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Gender gap in deep brain stimulation for Parkinson’s disease

Stefanie T. Jost1,16 ✉, Lena Strobel1,16, Alexandra Rizos2, Philipp A. Loehrer 3, Keyoumars Ashkan2, Julian Evans4, Franz Rosenkranz1,
Michael T. Barbe1, Gereon R. Fink 1,5, Jeremy Franklin6, Anna Sauerbier1, Christopher Nimsky 7, Afsar Sattari8,9, K. Ray
Chaudhuri 2,10,11, Angelo Antonini 12, Lars Timmermann3, Pablo Martinez-Martin13, Monty Silverdale4, Elke Kalbe14, Veerle Visser-
Vandewalle15, Haidar S. Dafsari 1 ✉ and EUROPAR and the International Parkinson and Movement Disorders Society Non-Motor
Parkinson’s Disease Study Group

Previous studies have shown less access to deep brain stimulation (DBS) for Parkinson’s disease (PD) in women compared to men
raising concerns about a potential gender gap resulting from nonclinical factors or gender differences in clinical efficacy for
postoperative quality of life (QoL), motor, and nonmotor symptoms (NMS) outcomes. This was a cross-sectional and a longitudinal,
prospective, observational, controlled, quasi-experimental, international multicenter study. A total sample size of 505 consisted of
316 consecutively referred patients for DBS indication evaluation at the University Hospital Cologne (01/2015–09/2020) and 189
consecutively treated patients at DBS centers in the University Hospitals Cologne and Marburg, Salford’s Royal Hospital Manchester,
and King’s College Hospital London. In the cross-sectional cohort, we examined gender proportions at referral, indication
evaluations, and DBS surgery. In the longitudinal cohort, clinical assessments at preoperative baseline and 6-month follow-up after
surgery included the PD Questionnaire-8, NMSScale, Scales for Outcomes in PD-motor scale, and levodopa-equivalent daily dose.
Propensity score matching resulted in a pseudo-randomized sub-cohort balancing baseline demographic and clinical characteristics
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between women with PD and male controls. 316 patients were referred for DBS. 219 indication evaluations were positive (women
n = 102, respectively n = 82). Women with PD were disproportionally underrepresented in referrals compared to the general PD
population (relative risk [RR], 0.72; 95%CI, 0.56–0.91; P = 0.002), but more likely to be approved for DBS than men (RR, 1.17; 95%CI,
1.03–1.34; P = 0.029). Nonetheless, their total relative risk of undergoing DBS treatment was 0.74 (95%CI, 0.48–1.12) compared to
men with PD. At baseline, women had longer disease duration and worse dyskinesia. Exploring QoL domains, women reported
worse mobility and bodily discomfort. At follow-up, all main outcomes improved equally in both genders. Our study provides
evidence of a gender gap in DBS for PD. Women and men with PD have distinct preoperative nonmotor and motor profiles. We
advocate that more focus should be directed toward the implementation of gender equity as both genders benefit from DBS with
equal clinical efficacy. This study provides Class II evidence of beneficial effects of DBS in women with PD compared to male
controls.
npj Parkinson’s Disease (2022)8:47 ; https://doi.org/10.1038/s41531-022-00305-y

INTRODUCTION disadvantages arise for women with PD. Furthermore, little is

Deep brain stimulation (DBS) is an effective treatment in advanced known about gender-related differences in postsurgical outcomes
Parkinson’s disease (PD) improving quality of life (QoL)1,2, motor3, or distinct nonmotor and motor profiles that could explain this
and nonmotor symptoms (NMS)4–6. PD affects men more ‘gender gap’. In particular, gender differences in nonmotor
frequently than women with an overall prevalence gender-ratio outcomes following DBS have not been systematically investi-
of 1.48:1 (M:F)7–9. In advanced stages of PD, women are at higher gated yet. Therefore, this study examined (1) gender proportions
risk than men to develop motor complications, such as dyskinesia at key steps from referral for indication evaluations until DBS
or motor fluctuations and manifest different nonmotor profiles surgery and (2) gender differences at preoperative baseline and in
than men10,11. Previous studies have shown disparities in access to postoperative outcomes at 6-month follow-up with respect to
DBS between men and women as women are less likely to QoL, nonmotor, and motor symptoms. We hypothesized that (1)
undergo DBS10,12,13, which is out of proportion to prevalence the gender gap at these key steps cumulates to an overall
data8. However, it is unclear, at which key steps from referral disadvantage for women with PD and (2) that there are distinct
through indication evaluation until surgical procedures the nonmotor and motor profiles in men and women undergoing DBS

1
Department of Neurology, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany. 2Parkinson Foundation International Centre of
Excellence, King’s College Hospital, London, UK. 3Department of Neurology, University Hospital Giessen and Marburg, Campus Marburg, Marburg, Germany. 4Department of
Neurology and Neurosurgery, Salford Royal NHS Foundation Trust, Manchester Academic Health Science Centre, University of Manchester, Greater Manchester, UK. 5Cognitive
Neuroscience, Institute of Neuroscience and Medicine (INM-3), Research Centre Jülich, Jülich, Germany. 6Institute of Medical Statistics and Computational Biology (IMSB),
University of Cologne, Cologne, Germany. 7Department of Neurosurgery, University Marburg, Marburg, Germany. 8University of Cologne, Faculty of Humanities, Cologne,
Germany. 9German Association of Women Engineers, Cologne, Germany. 10Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK. 11NIHR
Mental Health Biomedical Research Centre and Dementia Biomedical Research Unit, South London and Maudsley NHS Foundation Trust and King’s College London, London, UK.
12
Parkinson and Movement Disorders Unit, Department of Neurosciences (DNS), University of Padua, Padova, Italy. 13Center for Networked Biomedical Research in
Neurodegenerative Diseases (CIBERNED), Carlos III Institute of Health, Madrid, Spain. 14University of Cologne, Faculty of Medicine, Medical Psychology, Neuropsychology and
Gender Studies & Center for Neuropsychological Diagnostics and Interventions (CeNDI), Cologne, Germany. 15Department of Stereotactic and Functional Neurosurgery, Faculty of
Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany. 16These authors contributed equally: Stefanie T. Jost, Lena Strobe. A list of members and
their affiliations appears in the Supplementary Information. ✉email: stefanie.jost@uk-koeln.de; haidar.dafsari@uk-koeln.de

Published in partnership with the Parkinson’s Foundation

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and that nonetheless both genders postoperatively experience n = 1), and personal reasons undisclosed by patients (n = 11,
beneficial QoL, motor, and nonmotor effects. women: n = 4). Chi-squared statistics showed no significant
association between gender and these reasons.
DBS targeted the subthalamic nucleus in 157 patients (55
RESULTS women), the internal segment of the globus pallidus in 18 patients
Gender ratio in Parkinson’s disease: from indication (3 women), and the ventral intermediate nucleus of the thalamus
evaluation to deep brain stimulation surgery in 15 patients (5 women). We observed no significant relationship
In the cross-sectional cohort, 316 patients were referred for DBS between gender and DBS target (P > 0.05).
indication evaluations at the University Hospital Cologne during
the time period of January 2015 until September 2020 (see Table 1 Clinical differences of men and women with Parkinson’s
and Fig. 1, women: n = 102). The gender ratio men:women was disease undergoing deep brain stimulation
2.1:1 (32% women). The proportion of women with PD referred for Clinical assessments were conducted in a longitudinal multicenter
DBS indication evaluations was significantly lower than in the cohort of 189 patients (women: n = 68, 36%). The mean age at
known general PD population of 1.48:17 (40% women; one-sample preoperative baseline was 62.3 years ±8.5 and the mean time to
binomial test, P = 0.002), resulting in a 0.72 relative risk (RR, 0.72; follow-up was 0.5 ± 0.2 years.
95%CI, 0.56–0.91) of referral for women compared to men with PD.
229 patients were approved for DBS in the multidisciplinary
Baseline characteristics of the original cohort
indication evaluations with a gender ratio of 1.8:1 (women n = 82).
Of these, 190 patients underwent DBS surgery with a gender ratio Women with PD had a longer disease duration (Δ2.5 years; 95%CI,
of 2.0:1 (women n = 63). Female gender was associated with an 1.0–4.0; P = 0.001; see Table 2) and more severe dyskinesia (Δ13.1;
approval decision for DBS, P = 0.029, the probability of approval 95%CI, 4.2–22.0; P = 0.001). No significant gender differences were
was 17% higher in women with PD (RR, 1.17; 95%CI, 1.03–1.34). observed for the PDQ-8 SI, NMSS total score, and LEDD. Exploring
Indication evaluations were negative in 20 women with PD and PDQ-8 and NMSS domains (see Fig. 2), we observed that women
67 men with PD (22% women). The main reasons for negative with PD experienced worse PDQ ‘mobility’ (Δ0.3; 95%CI, 0.0–0.7;
P = 0.044) and ‘bodily discomfort’ (Δ0.6; 95%CI 0.2–0.9; P = 0.002),
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indication assessments were: clinically relevant neuropsychologi-

cal impairment (n = 17, women: n = 2) and neuropsychiatric whereas men with PD experienced worse NMSS ‘sexual functions’
symptoms, such as depression (n = 27, women: n = 10), impulse (women: median 0.0, IQR [interquartile range], 0.0–0.0; men:
control disorders not depending on dopaminergic medication median 0.0, IQR 0.0–6.0; P = 0.001).
(n = 25, women: n = 5), and hallucinations (n = 9, women: n = 0).
Other reasons were an insufficient levodopa responsiveness Clinical outcomes of the original cohort
(n = 19, women: n = 5) or a need for further medical optimization Women and men with PD experienced improvements of the PDQ-
(n = 27, women: n = 6). Less frequent reasons for negative 8 SI, NMSS total score, and SCOPA-M total score (see Tables 3 and 4)
indications assessments were abuse disorders, mania, diagnosis and LEDD reductions. We observed no gender differences in
of atypical PD, and a high risk for intraoperative bleedings because these outcomes at 6-month follow-up in the between-group
of previous illnesses. The proportion of rejections due to clinically comparison (all P > 0.05). However, post-hoc exploratory analyses
relevant depression was higher for women with PD (P = 0.037). No of domains of these scores revealed following differences: For
gender differences were observed for other rejection reasons the NMSS, beneficial effects were observed in both genders in
(all P > 0.05). the ‘sleep/fatigue’, ‘urinary’, and ‘miscellaneous’ domains. Only
Among patients approved for DBS, the proportion of women men with PD significantly improved in ‘mood/apathy’ and
who eventually underwent DBS surgery was smaller on trend level ‘perceptual problems/hallucinations’, whereas only women with
(RR, 0.89, m; 95%CI, 1.03–1.34; P = 0.065). The probability of PD experienced an improvement in ‘attention/memory’. In
undergoing DBS after positive indication evaluations was 11% SCOPA-M subscores, we observed an improvement in both
lower in women with PD. The total relative risk of undergoing DBS genders for ‘tremor’, ‘dyskinesia’, and ‘motor fluctuations’,
treatment for women compared to men with PD was 0.73 (95%CI, whereas ‘bradykinesia’ improved only in men with PD. For the
0.48–1.12, see Table 1). The reasons for not undergoing DBS PDQ-8, we observed an improvement in both genders in the
surgery despite positive indication evaluations were: patient wish ‘mobility’, ‘activities of daily living’, ‘cognition’, ‘bodily discom-
for an additional period of reflection (n = 10, women: n = 3), fort’, and ‘stigma’ domains, whereas ‘emotional well-being’
patient preference of further medical optimization (n = 8, women: improved only in men with PD.
n = 3), newly developed or worsened preexisting comorbid The strength of clinical responses for women and men with PD
diseases (n = 9, women: n = 8), language barrier (n = 1, women: and number needed to treat results are presented in

Table 1. Gender ratios at indication evaluations, approval for deep brain stimulation and surgical procedures in the cross-sectional cohort.

Steps to DBS surgery Women Men Total P Relative risk [95% CI]

Referred for DBS indication evaluation 102 214 316 0.002c 0.72 [0.56; 0.91]
Positive indication evaluation 82 (80.4%)a 147 (68.7%)a 229 (72.5%)a 0.029d 1.17 [1.03; 1.34]
DBS surgery 63 (76.8%)b 127 (86.4%)b 190 (83.0%)b 0.065e 0.89 [0.78; 1.02]
Significant results are highlighted in bold font. The total relative risk of DBS treatment for women with Parkinson’s disease compared to men was 0.73 (95% CI,
0.48; 1.12).
CI confidence interval, DBS deep brain stimulation.
a
Percentage of patients referred for DBS indication evaluation.
b
Percentage of patients with positive indication evaluation.
c
Binomial test comparison of gender ratios of prevalence data and patients referred for DBS indication evaluation.
d
Chi² test for gender ratio in patients with positive indication evaluation compared to patients referred for DBS indication evaluation.
e
Chi² test for gender ratio in DBS surgery compared to positive indication evaluation.

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Fig. 1 Gender ratio and reasons for not receiving deep brain stimulation in the cross-sectional cohort. In (A), pie charts illustrate ratios of
women (left) and men (right) with Parkinson’s disease who underwent DBS surgery, or did not undergo DBS surgery either despite positive
indication evaluation or due to negative indication evaluation. In (B), bar charts illustrate the percentage of women and men with PD rejected
for different reasons in DBS indication evaluations. 53 patients had one reason for rejection, 29 patients had at least two reasons for rejection,
5 patients had other reasons for rejection (mania, pre-existing orthopedic or cardiovascular conditions). The black star represents significantly
more rejections due to depression in women than in men with PD. DBS Deep brain stimulation, PD Parkinson’s disease.

Supplementary Tables 1 and 2. In summary, differences in effect PD population, (2) preoperatively, mean PD duration was longer
sizes were small and favorable for men in emotional well-being, and dyskinesia more severe in women with PD, and, (3)
SCOPA-M total, bradykinesia, motor fluctuations, and LEDD and for nonetheless, DBS was equally clinically efficacious on total QoL,
women in attention/memory. nonmotor, and motor symptoms burden in women and men with
PD (Class II evidence).
The matched sub-cohort: baseline characteristics and clinical In our cross-sectional cohort, disproportionally fewer women
outcomes were referred for DBS indication evaluations as the gender ratio
Propensity score matching resulted in a sub-cohort of 116 patients was (men:women) 2.1:1 as compared to the gender proportion in
(58 women and 58 men). Balance diagnostics indicated a good the known PD population 1.48:17,14. In women, 80% of referred
matching between the two groups with no significant differences patients were approved for DBS, which was significantly higher
for all main demographic and clinical outcome parameters. than the 69% approval rate in men.
Baseline characteristics of the matched sub-cohort are reported The observation that indication evaluations were negative in
in Supplementary Table 3 and clinical outcomes in Supplementary only 20% of women compared to 31% in men, however does not
Tables 4 and 5. No significant gender differences were observed indicate that the gender effect is beneficial for women with PD as
for all main outcomes at 6-month follow-up. The clinical outcomes women experienced more severe preoperative motor complica-
of the matched sub-cohort did not differ from the original cohort. tions10. This bias represents not a local, but a systematic effect and
has also been observed in other cohorts in the USA (Miami8 and
Medicare Services12) and Europe (Düsseldorf15 and Umeå16).
DISCUSSION Previous studies indicate that the gender gap in assessments of
Our study provides evidence of a gender gap in DBS for PD: (1) eligibility for DBS may result from nonclinical factors15,17 and
Disproportionally fewer women underwent DBS indication assess- possible explanations include gender referral biases to specialty
ments than to be expected from the gender ratio of the general care18,19, patient preferences regarding medical care8 including

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Table 2. Baseline characteristics of women and men with Parkinson’s disease in the original longitudinal cohort.

Women Men Women vs. Men

n Mean SD n Mean SD P Δ [95% CI]

Age 68 62.7 8.5 121 62.0 8.4 0.624 −0.6 [−3.2; 1.9]
Disease duration 68 11.9 5.2 120 9.4 4.2 0.001 −2.5 [−4.0; −1.0]
PDQ-8 SI 68 34.3 15.6 115 30.5 16.5 0.129 −3.8 [−8.6; 1.1]
Mobility 68 1.9 1.0 115 1.5 1.2 0.044 −0.3 [−0.7; 0.0]
Activities of daily living 68 1.5 1.3 115 1.5 1.2 0.970 0.0 [−0.4; 0.4]
Emotional well-being 68 1.1 0.9 115 1.0 0.9 0.240 −0.2 [−0.4; 0.1]
Social support 68 0.9 1.0 115 0.9 0.9 0.535 −0.1 [−0.4; 0.2]
Cognition 68 1.3 1.0 115 1.4 1.0 0.733 0.1 [−0.3; 0.4]
Communication 68 1.0 1.0 115 1.2 1.1 0.288 0.2 [−0.1; 0.5]
Bodily discomfort 68 1.9 1.2 115 1.4 1.2 0.002 −0.6 [−0.9; −0.2]
Stigma 68 1.2 1.3 115 0.9 1.2 0.090 −0.3 [−0.7; 0.0]
NMSS total (median) [IQR] 68 (57.5) [37.5; 75.5] 120 (48.5) [29.5; 86.8] 0.393 −1.3 [−13.0; 5.0]
Cardiovascular 68 (0.0) [0.0; 2.0] 120 (0.0) [0.0; 2.0] 0.887 0.0 [0.0; 0.0]
Sleep/fatigue 68 (14.5) [8.0; 23.5] 120 (15.0) [8.3; 24.0] 0.989 15.0 [−3.0 ;3.0]
Mood/apathy 68 (4.0) [1.0; 8.0] 120 (2.5) [0.0; 10.0] 0.369 3.0 [−2.0; 0.0|
Perceptual problems/hallucinations 68 (0.0) [0.0; 0.8] 120 (0.0) [0.0; 1.0] 0.983 0.0 [0.0; 0.0]
Attention/memory 68 (3.0) [0.3; 8.0] 120 (3.0) [0.0; 7.8] 0.923 3.0 [−1.0; 1.0]
Gastrointestinal 68 (4.0) [0.0; 8.0] 120 (4.0) [0.0; 8.0] 0.894 4.0 [−1.0; 1.0]
Urinary 68 (8.0) [0.4; 17.0] 120 (6.0) [2.0; 14.0] 0.294 6.0 [−4.0; 1.0]
Sexual function 68 (0.0) [0.0; 0.0] 120 (0.0) [0.0; 6.0] 0.001 0.0 [0.0; 0.0]
Miscellaneous 68 (10.0) [4.3; 17.8] 120 (8.0) [4.0; 16.0] 0.058 8.0 [−4.0, 0.0]
SCOPA-M total 66 23.3 9.1 117 23.0 7.7 0.827 −0.3 [−2.8; 2.2]
Tremor 67 13.2 15.8 118 18.4 21.2 0.079 5.2 [−0.6; 11.1]
Bradykinesia 67 35.3 20.7 118 39.0 21.0 0.254 3.7 [−2.6, 10.0]
Axial symptoms 67 32.3 18.8 114 28.5 16.2 0.177 −3.7 [−9.2; 1.7]
Dysphagia and dysarthria 67 22.9 16.6 114 23.0 16.2 0.963 0.1 [−4.9; 5.1]
Dyskinesia 66 46.7 29.8 115 33.6 28.8 0.004 −13.1 [−22.0; −4.2]
Motor fluctuations 66 47.7 24.1 115 42.8 25.9 0.204 −5.0 [−12.7; 2.7]
LEDD 68 1039.0 451.7 121 1146.0 536.1 0.166 107.0 [-44.8; 258.7]
Significant results are highlighted in bold font.
CI confidence interval, IQR interquartile range, LEDD levodopa equivalent daily dose, n number, NMSS Non-motor Symptom Scale, PDQ-8 SI Parkinson’s Disease
Questionnaire-8 Summary Index, SCOPA-M Scales for Outcomes in Parkinson’s Disease-motor scale.
The PDQ-8 SI ranges from 0 (no impairment) to 100 (maximum impairment). The NMSS total score ranges from 0 (no NMS impairment) to 360 (maximum NMS
impairment). SCOPA-M subscores are presented as percentage of maximum domain score. Tremor subscore was based on items 1 and 2; axial subscore on
items 5, 6, 7, 9, 15, and 16; bradykinesia subscore on items 3 and 4; dysphagia and dysarthria subscore on items 8, 10, and 11; dyskinesia subscore on items 18
and 19; and ON/OFF fluctuations subscore on items 20 and 21.

greater fear of surgery among women20, and unmeasured clinical evaluations until DBS surgery. Further studies are needed to
characteristics, such as socioeconomic status18. The proportion of investigate why women with PD approved for DBS treatment do
rejections due to clinically relevant depression was higher for not undergo DBS surgery eventually.
women with PD. Rejections were based on assessments in multi- Looking beyond DBS cohorts, women are also underrepre-
disciplinary team meetings in which patients also participated. In sented for invasive treatments in other diseases, such as
these meetings, patients’ history of affective and neurological cardiac22,23 or gastrointestinal conditions24. Future studies in
symptoms, evaluations of expert psychiatrists experienced in DBS gender medicine are needed to investigate the deliberation
indication evaluations for PD, and neuropsychological depression process of patients and the clinical reasoning of referring medical
test scores were taken into consideration. As previous studies professionals and of hospital staff in which patients undergo
show that <30% of PD patients consent to referral for DBS invasive treatments. These studies should focus on the decisional
evaluations, further research is needed regarding the referral process rather than the decision’s end results, which may help to
processes of general practitioners and neurologists21. Gender develop new approaches to understand and influence these
ratios in DBS cohorts seem to align better with the PD prevalence gender disparities.
when patients receive specially developed educational material In our longitudinal original cohort, in line with previous DBS
and referring medical professionals use DBS screening tools8,15. In studies for PD, disease duration was longer in women with PD8.
our study, the odds of undergoing DBS surgery after being This might be explained by the fact that women appear to have
evaluated as a good candidate for DBS was ~27% lower in women slower disease progression25. Confirming results of previous
than in men with PD. To our knowledge, our study is the first to studies, women reported more severe motor complications than
report gender ratios at key steps from referral through indication men before undergoing DBS surgery, which mainly resulted from

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Fig. 2 Preoperative gender differences in the original longitudinal cohort. Figure 2 illustrates motor (left), nonmotor (middle), and quality
of life (right) domains in women and men with Parkinson’s disease undergoing bilateral deep brain stimulation. NMSS Non-motor Symptom
Scale, PD Parkinson’s disease, PDQ-8 Parkinson’s Disease Questionnaire-8, SCOPA-M Scales for Outcomes in Parkinson’s Disease-motor scale.
Significant differences between women and men at preoperative baseline highlighted with: * for P < 0.05. ** for P < 0.01.

dyskinesia16,26. In line with a study by Hariz et al., we did not of patients who declined referral for DBS evaluations. Further
observe significant gender differences in total preoperative QoL studies including surveys in referring general practitioners and
and women specifically reported worse bodily discomfort and neurologists are needed. In the longitudinal cohort, although the
mobility16. We observed no preoperative gender differences in cohort size of 189 patients was one of the biggest in studies of its
overall NMS burden. Confirming previous studies27, we observed kind, especially the group of women with PD (n = 68) was
no gender differences in mood/apathy and attention/memory. relatively small. As this was a “real-world study” we did not
Men reported worse preoperative sexual functions than women examine motor OFF states and all assessments were conducted in
which is in line with previous research28. clinical ON states. However, NMS and QoL were surveyed over the
In line with previous studies, we observed similar improvements previous 4 weeks and, therefore, reflect ON and OFF states. Clinical
of total QoL and motor outcomes in women and men with PD ratings were performed by unblinded raters. However, raters were
undergoing DBS in our original cohort16,29,30. Our study expanded unaware of the research question regarding gender difference
on the existing literature by systematically comparing gender analyses, so a bias resulting from a lack of blinding is improbable.
differences in nonmotor effects of DBS for PD. We observed similar As this was a “real-world study”, we used abbreviated QoL and
beneficial effects in both genders on total NMS burden. However, motor scales (PDQ-8 and SCOPA-motor scale) which highly
we found distinct DBS effect profiles for specific NMS in women correlate with the scales from which they were derived (PDQ-39
and men with PD: Only women experienced an improvement in and UPDRS-III). However, the use of the latter scales may have
‘attention/memory’, whereas only men experienced beneficial revealed small differences amongst women and men with PD
effects in the ‘mood/apathy’ and ‘perceptual problems/hallucina- better due to their finer gradation. Furthermore, minimal clinically
tions’ domains. Further studies are needed to investigate possible important changes have not been published for the NMSS yet.
reasons for differential effects on specific NMS in women and men Therefore, the clinical relevance of our results was assessed based
with PD, in particular, considering gender differences in brain on Cohen’s d effect sizes34. In our cohort, baseline disease
structure and function in PD31.
duration was longer and dyskinesia more severe in women with
In summary, our study presents evidence that different
PD. Therefore, we used propensity scores to identify a sub-cohort
stakeholders may contribute to the gender gap observed in
which was precisely matched for these variables and, thereby,
DBS: (1) general practitioners and neurologists refer disproportion-
establish a quasi-experimental design to confirm results of the
ally fewer women than men for DBS indication evaluations, (2)
women with PD with positive indication evaluations undergo DBS original cohort. While propensity score matching has advantages
surgery less likely than men with PD, to which (3) hospital medical as a method providing a ‘pseudo-randomization’ in observational
staff may contribute as all indication assessments are conducted studies, it cannot replace a randomized clinical trial. However, in
in the setting of in-patient care which provides ample time to certain scenarios, such as in our database, the real-life presenta-
convey the rationale and clinical reasoning for a treatment with tion of women and men with PD may be of scientific interest.
DBS when indication evaluations are positive. Monitoring gender Here, propensity score matching provides an accurate approach to
ratios in DBS is informative, but this does not address the increase causal inference. An inclusion of demographic and
underlying reasons for gender disparities outlined here. Closely clinical parameters in the matching procedure and an implemen-
connected to this point, the gender gap is still evident despite the tation of strict comprehensive diagnostic statistics increase the
implementation of ‘gender mainstreaming strategies’ in health- validity of our results. However, this method can only be applied
care systems around the globe32. Therefore, we advocate that to parameters assessed clinically. Therefore, it should be noted,
more focus should be directed toward the decisional processes that there are other contributors to DBS outcomes beyond the
and the responsibilities of stakeholders in the implementation of factors, which are considered in the propensity score matching,
gender equity in the context of DBS treatment. A pioneer and that this method does not consider potentially relevant
interview study included 11 women with PD but lacked clinical parameters, which were not measured, for example impulse
data to investigate how patients’ nonmotor or motor symptom control disorders. Acknowledging the possibility of unknown
profiles influence decision-making processes33. confounders, we used independent samples tests for all further
The present work has limitations. In the cross-sectional cohort, statistical tests for comparisons between women and men with
the reasons why patients did not receive DBS were analyzed PD35. Furthermore, one has to acknowledge that DBS cohorts are
retrospectively and the reasons of DBS referrals were not assessed highly selected and that dementia and severe depression are
systematically. Therefore, this study does not consider the number considered to be contraindications for DBS. Therefore, our results

Published in partnership with the Parkinson’s Foundation npj Parkinson’s Disease (2022) 47
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Table 3. Non-motor and quality of life outcomes at baseline and 6-month follow-up in women and men with Parkinson’s disease.

Women Men
Baseline 6-MFU Baseline vs. 6-MFUa Baseline 6-MFU Baseline vs. 6-MFUa Women vs. menb

n Mean SD n Mean SD P Δ [95% CI] n Mean SD n Mean SD P Δ [95% CI] P Δ [95% CI]
PDQ-8 SI 68 34.3 15.6 67 26.5 15.7 <0.001 7.9 [4.1; 11.7] 115 30.5 16.5 117 23.4 16.1 <0.001 7.5 [4.5; 10.5] 0.991 −0.4 [−5.2; 4.4]
Mobility 68 1.9 1.0 68 1.5 1.2 0.049 0.4 [0.0; 0.7] 115 1.5 1.2 117 1.2 1.1 0.001 0.4 [0.1; 0.6] 0.971 0.0 [−0.4; 0.4]
Activities of daily living 68 1.5 1.3 68 1.2 1.2 0.034 0.3 [0.0; 0.7] 115 1.5 1.2 117 1.0 1.1 <0.001 0.6 [0.3; 0.8] 0.262 0.2 [−0.2; 0.6]
Emotional well-being 68 1.1 0.9 68 1.1 1.0 0.488 0.1 [−0.1; 0.3] 115 1.0 0.9 117 0.8 0.9 0.048 0.2 [0.0; 0.4] 0.437 0.1 [−0.2; 0.4]

npj Parkinson’s Disease (2022) 47

Social support 68 0.9 1.0 68 0.8 1.0 0.315 0.1 [−0.1; 0.4] 115 0.9 0.9 117 0.8 0.9 0.413 0.1 [−0.1; 0.2] 0.624 −0.1 [−0.4; 0.4]
Cognition 68 1.3 1.0 68 1.0 1.0 0.010 0.4 [0.1; 0.6] 115 1.4 1.0 117 1.1 1.0 0.005 0.3 [0.1; 0.5] 0.731 −0.1 [−0.4; 0.2]
Communication 68 1.0 1.0 68 0.9 1.1 0.336 0.1 [−0.1; 0.4] 115 1.2 1.1 117 1.0 1.0 0.050 0.2 [0.0; 0.4] 0.736 0.1 [−0.3; 0.4]
Bodily discomfort 68 1.9 1.2 67 1.4 1.2 0.001 0.6 [0.3; 0.9] 115 1.4 1.2 117 1.0 1.1 0.002 0.4 [0.1; 0.6] 0.294 −0.2 [−0.6;0.2]
Stigma 68 1.2 1.3 68 0.8 1.0 0.012 0.4 [0.1; 0.7] 115 0.9 1.2 117 0.6 1.0 0.002 0.3 [0.1; 0.5] 0.695 −0.1 [−0.4; 0.3]
NMSS total (median) [IQR] 68 (57.5) [37.5; 75.5] 68 (37.0) [24.3; 54.8] <0.001 16.0 [−24.0; −10.5] 120 (48.5) [29.5; 86.8] 119 (34.0) [18.0; 54.0] <0.001 15.0 [−22.0; −11.0] 0.991 1.0 [−9.0; 8.0]
Cardiovascular 68 (0.0) [0.0; 2.0] 68 (0.0) [0.0; 2.0] 0.435 0.0 [−0.5; 0.0] 120 (0.0) [0.0; 2.0] 119 (0.0) [0,0; 1.0] 0.063 0.0 [−0.5; 0.0] 0.456 0.0 [0.0; 0.0]
Sleep/fatigue 68 (14.5) [8.0; 23.5] 68 (8.0) [4.0; 14.8] <0.001 5.5 [−8.0; −3.5] 120 (15.0) [8.3; 24.0] 119 (6.0) [2.0; 12.0] <0.001 5.5 [−9.0; −5.0] 0.399 −0.5 [−2.0; 4.0]
Mood/apathy 68 (4.0) [1.0; 8.0] 68 (2.0) [0.0; 6.8] 0.129 1.0 [−2.5; 0.0] 120 (2.5) [0.0; 10.0] 119 (1.0) [0.0; 6.0] 0.022 1.0 [−2.5; 0.0] 0.860 1.0 [−1.0; 2.0]
Perceptual problems/ 68 (0.0) [0.0; 0.8] 68 (0.0 [0.0; 0,0] 0.176 0.0 [0.0; 0.0] 120 (0.0) [0.0; 1.0] 119 (0.0) [0.0; 0.0] 0.007 0.0 [0.0; 0.0] 0.393 0.0 [0.0; 0.0]
hallucinations
Attention/memory 68 (3.0) [0.3; 8.0] 68 (1.5) [0.0; 4.0] 0.008 1.0 [−3.0; −0.5] 120 (3.0) [0.0; 7.8] 119 (3.0) [0.0; 6.0] 0.548 0.0 [−1.0; 0.5] 0.077 1.0 [−3.0; 0.0]
Gastrointestinal 68 (4.0) [0.0; 8.0] 68 (2.0) [0.0; 8.0] 0.211 0.0 [−2.0; 0.0] 120 (4.0) [0.0; 8.0] 119 (2.0) [0.0; 8.0] 0.338 0.0 [−1.0; 0.0] 0.620 0.0 [−1.0;1.0]
S.T. Jost et al.

Urinary 68 (8.0) [0.4; 17.0] 68 (6.0) [2.0; 12.8] 0.012 1.5 [−4.5; −0.5] 120 (6.0) [2.0; 14.0] 119 (4.0) [0.0; 11.0] 0.006 1.5 [−3.5; −0.5] 0.668 1.5 [−3.0; 2.0]
Sexual function 68 (0.0) [0.0; 0.0] 68 (0.0) [0.0; 1.0] 0.525 0.0 [0.0; 0.0] 120 (0.0) [0.0; 6.0] 119 (0.0) [0.0; 4.0] 0.128 0.0 [−1.0; 0.0] 0.210 0.0 [0.0; 0.0]
Miscellaneous 68 (10.0) [4.3; 17.8] 68 (6.0) [2.3; 12.0] <0.001 4.0 [−6.0; −2.0] 120 (8.0) [4.0; 16.0] 119 (4.0) [1.0; 8.0] <0.001 3.0 [−5.0; −2.0] 0.598 1.0 [−3.0; 2.0]
Outcome parameters at baseline and follow-up for women and men with PD. Multiple comparisons due to multiple outcome parameters were corrected with the Benjamini–Hochberg method. Post-hoc, we
explored PDQ-8 and NMSS domain outcomes. Significant results are highlighted in bold font.
6-MFU 6-month follow-up, CI confidence interval, IQR interquartile range, LEDD levodopa equivalent daily dose, n number, NMSS Non-motor Symptom Scale, PDQ-8 SI Parkinson’s Disease Questionnaire-8
Summary Index.
a
Dependent sample t-tests were used to analyze within-group changes of outcome parameters between baseline and 6-month follow-up.
b
Independent sample t-tests were used to analyze between-group differences of change scores between women and men with PD.

Published in partnership with the Parkinson’s Foundation

 S.T. Jost et al.
7

68 1039.0 451.7 67 579.4 322.7 <0.001 458.7 [348.9; 568.4] 121 1146.0 536.1 121 583.1 336.9 <0.001 562.9 [463.5; 662.3] 0.376 104.2 [−51.5; 259.9]
cannot be generalized to PD patients with severe impairments in

Outcome parameters at baseline and follow-up for women and men with PD. Multiple comparisons due to multiple outcome parameters were corrected with the Benjamini–Hochberg method. Post-hoc, we
explored SCOPA-M domain outcomes. Significant results are highlighted in bold font. SCOPA subscores are presented as percentage of maximum domain score. Tremor subscore was based on items 1 and 2;
axial subscore on items 5, 6, 7, 9, 15, and 16; bradykinesia subscore on items 3 and 4; dysphagia and dysarthria subscore on items 8, 10, and 11; dyskinesia subscore on items 18 and 19; and ON/OFF fluctuations
−3.7 [−13.1; 5.7]
4.9 [−3.6; 13.4]
these NMS.

2.1 [−0.3; 4.4]

−1.2 [−7.0; 4.6]

2.4 [−2.4, 7.2]

7.6 [0.4; 14.9]

−0.7 [5.4; 4.0]

Another limitation of this study is the short time period of
Δ [95% CI]
6 months for the evaluation of the outcome of DBS in PD patients.
Women vs. menb

However, a similar improvement of both genders was also

observed in a study, which analyzed gender differences regarding

6-MFU 6-month follow-up, CI confidence interval, IQR interquartile range, LEDD levodopa equivalent daily dose, n number, SCOPA-M Scales for Outcomes in Parkinson’s Disease-motor scale.
motor function, dyskinesia, the 36-item Short Form Health Survey,
the Mini-Mental State Examination, and the Beck’s Depression
0.040
0.352
0.675

0.334
0.768
0.440
0.257
Inventory 5 years after STN-DBS27. In this study, Kim et al. reported
P

favorable long-term effects of DBS in men on QoL preservation.

Further studies are needed to investigate gender differences of
16.5 [10.8; 22.2]
22.3 [17.2; 27.5]
1.9 [−1.1; 5.0]
nonmotor long-term effects of DBS beyond depression and global
11.8 [7.3; 16.2]
7.8 [5.1; 10.6]
7.4 [6.0; 8.8]
5.4 [1.7; 9.1]

cognition.
Baseline vs. 6-MFUa
Δ [95% CI]

We observed a gender gap in patients undergoing DBS

indication evaluations and treatment. The reasons for this gender
gap seem to be nonclinical as the proportion of women with PD
Motor outcomes and changes in medication requirements at baseline and 6-month follow-up in women and men with Parkinson’s disease.

with positive indication evaluations who eventually underwent

16.9 0.005
7.4 <0.001

17.9 <0.001
15.1 <0.001

22.9 <0.001
23.2 <0.001

DBS was lower than in men with PD even though DBS efficacy was
0.241

equal regarding total QoL, nonmotor, and motor symptoms.

P

Therefore, to implement gender equity, we propose that more

16.1

focus should be spent on nonclinical factors, such as deliberation

Mean SD

processes of women with PD and clinical reasoning of referring

Dependent sample t-tests were used to analyze within-group changes of outcome parameters between baseline and 6-month follow-up.

general practitioners and neurologists. The observation of distinct

15.5
13.2
26.9
20.4
21.1
16.5
20.1

effect profiles in women and men with PD for specific NMS

Independent sample t-tests were used to analyze between-group differences of change scores between women and men with PD.
6-MFU

highlights the need of holistic assessments of nonmotor and

7.7 110
21.2 112
21.0 112
16.2 109
16.2 109
28.8 115
25.9 116

motor symptoms in patients with PD undergoing DBS. Therefore,

n

in accordance with the concept of personalized medicine, we

advocate considering nonclinical parameters and the evaluation
SD

of holistic clinical assessments side-by-side to tailor PD treatment

to patients’ individual needs36.
23.0
18.4
39.0
28.5
23.0
33.6
42.8
Mean
Baseline
Men

METHODS
117
118
118
114
114
115
115
n

Study design and ethical approval

We analyzed longitudinal data from the prospective, observational,
20.2 [12.5; 27.9]
17.4 [10.5; 24.3]
4.2 [−1.6; 9.9]

2.6 [−0.7; 5.9]

multicenter international NILS study37 including centers in Cologne,

6.6 [2.5; 10.8]
5.3 [3.3; 7.3]

5.5 [1.2; 9.7]

Marburg, Greater Manchester, and London. All patients gave written

a

Δ [95% CI]

informed consent before study procedures. The study was performed in

Baseline vs. 6-MFU

accordance with the Declaration of Helsinki (German ClinicalTrials Register

DRKS00006735, local ethics committees master votes for Germany:
Cologne #12/145, and for UK: NRES South-East London REC3-10/H0808/
141 #10084).
8.2 <0.001

25.2 <0.001
26.4 <0.001
0.002

0.013
0.155

0.125

In addition, we conducted a retrospective chart review of referrals and

indication evaluations for DBS in a cross-sectional cohort of the University
P

Hospital Cologne from January 2015 to September 2020.

12.3
22.0
17.2
16.5
Mean SD

Participants
17.9
6.3
31.9
26.9
20.7
26.1
29.9

PD diagnosis was based on the British Brain Bank criteria38 in women and
6-MFU

men. Patients were screened for DBS according to Movement Disorders

Society (MDS) guidelines39. DBS surgery was considered when levodopa
9.1 64
15.8 64
20.7 64
18.8 64
16.6 64
29.8 67
24.1 67
n

responsiveness was sufficient (>30% improvement in the Unified PD

Rating Scale-motor examination, UPDRS-III). Patients were not eligible for
DBS treatment if they suffered from clinically relevant psychiatric diseases
SD

or neuropsychological impairments40 as assessed by a multidisciplinary

23.3
13.2
35.3
32.3
22.9
46.7
47.7

team of specialized neurologists, neuropsychologists, stereotactic neuro-

Mean
Baseline
Women

surgeons, psychiatrists, speech and physiotherapists. In the longitudinal

cohort, all patients received bilateral STN-DBS. In the cross-sectional
66
67
67
67
Dysphagia and dysarthria 67
66
66

cohort, patients undergoing DBS were implanted in the STN, globus

n

pallidus internus or ventral intermediate nucleus.

subscore on items 20 and 21.

Clinical assessment
Motor fluctuations

Patients were assessed in the ON-medication state (MedON) at preopera-

Axial symptoms

tive baseline and in a clinical medication and stimulation ON state

Bradykinesia
SCOPA-M total

(MedON/StimON) at postoperative 6-month follow-up. The following scales

Dyskinesia

were assessed:
Tremor

QoL was assessed with the PD Questionnaire-8 (PDQ-8) which covers

Table 4.

eight QoL domains (mobility, activities of daily living, emotional well-being,

LEDD

social support, cognition, communication, bodily discomfort, and

b

stigma)41. It is recommended by the MDS Scales Committee for QoL

a

Published in partnership with the Parkinson’s Foundation npj Parkinson’s Disease (2022) 47
 S.T. Jost et al.
8
assessments42 and has been used in DBS studies43–46. The results are Reporting summary
presented as PDQ-8 Summary Index (PDQ-8 SI). Further information on research design is available in the Nature Research
NMS were assessed with the NMSScale (NMSS)47. The scale consists of 30 Reporting Summary linked to this article.
items for nine nonmotor domains of PD (cardiovascular, sleep/fatigue,
mood/apathy, perceptual problems/hallucinations, attention/memory,
gastrointestinal symptoms, urinary symptoms, sexual function, and DATA AVAILABILITY
miscellaneous symptoms). The data used to support the findings of this study are available from the
Motor disorder was assessed with the Scales for Outcomes in PD-motor corresponding authors upon reasonable request.
scale (SCOPA-M). The SCOPA-M is a modified version of the UPDRS48,
strongly correlates with the corresponding subscales of the UPDRS, and
has been used in DBS studies before37,49,50. The SCOPA-M was preferred CODE AVAILABILITY
because its assessment time is four times shorter than the MDS-UPDRS51. A Statistical analyses were performed using SPSS Statistics 25. SPSS codes are available
study by Rooden et al.52 combined items from the motor examination and upon reasonable request to the corresponding authors.
activities of daily living sections of the SCOPA-M and, using a data-driven
approach, identified the following motor aspects in an exploratory factor
Received: 17 September 2021; Accepted: 10 March 2022;
analysis: (1) axial (postural and locomotor) symptoms, (2) axial (general)
symptoms, such as speech and swallowing, and ‘freezing during on’, (3)
tremor, and (4) bradykinesia and rigidity. As published previously by our
group4, to better distinguish between these axial symptoms, we included
only speech and swallowing in a subscore for ‘dysphagia and dysarthria’
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AUTHOR CONTRIBUTIONS
32. Gupta, G. R. et al. Gender equality and gender norms: framing the opportunities
for health. Lancet 393, 2550–2562 (2019). S.T.J.—data acquisition, statistical analyses of longitudinal data, drafting of the paper.
33. Hamberg, K. & Hariz, G. M. The decision-making process leading to deep brain L.S.—data acquisition, data analysis, drafting of the paper. A.R.—data acquisition,
stimulation in men and women with parkinson’s disease - an interview study. critical revision of the paper. P.A.L.—data acquisition, critical revision of the paper. K.
BMC Neurol. 14, 89 (2014). A.—surgical procedures, critical revision of the paper. J.E.—surgical procedures,
34. Dafsari, H. S. et al. Beneficial nonmotor effects of subthalamic and pallidal neu- critical revision of the paper. F.R.—data acquisition, critical revision of the paper. M.T.
rostimulation in Parkinson’s disease. Brain Stimul. 13, 1697–1705 (2020). B.—critical revision of the paper. G.R.F.—critical revision of the paper. J.F.—statistical
35. Williamson, E., Morley, R., Lucas, A. & Carpenter, J. Propensity scores: from naive analysis of cross-sectional data, critical revision of the paper. A.S.—data acquisition,
enthusiasm to intuitive understanding. Stat. Methods Med. Res. 21, 273–293 critical revision of the paper. C.N.—surgical procedures, critical revision of the paper.
(2012). A.S.—critical revision of the paper. K.R.C.—study concept and design, data
36. Valentina, L. et al. Personalised Advanced Therapies in Parkinson’s Disease: The acquisition, critical revision of the paper. A.A.—critical revision of the paper. L.T.—
Role of Non-Motor Symptoms Profile. J. Pers. Med. 11, 773 (2021). study concept and design, critical revision of the paper. P.M.M.—study concept and
37. Jost, S. T. et al. Subthalamic stimulation improves quality of sleep in parkinson design, critical revision of the paper. M.S.—data acquisition, critical revision of the
disease: a 36-month controlled study. J. Parkinsons Dis. 11, 323–335 (2021). paper. E.K.—critical revision of the paper. V.V.V.—surgical procedures, critical revision
38. Hughes, A. J., Daniel, S. E., Kilford, L. & Lees, A. J. Accuracy of clinical diagnosis of of the paper. H.S.D.—study concept and design, data acquisition, data analysis,
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Published in partnership with the Parkinson’s Foundation npj Parkinson’s Disease (2022) 47
 S.T. Jost et al.
10
Britannia, US Worldmeds, and Otsuka Pharmaceuticals; and acted as a consultant for ADDITIONAL INFORMATION
AbbVie, UCB, and Britannia. A.A. reports personal consultancy fees from Zambon, Supplementary information The online version contains supplementary material
AbbVie, Boehringer Ingelheim, GE, Neuroderm, Biogen, Bial, EVER Neuro Pharma, available at https://doi.org/10.1038/s41531-022-00305-y.
Therevance, Vectura grants from Chiesi Pharmaceuticals, Lundbeck, Horizon 2020 -
PD_Pal Grant 825785, Ministry of Education University and Research (MIUR) Grant Correspondence and requests for materials should be addressed to Stefanie T. Jost
ARS01_01081, owns Patent WO2015110261-A1, owns shares from PD Neurotechnol- or Haidar S. Dafsari.
ogy Limited. L.T. reports grants, personal fees and non-financial support from
SAPIENS Steering Brain Stimulation, Medtronic, Boston Scientific and St. Jude Reprints and permission information is available at http://www.nature.com/
Medical. P.M-M. has received honoraria from National School of Public Health (ISCIII), reprints
Editorial Viguera and Takeda Pharmaceuticals for lecturing in courses; from Britannia
for writing an article in their Parkinson’s Disease Medical Journal-Kinetic; and from Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims
the International Parkinson and Movement Disorder Society (MDS) for management in published maps and institutional affiliations.
of the Program on Rating Scales. Grants: from the MDS for development and
validation of the MDS-NMS. Monty Silverdale has received honoraria from Bial,
Britannia and Medtronic. E.K. has received grants from the German Ministry of
Education and Research, the German Parkinson- Fonds, the German Parkinson Open Access This article is licensed under a Creative Commons
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