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Deep Brain Stimulation in Parkinson's Disease
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.266268
Keywords: Deep brain stimulation, dyskinesias, Parkinson's disease
Deep brain stimulation (DBS) has been in use for at least 60 years now, and with time have come major improvements in surgical techniques, stimulator hardware, and precision in identifying targets within the brain. This is reflected in the fact that over recent years DBS has been successfully used to treat patients with other movement disorders besides Parkinson's disease (PD) such as medication refractory essential tremor, dystonia, and Tourette's syndrome; a discussion of these conditions is beyond the scope of this article and the reader is referred to more detailed reviews on these aspects elsewhere.[1],[2],[3] In 1948, when Pool first implanted a DBS electrode in a PD patient, his target was the caudate nucleus in the brain and surprisingly the indication for treatment was not the patient's motor dysfunction but depression and anorexia. At that time, Pool considered DBS as an alternative to the prevalent surgical procedures for psychiatric comorbidity of PD.[4] However, since then, DBS has become a well-accepted treatment for patients with pharmaco-resistant motor fluctuations in PD and has almost completely replaced ablative surgery in the treatment of advanced PD in modern times, with better results, more flexibility, potential reversibility, less morbidity, and lower mortality. While Pool may have implanted the first DBS electrodes, modern day DBS for PD owes a lot to the pioneering work of Benabid et al. in France.[5] The decision and responsibility of selecting suitable PD candidates for DBS therapy is a multidisciplinary approach with input from the movement disorder neurologist, neurosurgeon, specialist nurses, and sometimes a neuropsychologist.[6] Post DBS implantation follow-up and care are generally provided by the movement disorder neurologist with his/her team that may include a trained nurse specialist to periodically interrogate the device and ensure that is functioning optimally. The neurologist may also be required to adjust therapy parameters of the DBS device to tailor the therapy to the patients' motor symptoms, troubleshoot the device when it malfunctions, and detect battery failure when a patient reports a lack of efficacy. An understanding of how the DBS device functions is a useful starting point for a neurologist who is about to start a career in movement disorders or a neurosurgeon about to start training in functional brain surgery. In the course of a life time they will probably come across scores of such patients and perhaps be involved in their long-term care. However, prior to understanding how the DBS device works, a brief overview of the pathophysiology of PD and how DBS affects the networks and pathways in the PD brain may be useful to put things into context.
The signs and symptoms of PD at the molecular level result from the deficiency of dopamine at the nigrostriatal terminals in the basal ganglia.[7] However, from a neurophysiological viewpoint, the motor symptoms of PD appear to result largely from abnormalities in one of the several parallels and largely segregated basal ganglia thalamocortical circuits (i.e., the motor circuits) in the human brain.[8] Current evidence suggests that dysfunction of one or more of these circuits singly or in combination result in the disruption of downstream network activity in the thalamus, cortex, and brainstem.[8] DBS in the simplest terms acts to free these downstream networks so that they are able to function relatively more normally.[8] The mechanisms of action of DBS discussed here relate to the most common modality of DBS used in PD i.e., subthalamic nucleus (STN) stimulation, and although there will be slight differences by stimulating different parts of the brain (such as the thalamus), the general principles discussed here may apply to basal ganglia stimulation in general, including STN and globus pallidus internal (GPi), as these may all be considered nodes in the overarching cortico-basal ganglia-thalamo-cortical network. The precise mechanism responsible for the clinical effects of DBS on the motor symptoms of PD such as tremor is still debated.[9] One proposed mechanism is that it results from the stimulation of certain structures in the basal ganglia by an electrical current produced by an implantable pulse generator (IPG) [Figure 1].[10] However, inhibition and disruption of hyperactive dysfunctional neural networks have also been proposed. More recently, it has been suggested that DBS dissociates input and output signals from the basal ganglia, resulting in the disruption of abnormal information flow through the stimulation site.[11]
Experimental work on primates and humans has shown that DBS (of STN) interacts with the diseased neural networks in PD in multiple ways, exciting some pathways while inhibiting others [12] to eliminate or subdue the underlying pathological neural activity in the basal ganglia loops.[13] This mechanism has been referred to as “jamming” the diseased network.[14] Other studies have suggested that altering neurotransmitter release at synapses may be an important mechanism by which DBS can to achieve clinical benefits. However, this remains to be confirmed by other research groups studying the biological basis of DBS amelioration of parkinsonian symptoms.[15]
To obtain the maximal benefit from DBS for PD, a careful selection of patients preoperatively to determine who will respond and tolerate the therapy is required [Table 1]. DBS usually does not improve any motor symptoms that do not respond to levodopa such as falls and freezing. While DBS is generally a well-tolerated therapy, severe depression leading to attempted suicide after bilateral STN DBS has been reported,[16] therefore careful patient selection and screening is crucial.
Preoperative cognitive function positively correlates with postoperative improvement from DBS in Unified Parkinson's disease rating scale (UPDRS) part III scores during long-term follow-up.[17] To aid in the screening process, questionnaires such as Florida Surgical Questionnaire for Parkinson Disease (FLASQ PD), for selecting appropriate surgical patients have been developed.[18] Disease duration of >5 years based on the Core Assessment Program for Surgical Interventions and Transplantation in Parkinson's Disease (CAPSIT-PD) and age <70 years are sometimes used as selection criteria; the former criterion allows sufficient time to determine sustained levodopa response, and age >70 years, although arbitrary, is considered a risk for a major surgical undertaking.[19] It must be highlighted here previous reports suggest one-third of patients with advanced PD eligible for deep DBS are not referred to specialized centers, which may reflect some overestimated fears of treating neurologists and their patients regarding complications of DBS. Therefore, education of patients and neurologists about DBS can be improved.[20] The evidence for its benefits and complications will be discussed in the next section. It is important for presurgical counseling that the neurologist explains to the patient (considering DBS surgery) the realistic expectations from this therapy. In general, as mentioned above, those aspects of PD that do not respond to dopaminergic medications will not respond to DBS. This includes some motor symptoms and most nonmotor symptoms including cognitive and neuropsychiatric symptoms [Table 2].
There are several guidelines for patients and health care providers in different countries. [Table 3] shows the criteria used by the United Kingdom (UK) National Health Service Commissioning Board to commission DBS for PD.[21] The National Institute for Health and Care Excellence (NICE) in the UK also offers information about DBS to guide patients considering this treatment.[22] In essence, these criteria highlight that those patients who have a clear and meaningful L-DOPA response (can be objectively measured on the UPDRS motor scale), are not cognitively impaired, and do not have frequent falls would be suitable candidates for DBS if drug therapy has not provided good symptom control; the corollary then would be, patients with poor response to L-DOPA (progressive supranuclear palsy, multiple system atrophy, corticobasal degeneration), patients with dementia, and patients with frequent falls are not suitable candidates for DBS.
DBS surgery is typically performed in an awake patient and involves the use of a stereotactic frame (e.g., Leksell frame) fitted around the patient's head followed by computed tomography (CT)/magnetic resonance imaging (MRI) imaging.[23] The CT/MRI scanner's computer, via a software program, spatially integrates the stereotactic frame with the CT/MRI images of the patient and with the scanner gantry to provide brain coordinates as well as calculate potential probe trajectories, which helps attain target accuracy within 1 mm.[24] Anatomical targeting intraoperatively consists of direct visualization of the target in CT/MR images besides using formula-derived coordinates based on the location of the anterior and posterior commissures, as well as reformatted images from standard anatomical stereotactic atlases.[23] Intraoperatively, the stimulating DBS electrodes are stereotactically implanted through burr holes created in the skull and guided to the intended target under imaging guidance.[25] Neurophysiological verification is achieved most commonly via microelectrode recording (MER) intraoperatively and later with intracranial DBS lead test stimulation (macrostimulation) to assess benefits and side effects of electrical stimulation.[23]
The standard brain targets for stimulation in PD include the STN and GPi. GPi stimulation maybe a more viable option for older patients, where STN stimulation may be less well tolerated. However, a meta-analysis comparing the efficacy of using GPi or STN as the therapeutic target showed no differences in efficacy between the two types of DBS for PD.[26] Ventral intermediate nucleus of the thalamus (VIM) is a target in both essential tremor and parkinsonian tremor but is rarely used now in PD as stimulating STN and GPi are effective not only for tremor control but also help other motor features such as bradykinesia and rigidity. The STN (or GPi) is localized with microelectrode recordings as a zone containing fast spiking cells (spiking frequency 37 ± 17 Hz)[27] [Figure 2].
Intraoperative macrostimulation via the DBS leads is used to guide the final positioning of the electrode by monitoring the clinical response obtained, i.e., amelioration of symptoms such as rigidity and/or tremor and/or the development of stimulation-induced side effects. This involves waking up the patient from anesthesia for 1–2 hours. However, it is important to mention here that not all centers use microelectrode recordings and do not wake up the patient from anesthesia but rely only on neuroanatomical localization of the intended target. This results in shorter operative times and there is a suggestion this may also reduce chances of an intraoperative deep brain hemorrhage.[28] A meta-analysis of operative techniques and outcomes suggested there is no significant difference in mean target error between “awake DBS” and general anesthesia (“asleep DBS”), but there is significantly less mean number of DBS lead passes with general anesthesia.[28] Mean length of in-hospital postoperative stay (1–3 days) is not significantly different between “awake DBS” and “asleep DBS.”[29] Postoperative imaging for lead confirmation using CT or MRI (device switched off) is done to confirm that the electrode is at the desired target and that there have been no acute intraoperative complications.
“Contacts” refers to the electrodes at the end of the DBS leads that delivers the current to the brain targets. There are usually 4 “contacts”† (quadripolar) on each lead tip [Figure 1], and one or more (on each side) can be programmed to act either as a cathode (negative “contact”) or as an anode (positive “contact”), although it is usually the casing of the IPG that is used as an anode in monopolar (unipolar) settings. Monopolar and bipolar refer to the number of active electrodes inside the brain tissue. Most commonly the monopolar configurations, that provide a wider field for stimulation, are used initially but are less intense than those provided by bipolar configurations. If side effects such as those arising from the stimulation of the internal capsule occur due to its proximity to the target area, a switch to a bipolar configuration, because of its narrower field, becomes useful. Bipolar stimulation mode has greater battery longevity than monopolar stimulation.[30] However, this is not the only consideration when making decisions about therapy settings. Carefully selecting electrode configurations, amplitude, frequency and pulse width allow optimal delivery of therapeutic efficacy while minimizing unintended side effects by stimulation of nearby structures. The active electrodes that are implanted deep in the brain tissue to stimulate specific target areas, which explains the acronym DBS, are connected by leads tunneled under the skin to the IPG. While unilateral DBS may have reasonable value in treating patients with symptoms/signs either only on one side of the body or highly asymmetrical parkinsonism; usually in advanced Parkinson's disease symptoms/signs are on both sides of the body, and therefore, bilateral DBS leads are routinely implanted in the surgical theatre unless otherwise required. The two DBS leads can be connected to two single channel IPGs one on either side [Figure 3] under the skin in the pectoral region, but commonly a single dual-channel IPG is chosen by most neurosurgeons.
The IPGs in routine use are non rechargeable devices, and hence, require battery replacements periodically, although rechargeable devices are also available on the market. The time (in years) for battery replacement depends on power consumption by the IPG, hence, the conventional upper limit of 3.6 V † in amplitude makes the device last longer. Another reason for limiting the amount of current delivered is to limit local brain tissue damage from the heat generated. This can also be minimized by adjusting the configuration of active contacts (electrodes) to deliver a narrower field of stimulation. There are several manufacturers marketing DBS devices including St. Jude's Medical, Boston Scientific, and Medtronic. IPGs, DBS leads, and clinician and patient programming devices will look different; for simplicity of purpose representative images from one manufacturer are shown (no conflict of interest involved) and a discussion of the basic configurations follow. The hardware and software on the devices from the different manufacturers may look different but the underlying basic principles are similar. Even the efficacy of constant current and constant voltage devices are also fairly similar for practical purposes (in clinical settings). Newer technologies are not discussed in detail here but will be briefly mentioned at the end of this paper.
Surgical techniques and implantation procedures may vary depending on the neurosurgical team involved, e.g., patients may undergo simultaneous bilateral DBS lead and pulse generator implantation on the same day, unilateral implantation of the DBS lead and pulse generator on the same day, bilateral implantation of the DBS lead on one day and subsequent staged implantation of the pulse generators, or unilateral DBS lead implantation on one day and secondary staged implantation of the pulse generator another day.[23] This variation partly reflects differences in patient symptoms, tolerance of surgery, team preference, available equipment, and the local healthcare system constraints.[23] More recently, frameless stereotaxis is emerging as an alternative to frame-based stereotaxis. Frameless systems for DBS lead implantation have been shown to be as accurate as frame-based systems. However, frameless techniques offer comparative advantages in terms of patient comfort, separation of imaging from surgery, and decreased operating time.[31] DBS surgery procedure can be carried out either with local anesthesia (with or without sedation) or with the patient under general anesthesia. Neither method has been proven superior, but awake procedures offer a number of advantages, including the ability to use MERs for accurate electrode placement, to macrostimulate, and to avoid complications related to general anesthesia.[25] Length of hospital stay and health care resource use can also be reduced by opting for the awake procedure. Although awake DBS is well-tolerated by most patients, pain and “off” period symptoms can be an issue for a significant number of patients.[25] In terms of choice of target, a large meta-analysis has shown that, although response for motor symptoms was better in patients who underwent STN DBS compared to those who underwent GPi DBS, the difference was not statistically significant.[32]
Amplitude, frequency, pulse width, and impedance are the four basic stimulation parameters [Figure 4] of electrical current that are adjusted (or in the case of impedance, recorded) in setting up [Figure 5] optimal device therapy output (program). These four keywords will ring in a movement disorder neurologist's mind whenever he deals with a patient sitting in front of him with a DBS device in situ. Hence, it is of paramount importance to have a clear understanding of this before proceeding further. A word of caution here is that the word “programmer” in this setting can refer both to the device that is used to set up the program (better called a clinician programming device) and the clinician programming the device (clinician programmer) [Figure 6]. We will use this convention hereafter to avoid ambiguity.
Amplitude refers to the amount of voltage fluctuation of the current delivered by the IPG. This is measured in volts (V) and can be set to a specific value with the aid of the clinician programming device that communicates with the IPG via a telemetry head. The range of standard clinical settings for this parameter is from 0.1–3.6 V (maximal programmable upper limit 10.5 V †). The usual starting point for this parameter is 0.5 V, which can be adjusted by increments of 0.1 V † by the clinician or the patient depending upon response in controlling Parkinsonian motor symptoms. Too high a setting will cause the motor side effects analogous to those that result from dopaminergic overdose, and too low a setting may lead to a compromise with efficacy. Frequency (rate) is the number of electrical pulses delivered by the IPG per second. This is measured in Hertz (Hz) and can also be adjusted with the clinician programming device. The range of standard clinical settings is 90–185 Hz (maximal programmable upper limit 250 Hz †). The usual starting point for this parameter is 130 Hz, which can be adjusted (depending upon the device) by increments of 10 Hz †. There is some evidence to show that low frequency stimulation (60 Hz) of STN can improve the freezing of gait in patients with PD.[33] Pulse width refers to the duration of each electrical pulse delivered by the IPG. This is measured in microseconds (μs) and can be adjusted with the clinician programming device. The range of standard clinical settings is 60–130 μs (maximal programmable upper limit 450 μs †). The usual starting point is 90 μs, which can be adjusted by increments of 30 μs. Impedance is the only parameter which is recorded rather than set by the clinician programmer. This is measured in ohms and is recorded at pairs of contacts (electrodes). It can range from 0 to infinity (>10,000 recorded as “High”† on the clinician programming device indicating an open circuit). An impedance <2000 ohm monopolar or <4000 ohm bipolar at the active contacts is ideal. If the impedance is >2000 ohm monopolar or >4000 ohm bipolar, then an alternative contact (with impedance <2000 ohm or <4000 ohm) should be selected with the clinician programming device. A marked change in impedance over time with reduced stimulation efficacy noticed by a patient can be a potential marker of DBS system malfunction such as lead fracture, which can be detected by X-ray series of the upper half of the body targeting the tracks of the DBS leads, analogous to an X-ray shunt series for a suspected blocked, disconnected, or displaced ventriculoperitoneal shunt in hydrocephalus.
The time to switch on the DBS device postoperatively (initial programming) varies from center to center. Some neurosurgeons do this initial programming at 2–4 weeks postoperatively to allow the brain to recover from the surgery and any local edema and “microlesioning” effect to resolve. The latter effect is anticipated, and therefore, a reduction of dopaminergic medications by one-third to half on the day of the surgery can be done to avoid overstimulation side effects and emergence of postoperative delirium. Other neurosurgeons perform the initial DBS programming immediately postoperatively or on postoperative day 1 but at low levels of current (amplitude). The initial programming session, while off anti-parkinsonian medication for 12 hours overnight, involves determining the amplitude threshold (incrementally increasing in steps of 0.1–0.2 V) for clinical benefits and side effects for each of the four electrode contacts for each lead while keeping the pulse width fixed at 60 μs and frequency at 130 Hz.[34] The electrode contact (s) with the lowest threshold for inducing a benefit and the largest therapeutic width (i.e., the highest threshold for side effects) is selected for chronic stimulation.[34] Subsequent programming sessions for assessment and fine tuning can be done periodically (physician preference) perhaps monthly initially to titrate therapy till adequate symptom control achieved and then every 6 months to check that the device is functioning optimally and battery life is sufficient. Additional sessions may also be required to troubleshoot the device on an as and when required basis due to emerging motor side effects such as dyskinesias (from overstimulation) or lack of efficacy (from under stimulation). When conventional programming results in suboptimal control of motor symptoms and stimulation-induced adverse effects, interleaving stimulation (ILS) can be used.[35] ILS enables two programming settings to be used in an alternating fashion (interleaved) on the same lead. Each program specifies the amplitude, pulse width, and electrode contacts used. This allows shaping of individualized current fields to fall below the side effect threshold and prevent stimulation of nontargeted anatomical regions and adjacent structures, thereby reducing side effects and preserving motor benefits.[35] The basic checks, such as battery life, or adjusting therapy parameters (amplitude) can also be done by the patient at home using his/her own controller handheld device (patient programmer) [Figure 6], but therapy limits for the patient's device set using the clinician programming device beforehand.
The birth of modern day DBS in PD [5] began with the demonstration of the efficacy of this treatment modality in patients with VIM thalamotomy on one side and VIM stimulation using stereotactically-implanted electrodes connected to subcutaneous neurostimulators on the other side. VIM stimulation at 130 Hz strongly decreased the tremor but failed to suppress it as completely as thalamotomy did. While VIM stimulation for treatment for PD has fallen out of favor, STN has emerged as the preferred target ahead of GPi stimulation, although both (STN and GPi) have beneficial effects on parkinsonian symptoms of bradykinesia and rigidity as opposed to VIM stimulation which only ameliorates tremor. A summary of the results from studies of DBS in PD from a PUBMED search is shown in [Table 4] (with search criteria: follow up of >12 months in >20 patients).[36],[37],[38],[39],[40],[41],[42],[43],[44],[45],[46],[47],[48],[49],[50],[51],[52],[53]
There have been numerous studies since then that have demonstrated the efficacy of this therapy in reducing dyskinesias, improving motor performance, reducing the requirement for dopaminergic medication, increasing independence in activities of daily living, and improving quality of life [Table 4]. The reduction in the prevalence of dyskinesias reported for STN DBS ranges from 23% at 1 year [52] to 90% at 2 years.[50] For GPi DBS, the reported reduction in dyskinesias ranges from 39% at 2 years [53] and 76% at 4 years.[44] Improvement in motor scores using UPDRS part 3 scale ranges from 17.5% at 2 years [48] to 61% at 1 year.[36] The reduction in levodopa equivalent daily dose (LEDD) for STN DBS ranges from 19.5% at 1 year [43] to 79% at 2 years.[50] For GPi DBS, the reported reduction in LEDD ranges from 15.6% at 1 year [52] to 36% at 3 years follow-up.[37] Improvement in scores of performance of activities of daily living (ADL) for STN DBS ranges from 11% at 2 years [48] to 49% at 5 years follow up.[39] For GPi DBS, the reported improvement in ADL scores ranges from 22% at 1 year [52] to 21% at 3 years follow-up.[37] The improvement in the quality of life (QoL) scores for STN DBS ranges from 19% at 1 year [52] to 11% at 2 years [53] follow-up. For GPi DBS, the reported improvement in QoL scores ranges from 12% at 1 year [52] to 10% at 2 years.[53] While most of these studies record good outcomes, in individual cases, outcomes are sometimes suboptimal even in the absence of common potentially reversible complications such as hardware infection, poor electrode placement, and poor programming parameters. Rescue procedures are sometimes offered to these patients but on a case by case basis.[54] Long-term data is emerging from trials of DBS in young onset PD (YOPD) as well. STN-DBS remained effective to improve motor disabilities over 7 years follow-up for YOPD and was a safe procedure regarding cognitive outcomes and morbidity. However, dopamine dysregulation syndrome with DBS can be problematic in YOPD.[55] Results from the EARLYSTIM trial suggest that DBS may be superior to medical therapy even in patients with PD who have early motor complications.[56] In advanced PD, both STN and GPi DBS remain effective in improving the motor UPDRS scores after 5-6 years of therapy.[57] In a 15-year follow-up post STN DBS-surgery of patients with advanced PD, sustained benefit (implying active stimulation at the last follow up) was maintained at 83%. However, over time, all patients deteriorated slowly, and a majority developed severe nonmotor and axial symptoms such as dementia, inability to talk, swallow and walk, urinary incontinence, psychosis, and need for nursing home care.[58] This reflects the inability of DBS to stop the progression of the underlying neurodegenerative process in the brain of PD patients.
Like any surgical procedure DBS is not without complications. These can be classified as immediate (perioperative) or medium to long-term complications that may include hardware problems as well as therapy-related adverse events. Immediate or perioperative complications can include intracerebral hemorrhage, infarction, scalp infections, foreign body intolerance, pain, and transient postoperative mental status changes. DBS hardware infection often results in multiple hardware salvage attempts, hospitalizations, and long-term antibiotic therapy.[59] Medium-to-long-term hardware-related complications may include increased electrode impedance (reducing efficacy), lead fracture, lead displacement, lead migration, skin erosion, battery drain, and device failure (including short circuits).[60] Complication rates can vary based on the experience of the surgeon. In a recent single center study, the most frequent overall complication for a PD cohort (n = 284) who had DBS surgery performed by a single surgeon, the prevalence of the most common reported complications were postoperative mental status change or confusion (4.6%), followed by intracerebral hemorrhage (1.4%), perioperative seizures (1.4%) and hardware-related infections (1.1%).[29] Perioperative mortality can also be influenced by neurosurgical center experience. In a large case series of 728 patients who underwent DBS surgery (STN, GPi, or VIM) by a single surgeon, of whom 452 suffered from medically refractory PD and had an average follow-up for 2 years, no perioperative or immediate postoperative deaths were recorded.[61] Therapy-related complications in the short term may include dyskinesia, hemiballismus, dysarthria, paraesthesia, and diplopia, which can happen any time after switching on the device while titrating device output for a suitable motor response, and in the long-term may include mild impairments in verbal fluency, learning, and executive function;[62] however, the effect was small in a meta-analysis and STN DBS seems relatively safe from a cognitive standpoint in terms of long-term postoperative complications.[63] Sudden device malfunction [64] due to battery failure or an open circuit, although rare, can lead to a very distressing situation for a patient with DBS due to a severe akinetic rigid state that needs emergency management. This may include admitting the patient in the hospital, interrogating the device to confirm battery failure and then getting the neurosurgeons to replace the battery as soon as possible [65] while dopaminergic drugs, including nasogastric administration of levodopa plus carbidopa if patients are unable to swallow are used as bridging therapies. On a more general note of caution, a patient with DBS undergoing general surgery will need to have the device switched off prior to general anesthesia and monopolar diathermy avoided as it can cause severe burns or death.[66] Performing any MRI >1.5 T using a full body transmit radiofrequency coil, a receive-only head coil, or a head transmit coil that extends over the chest area can cause tissue lesions from component heating, especially at the lead electrodes, resulting in serious and permanent injury. Newer leads (from some manufacturers) are certified as MRI compatible. However, if a patient has older leads † and the clinician is not sure (whether leads are MRI safe or not), then image acquisition performed with the DBS device switched off (as per manufacturer's recommendations) or an alternative imaging modality such as CT scanning can be used. Patients with DBS should inform the driving licencing agencies in their countries about their condition and consult local guidelines. In the UK, these patients can return to driving following their operation provided there is no residual disability that would affect safe driving.[67]
DBS is costly and there are health economic issues to be addressed. Alternative treatments for advanced PD, such as apomorphine and duodopa infusions, may have high recurrent treatment costs. A cost–benefit ratio of DBS entails an analysis of the cost of the equipment, use of operative facilities, staffing, hospital bed occupancy versus reduced medication requirements, and improved quality of life. A European study showed that mean cumulative 5-year cost per patient was significantly lower with DBS (€88,014) compared to continuous subcutaneous apomorphine infusion (€141,393) or continuous duodenal levodopa carbidopa infusion (€233,986) (P = <0.0001).[68] DBS has been shown to yield substantial improvements in health-related quality of life of patients at a value profile that compares favorably to other well-accepted therapies for advanced PD.[69] Future directions Finally, a brief overview of emerging trends and developments in the field of DBS. Newer targets for DBS in PD are emerging including the pedunculoptine nucleus (PPN)[70] to try to address symptoms such as postural instability and gait difficulty (PIGD) that do not respond to STN stimulation. A meta-analysis of six studies showed PPN DBS significantly improved PIGD as well as freezing of gait and falling in patients with PD.[71] MRI-guided STN DBS without microelectrode recordings has been in use for quite some time but better intraoperative confirmation of lead placement with intraoperative imaging as opposed to postoperative imaging is being used in some centers.[72] Real-time interventional MRI-guided methodology for DBS lead placement has been used and allows highly accurate implantation under general anesthesia with outcomes fairly similar to stereotactic frame-based approaches.[73] Rechargeable devices for DBS stimulation are available and this technology is going to get better. At present, these are more suitable for patients with PD who are motivated to recharge the IPG battery, have some technical understanding of the recharging system and have no cognitive impairment.[74] More intelligent DBS devices are going to be available in the market in the near future. Currently available DBS systems used in PD do not respond to variations in the patient's motor problems but rather produce fixed pre-programmed output stimulation.[75] A closed-loop DBS system offers a solution by allowing integration of feedback signals to continuously modulate the output stimulation using a built-in software algorithm.[75] Recent developments in DBS signal delivery can allow switching from voltage controlled (VC) stimulation to constant current (CC) controlled stimulation devices.[76] Over time, voltage-controlled stimulation exhibits an increase in the voltage magnitudes generated in the tissue near the DBS electrode because of electrode impedance fluctuations,[77] whereas current-controlled DBS shows minimal changes. The clinical outcome of CC stimulation has been tested and found to be similar to that obtained with VC devices and remained stable at 3 and 6 months of follow-up.[76] Newer technologies such as 8 contact leads, active tip contacts, horizontal steering of the electrical field that is possible with segmented contacts, and multiple independent current control are becoming available in many countries.[78] The reader is directed to an excellent review about these innovations recently published by Kuhn and Volkmann.[79] Very briefly, traditionally, DBS current has been delivered to brain targets using cylindrical electrodes, which stimulate groups of neurons around the entire circumference of the lead (omnidirectional).[80] Directional DBS leads have radially segmented electrodes which can be used for selective stimulation in directions orthogonal to the lead trajectory, e.g., Boston Scientific's Vercise PC IPG provides an independent current source for each of the 16 contacts on its leads. The movement disorder neurologist programming the device should therefore be capable of current steering to shape the area of stimulation in the plane orthogonal to the long axis of the lead (directional stimulation).[80]
DBS will continue to have a place in the treatment of PD (and other complex movement disorders). A clear understanding of the principles underlying this therapy, suitable patient selection, intended brain targets, technical aspects of programming the device, efficacy of this treatment in PD, and its possible complications is very important for the clinical management of patients who choose to opt for this therapy. †Medtronic device Acknowledgements Naveed Malek would like to thank Mr. Laurence Dunn, Consultant Neurosurgeon, in Glasgow and Dr. Uma Nath, Consultant Neurologist, in Sunderland, for their very helpful suggestions while writing this paper. Dr. Arup Mallik, Consultant Neurophysiologist, in Glasgow, has kindly provided the intraoperative microelectrode recordings from the STN and I wish to personally thank him and acknowledge his help. I am very grateful to Mr. Craig Magson for his help with the figures (MEDTRONIC ® owns copyright for the [Figure 1],[Figure 2],[Figure 4], [Figure 6] and 7). Financial support and sponsorship Nil. Conflicts of interest Industry sponsorship: This article is not industry sponsored. I have not obtained any financial gains from Medtronic or any other company for writing this manuscript. There is no ghost writing involved.
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]
[Table 1], [Table 2], [Table 3], [Table 4]
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