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Table of Contents    
SYMPOSIUM
Year : 2020  |  Volume : 68  |  Issue : 8  |  Page : 170-178

Neuromodulation Options and Patient Selection for Parkinson's Disease


1 Department of Neurology, All India Institute of Medical Sciences, New Delhi, India
2 Department of Neurology, P. J. Safarik University; Department of Neurology, University Hospital of L. Pasteur, Kosice, Slovakia, USA
3 Department of Neurology, University of Missouri-School of Medicine, Columbia, MO, USA
4 Department of Neurology, National Neuroscience Institute, King Fahad Medical City, Riyadh, Saudi Arabia
5 Department of Neurosurgery, National Neuroscience Institute, King Fahad Medical City, Riyadh, Saudi Arabia
6 Department of Neurological Surgery, West Virginia University, Morgantown, WV, USA

Date of Web Publication5-Dec-2020

Correspondence Address:
Dr. Jawad A Bajwa
Department of Neurology, National Neuroscience Institute, King Fahad Medical City, As Sulimaniyah, Riyadh – 12231
Saudi Arabia
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0028-3886.302473

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 » Abstract 


Neuromodulation therapies, including deep brain stimulation (DBS) and pump therapies, are currently the standard of care for PD patients with advanced disease and motor complications that are difficult to control with medical management alone. The quest for alternate lesser invasive approaches led to the development of several novel therapies like intrajejunal levodopa infusions (IJLI), continuous subcutaneous apomorphine infusions (CSAI) and Magnetic Resonance guided Focused Ultrasound (MRgFUS) in recent years. To achieve good outcomes with any of these therapeutic modalities, careful patient selection, multidisciplinary evaluation and technical expertise are equally important. In this review, we will provide an overview of the neuromodulation strategies currently available for PD, emphasizing on patient selection and choosing among the various strategies.


Keywords: Parkinson's disease; neuromodulation; deep brain stimulation; infusion therapies; lesioning
Key Message: Deep Brain Stimulation, infusion therapies and lesioning surgeries are all neuromodulation strategies that offer significant functional benefits in patients with Parkinson's disease. Closely weighing the benefits and limitations of each therapy in tandem with the patient's needs and expectations is important to achieve good clinical outcomes.


How to cite this article:
Rajan R, Skorvanek M, Magocova V, Siddiqui J, AlSinaidi OA, Shinawi HM, AlSubaie F, AlOmar N, Deogaonkar M, Bajwa JA. Neuromodulation Options and Patient Selection for Parkinson's Disease. Neurol India 2020;68, Suppl S2:170-8

How to cite this URL:
Rajan R, Skorvanek M, Magocova V, Siddiqui J, AlSinaidi OA, Shinawi HM, AlSubaie F, AlOmar N, Deogaonkar M, Bajwa JA. Neuromodulation Options and Patient Selection for Parkinson's Disease. Neurol India [serial online] 2020 [cited 2021 Feb 24];68, Suppl S2:170-8. Available from: https://www.neurologyindia.com/text.asp?2020/68/8/170/302473




The Global Burden of Disease study (2018) estimated that Parkinson's disease (PD) prevalence has risen exponentially over the past two decades, from 2.5 million patients in 1990 to 6.1 million patients in 2016.[1] Dopaminergic medications offer considerable symptomatic benefits in the early stages of PD. As PD progresses, motor complications related to levodopa replacement hamper the sustained benefit and quality of life for patients.[2] Neuromodulation therapies, including Deep Brain Stimulation (DBS) and pump therapies, are currently the standard of care for PD patients with advanced disease and motor complications that are difficult to control with medical management alone.[3],[4] The quest for alternate approaches led to the development of several novel strategies for continuous dopaminergic stimulation, including intrajejunal levodopa infusions (IJLI) and continuous subcutaneous apomorphine infusions (CSAI) [Figure 1].[5] More recently, innovative methods for non-invasive neurostimulation were developed and applied in PD, leading to FDA approval for magnetic resonance-guided focused ultrasound (MRgFUS) ablation to treat tremor in PD.[6] While the traditional non-invasive cranial stimulation strategies like Transcranial Magnetic Stimulation (TMS) are largely limited to research use to understand the physiological processes involving neuromodulation, promising short-term results have been reported following these modalities on specific domains of PD. Furthermore, the past few years have witnessed exciting progress with spinal cord stimulation, vagal nerve stimulation and near-infrared stimulation in various stages of development. For the practicing clinician, these have opened up a repertoire of strategies that may potentially benefit the patient. In this review, we will provide an overview of the neuromodulation strategies currently available for PD, emphasizing on patient selection and choosing among the various strategies.
Figure 1: Timeline of introduction of important neuromodulation therapies for PD. Schematic is not drawn to scale. DBS- Deep Brain Stimulation; FDA- Food and Drug Administration; LCIG- Levodopa Carbidopa Intestinal Gel; MRgFUS- Magnetic Resonance guided Focussed Ultrasound; PD- Parkinson's disease

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 » Intracranial Neuromodulation Top


Deep brain stimulation

DBS involves delivering electrical stimulation through intracranial electrodes implanted into a target nucleus and connected to an implanted pulse generator (IPG) located extracranially. The implanted electrodes (one on either side) have several contacts interspersed at regular intervals at their tips. During post-operative programming, each contact can be activated independently and programmed to deliver current of required pulse width, frequency, and amplitude. Accurate implantation of electrodes into the target nucleus is achieved by a three pronged strategy consisting of (1) Direct or indirect visualization of the target nucleus on cranial MRI and stereotactic localization, (2) Analysis of microelectrode recordings (MER) obtained intra-operatively to identify the borders of the target nucleus and (3) macrostimulation and clinical assessment of benefits and adverse events during surgery. The STN and GPi are the nuclei that are commonly targeted for DBS in PD, with majority of the centers targeting the STN.[7],[8]

Pre-operative levodopa responsiveness is the strongest predictor of good outcomes following DBS, and in general it is the levodopa responsive symptoms that improve after surgery. Tremor is an exception and that may respond to DBS even if levodopa unresponsive. Gait and axial symptoms are generally considered to be significantly unaltered by DBS; levodopa responsive gait disturbances including freezing of gait may respond to STN-DBS, though the effects maybe ill-sustained beyond the initial years.[9] The benefits of DBS on the quality of life maybe lesser in patients who are severely disabled in the ON time (other than disability attributable to dyskinesias or tremor), those with cognitive impairment, advanced age, levodopa unresponsive gait and axial symptoms, significant autonomic dysfunction and poor social support.[10],[11] In general, these factors are therefore considered to be relative contraindications to DBS [Table 1]. It is important to note that DBS is only a symptomatic therapy aimed at controlling the motor symptoms and improving the patient's quality of life without any proven effect on the progression of neurodegeneration.[12],[13]
Table 1: Indications and contraindications for DBS in PD

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Lesioning surgery

Advances in imaging and lesioning technologies in the last decade have rekindled interest in lesioning for the treatment of many movement disorders.[15] The limited resources in some centers to afford DBS costs and the difficulty for some patients to travel from remote areas to be monitored regularly makes lesioning therapy a valuable option.

Lesioning surgery can be done using several techniques:

  • Radiofrequency: is an invasive technique which creates a lesion using heat through an intracranially placed electrode coupled to an RF generator. This electrode is electrically insulated except at the tip, where the active electrode is located.[15] The benefits include distinct lesion borders, intraoperative physiological confirmation, no limitation of the region of treatment and immediate results. Surgical risks (intracerebral hemorrhage, loss of accuracy), lower predictability of lesion size and shape and the requirement for multiple passes for the ablation of large volumes are the drawbacks of this technique.
  • Radiosurgery: is a noninvasive radiation treatment and Gamma Knife is the most used modality. Most studies were performed unilaterally because of the potentially increased risk of adverse effects related to inadvertent involvement of the corticobulbar tract.[16] The non-invasive nature of the intervention, no limitation of the region of treatment, ablation of a large tissue volume, conformation of the lesion to complex geometries, and slower radiobiologic effect that may allow for more plasticity are the advantages of this technique. The drawbacks include delayed occurrence of effect and side-effects, inability for intraoperative feedback, graduated dose fall-off, less demarcated lesion borders and exposure to ionizing radiation.
  • Interventional MRI-guided laser ablation: Classically used for tumors and epilepsy, however first report of use for movement disorders and PD was in 2015.[17] It is an invasive procedure that utilizes fiber-optic lasers with real-time MRI feedback and thermal cut-off safety limit, to minimize spilled thermal damage to surrounding healthy tissue. The clinical effect of the ablation is immediate; however, the main disadvantage is long procedure time and patient discomfort.
  • Magnetic Resonance–Guided High-Intensity Focused Ultrasound (MRgFUS): Advances in intracranial ultrasound delivery enabled the development of non-invasive Magnetic Resonance guided Focused Ultrasound (MRgFUS) systems that can stereotactically target deep cerebral nuclei. A randomized controlled trial of MRgFUS unilateral thalamotomy that recruited 27 patients with tremor-dominant PD, showed 62% improvement in tremor scores in the treatment arm at 3 months, compared to 22% in the sham group.[6] Quality of life and off-medication UPDRS scores also improved at 3 months. Persistent paresthesiae, hemiparesis and hemiataxia were the adverse events encountered and long-term stability of effects need to be explored in future studies. A follow-up study of the same group of patients showed no significant effects on cognition, mood, and behavior.[18] In 2019, the FDA approved MRgFUS thalamotomy as a treatment for disabling PD tremor. In addition to the thalamic target, results of MRgFUS subthalamotomy and pallidotomy have been reported in small, open-label, single-arm studies. Most of these studies performed unilateral ablations and long-term outcomes need to be studied further.


The commonly targeted structures for lesioning in PD include the thalamus (VIM), pallidum (GPi) and STN. For thalamotomy, the VIM nucleus is considered the best target, with excellent short- and long-term tremor suppression in 80-90% of patients with PD.[19] Especially with bilateral interventions, the rate of adverse events is higher, they are associated with a higher risk of permanent dysarthria and imbalance.[20] For pallidotomy, the antidyskinetic posteroventrolateral part of the GPi is targeted most frequently. Pallidotomy studies have demonstrated significant improvements in the cardinal symptoms of PD (tremor, rigidity, bradykinesia), as well as a significant reduction in dyskinesia. Both RFA and Gamma-knife thalamotomy seems to result in comparable effects on both dyskinesia (83.3% and 86.6% improvement, respectively) and bradykinesia/rigidity (63.6% and 65.5% improvement, respectively).[19] The most serious and frequent (3.6%) adverse effect of pallidotomy is a scotoma in the contralateral lower-central visual field. Less frequent complications include injury to the internal capsule, facial paresis, and intracerebral hemorrhage (1-2%). Abnormalities of speech, swallowing, and cognition may also be observed. Unilateral pallidotomy is safe and well tolerated. Bilateral lesions are not recommended because there is a high risk of severe adverse effects, such as corticobulbar syndrome with dysarthria and dysphagia.[20] Subthalamotomy involves destruction of a part of the STN, although it is commonly avoided because of the concern of producing hemiballismus. Subthalamotomy has been typically performed unilaterally because of the higher risk of neurological side effects such as speech disturbances, ataxia, or generalized chorea associated with bilateral procedures.[21]


 » Extra Cranial Neuromodulation Top


Infusion therapies

Pump therapies are an integral part of neuromodulatory therapies for advanced Parkinson's disease. Currently there are 2 pump systems available – a) continuous subcutaneous apomorphine infusion (CSAI) and b) Levodopa/carbidopa intestinal gel (LCIG) pump. Major indication for both these pump therapies is advanced PD with motor fluctuations not controlled by oral or transdermal dopaminergic medications [Table 2]. Although both of them compete with DBS in these clinical settings, there are no randomized controlled comparative studies directly evaluating any of these systems and comparison is possible only based on smaller open-label studies.[22],[23]
Table 2: Indications and contraindications of CSAI and LCIG infusions, tips for management of side-effects

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 » Subcutaneous Apomorphine Pump Top


Apomorphine is a potent direct dopamine agonist (DA) with very fast onset of effect and short plasma half-life. Unlike other DA, it activates all dopamine receptors, including D1-like and D2-like receptors, similar to levodopa.[24] Apomorphine is currently available as a pen (for rescue injections in unpredictable OFF episodes) and as CSAI when continuous dopaminergic stimulation is desirable. CSAI is delivered via a subcutaneous catheter connected to a small portable pump, typically during waking hours.

Single apomorphine injection has a rapid onset of effect (typically within 4-12 min) with a rapid clearance half-life and a mean duration of anti-parkinsonian action lasting about 45-60 min.[25] As apomorphine was put in clinical use long before rigorous requirements for drug registration, there is only a very limited number of randomized trials for single injections and a single RCT for CSAI.[26] Despite this perceived “evidence disadvantage” compared to DBS and LCIG, a number of open-label trials report very consistent and substantial improvement of OFF time with a mean OFF time reduction of 59%.[27] Reported improvements in dyskinesia are variable and seem to be more pronounced in patients who achieve a more substantial reduction of levodopa after CSAI initiation.[24] Several open-label trials report improvement of non-motor symptoms (NMS) and quality of life (QoL).[22],[23]

Spectrum of CSAI side-effects include most commonly autonomic and vegetative symptoms, such as nausea, peripheral edema, orthostatic hypotension as well as neuropsychiatric symptoms typical for DAs.[28] It is, however, important to note that CSAI has a significantly lower propensity to induce both hallucinations and impulse control disorders compared to other currently used DAs such as ropinirole, pramipexole and rotigotine.[24] Mild to moderate skin nodules at the site of infusion are relatively common, may be bothersome and may lead to discontinuation of treatment if infection or necrosis occurs.


 » Levodopa/Carbidopa Intestinal Gel Infusion (LCIG) Top


LCIG is administered via jejunal extension tube-percutaneous endoscopic gastrostomy (JET-PEG) connected to a portable pump directly into the proximal segment of jejunum bypassing the stomach with its erratic emptying. This approach allows delivery of levodopa directly to the site of its absorption and leads to very stable plasma levels of levodopa compared to oral administration.[29] The infusion is typically administered during waking hours, although 24-hour infusions may be delivered in case of severe night-time problems. In many cases, the LCIG may be administered as a monotherapy, although combination with other medications such as COMT inhibitors, amantadine, dopamine agonists in specific indications or oral levodopa for night-time problems may be beneficial.

Several randomized trials have shown significant improvement of motor scores as well as a significant reduction of OFF time and increase in ON time without bothersome dyskinesia after LCIG compared to oral levodopa in patients with motor fluctuations.[30],[31] Reduction of dyskinesia severity and duration has been indirectly shown in previous trials, as well as in clinical practice. LCIG was shown to significantly improve QoL and NMS, especially in the sleep/fatigue, mood/cognition and gastrointestinal domains.[32]

Side-effects or treatment-related complications are relatively common, but in most cases well manageable. The most common complications are device- or stoma-related that occur basically in all patients over a long course of treatment but rarely lead to treatment discontinuation.[31],[32] These include e.g., JET-PEG or jejunal tube displacement or occlusion, leakage, unintentional removal, connection issues, infections or granulomas around stoma. Good multidisciplinary management involving a dedicated gastroenterologist and PD nurse is key to successful management of these issues. Medication side-effects are similar to oral levodopa, although an increased prevalence of polyneuropathy (PNP) has been noted in LCIG.[33] This may present as worsening of pre-existing PNP or onset of acute PNP (Guillian–Barre syndrome-like) requiring discontinuation of treatment. Polyneuropathy may be associated with decrease in vitamins B or folate levels and increase in homocysteine and methylmalonic acid in approximately 1/3 of patients and is commonly associated with significantly increased LCIG daily levodopa equivalents (LEDD) compared to LEDD on previous oral medication.[34]

Spinal cord stimulation

Spinal cord stimulation (SCS) is a quite common and safe procedure. It has been used for many years for the treatment of medically refractory neuropathic pain of the lower extremities and trunk and failed back surgery syndrome.[36–38] As we started to know about the central effects of SCS, a very helpful insight was obtained in central modulation due to spinal stimulation.[39] Our study in pain patients showed that analgesia offered by SCS is not only by closing the gate but by decreased connectivity between certain central neural circuits like that of perception (somatosensory) and affect (limbic).[39] This knowledge about the ability of SCS to modulate central circuits and accidental findings in patients with Parkinson's disease (PD) and chronic pain, led to the use of SCS for the treatment of disorders of movement.

The first report about use of SCS in a 6OHDA rat model of PD was published in Science in 2009.[40] They not only documented functional recovery but demonstrated disruption of anti-kinetic low-frequency synchronous cortico-striatal oscillations in animals with SCS. They also proposed the prokinetic effects of SCS are a result of antidromic or afferent stimulation of brainstem nuclei involved in initiation of locomotion.[41] After this multiple case reports and small studies have documented the benefit of SCS in patients with PD and chronic pain, for sensory symptoms of PD and in camptocormia in PD.[42–46]

Recent studies with long term follow up (3 years) have shown persistent benefits in the gait dysfunction in PD. Some recent studies have also proposed neuro-protective effect of cervical spinal cord stimulation in animal models of PD.[47],[48]

While selecting patients for SCS for PD, the following factors could be considered:

  1. SCS for PD is still an experimental or off-label procedure
  2. Patients should have predominant gait dysfunction (freezing of gait, bradykinesia) not responsive to levodopa
  3. They should have tried all other medical alternatives including gait therapy (physiotherapy)
  4. They should undergo extensive gait evaluation in gait lab
  5. They should not have previous extensive spinal surgery which will make spinal cord stimulation technically difficult.


The implantation of spinal cord leads should be at T8 to T10 levels (paddle or percutaneous leads) and programming should be at or around pulse-width of 400 microseconds with rates of 60 Hz. The stimulation should be continuous and amplitudes at the tolerable level.


 » Non-Invasive Neuromodulation Top


Transcranial magnetic stimulation (TMS) involves using an external magnetic stimulator to stimulate different areas of the cortex non-invasively to induce changes in cortical excitability. Depending on the frequency, intensity and duration of stimulus applied, the effects may be excitatory or inhibitory on the cortex.[49] Single-pulse and paired-pulse TMS have been used extensively as a research tool to understand the pathophysiology of movement disorders, including PD.[50] Repetitive TMS (rTMS) is the most commonly used protocol in a therapeutic setting.[51] In PD, excitatory rTMS (≥5 Hz) delivered to the primary motor cortex (M1) and inhibitory rTMS (≤1 Hz) delivered to the supplementary motor area (SMA) have been shown to improve motor symptoms like rigidity and bradykinesia.[52],[53] Some studies have also suggested efficacy of M1, SMA or cerebellar stimulation on levodopa-induced dyskinesias.[54–56] Among the non-motor symptoms, high-frequency rTMS of the left DLPFC is “probably efficacious” in depression associated with PD.[51] However, it is important to note that not all studies assessing rTMS in PD have shown positive or consistent results. The plasticity induction attributed to rTMS is transient, lasting about 30 min after a session. Hence, continued stimulation over multiple days is necessary for lasting effects, and heterogeneity in protocols could be a factor contributing to the inconsistent reports from studies.[50],[57] As of now, other than as a treatment for co-morbid depression, rTMS is generally offered in a clinical trial setting in PD.

Non-invasive vagus nerve stimulation (VNS) is postulated to modulate the activity of the locus coeruleus via the nucleus of the solitary tract, and hence of clinical interest particularly for locomotor disturbances in PD.[58] In an open-label pilot study, VNS improved freezing of gait in PD patients.[59] Another smaller randomized trial suggested beneficial effects on gastrointestinal symptoms in PD.[60] Although there is promising early evidence, further studies are required prior to clinical use.


 » Experimental Therapies Top


Experimental neuromodulation strategies for the treatment of PD include biological, genetic, stimulation and combined modalities. Optogenetics offers the ability for cell type-specific stimulation and is being studied in conjunction with DBS for delivery.[61] It acts by utilizing light-sensitive proteins that control particular cellular functions and can be used to selectively control cells that respond to “stop” and “go” lights delivered through fiber optics through different colored orders.

Stem cell therapy has attempted disease modification or cure for PD. Initial studies of fetal nigral transplant failed to show long term benefits and were complicated by severe dyskinesias.[62] Newer approaches have looked at development of neural progenitor cells and miniature SN-like structures (mini-SNLSs) for transplant. These remain in pre-clinical development while ongoing clinical trials are assessing the efficacy of fetal derived ventral mesencephalic tissue, embryonic stem cell-derived dopaminergic progenitor cells and induced pleuripotent stem cells.[63] Pending the results of these and future larger studies, stem cell therapy is not yet to be offered outside of a clinical trial setting in PD. Among novel stimulation strategies being explored, photobiomodulation using both extracranial and intracranial near-infrared stimulation is currently undergoing clinical testing.[64],[65]


 » Choosing among the Neuromodulation Strategies- Patient Selection Top


The idea to consider an interventional therapy should be introduced early on at the time of diagnosis of PD when presenting the patient with options that are available for PD management. This broadens the options for the patient and gives time for the patient to process these options when the time comes to make a choice.

The neurologist should be aware of when not to offer an invasive surgery like in the presence of significant cognitive impairment or medically refractory psychiatric conditions.[66] The provider should make a point to identify the features that are not expected to improve with neuromodulation like axial motor symptoms including freezing of gait (FOG), postural instability, camptocormia and Pisa syndrome, dysphagia, dysarthria and memory complaints. The motor complications that are expected to improve with neuromodulation should be emphasized and also the hope that it will address medication-resistant tremor in PD.

In general, the patient's age and cognitive functioning should be considered in parallel to the presence of complications like dyskinesia. Levodopa related motor complications including wearing off, delayed ON or failed ON, ON/OFF fluctuations, peak dose and biphasic dyskinesias and OFF dystonia should be recognized. Additionally, non-motor symptoms like pain, sleep disruption should also be considered. When a patient has significant cognitive impairment or language problems, then an interventional therapy especially DBS is less likely to be offered, for concerns of further decline.[67]

A systematic approach to patient characteristics, age and comorbidities can help decide what technique best suits a particular phenotype of PD patient [Figure 2].[68] Since PD is a progressive neurodegenerative condition, the ability to adapt to the changing disease would make that intervention superior. If there is medication-resistant tremor or severe dyskinesia in a young and cognitively intact patient, DBS would be a good option. If the patient prefers not to have brain surgery or has significant cognitive impairment or poorly controlled psychiatric comorbidities, then levodopa-carbidopa intestinal gel (LCIG) or subcutaneous apomorphine injection (SCAI) can be offered. It may be best to consider different patient profiles in an individualized manner and the match them to an interventional therapy.[68]
Figure 2: Algorithm for choosing among the available neuromodulatory strategies. CSAI: Continuous Subcutaneous Apomorphine Infusion; DBS - Deep Brain Stimulation; LCIG - Levodopa Carbidopa Intestinal Gel; MRgFUS - Magnetic Resonance guided Focussed Ultrasound; PD - Parkinson's disease

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DBS

The ideal DBS candidate is a patient with established PD, whose main disability is attributable to off-time motor symptoms like tremor, rigidity and bradykinesia which are present for considerable periods of time during awake hours accompanied by troublesome dyskinesias during the medication-ON time. Criteria for patient selection are broadly based on the inclusion and exclusion criteria for randomized controlled trials comparing STN-DBS to best medical therapy and GPi-DBS to STN-DBS.[7],[8],[14],[69],[70],[71],[72] In addition, long-term prospective follow-up studies are available for both STN and GPi DBS.[73],[74]

Emerging data promotes the idea of early intervention especially in the field of DBS. While the previous practice was to offer DBS for patients with a mean duration of illness of 12-15 years, evidence from the EARLYSTIM trial reported that “early DBS” (duration of PD ≈ 7.5 years) was superior to medical therapy.[14],[75] Clinical studies are now assessing DBS offered even before the onset of motor fluctuations- ‘very early DBS’.[76] At five years, patients receiving ‘very early DBS’ required lesser medication and had less tremor compared to those receiving optimal drug therapy.[77] A larger multicenter study comparing DBS and medical therapy for early-stage PD is ongoing. With these recent advancements in mind, it is reasonable to start moving the post of when to offer DBS and to consider offering it earlier in the course of the illness.

Lesioning

In comparison to lesioning techniques, advantages of DBS include reversibility of the effects/side effects; flexibility of the stimulation settings; easier identification of new targets and feasibility of bilateral surgeries that make DBS currently the first treatment option in terms of PD surgery.[78] However, a sub-population of PD patients may significantly benefit from lesioning procedures despite not being suitable candidates for DBS due to higher age, presence of neuropsychiatric symptoms (e.g., dementia, psychotic symptoms), higher risk of complications due to surgery, long term stimulation or implanted device (e.g., allergy to metals, uncontrolled diabetes mellitus with increased risk of device infections, etc.). Also, lesioning procedures present a significantly lower financial burden for low-income patients and healthcare systems, making them more widely available. As one-time procedures, lesioning also does not require regular follow-ups and this can be more practical for patients from remote regions who have problems with regular access to tertiary movement disorder centers.

Pump therapies

Both CSAI and LCIG significantly reduce OFF time, increase ON time, improve NMS and QoL. Although direct comparative studies are lacking, current limited evidence and clinical experience seems to favor LCIG over CSAI especially in patients with severe motor fluctuations and dyskinesia. LCIG has also less potential caveats compared to CSAI in terms of neurocognitive profile of patients (mild to moderate dementia, presence of hallucinations and impulse control disorder). Advantages of CSAI include especially its less invasive character and thus it may be favorable in patients with milder motor fluctuations or those who have not decided yet for DBS or LCIG. In both pump systems the major potential limitation is patient non-cooperation and inappropriate social background due to technical aspects of the therapy. Both pumps are typically administered only during waking hours and thus in patients with severe night-time problems DBS seems to be more favorable, although 24-hour infusions may still be an option.


 » Conclusion Top


The landscape of PD management has continuously evolved over the years and currently, there are a host of options that can be offered to the patient. Neuromodulatory strategies including DBS, lesioning and pump therapies can all contribute to improved quality of life in carefully selected patients. Patient education, comprehensive, multidisciplinary evaluation and technical expertise are equally important to achieve good outcomes.

Financial support and sponsorship

No targeted funding.

Conflicts of interest

There are no conflicts of interest.



 
 » References Top

1.
Ray Dorsey E, Elbaz A, Nichols E, Abd-Allah F, Abdelalim A, Adsuar JC, et al. Global, regional, and national burden of Parkinson's disease, 1990–2016: A systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol 2018;17:939–53.  Back to cited text no. 1
    
2.
Ahlskog JE, Muenter MD. Frequency of levodopa-related dyskinesias and motor fluctuations as estimated from the cumulative literature. Mov Disord 2001;16:448–58.  Back to cited text no. 2
    
3.
Blond S, Caparros-Lefebvre D, Parker F, Assaker R, Petit H, Guieu JD, et al. Control of tremor and involuntary movement disorders by chronic stereotactic stimulation of the ventral intermediate thalamic nucleus. J Neurosurg 1992;77:62–8.  Back to cited text no. 3
    
4.
Siegfried J, Lippitz B. Bilateral chronic electrostimulation of ventroposterolateral pallidum: A new therapeutic approach for alleviating all parkinsonian symptoms. Neurosurgery 1994;35:1126–30.  Back to cited text no. 4
    
5.
Prakash N, Simuni T. Infusion therapies for Parkinson's disease. Curr Neurol Neurosci Rep 2020;20:44.  Back to cited text no. 5
    
6.
Bond AE, Shah BB, Huss DS, Dallapiazza RF, Warren A, Harrison MB, et al. Safety and efficacy of focused ultrasound thalamotomy for patients with medication-refractory, tremor-dominant Parkinson disease a randomized Clinical trial. JAMA Neurol 2017;74:1412–8.  Back to cited text no. 6
    
7.
Odekerken VJJ, Boel JA, Schmand BA, De Haan RJ, Figee M, Van Den Munckhof P, et al. GPi vs STN deep brain stimulation for Parkinson disease. Neurology 2016;86:755–61.  Back to cited text no. 7
    
8.
Follett KA, Weaver FM, Stern M, Hur K, Harris CL, Luo P, et al. Pallidal versus subthalamic deep-brain stimulation for Parkinson's disease. N Engl J Med 2010;362:2077–91.  Back to cited text no. 8
    
9.
Schlenstedt C, Shalash A, Muthuraman M, Falk D, Witt K, Deuschl G. Effect of high-frequency subthalamic neurostimulation on gait and freezing of gait in Parkinson's disease: A systematic review and meta-analysis. Eur J Neurol 2017;24:18–26.  Back to cited text no. 9
    
10.
Welter ML, Houeto JL, Tezenas Du Montcel S, Mesnage V, Bonnet AM, Pillon B, et al. Clinical predictive factors of subthalamic stimulation in Parkinson's disease. Brain 2002;125:575–83.  Back to cited text no. 10
    
11.
Chiou SM. Benefits of subthalamic stimulation for elderly parkinsonian patients aged 70 years or older. Clin Neurol Neurosurg 2016;149:81–6.  Back to cited text no. 11
    
12.
Lilleeng B, Brønnick K, Toft M, Dietrichs E, Larsen JP. Progression and survival in Parkinson's disease with subthalamic nucleus stimulation. Acta Neurol Scand 2014;130:292–8.  Back to cited text no. 12
    
13.
Hilker R, Portman AT, Voges J, Staal MJ, Burghaus L, Van Laar T, et al. Disease progression continues in patients with advanced Parkinson's disease and effective subthalamic nucleus stimulation. J Neurol Neurosurg Psychiatry 2005;76:1217–21.  Back to cited text no. 13
    
14.
Schuepbach WMM, Rau J, Knudsen K, Volkmann J, Krack P, Timmermann L, et al. Neurostimulation for Parkinson's disease with early motor complications. N Engl J Med 2013;368:610–22.  Back to cited text no. 14
    
15.
Franzini A, Moosa S, Servello D, Small I, DiMeco F, Xu Z, et al. Ablative brain surgery: An overview. Int J Hyperthermia 2019;36:64–80.  Back to cited text no. 15
    
16.
Kern DS, Forbes E, Shah BB. Surgical interventions for Parkinson's disease. Pract Neurol 2018;20:12.  Back to cited text no. 16
    
17.
San Luciano M, Katz M, Ostrem J, Martin A, Starr P, Ziman N, et al. Effective interventional magnetic resonance image-guided laser ablations in a Parkinson's disease patient with refractory tremor. Mov Disord Clin Pract 2016;3:312–4.  Back to cited text no. 17
    
18.
Sperling SA, Shah BB, Barrett MJ, Bond AE, Huss DS, Mejia JAG, et al. Focused ultrasound thalamotomy in Parkinson disease nonmotor outcomes and quality of life. Neurology 2018;91:E1275–84.  Back to cited text no. 18
    
19.
Stereotactic Surgery in Parkinson Disease: Overview, Deep Brain Stimulation, Neuroablative Lesion Surgeries [Internet]. [cited 2020 Oct 28]. Available from: https://emedicine.medscape.com/article/1153743-overview.  Back to cited text no. 19
    
20.
Frighetto L, Bizzi J, Silva RS, Oppitz P, Annes R. Stereotactic radiosurgery for movement disorders. Surg Neurol Int 2012;3:10.  Back to cited text no. 20
[PUBMED]  [Full text]  
21.
Guridi J, Herrero MT, Luquin MR, Guillen J, Ruberg M, Laguna J, et al. Subthalamotomy in parkinsonian monkeys Behavioural and biochemical analysis. Brain 1996;119:1717-27.  Back to cited text no. 21
    
22.
Martinez-Martin P, Reddy P, Katzenschlager R, Antonini A, Todorova A, Odin P, et al. EuroInf: A multicenter comparative observational study of apomorphine and levodopa infusion in Parkinson's disease. Mov Disord 2015;30:510–6.  Back to cited text no. 22
    
23.
Dafsari HS, Martinez-Martin P, Rizos A, Trost M, Santos Ghilardi MG, Reddy P, et al. EuroInf 2: Subthalamic stimulation, apomorphine, and levodopa infusion in Parkinson's disease. Mov Disord 2019;34:353–65.  Back to cited text no. 23
    
24.
Jenner P, Katzenschlager R. Apomorphine-Pharmacological properties and clinical trials in Parkinson's disease. Parkinsonism Relat Disord 2016;33:S13–21.  Back to cited text no. 24
    
25.
LeWitt PA. Subcutaneously administered apomorphine: Pharmacokinetics and metabolism. Neurology 2004;62:S8-11.  Back to cited text no. 25
    
26.
Katzenschlager R, Poewe W, Rascol O, Trenkwalder C, Deuschl G, Chaudhuri KR, et al. Apomorphine subcutaneous infusion in patients with Parkinson's disease with persistent motor fluctuations (TOLEDO): A multicentre, double-blind, randomised, placebo-controlled trial. Lancet Neurol 2018;17:749–59.  Back to cited text no. 26
    
27.
Todorova A, Ray Chaudhuri K. Subcutaneous, intranasal and transdermal dopamine agonists in the management of Parkinson's disease. In: Parkinson's Disease: Current and Future Therapeutics and Clinical Trials. Cambridge University Press; 2016. p. 48–62.  Back to cited text no. 27
    
28.
Trenkwalder C, Chaudhuri KR, García Ruiz PJ, LeWitt P, Katzenschlager R, Sixel-Döring F, et al. Expert Consensus Group report on the use of apomorphine in the treatment of Parkinson's disease-Clinical practice recommendations. Parkinsonism Relat Disord 2015;21:1023–30.  Back to cited text no. 28
    
29.
Nyholm D, Aquilonius SM. Levodopa infusion therapy in Parkinson disease: State of the art in 2004. Clin Neuropharmacol 2004;27:245–56.  Back to cited text no. 29
    
30.
Nyholm D, Nilsson Remahl AIM, Dizdar N, Constantinescu R, Holmberg B, Jansson R, et al. Duodenal levodopa infusion monotherapy vs oral polypharmacy in advanced Parkinson disease. Neurology 2005;64:216–23.  Back to cited text no. 30
    
31.
Olanow CW, Kieburtz K, Odin P, Espay AJ, Standaert DG, Fernandez HH, et al. Continuous intrajejunal infusion of levodopa-carbidopa intestinal gel for patients with advanced Parkinson's disease: A randomised, controlled, double-blind, double-dummy study. Lancet Neurol 2014;13:141–9.  Back to cited text no. 31
    
32.
Antonini A, Poewe W, Chaudhuri KR, Jech R, Pickut B, Pirtošek Z, et al. Levodopa-carbidopa intestinal gel in advanced Parkinson’s: Final results of the GLORIA registry. Parkinsonism Relat Disord 2017;45:13–20.  Back to cited text no. 32
    
33.
Uncini A, Eleopra R, Onofrj M. Polyneuropathy associated with duodenal infusion of levodopa in Parkinson's disease: Features, pathogenesis and management. J Neurol Neurosurg Psychiatry 2015;86:490–5.  Back to cited text no. 33
    
34.
Havrankova P, Klempir J, Ruzicka R, Balaz M, Bares M, Rektorova M, et al. Neuropathy in patients treated with LCIG in the Czech and the Slovak Republic [abstract]. Mov Disord 2019;34.  Back to cited text no. 34
    
35.
Valkovič P, Benetin J, Blažíček P, Valkovičová L, Gmitterová K, Kukumberg P. Reduced plasma homocysteine levels in levodopa/entacapone treated Parkinson patients. Parkinsonism Relat Disord 2005;11:253–6.  Back to cited text no. 35
    
36.
Sears NC, MacHado AG, Nagel SJ, Deogaonkar M, Stanton-Hicks M, Rezai AR, et al. Long-term outcomes of spinal cord stimulation with paddle leads in the treatment of complex regional pain syndrome and failed back surgery syndrome. Neuromodulation 2011;14:312–8.  Back to cited text no. 36
    
37.
Shaw A, Sharma M, Deogaonkar M, Rezai A. Technological innovations in implants used for pain therapies. Neurosurg Clin N Am 2014;25:833–42.  Back to cited text no. 37
    
38.
Deogaonkar M, Zibly Z, Slavin KV. Spinal cord stimulation for the treatment of vascular pathology. Neurosurg Clin N Am 2014;25:25–31.  Back to cited text no. 38
    
39.
Deogaonkar M, Sharma M, Oluigbo C, Nielson DM, Yang X, Vera-Portocarrero L, et al. Spinal cord stimulation (SCS) and Functional Magnetic Resonance Imaging (fMRI): Modulation of cortical connectivity with therapeutic SCS. Neuromodulation 2016;19:142–52.  Back to cited text no. 39
    
40.
Fuentes R, Petersson P, Siesser WB, Caron MG, Nicolelis MAL. Spinal cord stimulation restores locomotion in animal models of Parkinson's disease. Science 2009;323:1578–82.  Back to cited text no. 40
    
41.
Fuentes R, Petersson P, Nicolelis MAL. Restoration of locomotive function in Parkinson's disease by spinal cord stimulation: Mechanistic approach. Eur J Neurosci 2010;32:1100–8.  Back to cited text no. 41
    
42.
Agari T, Date I. Spinal cord stimulation for the treatment of abnormal posture and gait disorder in patients with Parkinson's disease. Neurol Med Chir (Tokyo) 2012;52:470–4.  Back to cited text no. 42
    
43.
Fénelon G, Goujon C, Gurruchaga JM, Cesaro P, Jarraya B, Palfi S, et al. Spinal cord stimulation for chronic pain improved motor function in a patient with Parkinson's disease. Parkinsonism Relat Disord 2012;18:213–4.  Back to cited text no. 43
    
44.
Hassan S, Amer S, Alwaki A, Elborno A. A patient with Parkinson's disease benefits from spinal cord stimulation. J Clin Neurosci 2013;20:1155–6.  Back to cited text no. 44
    
45.
Landi A, Trezza A, Pirillo D, Vimercati A, Antonini A, Sganzerla EP. Spinal cord stimulation for the treatment of sensory symptoms in advanced Parkinson's disease. Neuromodulation 2013;16:276–9.  Back to cited text no. 45
    
46.
Akiyama H, Nukui S, Akamatu M, Hasegawa Y, Nishikido O, Inoue S. Effectiveness of spinal cord stimulation for painful camptocormia with Pisa syndrome in Parkinson's disease: A case report. BMC Neurol 2017;17:148.  Back to cited text no. 46
    
47.
Samotus O, Parrent A, Jog M. Long-term update of the effect of spinal cord stimulation in advanced Parkinson's disease patients. Brain Stimul 2020;13:1196–7.  Back to cited text no. 47
    
48.
Kuwahara K, Sasaki T, Yasuhara T, Kameda M, Okazaki Y, Hosomoto K, et al. Long-term continuous cervical spinal cord stimulation exerts neuroprotective effects in experimental Parkinson's disease. Front Aging Neurosci 2020;12:164.  Back to cited text no. 48
    
49.
Latorre A, Rocchi L, Berardelli A, Bhatia KP, Rothwell JC. The use of transcranial magnetic stimulation as a treatment for movement disorders: A critical review. Mov Disord 2019;34:769–82.  Back to cited text no. 49
    
50.
Chen R, Cros D, Curra A, Di Lazzaro V, Lefaucheur JP, Magistris MR, et al. The clinical diagnostic utility of transcranial magnetic stimulation: Report of an IFCN committee. Clin Neurophysiol 2008;119:504–32.  Back to cited text no. 50
    
51.
Lefaucheur JP, Aleman A, Baeken C, Benninger DH, Brunelin J, Di Lazzaro V, et al. Evidence-based guidelines on the therapeutic use of repetitive transcranial magnetic stimulation (rTMS): An update (2014–2018). Clin Neurophysiol 2020;131:474–528.  Back to cited text no. 51
    
52.
Chou YH, Hickey PT, Sundman M, Song AW, Chen NK. Effects of repetitive transcranial magnetic stimulation on motor symptoms in parkinson disease: A systematic review and meta-analysis. JAMA Neurol 2015;72:432–40.  Back to cited text no. 52
    
53.
Zanjani A, Zakzanis KK, Daskalakis ZJ, Chen R. Repetitive transcranial magnetic stimulation of the primary motor cortex in the treatment of motor signs in Parkinson's disease: A quantitative review of the literature. Mov Disord 2015;30:750–8.  Back to cited text no. 53
    
54.
Wagle-Shukla A, Angel MJ, Zadikoff C, Enjati M, Gunraj C, Lang AE, et al. Low-frequency repetitive transcranial magnetic stimulation for treatment of levodopa-induced dyskinesias. Neurology 2007;68:704–5.  Back to cited text no. 54
    
55.
Koch G, Brusa L, Carrillo F, Lo Gerfo E, Torriero S, Oliveri M, et al. Cerebellar magnetic stimulation decreases levodopa-induced dyskinesias in Parkinson disease. Neurology 2009;73:113–9.  Back to cited text no. 55
    
56.
Filipović SR, Rothwell JC, van de Warrenburg BP, Bhatia K. Repetitive transcranial magnetic stimulation for levodopa-induced dyskinesias in Parkinsons’ disease. Mov Disord 2009;24:246–53.  Back to cited text no. 56
    
57.
Lefaucheur JP, Drouot X, Von Raison F, Ménard-Lefaucheur I, Cesaro P, Nguyen JP. Improvement of motor performance and modulation of cortical excitability by repetitive transcranial magnetic stimulation of the motor cortex in Parkinson's disease. Clin Neurophysiol 2004;115:2530–41.  Back to cited text no. 57
    
58.
Farrand AQ, Verner RS, McGuire RM, Helke KL, Hinson VK, Boger HA. Differential effects of vagus nerve stimulation paradigms guide clinical development for Parkinson's disease. Brain Stimul 2020;13:1323–32.  Back to cited text no. 58
    
59.
Mondal B, Choudhury S, Simon B, Baker MR, Kumar H. Noninvasive vagus nerve stimulation improves gait and reduces freezing of gait in Parkinson's disease. Mov Disord 2019;34:917–8.  Back to cited text no. 59
    
60.
Kaut O, Janocha L, Weismüller TJ, Wüllner U. Transcutaneous vagal nerve stimulation improves gastroenteric complaints in Parkinson's disease patients. NeuroRehabilitation 2019;45:449–51.  Back to cited text no. 60
    
61.
Gittis AH, Yttri EA. Translating insights from optogenetics into therapies for Parkinson's disease. Curr Opin Biomed Eng 2018;8:14–9.  Back to cited text no. 61
    
62.
Barker RA, Barrett J, Mason SL, Björklund A. Fetal dopaminergic transplantation trials and the future of neural grafting in Parkinson's disease. Lancet Neurol 2013;12:84–91.  Back to cited text no. 62
    
63.
Parmar M, Grealish S, Henchcliffe C. The future of stem cell therapies for Parkinson disease. Nat Rev Neurosci 2020;21:103–15.  Back to cited text no. 63
    
64.
Hamilton CL, El Khoury H, Hamilton D, Nicklason F, Mitrofanis J. “Buckets”: Early observations on the use of red and infrared light helmets in Parkinson's disease patients. Photobiomodul Photomed Laser Surg 2019;37:615–22.  Back to cited text no. 64
    
65.
Near Infrared Chronic Intracranial Illumination for Neuroprotection in Parkinson's Disease | Parkinson's Disease [Internet]. [cited 2020 Oct 28]. Available from: https://www.michaeljfox.org/grant/near-infrared-chronic-intracranial-illumination-neuroprotection-parkinsons-disease.  Back to cited text no. 65
    
66.
Voon V, Krack P, Lang AE, Lozano AM, Dujardin K, Schüpbach M, et al. A multicentre study on suicide outcomes following subthalamic stimulation for Parkinson's disease. Brain 2008;131:2720–8.  Back to cited text no. 66
    
67.
Zangaglia R, Pacchetti C, Pasotti C, Mancini F, Servello D, Sinforiani E, et al. Deep brain stimulation and cognitive functions in Parkinson's disease: A three-year controlled study. Mov Disord 2009;24:1621–8.  Back to cited text no. 67
    
68.
Siddiqui J, Aldaajani Z, Mehanna R, Changizi BK, Bhatti D, Al-Johani ZG, et al. Rationale and patient selection for interventional therapies in Parkinson's disease. Expert Rev Neurother 2018;18:811–23.  Back to cited text no. 68
    
69.
Deuschl G, Schade-Brittinger C, Krack P, Volkmann J, Schäfer H, Bötzel K, et al. A randomized trial of deep-brain stimulation for Parkinson's disease. N Engl J Med 2006;355:896–908.  Back to cited text no. 69
    
70.
Weaver FM, Follett KA, Stern M, Luo P, Harris CL, Hur K, et al. Randomized trial of deep brain stimulation for Parkinson disease: Thirty-six-month outcomes. Neurology 2012;79:55–65.  Back to cited text no. 70
    
71.
Williams A, Gill S, Varma T, Jenkinson C, Quinn N, Mitchell R, et al. 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;9:581–91.  Back to cited text no. 71
    
72.
Okun MS. Deep-brain stimulation for Parkinson's disease. N Engl J Med 2012;367:1529–38.  Back to cited text no. 72
    
73.
Kishore A, Rao R, Krishnan S, Panikar D, Sarma G, Sivasanakaran MP, et al. Long-term stability of effects of subthalamic stimulation in Parkinson's disease: Indian Experience. Mov Disord 2010;25:2438–44.  Back to cited text no. 73
    
74.
Moro E, Lozano AM, Pollak P, Agid Y, Rehncrona S, Volkmann J, et al. Long-term results of a multicenter study on subthalamic and pallidal stimulation in Parkinson's disease. Mov Disord 2010;25:578–86.  Back to cited text no. 74
    
75.
Kleiner-Fisman G, Herzog J, Fisman DN, Tamma F, Lyons KE, Pahwa R, et al. Subthalamic nucleus deep brain stimulation: Summary and meta-analysis of outcomes. Mov Disord 2006;21 Suppl 14:S290-304.  Back to cited text no. 75
    
76.
Maesawa S, Kaneoke Y, Kajita Y, Usui N, Misawa N, Nakayama A, et al. Long-term stimulation of the subthalamic nucleus in hemiparkinsonian rats: Neuroprotection of dopaminergic neurons. J Neurosurg 2004;100:679–87.  Back to cited text no. 76
    
77.
Hacker ML, Turchan M, Heusinkveld LE, Currie AD, Millan SH, Molinari AL, et al. Deep brain stimulation in early-stage Parkinson disease: Five-year outcomes. Neurology 2020;95:e393–401.  Back to cited text no. 77
    
78.
Taira T, Horisawa S, Takeda N, Ghate P. Stereotactic radiofrequency lesioning for movement disorders. Prog Neurol Surg 2018;33:107–19.  Back to cited text no. 78
    


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