Safety precautions with deep brain stimulation in Parkinson’s disease

Deep brain stimulation (DBS) is a recognised treatment option for patients with movement disorders, particularly Parkinson’s disease. There has been an exponential rise in the number of patients with a DBS device in situ in Ireland and therefore a corresponding need for extra safety considerations in the wider medical treatment of such patients. 

The nervous system is responsible for the control of the body and communication between the various parts. It mainly comprises the brain, spinal cord, sensory organs and nerves, which connect them all together. Dysfunction in the nervous system can cause diseases such as chronic pain, epilepsy, Parkinson’s disease, Alzheimer’s disease, Huntington’s disease and multiple sclerosis. 

Treatment can be by neuromodulation, which is the alteration of nerve activity and consequently overall brain activity.¹ Neuromodulation therapies have existed since the 1960s, using advanced medical device technologies to transmit and deliver electrical and/or chemical agents to improve neural function.² The therapies, which have consistently been improved, range from non-invasive techniques to techniques involving surgical implantation of devices.² They target specific areas of the brain or spinal cord rather than the entire system; they offer continuous therapeutic compliance and are reversible, if required.

Examples of neuromodulation devices are:

• Deep brain stimulation (DBS) device used for Parkinson’s disease, dystonia, epilepsy, essential tremors and, more recently, pain syndromes, obsessive compulsive disorder and treatment resistant depression
• Spinal cord stimulation (SCS) device used for chronic pain relief and rarely for ischaemic disorders such as angina and peripheral vascular disease.²

DBS is a surgical treatment where electrodes are implanted to send electrical impulses through leads to specific parts of the brain to manage the motor functions in patients with movement disorders.³ This review specifically relates to DBS and its use for people with Parkinson’s disease.

Parkinson’s disease

Parkinson’s disease is one of the most common neurodegenerative movement disorders⁴ caused by the progressive loss of dopamine producing neurons in a specific area of the brain, called the substantia nigra, leading to a significant reduction in dopamine level causing a biochemical imbalance in the target region – the striatum.^5,6 It is a chronic, disabling and progressive disease characterised predominantly by motor dysfunction symptoms such as bradykinesia, tremors, rigidity and postural instability, as well as a diverse range of non-motor symptoms such as sleep behaviour disorder, speech and swallowing difficulties, constipation, urinary disturbances, rapid eye movements, pain, impaired olfaction and depression, which all impact on human function to varying degrees and varies from person to person.^7,8,9

Bradykinesia, a major clinical feature of Parkinson’s disease, refers to slowness of initiation of voluntary movement and may be noticed before any other symptom.^7,8 Tremors can occur in the hands, lips, jaws and legs and are easily recognised; they differ from tremors in the neck, head or the voice as evident in essential tremors – another movement disorder.⁸ Increased resistance to the movement of a limb is rigidity. Postural instabilities are associated with rigidity, evident by abnormal axial postures and not caused by visual, cerebellar, vestibular or sensory dysfunction.^7,8

Parkinson’s disease is a worldwide disorder although the prevalence is higher in Europe and North and South Americas compared to Asia, Africa and Arab countries.^5,7 It affects about 1% of adults over 65 years,¹⁰ median age of onset is 60 years of age and its prevalence and incidence increases with age.¹¹ Parkinson’s disease affects more males than females and its incidence can be influenced by environmental factors such as pesticides exposure, smoking and caffeine intake.⁷ There are no definitive biological markers yet but this is an active area of research and there are 18 different genetic mutations now known to cause Parkinson’s disease. For the majority of cases the diagnosis of Parkinson’s disease is exclusively on a clinical examination and history-taking basis, but atypical cases and younger patients will often have a dopamine transporter (DAT) scan to assist with the diagnosis⁸ and then a definitive diagnosis following a histopathological assessment that aims to identify Lewy bodies or alpha-synuclein proteins,^12,13 There is currently no cure for Parkinson’s disease or any disease modifying therapy. Current therapies treat disease symptoms, helping to maintain or improve function and consequently the quality of life of individuals for as long as possible. Pharmacological interventions such as the use of dopaminergic drugs which replace dopamine in the striatum are useful at the early and moderately advanced stages of the disease; at advanced stages, motor and non-motor fluctuations begin when the therapeutic effect wanes, which is when surgery may be considered.^4,14 Treatment is generally individualised and adjusted based on outcomes.

Deep brain stimulation

DBS as a neuromodulation therapy has evolved significantly in the past 30 years to become a well recognised surgical intervention of choice for Parkinson’s disease due to its effectiveness in improving the motor symptoms of Parkinson’s such as involuntary movements and tremors.^3,4,15,16 The responsive symptoms are those that are improved by the pharmacological drug levodopa.¹⁷ The DBS device comprises an implantable pulse generator (IPG) connected to one or more leads and extensions which have electrodes implanted in the target area of the brain.¹⁸ The IPG supplies consistent low level electrical stimulation to the selected target area and is usually sited in the pectoralis major.^2,3,18 The stimulation is expected to interrupt the dysfunctional communication between the brain and the muscles for improved motor function, thereby allowing the patient an improved quality of life.¹⁷

Brain target areas in Parkinson’s disease are the subthalamic nuclei (STN), the ventral intermediate nucleus of the thalamus (Vim) or the globus pallidus internus (GPi).¹⁷ Both STN-DBS and GPi-DBS are proven to be effective in improving the motor symptoms of Parkinson’s disease.^17,18 The Vim is no longer routinely used in Parkinson’s disease as it has been observed to be only effective for improving tremors.¹⁸ There continues to be debate about which is safer or more effective between the STN-DBS and the GPi-DBS; comparative studies between the two show slight differences in the beneficial effects with no compelling advantage of one over the other.^14,19 However, STN-DBS is used as the standard because of studies that indicate it is effective at improving motor and non-motor symptoms.¹⁵ There are much fewer studies available evaluating the efficacy of GPi-DBS for Parkinson’s disease patients.¹⁵ However it is stated that GPi-DBS has been used for patients with cognitive impairment and depression due to studies suggesting worsening depressive symptoms and suicide attempts following STN-DBS.¹⁴

Patient selection and consideration for DBS

Careful selection of patients for DBS remains a key factor in achieving a satisfactory outcome from DBS surgery. The Parkinson’s disease diagnosis of such patients must be confirmed;¹⁵ patients considered for DBS are those shown to be levodopa-responsive, those with uncontrollable motor fluctuations and whose tremors are resistant to medication changes and/or intolerance of side-effects from the medical therapy.^17,20 The Core Assessment Program for Neurosurgical Interventions and Transplantation in Parkinson’s Disease (CAPSIT-Parkinson’s disease) recommends that patients must have had Parkinson’s disease for a minimum duration of five years to further ascertain the Parkinson’s disease diagnosis.¹⁴ Guidelines for patient consideration used in Germany are that the patient must have motor fluctuations that have over 33% levodopa responsiveness based on the Unified Parkinson Disease Rating Scale (UPDRS), their tremors medication resistant and must have no active cognitive or psychiatric comorbidities such as dementia, acute psychosis or major depression.^14,20,21 DBS is contraindicated for Parkinson’s disease patients with dementia because of an increased surgical risk associated with placing the DBS electrode near an atrophied cerebellum common in dementia.²¹ DBS can however be performed for Parkinson’s disease patients with stable mild cognitive impairments.²² Patients at risk of perioperative complications must be fully evaluated and steps taken to bridge the risk before any planned neurosurgery.^14,21 More restrictive considerations are given for patients younger than 60 years and those with less than three years of Parkinson’s disease diagnosis.

DBS procedure

Pre-DBS: Following meeting the criteria for patient consideration for DBS surgery, a comprehensive patient assessment follows to assess patient suitability. This assessment will include, but is not limited to, psychological tests or a full neuropsychological assessment where necessary, a UPDRS I-IV assessment, CAPSIT, Tinetti balance and gait, non-motor symptoms evaluation, Beck’s Depression Scale, fall and freezing records and video assessments; all of these are done during medications on and off conditions to help evaluation of drug responsiveness. The UPDRS is one of the most reliable rating scales for assessing motor impairment and disability in patients with Parkinson’s disease²³ by evaluating mentation, behaviour and mood, activities of daily living (ADLs), motor examination and complications of ongoing therapy. All the other physical, psychological and quality of life assessments are used as a baseline for patients’ symptoms. Patient expectation management should also be attended to at this stage; patients’ post-operative expectations are to be assessed and clarified should the need arise. The patient must clearly understand that DBS is not a cure; although its aim is to improve motor functions, the underlying Parkinson’s disease will still progress. Possible risks of the surgery must also be clearly explained.¹⁴

Perioperative DBS: The procedure is usually carried out by an experienced neurosurgeon as part of a multidisciplinary team.¹⁷ An MRI is used to plan a safe pathway for the DBS electrodes and helps rule out the risk of previous brain injury or minimise future brain injury. Stereotactic surgery, a minimally invasive form of surgical intervention, is then used to implant the electrodes in the mapped-out target area of the brain. The leads are then inserted into one or both sides of the basal ganglia of the brain through small holes drilled in the skull while under general anaesthesia or in conscious analgo-sedation (where the patient is conscious but feels no pain).^14,17,20 The electrodes are then manipulated relative to the evoked responses. The apparatus can be activated immediately after surgery or a few weeks later, depending on the patient and stimulation parameters then programmed by specialised personnel using an external programming unit to maximise symptoms reduction and/or elimination and function improvement.^14,17,20 Awake surgery is preferred for STN-DBS due to possible patient interaction and simulation testing intraoperatively. Asleep surgery is, however, considered where patients are not suitable based on assessments.²⁴

Postoperative management: This phase is important as it is used to find an optimal balance between stimulation from the DBS device and medication modifications.²⁵ Stimulation may first be activated at the first follow up appointment between six and eight weeks after surgery. Stimulation is then adjusted for on and off meds state, as required depending on patient’s progress. Subsequent follow-up appointments would typically be between four and six months after surgery and a year after review, during which there might be the need for adjustment of stimulation parameters depending on individual patients and their respective needs. All adjustments and programming should be done by a highly skilled clinician and may take repeated adjustments to achieve optimal results.^17,20

Advantages of DBS

DBS improves symptoms of dyskinesia, tremors and motor fluctuations for Parkinson’s disease patients with longer disease durations that have become medication resistant.²⁶ Motor score evaluations show a 30-60% improvement in motor functions with DBS.^14,17,27 It was found that after a period of six months, DBS patients had an average of 4.6 hours of greatly improved motor functions each day compared to 0 hours for those in the best medical therapy group which combined medication and other non-pharmacological therapy.³ However, they point out that those with DBS are at a higher risk of experiencing an adverse event than the best medical therapy group and for this, clinicians and patients are advised to explore whether the improvement of motor function and quality of life outweigh possible serious adverse events. With improved symptoms, DBS improves the quality of life,^28,29 though there has been debate on the influence of age and disease duration on its supposed benefits. DBS is said to be less effective at increased age such as in patients over 70 years^30,31,32 but patients younger than 60 years are said to show significant marked improvement in their quality of life and lower complications following DBS.^30,33 It is argued, however, that age should not be looked upon as an independent factor when considering the outcome of DBS, but rather as a causative factor for increased risks due to increased comorbidities at older ages.³⁴

DBS also has advantages of adaptability with regards to adapting stimulation parameters:; reversibility where the device can be removed, the possibility of bilateral surgeries without significant increase in adverse effects^15,35 and more recently the development of brain-wave sensing technology in conjunction with DBS. While reversibility is possible, an abrupt cessation of stimulation must be avoided as it may cause a return of disease symptoms and in some cases even worse symptoms may be experienced.³⁶

Complications and possible adverse events of DBS

DBS surgeries are relatively safe with low complication rates.^17,37,38 However, surgical and hardware adverse events may occur for some individuals. Surgical complications include infections, intracranial haemorrhage, stroke, post-operative respiratory distress, epilepsy, neuroleptic malignant syndrome and even death.^15,17,38,39 Hardware related complications are infection (which is most common), electrode breakage, lead migration, misplacement or erosion; possible formation of stricture(s), and IPG malfunction.^37,38,39 Following programming and use, impairments in non-motor functions such as speech disturbances and postural instability have been reported,¹⁵ neuropsychiatric adverse effects such as cognitive dysfunction, depression, anxiety, apathy, hyper-sexuality, euphoria and hallucinations are also possible,^15,35,39,40 and the risk of suicide has been mentioned in some literature.^39,40,41 Though permanent cognitive impairment is said to be rare,³⁵ personality changes have been mentioned as an adverse effect of DBS,⁴² although it is pointed out that there are minimal first-hand studies to evidence the claim.⁴³ Complication rates vary across patients.

Management of patients with DBS for other surgeries and comorbidities

Safety concerns arise when Parkinson’s disease patients with DBS devices present to hospital for incidental non-related emergencies – surgical or otherwise. DBS devices, like other implantable devices, can be sensitive to external electrical currents and magnetic fields from monitoring and electromagnetic devices which may be found in operating or consultation rooms in hospitals.⁴⁴ Interference can be in the form of device damage or loss of function, device output program change, neural thermal injury, trauma to surrounding tissue, lead migration, lead dislodgement and even possibly death.⁴⁴

The use of MRI in patients with an implanted DBS device was previously contraindicated for all devices because of electromagnetic interactions with the DBS device that may cause functional disruption of the system, heating of the electrode tips and image distortions.^16,45,46 However, DBS manufacturers now allow limited conditional MRI access for patients with certain DBS systems under specified conditions that are stipulated in their individual MRI guidelines. Similarly, safety concerns arise for electrocautery and electroconvulsive therapy (ECT) for patients with DBS because of possible heat generation at the electrodes or their displacement from seizures and loss of function of the device.^16,45,47

For surgeries, the anaesthetic management of patients with DBS include the preoperative, intraoperative and postoperative considerations because of the risk of electromagnetic interference between the neurostimulator and other devices such as MRI and electrocautery use.^45,48 With proper management and taking necessary precautions, the potential for serious complications is minimised.⁴⁸ The involvement of a multidisciplinary team during all the stages is a key factor in the management of patients.⁴⁶

Pre-operative management: Patients with a DBS device require meticulous pre-operative assessment planning to consider the need for continuation or cessation of Parkinson’s disease drugs, with drug interactions as a factor and to consider precautions to avoid DBS malfunction or adverse events.⁴⁶ The assessment would focus on the device type, date of implantation, exact location of the device and existing complications relating to the underlying Parkinson’s disease.⁴⁷ The device should be interrogated at this stage (noting the date of last interrogation, settings and impedance readings) for possible complications that may arise when the device is turned off.⁴⁷ Where the patient has communication difficulties that may affect the relaying of device information, a preoperative x-ray can trace the location of the leads and nature of the device.¹⁶

Intra-operative: Intraoperative considerations relate mainly to device interactions with the DBS.^45,47 Medical devices including diathermy, electrocautery, external cardiac defibrillator and peripheral nerve stimulators produce electromagnetic interference (EMI) that may affect the function of the DBS. Electrocautery can damage the IPG or cause its malfunction and can lead to thermal injury to the brain.¹⁶ Anaesthesia in patients with DBS require special considerations because of the interaction between neurostimulator and the diathermy, such as in the case of a radical nephrectomy for a renal cell carcinoma where diathermy is required during surgery. Energy during diathermy can be transferred through the generator to cause brain damage at the site of the implanted electrodes.⁴⁸

A plan that will minimise the risk of damage to the device and that may cause its malfunction will need to be developed. Manufacturers recommend that the device be switched off and amplitude turned down to 0 volts (for older versions) to prevent EMI from electrosurgical equipment that may lead to device damage, cause a change in the programming, a change in the output or catastrophic tissue injury. A specialist DBS team member as part of the multidisciplinary team can be available to take this role and hence reduce risks.^47,48 Pressure points and DBS skin site can be padded to prevent trauma to surrounding tissues.⁴⁶

Post-operative management: DBS needs to be turned back on before reversal of anaesthesia by the DBS specialist, reprogrammed to original settings and checked to be functional and that effective therapeutic effect is resumed, including post-operative impedance checks. Switching on the stimulator at immediate postoperative period is also important to reduce the risk of the patient developing rigidity and tremors.⁴⁸ Neurological examinations may be conducted to rule out any adverse events related to device interaction.⁴⁵ DBS offers the advantages of reversibility, adjustability and long-term treatment.⁴⁶ When DBS patients present for coincidental surgery, functionality of DBS should always be assessed in the preoperative period, precautions taken to prevent DBS malfunction intra-operatively and its function reassessed postoperatively.⁴⁶ Technical problems such as wire breakage, lead migration and Twiddler syndrome should also be ruled out.^{39,46,49,50,51} Twiddler syndrome is device damage caused by the manipulation of the leads or the implantable generator.^18,51

Implications for practice

The number of patients with DBS devices have increased and will continue to rise with DBS now being a standard of care for patients with specific neurological conditions as well as with the current ageing population and its corresponding health issues. Accordingly, there will be a corresponding increase in the number of patients with DBS coming into hospitals for emergencies, surgeries or otherwise. It is imperative that surgeons, anaesthetists and treating physicians are aware of the complications or adverse events that may arise without due consideration for the DBS device in its entirety. The successful management of Parkinson’s disease patients with DBS requires a good knowledge of Parkinson’s disease drugs and their interactions with other drugs that may cause parkinsonian symptoms, a good knowledge of the DBS device and necessary precautions to be taken during interaction with other medical devices to prevent DBS malfunction or damage, and more importantly, patient safety. It also requires meticulous assessment, planning, implementation and evaluation of patients during the perioperative stages of any non-related comorbid surgeries. The DBS specialist or clinical nurse specialist is central to this process.

Policy makers make decisions based on information available to them, the information may be from professionals, political judgement, interpretation of values and traditions and the views of stakeholders. Decision makers need to look carefully at evidence presented to decide how services can be configured to ensure maximum health gain at minimum additional cost. Patient safety will be compromised should DBS patients not have available expertise when the need arises, resulting in ethical and legal implications. It is suggested that DBS specialists be readily available through a 24-hour continuing service to attend to the precautionary and assessment needs of DBS patients when they present to hospital for emergencies.⁴⁴ This ensures the ethical principles of beneficence, justice and non-maleficence are upheld, and the best interests of the patients come first. 

Conclusions

Deep brain stimulation (DBS) is a recognised treatment option for patients with movement disorders and particularly Parkinson’s disease. With an ageing population and an exponential increase in patients with DBS in Ireland, it is pertinent that precautions are put in place to protect patients from the complications that may arise from the treatment of such non-related DBS emergencies. The multidisciplinary team that will attend to such emergencies will need to include a DBS specialist who will identify the DBS device implanted, and take all necessary precautions including turning off device and switching voltage to zero before surgery, minimise the risk of electromagnetic interference, switching on the device following surgery, and evaluating the device and reprogramming where necessary postoperatively. Emergencies can occur at any time and a DBS specialist should always be available to prevent additional patient morbidity or even mortality. Patient safety must not be compromised.

References

1. Richards B, Whittle S, Buchbinder R. Neuromodulators for pain management in rheumatoid arthritis. Cochrane Database of Systematic Reviews 2012; Issue 1. Art. No. CD008921. DOI: 10.1002/14651858.CD008921.pub2
2. International Neuromodulation Society (INS). Neuromodulation therapies [Online] 2019; http://www.neuromodulatio.com/for-medical-providers Accessed 13/5/19
3. Weaver F, Follett K, Stern M et al. Bilateral deep brain stimulation vs best medical therapy for patients with advanced Parkinson disease. JAMA 2009; 301(1):63-73
4. Hickey P, Stacy M. The surgical management of Parkinson’s disease, Neurodegener Dis Manag 2011; 1(3) doi.org/10.2217/nmt.11.25
5. World Health Organization. Neurological disorders: public health challenges. World Health Organization, Switzerland. 2006
6. Lotharius J, Brundin P. Pathogenesis of Parkinson’s disease: dopamine, vesicles and alpha-synuclein. Nat Rev Neurosci 2002 Dec; 3(12):932-42 doi: 10.1038/nrn983
7. Kalia L, Lang A. Parkinson’s Disease. The Lancet 2015; 386(9996):896-912.
8. Jankovic J. Parkinson’s disease: clinical features and diagnosis. J Neurol Neurosurg Psychiatry 2008; 79(4):368-76
9. Chaudhuri K, Yates L, Martinez-Martin P. The non-motor symptom complex of Parkinson’s disease: a comprehensive assessment is essential. Curr Neurol Neurosci Rep 2005; 5:275-83
10. Lang A, Lozano A. Parkinson’s disease - first of two parts. New Engl J Med 1998; 339(15):1044-53
11. Pringsheim T, Jette N, Frolkis A, Steeves T. The prevalence of Parkinson’s disease: a systematic review and meta-analysis. Mov Disord 2014; 29(13):1583-90
12. Kouli A, Torsney K, Kuan W. Parkinson’s disease: etiology, neuropathology and pathogenesis. In Parkinson’s disease: Pathogenesis and clinical aspects. (Stoker T, Greenland J eds), Codon Publications, Brisbane [Online}. 2018; https://www.ncbi.nlm.nih.gov/books/NBK536721/ Accessed 12/7/19
13. Halliday M, McCann H. The progression of pathology in Parkinson’s disease. Ann N Y Acad Sci 2010; 1184:188-95
14. Dallapiazza R, Vloo P, Fomenko A et al. Considerations for patient and target selection in deep brain stimulation surgery for Parkinson’s disease. In Parkinson’s disease: Pathogenesis and clinical aspects. (Stoker T, Greenland J eds), Codon Publications, Brisbane [Online]. 2018; Available from: https://www.ncbi.nlm.nih.gov/books/NBK536721/ Accessed 6/6/19
15. Hartmann C, Fliegen S, Groiss S, Wojtecki L, Schnitzler A. An update on best practice of deep brain stimulation in Parkinson’s disease. Ther Adv Neurol Disord 2019; 12:1-20
16. Poon C, Irwin M. Anaesthesia for deep brain stimulation and in patients with implanted neurostimulator devices. Br J Anaesth 2009; 103:152-65
17. Bronstein J, Tagliati M, Alterman et al. Deep brain stimulation for Parkinson’s disease: an expert consensus and review of key issues. Arch Neurol 2011; 68(2):165
18. Rakesh G, Borthakur B, Pawar M. Management of patient with deep brain stimulator for emergency laparotomy. J Neurosurg Anesthesiol 2011; 23(2):168
19. Odekerken V, Boel J, Schmand B et al & NSTAPS Study Group. GPI vs STN deep brain stimulation for Parkinson’s disease: three-year follow-up. Neurology 2016; 86(8):755-61
20. Worth P. When the going gets tough: how to select patients with Parkinson’s disease for advanced therapies. Practical Neurology 2013; 13(3):140-52
21. Grill W. Safety considerations for deep brain stimulation: review and analysis. Expert Review on Medical Devices 2005; 2(4):409-20
22. Merola A, Rizzi L, Artusi C et al. Subthalamic deep brain stimulation: clinical and neuropsychological outcomes in mild cognitive impaired Parkinsonian patients. J Neurol 2014; 261(9):1745-51
23. Ramaker C, Marinus J, Stiggelbout A, Johannes van Hilten B. Systematic evaluation of rating scales for impairment and disability in Parkinson’s disease. Movement Disorders 2002; 17(5):867-76
24. Blasberg F, Wojtecki L, Elben S et al. Comparison of awake vs. asleep surgery for subthalamic deep brain stimulation in Parkinson’s disease. Neuromodulation 2018; 21(6):541-7
25. Castrioto A, Volkman J, Krack P. Postoperative management of deep brain stimulation in Parkinson’s disease. Handb Clinl Neurol 2013; 116:129-46
26. Williams A, Gill S, Varma T et al [PD SURG Collaborative Group]. Deep brain stimulation plus best medical therapy versus best medical therapy alone for advanced Parkinson’s disease (PD SURG trial): A randomised, open-label trial. Lancet Neurol 2010; 9(6):581-91
27. Schupbach W, Maltete D, Houeto J et al. Neurosurgery at an earlier stage of Parkinson disease: a randomised controlled trial. Neurology 2007; 68(4): 267-71
28. Frizon LA, Hogue O, Achey R et al. Quality of life improvement following deep brain Parkinson’s disease: development of a prognostic model. Neurosurgery 2019 Sep 1; 85(3):343-349. doi: 10.1093/neuros/nyy287.
29. Diamond A, Jankovic J. The effect of deep brain stimulation on quality of life in movement disorders. Neurol Neurosurg Psychiatry 2005; 76(9):1188-93
30. Schupbach M, Gargiulo M, Welter M et al. Neurosurgery in Parkinson disease: a distressed mind in a repaired body? Neurology 2006; 66(12):1811-6
31. Russmann H, Ghika J, Villemure J et al. Subthalamic nucleus deep brain stimulation in Parkinson disease patients over age 70 years. Neurology 2004; 63(10):1952-4
32. Welter ML, Houeto JL, Tezenas du Montcel S et al. Clinical predictive factors of subthalamic stimulation in Parkinson’s disease. Brain 2002; 125:575-83
33. Dafsari H, Reker P, Stalinski L et al [EUROPAR (Non-Motor Parkinson’s Disease Study Group) & International Parkinson’s and Movement Disorders Society (IPMDS).] Quality of life outcomes after subthalamic stimulation in Parkinson’s disease depends on Age. Movement Disorders 2018; 33(1): 99-107
34. DeLong M, Huang KT, Gallis J et al. Effect of advancing age on outcomes of deep brain stimulation for Parkinson disease. JAMA Neurology 2014; 71(10):1290-95
35. Burn D, Troster A. Neuropsychiatric complications of medical and surgical therapies for Parkinson’s disease. J Geriatr Psychiatry Neurol 2004; 17(3):172–80
36. Medtronic Neuromodulation Technical services. Neuromodulation Standard Letter: Deep brain stimulation systems. 8 August 2014; Version 2.0. Medtronic, Minneapolis, US
37. Doshi P. Long term surgical and hardware related complications of DBS.Stereotact Funct Neurosurg 2011; 89(2), 89-95.
38. Boviatsis E, Stavrinou L, Themistocleous M, Kouyialis A, Sakas D. Surgical and hardware complications of deep brain stimulation: A seven-year experience and review of the literature. Acta Neurochirrurgica (Wien) 2010; 152(12):2053-62
39. Morishita T, Foote K, Burdic A et al. Identification and management of deep brain stimulation intra- and postoperative urgencies and emergencies. Parkinsonism and Related Disorders 2010; 16(3):153-62
40. Weintraub D, Duda J, Carlson K et al & CSP 468 Study Group. Suicide ideation and behaviours after STN and GPI DBS surgery for Parkinson’s disease: Results from a randomised, controlled trial. J Neurol Neurosurg Psychiatry 2013; 84(10):1113-8
41. Voon V, Howell N, Krack P Psychiatric considerations in deep brain stimulation for Parkinson’s disease. Handbook of Clinical Neurology 2013; 116:147-54
42. Glannon, W. Stimulating brains, altering minds. J Med Ethics 2009; 35(5):289-92 
43. Gilbert F, Viana J, Ineichen C. Deflating the ‘DBS causes personality changes’ bubble. Neuroethics 2018; DOI: 10.1007/s12152-018-9373-8
44. Ghalys R, Tverdohleb T, Candido K, Knezevic NN. Do we need to establish guidelines for patients with neuromodulation implantable devices, including spinal cord stimulators undergoing non-spinal surgeries? Surg Neurol Int 2016; 7(18):1-6
45. Yeoh T, Manninen P, Kalia S, Venkatraghavan L. Anaesthesia considerations for patients with an implanted deep brain stimulator undergoing surgery: a review and update. Can J Anaesth 2017; 64:308-31
46. Chawla R, Gandhi R. Anaesthetic management of shoulder arthroscopic repair in Parkinson’s disease with deep brain stimulator. Indian J Anaesth 2014; 58(3):309-11
47. Ramos J, Brull S. Perioperative management of multiple non-cardiac implantable electronic devices. A&A Case Reports 2015; 5(11):189-91
48. Kheterpal M, Yadav M, Kulkarni D, Gopinath R. Anaesthetic management of a patient with deep brain stimulation implant for radical nephrectomy. Indian J Anaesth 2014; 58:461-3
49. Jackowiak E, Patil P, Chou K. The deep brain stimulation ‘Twiddler syndrome’. JAMA Neurol 2019; 76(5):620. doi:10.1001/jamaneurol.2019.0691
50. Tymchak Z, Vitali A. What’s the twist? Twiddler’s syndrome in deep brain stimulation. Can J Neurological Sc 2017; 44:726-7
51. Sobstyl M, Zabek M, Gorecki W, Bruszkiewicz-Kuzmicka G. Twiddler syndrome in a patient with tremor dominant parkinson’s disease. a case report and literature review. Polish J Neurol Neurosurg 2015; 49:467-71