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Movement disorders

RESEARCH PAPER

Deep brain stimulation improves survival in severe Parkinson s disease

Desire Ngoga, 1 Rosalind Mitchell, 2 Jamilla Kausar, 2 James Hodson, 3 Anwen Harries, 2 Hardev Pall 4

Additional material is published online only. To view please visit the journal online

1 School of Cancer Sciences, The University of Birmingham,

Birmingham, UK

Department of Neurosurgery Birmingham, Queen Elizabeth

Hospital, Birmingham, UK

Wolfson Computer Laboratories, Queen Elizabeth Hospital Birmingham,

Birmingham, UK

School of Clinical and Experimental Medicine, College of Medicine, The University of Birmingham, Birmingham, UK

4

3

2

Correspondence to Dr Desire Ngoga, Clinical research fellow, The University of Birmingham, School of Cancer Sciences, Vincent Drive, Birmingham B15 2TT, UK; d.g.ngoga@bham.ac.uk

Received 4 December 2012 Revised 21 March 2013 Accepted 30 April 2013 Published Online First 10 July 2013

To cite: Ngoga D, Mitchell R, Kausar J, et al. J Neurol Neurosurg Psychiatry 2014;85:17 22.

ABSTRACT Objectives Levodopa and other dopaminergic treatments have not had the expected effect on survival in Parkinson s disease (PD). Bilateral subthalamic nucleus deep brain stimulation (STN-DBS) has been shown to improve motor function, motor uctuations, health- related quality of life, and to reduce medication usage

and drug-induced dyskinesia in patients with severe PD refractory to medical therapy. Little however, has been

described on the impact of STN-DBS on the survival of these patients. We aim in this study to examine the impact of STN-DBS on the survival of patients with

severe PD. Methods Patients who were eligible for STN-DBS were given the choice of undergoing surgery or continuing on medical treatment. Those who exercised patient choice and preferred to continue with medical treatment formed a control population. All eligible patients seen in a 10-year period are included in this study. Our primary outcome measure is a difference in mortality between the two groups with a secondary measure of admission rates to residential (nursing home) care. Results 106 patients underwent STN-DBS, and 41 patients exercised patient choice and declined the procedure. The two groups were matched for age, gender, ethnicity, duration of disease, rates of pre- existing depression and Levodopa equivalent doses of anti-Parkinson s medications taken. Patients undergoing STN-DBS had signicantly longer survival and were signi cantly less likely to be admitted to a residential

care home than those managed purely medically. The statistical signi cance of these ndings persisted after adjusting for potential confounding factors (survival:

p=0.002, HR 0.29 (0.13 to 0.64) (residential care home admission: OR: 0.1 (95% CI 0.0 to 0.3; p<0.001).

Interpretation

We show for the rst time that there is

a survival advantage of DBS surgery in advanced PD. The effect of potential bias factors is examined. The survival advantage may arise for several postulated reasons, ranging from improvement in axial functions, such as swallowing, to some as yet unrecognised benet of reduction in dopaminergic medication. These ndings are of great interest to both patients with PD and the health professionals considering the treatment options for patients with severe PD.

INTRODUCTION

Parkinsons disease (PD) is a major cause of neuro- logical disability in the UK, with a prevalence of 100180 per 100 000 and an increasing incidence with age. 1 Medical treatment of the motor manifesta- tions is very successful in the early stages of the

disease, but in advanced disease, motor uctuations comprising alternating dyskinesia and akinesia become suboptimally controlled with drug changes. 2 Bilateral subthalamic nucleus deep brain stimula- tion (STN-DBS) using high-frequency continuous electrical stimulation to the subthalamic nucleus through a surgically implanted device, 3 has become established as an effective treatment for the motor symptoms of patients with advanced PD refractory to medical management. 2 4 Improvements have been demonstrated in Motor function, Quality of life (using generic scales such as health-related quality of life and disease-speci c ones such as PDQ 39), and reductions in motor uctuation, reduced medication usage and, there- fore, alleviation of drug-induced dyskinesia. 5 Life expectancy is decreased in PD with an OR of 2.56 (95% CI 2.46 to 2.66; p<0.001), and the advent of medical treatments does not appear to have altered either mortality from the condition or signi cantly delayed the onset of non-motor fea- tures of the disease. 6 The impact of STN DBS on survival has not pre- viously been studied. In this study, we examined the impact of STN-DBS on the survival of patients with severe PD in a single institution.

METHODS

All patients referred to the joint medical/surgical movement disorder clinic at our institution during the 10-year period from January 2002 to 2012 who were eligible for and offered STN DBS were included in this study. Patients either accepted the offer of surgery or elected to continue with medical treatment. We compared the survival of patients undergoing STN-DBS as part of their PD management with that of patients who were offered the procedure but declined, and therefore continued with maximal medical therapy. Survival data and that of admission to residential (nursing) home care were obtained from follow-up at the movement disorder clinic, from general medical practitioners and from enquiries to the Registrar of Deaths (National Statistics). In order to compare possible confound- ing factors in both groups, we analysed: age, gender, ethnicity, duration of disease, past medical history, including depression and Parkinsons medi- cation taken at the time surgery was offered. Levodopa equivalent doses were used to compare the medication taken by patients. 7 8 Patients consid- ered for surgery have severe PD demonstrated by Hoehn & Yahr severity scores of 34 in their worst

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Movement disorders

off states, Dopa-responsive disease and display motor complica-

tions of therapy including dyskinesia and on/off uctuations. Patients who agree to have surgery undergo psychometric testing which includes: a Dementia Rating Scale II, a Wechsler Memory Scale 3rd edition (WMS III), an IQ test, and a

Hospital Anxiety and Depression Scale assessment. 4 9 Those patients showing satisfactory psychometric testing proceed to surgery. Patients showing evidence of neuropsychological

impairment are deemed unsuitable for surgery. Patients with sig-

nicant apathy or off periodhallucinations were excluded

from both groups. The presence or absence of depressive symp- toms was corroborated by a neurologist in a neuropsychiatry movement disorder clinic aided by a consultant psychiatrist. Those patients declining surgery are referred back to their treating physician for ongoing medical therapy. Nearly half these patients were subsequently looked after by the DBS team neurologist. The opportunity exists for patients to be rereferred if they change their minds.

The majority of patients considered for surgery are aged between 40 years and 70 years, though age is not considered an absolute criterion for surgical eligibility.

Statistical analysis

A range of variables was compared between those who

underwent STN-DBS, and those who were deemed suitable but declined. KaplanMeier curves were then produced for these two groups, with a Log-Rank test used for comparing survival. In order to adjust for any differences between the two groups

at baseline, multivariable Cox regression models were produced.

To account for delay between being offered surgery, and the

surgery being performed, a time-dependent covariate was used. This treated all patients as being medically managed from the offer of surgery until surgery was performed, at which point they moved to the surgical group. A logistic regression model was then produced from the same factors, to compare the rates of admission to residential care between the two treatment groups. All analyses were performed using IBM SPSS V.19 (IBM SPSS, Chicago, Illinois, USA), with p<0.05 deemed to be indicative of statistical signi cance.

RESULTS

A total of 151 patients were offered surgery during the period studied, of whom 110 agreed to the procedure. Four of these patients were refused surgery due to failed psychometric analysis, and were excluded. This left 106 patients who underwent STN-DBS (surgical group) and 41 patients who declined the pro- cedure and continued with full medical management (medical group) for analysis; 50 of these patients underwent Unied Parkinsons disease rating scale (UPDRS) motor score recording. (Mean off score 47.0, mean onscore 20.6). Three patients, who initially turned down the offer of surgery, later had a review and still reafrmed their wish to continue with medical treatment. The median age in the surgical group was 60 years (IQR: 5363), with the majority of patients being male (72%) and of Caucasian ethnicity (94%). The remaining 41 (28%) patients (median age=61, IQR: 5766; 78% male; 93% Caucasian) were managed purely medically. Univariate analysis found no signi cant differences between either the ages (p=0.057), genders (p=0.534) or ethnicities (p=0.710) in the two treat- ment groups (table 1). Similarly, the duration of disease at the point that surgery was offered was comparable across the treatment groups, with a median of 11.0 years (IQR: 8.813.0) in the surgical group, and 10.0 years (IQR: 9.014.0) in the medically managed patients

(p=0.413).

In addition to this, the amount of medication prescribed to patients did not differ signi cantly between groups, with median Levodopa equivalent doses of 1192 (IQR: 6721983) and 1500 (IQR: 911 2053) in the medical and surgical groups, respectively (p=0.082). There was also no signi cant difference in the rates of a pre- existing diagnosis of depression (either treated or untreated) in the two groups, with 23.6% of surgical and 17.1% of medical patients being affected (p=0.505). The durations of follow-up were also comparable across the groups, with a median of 6.7 years (IQR: 5.58.7) for medical and 7.4 years (IQR: 4.48.8) for surgical patients. 10 Univariate survival analysis was performed using KaplanMeier survival curves, and a Log-Rank test ( gure 1). This found that patients managed with STN-DBS had signi cantly longer survival than those managed purely medically

(p=0.001).

Table 1 Univariable comparisons

 

Full medical management (n=41)

Underwent STN-DBS (n=106)

p Value

Age when offered surgery (years) Gender Male (%) Female (%) Ethnicity Caucasian (%) Asian (%) Duration of disease when offered surgery (years) Levodopa equivalent dose Preoperative depression (%) Admitted to residential nursing home (%) Mortality rate (%)

61 (57 66)

60 (5363)

0.057

 

0.534

32 (78.0)

76 (71.7)

9 (22.0)

30 (28.3)

 

0.710

38 (92.7) 3 (7.3) 10.0 (9.0 14.0) 1192 (672 1983) 7 (17.1) 15 (36.6) 17 (41.5)

100 (94.3) 6 (5.7) 11.0 (8.813.0) 1500 (911 2053) 25 (23.6) 6 (5.7) 18 (17.0)

0.413

0.082

0.505

<0.001*

0.004*

Dichotomous data displayed as: n (%) , with p values from Fisher s exact tests. Continuous data displayed as: median (quartiles) , with p values from Mann Whitney tests. *Significant at p<0.05. STN-DBS, subthalamic nucleus deep brain stimulation.

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Movement disorders

14, 2014 - Published by group.bmj.com Movement disorders Figure 1 Kalpan – Meier survival curves. This

Figure 1 KalpanMeier survival curves.

This analysis was then extended to consider other potentially confounding factors using a Cox regression model (table 2). Of the additional variables considered, gender was found to signi - cantly affect survival, with a HR of 3.03 (95% CI 1.47 to 6.24, p=0.003), implying that females had the higher risk of mortal- ity. In addition to this, the duration of disease prior to the offer of surgery was also found to be signi cant, with a HR of 2.3 (95% CI 1.0 to 5.2) for patients with disease durations greater than 10 years, relative to shorter durations (p=0.042).

Table 2 Cox regression model of patient survival

Factor

HR (95% CI)

p Value

 

0.002*

 

0.29 (0.13 to 0.64)

0.002*

 

0.003*

 

3.03 (1.47 to 6.24)

0.003*

 

0.916

 

0.92 (0.19 to 4.37)

0.916

 

0.042*

 

2.31 (1.03 to 5.17)

0.042*

 

0.615

Treatment group Surgical Medical †– Gender Female Male †– Ethnic group Asian Caucasian †– Duration of disease at offer <10 years†– 10+ years Age at offer (years) <55 55 59 60 64

––

 

2.15 (0.63 to 7.36)

0.224

2.01 (0.64 to 6.38)

0.234

65+

2.19 (0.62 to 7.74)

0.225

Levodopa equivalent dose <1000 †– 1000 1999

0.412

 

1.81 (0.75 to 4.37)

0.752

2000+

1.54 (0.58 to 4.09)

0.583

Preoperative depression

0.948

No

––

Yes

1.029 (0.44 to 2.41)

0.948

Cox Regression model with a time-dependent covariate. Follow-up commences at the time that surgery was offered, with all patients starting in the medical group, moving to the surgical group postsurgery. *Significant at p<0.05. Reference category.

However, even after adjusting for these effects, the signi cant difference in survival between the two treatment groups per- sisted (p=0.002). The HR for surgical patients, with respect to medical patients, was 0.29 (0.13 to 0.64). The secondary outcome of admission to residential care was then considered. Univariable analysis showed that this was sig- nicantly more likely in medical patients than in surgical patients, with rates of 37% and 6%, respectively (p<0.001). Binary logistic regression analysis (table 3) showed that this dif- ference persisted, even after adjustment for other potential con- founding variables, with an OR for surgical, relative to medical patients, of 0.1 (95% CI 0.0 to 0.3; p<0.001). We also looked at the causes of death in both cohorts and found a broader range in the surgical group compared with the medically managed patients (table 4 with detailed comparison of deceased patients in both groups presented in online supplementary table S1). We found that 20% (8 out of 41) of purely medically managed patients died from respiratory causes. The rate was sig- nicantly lower in surgical patients, with only 2% (2 out of 106) having a main cause of death related to respiratory complications (Bonferroni adjusted p=0.005) ( gure 2). In order to ensure that the additional mortality in the medic- ally managed cohort was not related to medical conditions that predate their review in the movement disorder clinic, we assessed the past medical history of all medically managed patients and found depression to be the most commonly listed previous medical condition and the only one present in more than one patient. Signicantly more patients having surgery were receiving apo- morphine by subcutaneous injection or infusion at the time of

Table 3 Logistic regression model of admission to residential care home

Factor

OR (95% CI)

p Value

Treatment group Surgical Medical †– Gender Female Male †– Ethnic group Asian

–‡

0.10 (0.03 to 0.29)

1.90 (0.61 to 5.96)

<0.001*

<0.001*

0.270

0.270

–‡

Caucasian

– ‡

Duration of disease at offer <10 years†– 10+ years Age at offer (years)

0.66 (0.23 to 1.90)

0.440

0.440

0.890

<55 †––

55 59

0.59 (0.13 to 2.77)

0.503

60 64

0.65 (0.15 to 2.75)

0.557

65+

0.62 (0.14 to 2.81)

0.537

Levodopa equivalent dose

0.727

<1000 †– 1000 1999

0.445

2000+

0.62 (0.18 to 2.12) 0.70 (0.18 to 2.65)

0.598

Preoperative depression

0.984

No

Yes

–– 0.99 (0.24 to 4.01)

0.984

Outcome=admission to residential care home. *Significant at p<0.05. Reference category. Incalculable due to lack of events in the Asian group.

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Movement disorders

Table 4 Mortality rates by cause of death

 

Full medical

Underwent

Bonferroni

management

STN-DBS

adjusted

Cause of death

(n=41) (%)

(n=106) (%)

p value

Parkinson s disease Cardiovascular Stroke IHD/MI Cardiomyopathy Gastrointestinal (GI) GI malignancy GI obstruction GI ischaemia Respiratory PE Pneumonia Other causes UTI Unknown Accidental Lewy body disease

3 (7)

5 (5)

1.000

5 (12)

4 (4)

0.580

2 (5)

1 (1)

3 (7)

2 (2)

0 (0)

1 (1)

0 (0)

3 (3)

1.000

0 (0)

1 (1)

0 (0)

1 (1)

0 (0)

1 (1)

8 (20)

2 (2)

0.005*

1(2)

0 (0)

7 (17)

2 (2)

1 (2)

4 (4)

1.000

0 (0)

1 (1)

0 (0)

2 (2)

0 (0)

1 (1)

1 (2)

0 (0)

Data displayed as: n (% of total cohort) . *Significant at p<0.05. Adjusted for five comparisons. STN-DBS, sub-thalamic nucleus deep brain stimulation.

offer of surgery compared with fully medically managed patients. (35% surgical, 7% medical, p=0.006). However, of the 19 medically treated patients followed-up at our hospital, two were on apomorphine prior to the offer of surgery and another seven went onto apomorphine subsequently, that is, 47% were on apomorphine during follow-up.

DISCUSSION

A recent study commented Unfortunately, there are currently no longitudinal studies of patients with PD who are candidates for DBS but who did not get DBS surgery to compare the natural history of symptom progression at this stage of the disease. 11 This study, examining patients considered for STN-DBS over a 10-year period, compares two well-matched cohorts of patients with severe PD, all deemed suitable for surgery, but through patient choice were managed either with maximal medical therapy, or undergoing STN-DBS. Though not a randomised comparison, patients proved to be matched in age, gender, ethnicity, duration of disease, rates of

in age, gender, ethnicity, duration of disease, rates of Figure 2 Causes of death for medical

Figure 2 Causes of death for medical and surgically managed patients.

pre-existing depression and dopa-equivalent dosage of Parkinson s medications taken at the time of initial consultation. Additionally, all patients offered surgery had severe PD (Hoehn & Yahr 3 4 in the off state improving to 2 or better in the onstate). This gives some, albeit imperfect evidence of match- ing of severity of disease between the two groups. The most striking ndings in this study were signi cant increases in both mortality and admissions to a residential care home in patients declining surgery compared with patients undergoing STN-DBS. The signi cance of these ndings per- sisted when variables including age, sex, ethnicity and duration of disease were accounted for. The additional mortality in med- ically managed patients could not be attributed to past medical history given that all patients were deemed medically t for surgery, and an analysis of the past medical history failed to show any increased medical risk factors in the medically managed patients. A number of long-term studies have demonstrated the ef cacy of DBS in improving quality of life, motor function and reduc- tions in drug-related dyskinesia. 5 12 It would seem reasonable, therefore, to suggest that this improved mobility and reduction in drug-related side effects would reduce the risk of respiratory disease. This does appear to have been the case in our study, where a signi cantly higher proportion of medically managed patients died of respiratory causes (pneumonia and pulmonary embol- ism) than among surgically treated patients (p=0.005). It is interesting to note that of the patients whose primary cause of death was pneumonia, 42% had these attributed on their death certicates to aspiration. Indeed aspiration pneumonia is recognised as the most fre- quent cause of death in PD, 13 14 caused by the effect of bradyki- nesia, rigidity and dyskinesia on swallowing, as well as pharyngeal sensory impairment. 15 There has been no long-term systematic study of the effect of STN-DBS on axial symptoms such as swallowing. It has been reported that following STN- DBS swallowing may fail to improve or in some cases deterior- ate. 16 17 However, a number of studies comparing STN-DBS patients in the DBS onand off state, some using videouoro- graphic swallowing studies, suggest that individuals with PD exhibited improved oropharyngeal phase of swallowing in the stimulator ON compared with OFF state. 18 22 This may offer a possible mechanism for the improved survival among surgical patients since possible improvements in the oropharyngeal phase of deglutition may reduce the risk of aspiration pneumo- nia in patients undergoing STN-DBS. The improvements in motor function, mobility and quality of life demonstrated with DBS 2 appear crucial and may explain the signi cantly reduced need for residential nursing care among patients having surgery (p 0.001), since they are more likely to remain mobile, active and independent for longer. We considered the possibility that patients declining surgery may have had more severe PD and either consciously or uncon- sciously clinicians or patients were more apprehensive about surgery. It would appear, however, that this was not the case in this study, since there was no signi cant difference in duration of disease, or dopa-equivalent medication doses between the groups. In fact, a signi cantly higher proportion of patients undergoing STN-DBS were receiving apomorphine at the time of initial consultation suggesting that they may have suffered with more severe PD. The potential role of depression and the neuropsychological effects of both PD and its management with DBS is an import- ant one. As expected, the rate of depression among the PD

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Movement disorders

patients in our study was high (17% in the medical and 24% in

the surgical group) but slightly less than reported in the litera-

ture. 23 There was no signi cant difference, however, in the inci- dence of depression as a clinical diagnosis or treatment with antidepressant medication in the surgical and medical patients at

initial consultation, suggesting this is unlikely to have played a

role either in the decision to consent to the procedure, or to dif- ferences in patient outcome. The same neurologist and neurosurgeon in a joint clinic saw

all patients in this study, reducing the potential bias that would

come from variations in explanations of procedural risk and benet ratios. All patients were given the same written materials and/or audiovisual aids to inform consent to surgery, and had access to the same PD surgery specialist nurse. This makes it unlikely that the patients who declined surgery were selectively discouraged by the counselling they had from the DBS team. Patients declining surgery did not undergo formal neuro- psychological testing. It is therefore difcult to eliminate the

possibility that baseline psychometric differences between the two groups may have contributed to their differences in sur- vival. However, four patients were declined surgery due to failed psychometry, one of whom is deceased and the remaining three are in a residential care home. In order to eliminate the bias of this selection in the surgical group which was not per- formed in the medical group, we included the four patients failing psychometry considering the surgical group on an inten-

tion to treat basis. Even with these patients included, there was

a statistically signi cant improvement in survival in patients undergoing STN-DBS (Log-Rank test p=0.001). We noted signi cant gender differences in the survival of both medical and surgical patients in our study, with women showing a higher risk of mortality than men (HR of 3.03 (95%

CI 1.47 to 6.24, p=0.003). Gender differences in both motor

and non-motor effects of PD have been described in the litera-

ture, showing that women experience more levodopa-induced dyskinesia. 24 25 The evidence on the impact of these gender differences in the survival of patients with PD however is mixed. A large population-based cohort of nearly 5000 incident PD pharmacy- based patients showed an improved survival among women, 26 though this study being a pharmacy-based population study is likely to have included all severities of PD and patients with

Parkinsonism. Data from ve European population-based studies, however, does seem to support this, and also found that

the risk of death in men with PD was higher than in women. 27

However, other population-based studies have demonstrated a reduced life expectancy among women with PD. 28 Though based on much smaller numbers, our study looked specically at a selected group of patients with severe PD. We believe the signi cance of the gender differences in survival war- rants further investigation in this group of patients. In conclusion, improved survival is not usually among the benets cited when discussing the option of undergoing STN-DBS with patients suffering from severe PD. This study comparing patients with severe PD managed purely medically, and those undergoing STN-DBS, shows that surgical patients

have a signi cantly better survival and reduced admission to residential care, and that this effect appears independent of age, gender, duration of disease, medication doses and rates of treated depression at initial consultation. It also shows a signi - cantly increased mortality among women compared with men

in both groups.

We believe that these ndings are of great interest to patients with severe PD and doctors involved in their care, and that

these ndings warrant further investigation among larger patient cohorts, recognising that randomised comparisons may no longer be feasible.

Contributors DGN: conception and design, acquisition of data, analysis and interpretation of data and drafting the manuscript. RM: conception and design, acquisition of data, analysis and interpretation of data, study supervision. JK:

conception and design, acquisition of data, analysis and interpretation of data. JH:

statistical analysis, drafting the manuscript. AH: conception and design, analysis and interpretation of data. HP: conception and design, analysis and interpretation of data, study supervision.

Funding Funding for the acquisition of death certicates from the General Register Ofce for England and Wales was obtained from the Queen Elizabeth Hospital movement disorder charitable fund for research. This fund is generated through individual charitable donations only and no contributions are received from corporate sources. There has been no payment received by any of the authors to write this article by a pharmaceutical company or other agency.

Competing interests DGN, RM, JK, and AH have received a travel grant and accommodation from Medtronic for the attendance of a scientic meeting (ESSFN, October 2012). HP has received support for attendance at a meeting of the Movement Disorders Society from Medtronic (2012). James Hodson has no conicts of interest in relation to this work.

Ethics approval Ethics committee approval was not sought for this study. This study is a retrospective review of data collected during the clinical follow-up of patients treated in two different ways. No patient identiable information has been included in this publication.

Provenance and peer review Not commissioned; externally peer reviewed.

Data sharing statement Some additional data relating to prescribed medication during the follow-up period for medically treated patients managed at our institution, reasons given for declining surgery and follow-up institution for medically treated patients are available and can be provided upon request.

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1990;40:7636.

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on November 14, 2014 - Published by group.bmj.com Deep brain stimulation improves survival in severe

Deep brain stimulation improves survival in severe Parkinson's disease

Desire Ngoga, Rosalind Mitchell, Jamilla Kausar, James Hodson, Anwen Harries and Hardev Pall

J Neurol Neurosurg Psychiatry 2014 85: 17-22 originally published online July 10, 2013

doi: 10.1136/jnnp-2012-304715

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