Health Science Journal

Keywords

Parkinson sisease; Deep brain stimulation; Cost benefit

Introduction

Parkinson’s disease and economical impacts

In 1817 Parkinson's disease was first medically described as a neurological syndrome by James Parkinson [1]. Parkinson's Disease (PD) is the most common neurodegenerative disease after Alzheimer's disease [2]. PD prevalence is increasing with age and PD affects 1% of the population above 60 years [3]. It is also known that the disease begins before the age of 40 for 5% population of all PD patients [4]. If the symptoms start before the age of 40, PD is likely developed because of the genetic mutations [5]. It has been also reported in another study that PD population increases after the age 80 with 4% [6]. This increase will bring social and economic burden directly and indirectly. In a recent study conducted in the United States, PD patients’ annual health expenditure per case have been reached to 22K US$ level [7]. In another literature from England, the impact of PD to the health care system with direct and indirect cost evaluation has been found out between 449 million-3.3 billion pounds [8]. And in other recent study from Japan, the annual direct cost has been found with 37,9 K US$ and indirect costs were 25,3K US$ levels [9].

Treatment options in Parkinson’s disease and deep brain stimulation therapy

Dopamine agonists and levodopa are the gold standard agents or the best medical treatment option for PD [10]. Levodopa, dopamine receptor agonists, anticoliergic drugs, monoamine oxidase B inhibitors (MOA B inhibitors), catechol O methyl transferase inhibitors and amandatin are the most frequently used pharmaceutical treatment options [11]. Mesenchymal Stem Cells applications are investigated to create a different treatment method for PD by molecular biologists, tissue and bioengineers [12]. Device supported therapies are also needed in the advance stage of PD. Apomorphine (Apomorphine pump), Levedope and Carbidopa Gel and Deep Brain Stimulation(DBS) therapy are new solutions [13].

Deep Brain Stimulation surgery has been applied first time by a French scientist group from the University of Grenoble (France), led by the neurosurgeon AL Benabid, applied the deep brain stimulation (DBS) technique for the treatment of parkinsonian tremor [14]. DBS has been used successfully to treat various diseases of neurological and psychiatric disorders including Parkinson’s disease, neuropathic pain and dystonia and has shown great promise in treating addiction, Tourette syndrome, obsessive compulsive disorder [15]. In addition, there are also some beneficial clinic outcomes for the resistant hypertension [16]. There are also some undergoing clinical trials with DBS technology in various critical diseases such as; Alzheimer, Schizophrenia and Stroke [17-19].

DBS system contains tree main implantable and biocompatible materials; a)active implantable pulse generator (IPG) – it is subcutaneously implanted on right or left clavicula bone, b) second part is extensions which are introduced under tissue from scalp base region to clavicula area by tunneling, c) the one of the most important part is the Lead, it is implanted to brain nucleuses [20].

DBS is firstly FDA approved in 1997 for the Essential Tremor and Tremor disease. Later in 2002 it has been also approved for advanced Parkinson Disease by FDA. In 2016, DBS has been approved Earlier Stage of Parkinson Disease by FDA [21]. There are 3 main manufacturers in global market for DBS products: (alphabetically); Abbot (Illinois-USA), Boston Scientific (California, USA) and Medtronic (Minnesota, USA) [22]. According to outcome from 143 different centers’ survey for DBS surgery steps: the result is mostly applied with 3 main sessions. First part is pre-operative scans with MRI and CT, fusion the images from planning software and obtaining DBS lead target on brain nucleus area. Second part is intraoperative tests (with microelectrode recording or direct targeting), surgical lead implantation (under general or local anesthesia). Final part is verification of DBS Lead implantation by CT (Computer Tomography) scans, MRI (Magnetic Resonance Imaging) or any other intra operative technique and later implanting the IPG [23].

DBS therapy clinical evaluation

Although DBS treatment has started to be used since 1997; there are still ongoing studies about this therap. DBS is surgically applied by neurosurgeons however in terms of diagnosing the proper indication for the surgery; intra operative tests, neurological follow up after the surgery, it is also definitely managed by Neurologists. In terms of psychiatric disorders and patients’ psychiatric evaluation, psychiatrists are also involving to this multi-disciplinary study group [24]. The ideal multidisciplinary DBS center should contain neurology, neurosurgery, neuropsychiatry and neurophysiology specialties [25,26]. DBS battery on stage changes according to different center from 5 day to 30 days during the follow up period [27-29]. In order to improve the clinical effectiveness and benefits, it is recommended that frequent follow up procedure after DBS surgery should be done with the cycle 3, 6-12 months period [30]. In terms of rating scales for PD before and after DBS clinical follow up, UPDRS (UnifiedParkinsonDiseaseRatingScale) IIIand H&Y (Hoehn Yahr) scales are used a kind of the actual literature [31]. In terms of the verification of DBS patients data’s; there are some statistical analyses and methods are preferred such as; Wilcoxon One Sample Pairing Test, Markov and Monte Carlo Simulations [32,33].

DBS cost evaluation and our study aim

The annual cost (direct and indirect) related to Parkinson’s Disease (PD) has been evaluated with 645.000 patients in a research in USA and the total outcome was 23 billion US dolars impact to annual heath care budget in 2005 [34]. In same country in 2019, there is a published another study which presents annual cost (direct and indirect) per case from PD is 23 thousand US dollars [35]. In another literature for the cost evaluation research about the assessment of PD with 5 years data from business efficacy, life quality and cost effectiveness values present annual direct cost 37,9 K US dolars and indirect cost 25,3K US dolars impact per case to the Japanese health care system [36]. This kind of outcomes initiate the demands for the cost and quality analyses in PD and related new treatment options like DBS Therapy [37,38].

The DBS Therapy annual cost impact to the US health care system per case is around 35K-100K US dolars [39] and for other health care systems like in Japan is around 29,7K US dolars per case [40], in Germany is around 30K euro per case [41] and in Canada is around 21-24 K Canadian dolars per case [42].

In Turkey, DBS is reimbursed since 2014 by Turkish Republic Social Security Institution with 3rd stage hospital category at university and research educational hospitals for PD, Dystonia and Essential Tremor indicated patients. The aim of our study is to make analyses and comparison with 60 PD patients from 4 different university hospitals using cost data such as; DBS, surgery hospitalization, policlinic visit and the clinical data such as; UPDRSIII and Hoehn and Yahr rating scales, medication usage level in same patients in the different time frames; 1 year before and 6 months - 1 year after from the DBS surgery.

Material and Methods

Aim of the study

The type of the study is retrospective data analyses. The Ethical Committee submission has been done and the approval has been received on 22nd May 2019.

The study has been performed in June 2017-May 2019 time frame with two different state university hospital and two foundation university hospital. Total number of centers is four.

All Deep Brain Stimulator (DBS) system suppliers in Turkey are US manufacturers such as (alphabetically); Abbot (Austin, Texas), Boston Scientific Neuromodulation (Valencia, California) and Medtronic (Minneapolis, Minnesota). All this three companies’ DBS products have reimbursement according to Turkish Social Security System. There is no disclosure with this study with any of above written companies’ name. There is no conflict of interest.

The aim of the study is to evaluate the cost and clinical outcomes of DBS therapy and best medical therapy in sixty DBS implanted patients with comparison one year before DBS surgery and six months – one year after DBS surgery.

Universe, sample and the time interval

Deep Brain Stimulation (DBS) therapy is currently applied around 35 different centers in government university hospital, government research and educational hospital, foundation university hospital and private hospital status in Turkey. Two government university hospitals and two foundation university hospitals which have approved, were included in study and the details about the centers are below in Table 1.

Table 1 Physician and Clinical Detail Information of the Study Centers.

Center No	Study Center Name	Study Center Status	Participant Physicians' Names and Titles	Participants' Specialities	Experience in DBS
1	Bahçe?ehir University Medicalpark Hospital	Foundation University Hospital	Ak?n Akak?n - Associate Professor	Neurousurgeon	8 years
2	Koç University Hospital	Foundation University Hospital	Özgür Öztop Çakmak - Medical Doctor	Neurologist	2,5 years
3	Erzurum Atatürk University Hospital	Government University Hospital	Mürteza Çak?r - Associate Professor Mustafa Ceylan - Associate Professor	Neurosurgeon      Neurologist	2 years
4	Hatay Mustafa Kemal University Hospital	Government University Hospital	Atilla Y?lmaz - Associate Professor	Neurosurgeon	3,5 years

The time interval of the study between June 2017 – May 2019 with sixty patients which have been selected for DBS therapy and evaluated one year before and after six months – one year from the surgery.

Data sources

All sixty patients who have undergone DBS surgery have been included by four different university hospitals according to the patient selection criteria by Turkish Social Security Directives. Centers and patient numbers are respectively 26 patient data from Bahçe?ehir University Hospital, 15 patient data from Erzurum Atatürk University Hospital, 15 patient data from Hatay Mustafa Kemal University Hospital and 4 patient data from Koç University Hospitals.

Patient inclusion criteria

All sixty patients were included and selected to this study from each clinics Psychiatry, Neurology and Neurosurgery departments approvals according to Turkish Social Security Directives which have been issued on 1st October 2014. In this directive, all sixty PD patients have been diagnosed with bradykinesia and dyskinetic movement from each centers’ Neurology clinics although all medical treatments have been applied to each patient. And it must be written in each patient’s committee report like that all medical and any other treatment methods have been trialed for each patient and to get better outcome DBS surgery is necessary. All committee reports must be approved by psychiatrist, neurologist and neurosurgeons as three multi-disciplinary physician group and finally approved by each center’s medical director. For reimbursement of the DBS therapy, the status of each hospital should be at 3rd step which could be government university or research and educational clinic and foundation university hospitals.

Cost data

The following cost criterias have been used for comparing the increased cost effectiveness rate from each patient’s files: Before the DBS surgery

The cost of the best medical treatment used

1. The drug doses used by patients were determined as the equivalent dose of levodopa

2. Outpatient clinic cost

3. The cost which have been invoiced to Social Security Institute by Government university hospitals, were included.

4. In addition to the cost related by foundation university hospitals to the Social Security Institute, copayments which have been collected from each patient according to the limitation with the legal rules.

Hospital and Physician visit cost

• The transportation and related costs were included to the total cost which were collected by each patient’ with aid of physician side data sharing.

After the DBS surgery

DBS surgery cost:

• For government university hospitals, the cost according to Social Security Institute Directive have been included and for foundation university hospitals, copayments which have been collected from each patient according to the limitation with the legal rules have been included.

DBS device cost:

• All DBS devices for each 60 patients was rechargeable technology and the cost was fixed according to Turkish Social Security Institute Directive. The device from any company was not specifically selected and was not referenced. The cost of the best medical treatment used:

• The drug doses used by patients were determined as the equivalent dose of levodopa

Outpatient clinic cost:

• The cost which have been invoiced to Social Security Institute by Government university hospitals, were included.

• In addition to the cost related by foundation university hospitals to the Social Security Institute, copayments which have been collected from each patient according to the limitation with the legal rules

. Hospital and Physician visit cost:

• The transportation and related costs were included to the total cost which were collected by each patient’ with aid of physician side data sharing.

Clinical outcome data

All the clinical data for each 60 participated patients to the study were evaluated by their same Neurologists and Neurosurgeons. In the study, first one year follow up data of the patients were obtained before the DBS surgery. The study was designed as Retrospective Cost Analysis. The scope of the study was the study consisted only of Parkinson’s Patients and clinical outcomes and costs associated with pharmaceutical therapy before and after DBS surgery were taken as a method of the treatment. UPDRSIII (Unified Parkinson Disease Rating Scale III) and Hoehn and Yahr scales were used before and after the DBS therapy. The clinical outcomes and disease progress have been measured and scored.

Results

The results of the study have been evaluated in three main approaches such as clinical outcome, cost outcome and cost effectiveness analysis.

Clinical outcome analysis

The clinical data from sixty patients have been analyzed with 4 different clinical outcomes such as Drug Dosage Changes Analysis, The changes of UPDRSIII outcome, The changes of Hoehn and Yahr outcome and outpatient visit numbers outcomes.

Drug dosage changes analysis

Mean Levadopa Equivalent doses were taken from each of the four clinics for sixty patients in 3 different time frames below.

I. Daily Drug Dosage Using Rate (1 year before DBS surgery)

II. Daily Drug Dosage Using Rate (6 months after DBS surgery)

III. Daily Drug Dosage Using Rate (1 year after DBS surgery)

The Table 2 has been created with the outcome of 60 patient pharmaceutical dosage change below

Table 2 Changes in mean drug dosage using rates of four clinics and sixty patients.

Daily Drug Dosage Using Rate I	Daily Drug Dosage Using Rate II	Daily Drug Dosage Using RateIII
Starting Level = 100%	46,18 %	42,50 %

In the first six months after the DBS surgery, a decrease in the daily dosage of Levadopa equivalent was found in a mean of 53,82% in 60 patients. This rate has increased to a mean of 57,50 % in the first year after DBS surgery (Table 2).

The changes of UPDRSIII outcome

UPDRSIII Outcomes from sixty patients and four different centers have been obtained in 3 different time frames below.

A) 1 year before DBS surgery

B) 6 months after DBS surgery

C) 1 year after DBS surgery

The Table 3 has been created according to the UPDRSIII outcome changes of 60 patients below.

Table 3 UPDRSIII outcomes for 60 patients with mean, standard deviation and confidence interval statistical values.

	UPDRS III (A)	UPDRS III (B)	UPDRS III (C)
Mean	32,77	18,27	16,32
Standard Dev	10,50	10,34	10,56
Confidence Interval	2,64	2,60	2,65
	A-B Difference	A-C Difference	B-C Difference
P	<0,001	<0,001	<0,001

The preliminary comparison outcomes between before DBS and after sixt months from DBS was decreased the mean UPDRSIII from 32,77 to 18,27. The mean UPDRSIII outcome decrease after one-year DBS was to 16,32. P value, standard deviation and confidence interval values were highly significant. Wilcoxon, Friedman Test and One Sample Kolmogorov test analyses outcomes were statistically significant for sixty patients’ UPDRSIII data (Table 3).

The changes of Hoehn and Yahr outcome

Hoehn and Yahr Outcomes from sixty patients and four different centers have been obtained in 3 different time frames below.

A) 1 year before DBS surgery

B) 6 months after DBS surgery

C) 1 year after DBS surgery

The Table 4 has been created according to the UPDRSIII outcome changes of 60 patients below.

Table 4 Hoehn and Yahr outcomes for 60 patients with mean, standard deviation and confidence interval statistical values.

	HOEHN YAHR A	HOEHN YAHR B	HOEHN YAHR C
Mean	2,98	1,58	1,27
Standart Dev	0,77	0,54	0,43
Confidence Interval	0,19	0,14	0,11
p value	p<0,001	p<0,001	p<0,001

The preliminary comparison outcomes between before DBS and after sixt months from DBS was decreased the mean Hoehn and Yahr from 2,98 to 1,58 for sixt patients. The mean Hoehn and Yahr outcome decrease after one-year DBS was to 1,27 for sixt patients. P value, standard deviation and confidence interval values were highly significant. Wilcoxon, Friedman Test and One Sample Kolmogorov test analyses outcomes were statistically significant for sixty patients’ Hoehn and Yahr data (Table 4).

3.1.4 Outcome from the Outpatient Visit Numbers

Outcomes from the Polyclinic Visit numbers of sixty patients and four different centers have been obtained in 3 different time frames below.

A) 1 year before DBS surgery.

B) 6 months after DBS surgery.

C) 1 year after DBS surgery.

The Table 5 has been created according to the UPDRSIII outcome changes of 60 patients below.

Table 5 Analysis of 60 patients outpatient visit number outcomes.

	Outpatient Visit Numbers A	Outpatient Visit Numbers B	Outpatient Visit Numbers C
Mean	3,88	5,25	8,95
Standart Dev	4,15	2,49	4,17
Confidence Interval	1,16	0,72	1,22
		A-B Difference	A-C Difference
	P	0,02	<0,001

When the outcome data of sixt patients were analyzed, the number of outpatient visits one-year before the DBS surgery and six months and one year after the DBS surgery presented a statistically significant difference. P value is significant according to the calculated confidence interval. One-year before DBS surgery and one-year after the DBS surgery outpatient visits data results shows that the number of outpatient visits increased higher than expected. All sixty patients’ outpatient visit number data have been verified as a significant by Wilcoxon, Friedmann and One Sample Kolmogorov Test analysis (Table 5).

Cost outcome analysis

Mean drug, outpatient and surgical cost data have been analyzed for all four centers and sixty patients. All cost data have been verified as a significant by Wilcoxon, Friedmann and One Sample Kolmogorov Test analysis.

Mean drug cost analysis

Outcomes of sixty patients’ drug usage cost have been obtained in 3 different time frames below.

A) 1 year before DBS surgery.

B) 6 months after DBS surgery.

C) 1 year after DBS surgery.

The Table 6 has been created according to the average drug cost changes of 60 patients below.

Table 6 Mean Drug Cost Outcome for 60 patients.

	Durg Cost A (TL)	Durg Cost B (TL)	Durg Cost C (TL)
Mean	12.260,17	3.710,27	5.515,62
Standart Dev	3.625,06	1.325,65	2.306,77
Confidence Interval	10.915,70	3.224,84	3.350,87
	A-B Difference	A-C Difference	B-C Difference
P	<0,001	<0,001	<0,001

One-year before the DBS surgery the mean drug cost per person was 12.260,17 TL in a year and after 6 months from DBS surgery the mean drug cost decreased significantly to 3.710,27 TL and after 1 year from DBS surgery the mean drug cost has been obtained 5.515,62 TL almost 55% changes in annual cost. P value is highly significant according to the calculated confidence interval (Table 6).

Outpatient cost analysis

Outcomes of sixty patients’ outpatient cost have been obtained in 3 different time frames below.

A) 1 year before DBS surgery.

B) 6 months after DBS surgery.

C) 1 year after DBS surgery.

The Table 7 has been created according to the outpatient cost changes of 60 patients below.

Table 7 The Mean Outpatient visit cost of 60 patients.

	Outpatient Cost A (TL)	Outpatient Cost B (TL)	Outpatient Cost C (TL)
Mean	515,83	1.626,07	2.676,82
Standart Dev	348,45	1.398,82	2.137,90
Confidence Interval	88,17	353,94	540,95
	A-B Difference	A-C Difference	B-C Difference
P	<0,001	<0,001	<0,001

In the one-year before the DBS surgery the cost was 515.81 TL and in six-month after DBS surgery increased to 1.626,07 TL and in one-year after the DBS surgery increased to 2.676,82 TL. This increase shows statistically significant difference for outpatient cost. P value is highly significant according to the calculated confidence interval (Table 7).

The mean surgery cost analysis

In all four hospitals, the cost of the surgery and the payment for DBS device was constant and same numbers and therefore the total cost was 58.079,82 TL per patient.

The cost effectiveness analysis

In the cost-effectiveness analysis, the costs of drug treatment and one-year period of after the DBS surgical treatment were compared and calculated. Hoehn and Yahr and UPDRS III scores have been obtained one-year before and one-year after the DBS surgical treatment. Two different group of Monte Carlo Analyses has been performed for each comparing scenario by calculated standard deviation of the outcomes.

Analysis in terms of UPDRS III outcomes

The drug usage and DBS surgery cost have been compared before and after DBS surgery and evaluated with UPDRSIII outcomes for all sixty patients.

Table 8 has been created with ICER (incremental cost effectiveness ratio) calculation according UPDRSIII outcome in terms of drug usage and DBS surgery cost.

Table 8 One-Year Markov Simulation of DBS and Drug Costs based on 60 patients’ UPRDRIII Outcome.

	Cost (TL)	UPDSIII Outcome
DBS	58.079,82	7,1
Drug Therapy	21.218,39	24,47
Cost Difference (TL)	UPDRS III Difference	1 UPDRS III Decrease Cost / ICER (TL)
36.861,43	17,37	2.122,13

In the first year after the comparison, the DBS cost is higher than drug cost. But the additional cost ratio (ICER) based on UPDRS III change after DBS surgery is 2.122,13 TL. The difference in the total UPDRSIII scale is 17.37 in one year. This UPDRSIII decrease has showed clinical improvement with DBS surgery and this surgery has cost benefit outcome (Table 8).

Analysis in terms of Hoehn and Yahr outcomes

The drug usage and DBS surgery cost have been compared before and after DBS surgery and evaluated with Hoehn and Yahr outcomes for all sixty patients.

Table 9 has been created with ICER (incremental cost effectiveness ratio) calculation according Hoehn and Yahr outcome in terms of drug usage and DBS surgery cost.

Table 9 One-Year Markov Simulation of DBS and Drug Costs based on 60 patients’ Hoehn and Yahr Outcome.

	Cost (TL)	Hoehn and Yahr Outcome
DBS	58.079,82	1,13
Drug cost	21.218,39	2,57
Cost Difference (TL)	Hoehn Yahr Difference	1 Hoehn Yahr Decrease Cost / ICER (TL)
36.861,43	1,44	25.598,22

In the first year after the comparison, the DBS cost is higher than drug cost. But the additional cost ratio (ICER) based on Hoehn and Yahr change after DBS surgery is 25.598,22 TL. The difference in the total Hoehn and Yahr scale is 1.44 in one year. This Hoehn and Yahr decrease has showed clinical improvement with DBS surgery and this surgery has cost benefit outcome (Table 9).

Discussion

In the past randomized controlled clinical trial study, DBS surgery and drug therapy have been compared and DBS was clinically more effective than the best drug treatment in the first six-month period. However, in the literature, DBS may have clinical side effects [42]. In another literature multi-central randomized control study, DBS surgical therapy has better clinical effectiveness than drug therapy [43]. As far as for the clinical rating scales UPRDRSIII and Hoehn and Yahr are preferred like with the study in 2018 [44]. The comparison clinical outcome DBS versus drug therapy of our study which is included 4 university hospitals 60 patients; UPRDS III decreased from 24,7 to 7,4 and the Hoehn Yahr decreased from 2,57 to 1,53 for one-year period from DBS therapy. This clinical progress has supported literature however the different rating scales like UPDRSIV, Schwab England and PDQ39 data should be included for supporting our clinical outcome from the study.

All four university hospitals data have been adapted to the equivalent Levadopa Dose Technique and the preliminary outcome sixt-months after DBS therapy outcome was 53.83% decrease and one year after DBS therapy outcome was 57.1% decrease when comparing both time frames with one year before DBS with drug usage dose. Both outcomes have been supported by known literature [45].

The statistical methods Wilcoxon, Friedman and One Sample Kolmogorov Analysis which have been used for clinical and cost data verification, were also used in literature for 41 and 62 number of patients’ DBS literature studies [46,47].

Although the clinical outcomes in terms of UPDSIII and Hoehn and Yahr resulted data, DBS therapy has clinical benefit however, the number of outpatient visits has resulted to increase in our study. This number of outpatients visit increase has not only affected clinical outcome but also the cost of follow up has increased. Our result supports the literature in 2016 which has created the DBS device follow up protocol as a Toronto Western Hospital Algorithm [48-50].

Conclusion

The comparison cost outcome in our study between DBS and best medical treatment (drug therapy) could not reach the cost effectiveness result in one-year term. However, the DBS therapy has cost benefit results and our study might be evaluated and continued for long term in order to reach cost effectiveness results like the update literatures.

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References

1. Parkinson J (2002) An Essay on the Shaking Palsy. 1817. J Neuropsychiatry Clin Neurosci 14: 223-236.
2. Lebouvier T, Chaumette T, Paillusson S, Duyckaerts C, Varannes S, et al. (2009) The Review Article The Second Brain and Parkinson’s Disease. European Journal of Neuroscience 1: 735-741.
3. Tysens O, Storstein A (2017) Epidemiology of Parkinson’s disease, J Neural Transm 124: 901-905.
4. Rajput AH, Birdi S (1997) Epidemiology of Parkinson’s disease. Parkinsonism & Related Disorders 3: 175-186.
5. Wickremaratchi MM, Ben-Shlomo Y, Morris HR (2009) The effect of onset age on the clinical features of Parkinson’s disease. European Journal of Neurology 16: 450-456.
6. Marder K, Levy G, Louis ED, Santana HM, Cote L, et al. (2003) Accuracy of family history data on Parkinson’s disease. The Neurology 61: 18-23.
7. Mantri S, Fullard ME, Beck J, Wills AW (2019) State-level prevalence, health service use, and spending vary widely among Medicare beneficiaries with Parkinson disease. NJP Parkinson’s Disease 5: 1.
8. Findlye L (2007) The economic impact of Parkinson’s Disease. Parkinsonism& Related Disorders 13: S8-S12.
9. Yamabe K, Liebert R, Flores N, Pashos C (2018) Health related quality of life, work productivity and economic burden among patients with Parkinson’s disease in Japan. Medical Economics 21: 1-14.
10. Katzenschlager R, Lees AJ (2002) Treatment of Parkinson's disease: levodopa as the first choice. Journal of Neurology 249: ii19-ii24.
11. Rezak M (2007) Current Pharmacotherapeutic Treatment Options in Parkinson’s Disease. Disease-a-Month 53: 214-222.
12. Omar R, Beroud J, Stoltz J, Menu P, Velot E, et al. (2014) Umbilical Cord Mesenchymal Stem Cells: The New Gold Standard for Mesencymal Stem Cell Based Therapies? Tissue Engineering B Rev 20: 523-544.
13. Richter D, Bartig D, Jost W, Jörges C, Stumpe B, et al. (2019) Dynamics of device-based treatments for Parkinson’s disease in Germany from 2010 to 2017: application of continuous subcutaneous apomorphine, levodopa–carbidopa intestinal gel, and deep brain stimulation. Journal of Neural Transmission 126: 879 -888.
14. Benabid AL, Pollak P, Louveau A, Henry S, de Rougemont J (1987) Combined (thalamotomy and stimulation) stereotactic surgery of the VIM thalamic nucleus for bilateral Parkinson disease. Appl Neurophysiol 50: 344-346.
15. Holtzheimer PE, Mayberg HS (2011) Deep brain stimulation for psychiatric disorders. Annu Rev Neurosci 34: 289-307.
16. O’Callaghan EL, McBryde FD, Burchell AE, Ratcliffe LEK, Nicolae L, et al. (2014) Deep Brain Stimulation for the Treatment of Resistant Hypertension. Current Hyper Tension Rep.
17. Jakobs M, Lee DJ, Lozano AM (2019) Modifying the progression of Alzheimer’s and Parkinson’s disease with deep brain stimulation. Neuropharmacology.
18. Corripio I, Clotet EP, McKenna P, Sarro S, Roldan A (2018) Deep brain stimulation: first trial in treatment-ressistant schizophrenia. Brain Stimulation.
19. Cooperider J, Momin A, Baker KB, Machado AG (2020) Cerebellar Neuromodulation for Stroke. Curr Phys Med Rehabil Rep 8: 57-63.
20. Machado A (2012) Deep brain stimulation: What can patients expect from it?. Cleveland Clinic Journal of Medicine 79: 2.
21. Suarez Cedeno G, Suescun J, Shiess MC (2017) Earlier Intervention with Deep Brain Stimulation for Parkinson's Disease. Parkinsons Dis 2017: 9358153.
22. Aslani A, Mullet K (2012) Industrial perspective on deep brain stimulation: history, current state, and future development. Frontiers in Integrative Neuroscience 5: 1-6.
23. Abosch A, Timmermann L, Bartley S, Rietkerk HG, Whiting D, et al. (2013) An international survey of deep brain stimulation procedural steps. Stereotactic&Functional Neurosurgery 91: 1-11.
24. Coenan AE, Amtage F, Volkmann J, Schlaepfer TE (2015) Deep Brain Stimulation in Neurological and Psychiatric Disorders. Dtsch Arztebl Int.
25. Kupsch A, Tagliati M, Vidailhet M, Aziz T, Krack P, et al. (2011) Early postoperative management of DBS in dystonia: Programming, response to stimulation, adverse events, medication changes, evaluations and troubleshooting. Movement Disorders 26: 37-53.
26. Cohen DB, Oh MY, Baser SM, Angle C, Whiting A, et al. (2007) Fast Track Programming and Rehabilitation Model: A Novel Approach to Postoperative Deep Brain Stimulation Patient Care. Archives of Physical Medicine and Rehabilitation 88: 1320-1324.
27. Marceglia S, Prenassi M, Priori A (2019) Adaptive Deep Brain Stimulation for Parkinson’s Disease : Safety and Effectiveness. Brain Stimulation 12: e46.
28. Sato K, Aita N, Hokari Y, Kitahara E, Tani M, et al. (2019) Balance and Gait Improvements of Postoperative Rehabilitation in Patients with Parkinson’s Disease Treated with Subthalamic Nucleus Deep Brain Stimulation (STN DBS). Parkinson’s Dis.
29. Nathoo N, Sankar T, Suchowersky O, Ba F (2019) Deep Brain Stimulation as a Rescue When Duedonal Levedopa Infusion Fails. Canadian Journal of Neurlogical Scineces 46: 130-132.
30. Mazur AG, Furgala A, Wajs AK, Pietraszko W, Kwinta B, et al. (2019) Activities of Daily Living and their relationship to health related quality of life in patients with Parkinson Disease After Subthalamic Nucleus Deep Brain Stimulation. World Neurosurgery 125: E552-E562.
31. Kahn L, Mathkour M, Lee SX, Gouveia EE, Hanna JA, et al. (2019) Long-term outcomes of deep brain stimulation in severe Parkinson's disease utilizing UPDRS III and modified Hoehn and Yahr as a severity scale. Clinical Neurology & Neurosurgery 179: 67-73.
32. Yamada K, Goto S, Kuratsu J, Matsuzaki K, Tamura T, et al. (2007) Stereotactic surgery for subthalamic nucleus stimulation under general anesthesia: A retrospective evaluation of Japanese patients with Parkinson’s disease. Parkinsonism and Related Disorders 13: 101-107.
33. Wooten GF, Currie LJ, Bovbjerg VE, Lee JK, Patrie J (2004) Are men at greater risk for Parkinson’s disease than women?. J Neural Neurosurgery Psychiatry 75: 637-639.
34. Huse DM, Schulman K, Orisini L, Haley J, Kennedy S, Lenhary G (2005) Burden of illness in Parkinson’s disease. Movement Disorders 20: 1449-1454.
35. Mantri S, Fullard ME, Beck J, Wills AW (2019) State-level prevalence, health service use, and spending vary widely among Medicare beneficiaries with Parkinson disease. NPJ Parkinson’s Disease 5: 1.
36. Yamabe K, Liebert R, Flores N, Pashos C (2018) Health related quality of life, work productivity and economic burden among patients with Parkinson’s disease in Japan. Medical Economics 21: 1-14.
37. Dams J, Sieber U, Bornschein B, Volkmann J, Deuschl G, et al. (2013) Cost-effectiveness of deep brain stimulation in patients with Parkinson’s disease. Movement Disorders 28: 763-771.
38. Lozano AM, Lipsman N, Bergman H, Brown P, Chabardes S, et al. (2019) Deep brain stimulation: current challenges and future indications. Nature Reviews Neurology 15: 148-160.
39. Pietzsch JB, Garner AM, Marks WJ (2016) Cost effectiveness of Deep Brain Stimulation for Advanced Parkinson’s Disease in United States. Neuromodulation 19: 689-697.
40. Kawarnoto Y, Mouri M, Taira T, Masamune K (2016) Cost Effectiveness Analysis of Deep Brain Stimulation in Patients with Parkinson’s Disease in Japan. World Neurosurgery 89: 628-635.
41. Weaver F, Follet K, Stern M (2009) Bilateral Deep Brain Stimulation Vs Best Medical Therapy for Patients with Advanced Parkinson Disease A Randomized Clinical Trial. JAMA Neurology 301: 63-73.
42. Günther D, Brittinger C, Krack P, Volkmann J, Schaefer H, et al. (2006) A Randomized Trial of Deep Brain Stimulation for Parkinson’s Disease. The New England Journal of Medicine 355: 896-908.
43. Duncan R, Dillen L, Garbutt J, Earhart G, Perlmutter J (2018) Physical Therapy and Deep Brain Stimulation in Parkinson’s Disease: protocol for a pilot randomized control trial. Pilot Feasibility Stud 4: 54.
44. Charles PD, Padaliya BB, Newman WJ, Gill CE, Covington CD, et al. (2004) Deep Brain Stimulation of the subthalamic nucleus reduces antiparkinsonian medication costs. Parkinsonism & Related Disorders 10: 475-479.
45. Vercruysse S, Vandenberghe W, Münks L, Nuttin B, Devos H, et al. (2014) Effects of deep brain stimulation of subthalamic nucleus on freezing of gait in Parkinson’s disease: a prospective controlled study. J Neurol Neurosurg Psychiatry 84: 872-878.
46. Chiou SM, Lin YC, Huang HM (2015) One-year Outcome of Bilateral Subthalamic Stimulation in Parksinson Disease: An Eastern Experience. World Neurosurg 84: 1294-1298.
47. Picillo M, Lozano A, Kou N, Munhoz R, Fasano A (2016) Programming Deep Brain Stimulation for Parkinson’s Disease: The Toronto Western Hospital Algorithms. Brain Stimulation 9: 425-437.
48. Becerra J, Zorro O, Ruiz R, Castaneda C, Otolora M, et al. (2016) Economic Analysis of Deep Brain Stimulation in Parkinson’s Disease: Systematic Review of The Literature. Value in Health 19: A1-318.
49. Aftenou N, Jarl J, Gerdtham U, Saha S (2019) Economic Evaluation of Interventions in Parkinson’s disease – A Systematic Literatür Review. Movement Disorder Clinical Practice 6: 282-290.