in whom gender was reported, 37% were women and 63% men. These proportions of men and women were approximately similar in all world regions represented, except in publications from Asia where STN DBS showed almost equal distribution between women and men. Table 2 shows results from the three multinational multicentre studies [13,18,19] on a total of 285 patients, 39.3% of whom were women. 4. Discussion Our survey of the English language literature on STN DBS published between 2000 and 2009 revealed that, on a global scale, women represented roughly 37% of the operated patients. Europe and North America accounted for 88% of published papers including 89% of reported patients. While women constituted 38%
Table 1 Distribution of women and men with subthalamic nucleus (STN) deep brain stimulation (DBS) for Parkinson’s disease, in publications worldwide and in specific parts of the world.
No of papers (%) No of papers (%) in which gender was specified Total no (%) of reported patients No (%) of patients with gender reported No (%) of men No (%) of women
Worldwide
North America
Europe
Australia
Asia
135 119 (88.1) 4700 3880 (82.6) 2445 (63.0) 1435 (37.0)
43 37 1461 1082 735 347
76 68 2736 2432 1513 919
4 3 135 77 53 24
12 11 368 289 144 145
(31.9) (86.0) (31.1) (74.1) (67.9) (32.1)
(56.3) (89.5) (58.2) (88.9) (62.2) (37.8)
(3.0) (75.0) (2.9) (57.0) (68.8) (31.2)
(8.9) (91.7) (7.8) (78.5) (49.8) (50.2)
148
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of European patients and 32% of North American patients, the proportion of women in the Asian studies was close to 50%. 4.1. Specifying gender in DBS publications Our study showed that gender of patients who had DBS of the STN was specified in 88% of the papers (Table 1). According to a meta-analysis on adverse events of DBS by Appleby et al, including 546 papers dealing with DBS for any indication and in any brain target, published between 1996 and 2005, gender was specified in 51% of the papers [20]. In a meta-analysis by KleinereFisman et al. on outcomes of STN DBS [21], five of the 34 reviewed publications did not specify the gender of patients. Since there may be differences between men and women in symptom profile of advanced PD [22], such as the observation that women more than men exhibit dyskinesias [23,24,25], as well as differences in effects and side effects of surgery [23,26,27], it is important to specify the sex of operated patients in clinical publications. 4.2. Gender distribution of STN DBS Comparison of the gender distribution of STN DBS in the present study with that of PD patients undergoing DBS between 1985 and 1999 in any brain target, i.e. pallidum, thalamus or STN [14], revealed a small increase in the percentage of female patients from 34% ten years ago to 37% in this study. In 2003, Eskandar et al. reported that among the 573 patients who underwent DBS in the US between 1996 and 2000, 70% were male [15]. Kenney et al. from Houston [28] evaluated 5290 patients with PD, of whom 60.6% were male. From this population, 182 patients were selected to receive DBS, and among these patients 73.1% were men. The authors concluded: “Like other authors, we found that more male patients were treated with DBS in our centre, and the proportion of male patients exceeded the usual male/female predominance of PD” [28]. These figures are close to those we found in our review concerning gender distribution of STN DBS in North American publications (Table 1). KleinereFisman et al. reported 63.8% male patients in their meta-analysis of outcomes of STN DBS studies published between 1993 and 2004, with a total of 921 patients [21]. Hamani et al. [29] also found a 63% male preponderance in 38 studies from 34 centres in 13 countries. These figures are similar to our findings when taking into account all STN DBS publications regardless of geographical origin (Table 1). In order to avoid duplication of patients’ inclusions in this survey of the literature, the gender distribution of patients in the three multinational multicentre studies was reported separately (Table 2). Here, the percentage of females in a total of 285 patients ranged from 37.5% to 43%. Hence, the results of our survey call into question whether the distribution of STN DBS in women and men mirrors the gender distribution of PD itself [28]. 4.3. Gender prevalence of PD Clear evidence of any gender preponderance in prevalence of PD is lacking [6,8,11]. The prevalence of PD in the general population varies according to applied methodology, diagnostic criteria, age distribution and case finding strategy [30,31]. Some authors reported a male predominance [2,3,4,5,6], while others found no difference of PD prevalence between women and men, [7,8,9,10,11,12]. Further, some studies found a higher prevalence of PD in women [32,33]. Methodologies using door-to-door surveys are generally considered the most accurate methods or “the gold standard” [34] when determining prevalence. In the European collaborative study using door-to-door surveys, de Rijk et al. found no differences in prevalence of PD between men and women [7,8].
A systematic review of prevalence and incidence of PD in Asia [31] revealed that the prevalence of PD was slightly lower in Asia compared to western countries and epidemiological studies from Japan [33,35,36], as well as from Taiwan [37] found a preponderance of PD in women. Publications on STN DBS from Asian countries accounted, however, only for 8% of the reported patients worldwide, and here the distribution of women and men was equal (Table 1). 4.4. Possible reasons for male preponderance among STN DBS patients The observation that in the western world the proportion of male patients who receive STN DBS exceeds “the usual male/female predominance of PD” [28], eassuming that such predominance existse has no simple answer. Eskandar et al, in their review of surgery for PD in the US, stated that surgically treated patients were more likely to be male, Caucasian, and to have higher incomes, perhaps reflecting biases on the part of the medical caregivers, the patients, or their interactions [15]. Seitawan et al. from Canada acknowledged that women were under-represented in those referred for surgery, and they advocated education of both physicians and patients, as well as different strategies to approach females with regard to surgery, in order to allow more patients to benefit from this treatment [16]. Pavon et al. in their “call for improved clinical studies and for comparative effectiveness research” [17] suggested studies on gender differences in PD presentation and symptoms and more specifically on medical decision-making processes that may explain gender-based referral biases for surgery. In a wider perspective, some authors have discussed discrepancies between women and men in access to secondary or tertiary health care that may be due to barriers at the referral, diagnosis or treatment stage of health care provision [34,38,39,40]. In the case of STN DBS for PD, further studies need to investigate issues such as: does the neurosurgeon or the neurologist unconsciously favour selection of men for surgery? Could it be that men with PD require surgery more often than women? Are women more concerned with the potential complications of surgery, while men are higher risk takers? Do women cope better than men with the symptoms of the disease? These are some of the issues that deserve further evaluation other than by mere review of the literature. 4.5. Weaknesses and pitfalls of this study In this survey of the literature, only papers published in the English language were considered, and published patients are likely to represent only a tiny part of all operated patients worldwide. More importantly, despite our efforts to ascertain accuracy in compilation of numbers of published patients, we cannot exclude that some patients were accounted for twice or more, especially from centres with prolific publication outputs. Notwithstanding these aspects, it appears that fewer women than men receive STN DBS than what would be expected from the gender distribution of PD found in community-based studies. Financial disclosures/conflict of interest Gun-Marie Hariz: Nothing to declare, Takeshi Nakajima: Nothing to declare, Patricia Limousin: Nothing to declare. Tom Foltynie receives research support from the Cure Parkinson’s Trust, Parkinson’s UK, and the Brain Research Trust. He has received honoraria for speaking at academic meetings sponsored by Teva Lundbeck, GSK, Solvay, Orion & UCB Pharma. Ludvic Zrinzo: Nothing to declare, Marjan Jahanshahi: Nothing to declare. Katarina Hamberg: Nothing to declare.
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