A 68-year-old male with a 16-year history of Parkinson’s disease (PD) underwent bilateral globus pallidus internus (GPi) deep brain stimulation (DBS) at the University of Florida. He was treated with DBS for the management of motor fluctuations, levodopa-induced dyskinesia (LID), and dystonia. Surgery was performed with microelectrode recording (MER) guidance. During the initial postoperative monopolar threshold review (Table 1), he developed stimulation-induced dyskinesia (SID) in the right hemibody with monopolar activation of the dorsal contacts (contacts 2 and 3) of the left GPi lead. No SID was noted with the stimulation of the ventral contacts (contacts 0 and 1) of the left GPi lead or with the stimulation of any of the contacts of the right GPi lead. Contact 1 stimulation on the left DBS lead provided benefit for tremor, bradykinesia, and rigidity. Contact 2 provided a more robust improvement in bradykinesia and rigidity but the benefit was limited by SID.
|Contact Number||Left GPI DBS||Right GPI DBS|
|Therapeutic Benefit Threshold (in Volts)||Side Effect Threshold (in Volts)||Therapeutic Benefit Threshold (in Volts)||Side Effect Threshold (in Volts)|
|0||1||1.6 (right leg and neck muscle pulling, capsular side effect)||0.9||1.2 (left facial muscle pulling, capsular side effect)|
|1||1.1||2.7 (right neck muscle pulling, capsular side effect)||1||2.7 (left face and hand muscle pulling, capsular side effect)|
|2||0.9||1.3 (SID)||1.1||2.4 (left face and left hand muscle pulling, capsular side effect)|
|3||1||1.4 (SID)||1.2||3 (left face and left arm muscle pulling, capsular side effect)|
Postoperative lead localization and three-dimensional (3D) mapping identified that both leads were appropriately placed in the postero-latero-ventral GPi (Figure 1). Contact 2 is located in the dorsal GPi/GPe area and contact 3 is located in the GPe area.
This case represents dorsal GPi and GPe SID in a patient with PD. On the left GPi DBS lead, contacts 1 and 2 provided the best clinical benefit. Contact 1 monopolar stimulation improved the tremor but did not have a robust effect on bradykinesia and rigidity. Contact 2 stimulation on the other hand, improved tremor, rigidity, and bradykinesia, but the benefit was limited by SID. The development of SID in this case raises two important questions: First, what is known about the target-specific pathophysiology of SID in DBS for PD? And second, what are the proposed strategies to manage this stimulation-induced complication?
To overcome the SID noted on contact 2, we considered two strategies: (1) avoiding programs that involve either anodic or cathodic stimulation of contact 2; and (2) stimulation in a bipolar configuration using contact 2. Table 2 summarizes the programming attempts made. We chose a bipolar configuration with contact 2 as cathode and contact 1 as anode. This configuration helped with the tremor, rigidity, and bradykinesia, without the side effect of SID (Table 2).
|Contacts Used for Programming||Stimulation Configuration||Voltage (in Volts)||Frequency (in Hz)||Pulse Width (in μs)||Effect on Symptoms Compared to Baseline OFF Medication Exam. Presence of SID in Right Hemibody|
|1||Monopolar (1-;C+)||2.4||130||90||Decreased tremor, minimal effects on rigidity and bradykinesia|
|2||Monopolar (2-;C+)||2.0||130||90||Decreased tremor and rigidity but minimal effect on bradykinesia. Benefit limited by SID in right hemibody when voltage increased more than 2V|
|2||Monopolar (2-;C+)||1.8||180||90||Decreased tremor and rigidity. The higher frequency was used in an attempt to better control the tremor. Minimal effect on bradykinesia. SID in right hemibody occurring at lower threshold and are more pronounced|
|1;2||Bipolar (1-;2+)||2.5||130||90||Decreased tremors, but minimal effect on bradykinesia and rigidity. No SID|
|1;2||Double monopolar (1-2-;C+)||2.5||130||90||Decreased tremors and rigidity but minimal effect on bradykinesia. SID at 3V|
|1;2||Bipolar (2-;1+)||2.5||130||90||Decreased tremors, rigidity and bradykinesia. No SID|
Either STN or GPi stimulation shows comparable motor benefit in PD1,2 and the choice of target is ideally made after a multidisciplinary team assessment and tailored to the individual needs of the patient.3 Balancing the potential improvement in motor symptoms against the risk of SID is a particular challenge for clinicians and surgeons. GPI targeting is favored by some groups4 for the treatment of disabling refractory levodopa-induced dyskinesia (LID) or as a rescue target in cases of severe disabling STN DBS-induced dyskinesia.5 “Brittle dyskinesia” is a term used to describe cases of SID in PD patients who were treated with STN DBS, drawing a parallel to brittle diabetes. In a series of 179 patients with STN DBS and 75 patients with GPi DBS, 4 experienced SID (all in the STN DBS group).5 It was then postulated that STN DBS carries a higher risk of SID compared to GPi DBS. Classically, dyskinesia induced by subthalamic nucleus (STN) stimulation manifests as hemiballism, choreoathetosis, or dystonia6 and can occur immediately postoperatively (potentially due to a subthalamotomy effect7) or have a more delayed onset.8,9 Female sex, lower BMI, longer disease duration, and longer duration of treatment with levodopa correlated with a higher risk of SID with STN DBS.5
Previous studies examined the variable effects of GPi DBS along a ventro-dorsal axis.10–12 The upper contacts in these studies were located in the dorsal GPi or GPe. Dorsal GPi/GPe stimulation improved parkinsonism but could cause SID that may mimic LID10; conversely, ventral GPi stimulation suppressed LID but may potentially worsen hypokinesia.10,11 This was also observed in dystonia patients, in whom ventral GPi stimulation improved dystonia but induced hypokinesia.12–14 This distinct effect of ventral versus dorsal GPi/GPe stimulation has been attributed to the pallidothalamic tracts, which are GPi efferent fibers consisting of the dorsally located fasciculus lenticularis and the ventrally located ansa lenticularis. 10 Moreover, diffusion tensor imaging (DTI) studies suggest that the ventral GPi has stronger connectivity to the primary sensorimotor cortex and supplementary motor area, whereas the dorsal GPi has stronger connectivity to the pre-supplementary motor area and premotor cortex.15,16 The mechanism of SID after GPi DBS remains unclear; however, the distinct connectivity between ventral and dorsal GPi might explain why dyskinesia occurs more frequently with dorsal stimulation in the GPi. Another compelling hypothesis is that the dyskinesia occurs due to spread of the current to the adjacent GPe or due to GPe stimulation. It is possible that the stimulation of the inhibitory efferent GPe axons or excitatory efferent STN axons is implicated in the dyskinesia.
Some insight can be possibly gleaned from the similar phenomenon of LID. The classic model of PD involves loss of dopaminergic input to the striatum resulting in pathologically increased activity of the STN and GPi, and increased inhibition of thalamocortical circuitry. This produces the clinical syndrome of bradykinesia and rigidity.17–21 Studies in parkinsonian primates and PD patients consistently show decreased activity of the STN and GPi with LID.22–26 Additional animal studies have linked LID to alterations of striatal projection neuron firing rates and D1 receptor sensitization.27–30 At a neurotransmitter level, dopamine does not appear to be solely implicated in LID as more evidence suggests that glutamate may play a role; in a rodent model of PD, high frequency stimulation of the STN increased the expression of the vesicular glutamate transporters 1–3 (VGLUT 1–3) in the basal ganglia.31,32 Moreover, glutamate receptor antagonists blocked dyskinesia in the same PD model. The serotonergic system has also been implicated in LID as shown by preclinical and clinical models.33 Selective serotonergic agonists have been shown to reduce LID in rodent34 and primate models of PD.35 The mechanism by which the serotonergic neurons facilitate LID remains to be elucidated; some studies suggest that dopamine gets released as a “false” neurotransmitter from striatal serotonergic terminals but more work is needed.36
The management of SID can be particularly challenging for clinicians as finding the appropriate balance to improve motor symptoms while avoiding SID may not be easily achieved. The recommendations for the management of SID in GPi-DBS are limited to expert opinion, with scarce evidence-based recommendations for SID in STN-DBS. Initial management approaches for STN DBS patients with SID include decreasing the volume of tissue activated around the optimal contact (e.g., by decreasing the voltage or pulse width of the stimulation), programming alternative contacts (e.g., more dorsal contacts in the posterior STN may have a direct anti-dyskinetic effect 37,38), and programming alternative stimulation configurations (e.g., bipolar, double monopolar or interleaved configurations 6). Additionally, increasing the amplitude of stimulation by smaller increments, and with longer durations of time between changes 6,39 may also limit SID. Finally, modifying the patient’s medication regimen (e.g., decreasing the levodopa equivalent dose or changing levodopa to an extended release formulation) should always be considered in the management of dyskinesia in patients with STN DBS. We would propose applying similar principles to SID due to GPi DBS with the only difference that the more ventral stimulation minimizes the SID. Based on the experience with our patient, we were successful in providing adequate clinical benefit by using a bipolar configuration. Larger cohorts are needed in the future to draw a potential algorithm or guideline for the management of SID in GPI PD patients.
In addition to adjustments in medications and programming strategies, it is important to confirm lead and contact placement as the literature describes a higher risk of SID associated with stimulation of contacts located in or near the globus pallidus externus (GPe).40–43 In our case, contact 2 is located at the GPi/GPe border and contact 3 is in the GPe. A contribution of GPe in the pathophysiology of SID in this case and in other published GPi DBS-induced SID cases is possible. In our patient, a Medtronic 3387 DBS lead was used. Implanting a Medtronic 3389 DBS lead could potentially limit the spread of the current and avoid SID. One can also see the benefit of a directional lead in cases of SID with GPi DBS as stimulation away from the GPe can be helpful in cases where the GPe is determined to be the source of the SID. Further evaluation using DTI studies and calculation of volume of tissue activated around the implicated contact may be needed to further understand the pathophysiology of the SID with GPi DBS.
Expert Commentary: This case highlights a common challenge for the DBS programmer: the induction of dyskinesia by stimulation. When programming patients with STN DBS, dyskinesia is typically the sign of a well-placed lead and can be managed with an appropriate reduction in medication. Programming strategies to compensate for dyskinesia in STN DBS (e.g., stimulation of cZi) are also commonly known. Similarly, the functional anatomy of the GPi often guides programming decisions for active contact selection. However, objective data confirming this practical experience are limited. As DBS is utilized in greater numbers, standardizing the approach to the patient with SID will be necessary to maximize outcomes. As novel stimulating technologies and programming platforms emerge, with corresponding increasingly complex programming options, the need for evidence-based standardization will become ever more important. At the same time, programming platforms that utilize patient-specific anatomic-based models to identify the volume of tissue activated may help clarify the role that target functional anatomy plays in causing SID. Adaptive DBS systems which can reliably detect cortical biomarkers of dyskinesia and adjust stimulation to compensate may eventually help to reduce or eliminate the challenge of troubleshooting SID patients.
1 Citation: Elkouzi A, Tsuboi T, Burns MR, Eisinger RS, Patel A, Deeb W. Dorsal. GPi/GPe Stimulation Induced Dyskinesia in a Patient with Parkinson’s Disease. Tremor Other Hyperkinet Mov. 2019; 9. doi: 10.7916/tohm.v0.685
2 Editor: Julian Benito-Leon, Hospital “12 de Octubre”, Spain
3 Funding: None.
4 Financial disclosures: None.
5 Conflict of interest: The authors report no conflicts of interest.
6 Ethics statement: This study was performed in accordance with the ethical standards detailed in the Declaration of Helsinki. The authors’ institutional ethics committee has approved this study and all patients have provided written informed consent.
Follett, KA , Weaver, FM , Stern, M , et al. Pallidal versus subthalamic deep-brain stimulation for Parkinson’s disease. N Engl J Med 2010;362(22):2077–2091. doi: https://doi.org/10.1056/NEJMoa090708320519680
Okun, MS , Fernandez, HH , Wu, SS , et al. Cognition and mood in Parkinson’s disease in subthalamic nucleus versus globus pallidus interna deep brain stimulation: the COMPARE trial. Ann Neurol 2009;65(5):586–595. doi: https://doi.org/10.1002/ana.2159619288469
Higuchi, MA , Martinez-Ramirez, D , Morita, H , et al. Interdisciplinary Parkinson’s disease deep brain stimulation screening and the relationship to unintended hospitalizations and quality of life. PLoS One 2016;11(5):586–595. doi: https://doi.org/10.1371/journal.pone.0153785
Oyama, G , Foote, KD , Jacobson, CE , et al. GPi and STN deep brain stimulation can suppress dyskinesia in Parkinson’s disease. Park Relat Disord 2012;18(7):814–818. doi: https://doi.org/10.1016/j.parkreldis.2012.03.022
Sriram, A, , Foote, KD, , Oyama, G and , Kwak, J, , Zeilman, PR, , Okun, MS, Brittle Dyskinesia following STN but not GPi Deep Brain Stimulation. Tremor Other Hyperkinet Mov (N Y) 2014;4:242. doi: https://doi.org/10.7916/D8KS6PPR24932426
Picillo, M, , Lozano, AM, , Kou, N , Puppi Munhoz, R, , Fasano, A, Programming deep brain stimulation for Parkinson’s disease: the Toronto Western Hospital Algorithms. Brain Stimul 2016;9(3):425–437. doi: https://doi.org/10.1016/j.brs.2016.02.00426968806
Krack, P, , Pollak, P, , Limousin, P and , Benazzouz, A, , Deuschl, G, , Benabid, AL, From off-period dystonia to peak-dose chorea. The clinical spectrum of varying subthalamic nucleus activity. Brain 1999;122(6):1133–1146. doi: https://doi.org/10.1093/brain/122.6.113310356065
Limousin, P, , Pollak, P, , Hoffmann, D and , Benazzouz, A, , Perret, JE, , Benabid, AL, Abnormal involuntary movements induced by subthalamic nucleus stimulation in parkinsonian patients. Mov Disord 1996;11(3):231–235. doi: https://doi.org/10.1002/mds.8701103038723137
Krack, P , Pollak, P , Limousin, P , et al. Opposite motor effects of pallidal stimulation in Parkinson’s disease. Ann Neurol 1998;43(2):180–192. doi: https://doi.org/10.1002/ana.4104302089485059
Bejjani, B , Damier, P , Arnulf, I , et al. Pallidal stimulation for Parkinson’s disease: two targets? Neurology 1997;49(6):1564–1569. doi: https://doi.org/10.1212/WNL.49.6.15649409347
Houeto, JL , Yelnik, J , Bardinet, E , et al. Acute deep-brain stimulation of the internal and external globus pallidus in primary dystonia: functional mapping of the pallidum. Arch Neurol 2007;64(9):1281–1286. doi: https://doi.org/10.1001/archneur.64.9.128117846266
Mahlknecht, P , Georgiev, D , Akram, H , et al. Parkinsonian signs in patients with cervical dystonia treated with pallidal deep brain stimulation. Brain 2018;141(10):3023–3034. doi: https://doi.org/10.1093/brain/awy21730165511
Huebl, J, , Brücke, C, , Schneider, GH and , Blahak, C, , Krauss, JK, , Kühn, AA, Bradykinesia induced by frequency-specific pallidal stimulation in patients with cervical and segmental dystonia. Park Relat Disord 2015;21(7):800–803. doi: https://doi.org/10.1016/j.parkreldis.2015.04.023
Middlebrooks, EH , Tuna, IS , Grewal, SS , et al. Segmentation of the globus pallidus internus using probabilistic diffusion tractography for deep brain stimulation targeting in Parkinson disease. Am J Neuroradiol 2018;39(6):1127–1134. doi: https://doi.org/10.3174/ajnr.A564129700048
Rozanski, VE , Vollmar, C , Cunha, JP , et al. Connectivity patterns of pallidal DBS electrodes in focal dystonia: a diffusion tensor tractography study. Neuroimage 2014;84:435–442. doi: https://doi.org/10.1016/j.neuroimage.2013.09.00924045076
Albin, RL, , Young, AB , Penney, JB, The functional anatomy of basal ganglia disorders. Trends Neurosci 1989;12(10):366–375. doi: https://doi.org/10.1016/0166-2236(89)90074-X2479133
DeLong, MR Primate models of movement disorders of basal ganglia origin. Trends Neurosci 1990;13(7):281–285. doi: https://doi.org/10.1016/0166-2236(90)90110-V1695404
Hutchison, WD, , Lozano, AM, , Davis, KD and , Saint-Cyr, JA, , Lang, AE, , Dostrovsky, JO, Differential neuronal activity in segments of globus pallidus in parkinson’s disease patients. Neuroreport 1994;5(12):1533–1537. doi: https://doi.org/10.1097/00001756-199407000-000317948856
Rodriguez-Oroz, MC The subthalamic nucleus in Parkinson’s disease: somatotopic organization and physiological characteristics. Brain 2002;124(9):1777–1790. doi: https://doi.org/10.1093/brain/124.9.1777
Reichmann, H Modern treatment in Parkinson’s disease, a personal approach. J Neural Transm 2016;123(1):73–80. doi: https://doi.org/10.1007/s00702-015-1441-126293352
Filion, M and , Tremblay, L, Abnormal spontaneous activity of globus pallidus neurons in monkeys with MPTP-induced parkinsonism. Brain Res 1991;547(1):140–144. doi: https://doi.org/10.1016/0006-8993(91)90585-J
Mitchell, IJ, , Boyce, S and , Sambrook, MA, , Crossman, AR, A 2-deoxyglucose study of the effects of dopamine agonists on the parkinsonian primate brain. Implications for the neural mechanisms that mediate dopamine agonist-induced dyskinesia. Brain 1992;115:809–824.1628204
Papa, SM, , Desimone, R and , Fiorani, M, , Oldfield, EH, Internal globus pallidus discharge is nearly suppressed during levodopa- induced dyskinesias. Ann Neurol 1999;46(5):732–738. doi: https://doi.org/10.1002/1531-8249(199911)46:5<732::AID-ANA8>3.0.CO;2-Q10553990
Lozano, AM, , Lang, AE, , Levy, R , Hutchison, W, , Dostrovsky, J, Neuronal recordings in Parkinson’s disease patients with dyskinesias induced by apomorphine. Ann Neurol 2000;47(4 Suppl 1):S141–146.10762141
Levy, R, , Dostrovsky, JO, , Lang, AE and , Sime, E, , Hutchison, WD, , Lozano, AM, Effects of apomorphine on subthalamic nucleus and globus pallidus internus neurons in patients with Parkinson’s disease. J Neurophysiol 2001;86(1):249–260. doi: https://doi.org/10.1152/jn.2001.86.1.24911431506
Suárez, LM , Solís, O , Caramés, JM , et al. L-DOPA treatment selectively restores spine density in dopamine receptor d2-expressing projection neurons in dyskinetic mice. Biol Psychiatry 2014;75(9):711–722. doi: https://doi.org/10.1016/j.biopsych.2013.05.00623769604
Pavón, N, , Martín, AB and , Mendialdua, A, , Moratalla, R, ERK phosphorylation and FosB expression are associated with L-DOPA-induced dyskinesia in hemiparkinsonian mice. Biol Psychiatry 2006;59(1):64–74. doi: https://doi.org/10.1016/j.biopsych.2005.05.04416139809
Darmopil, S, , Martín, AB, , De Diego, IR , Ares, S, , Moratalla, R, Genetic inactivation of Dopamine D1 but Not D2 receptors inhibits L-DOPA-induced dyskinesia and histone activation. Biol Psychiatry 2009;66(6):603–613. doi: https://doi.org/10.1016/j.biopsych.2009.04.02519520364
Ruiz-Dediego, I, , Mellstrom, B, , Vallejo, M , Naranjo, JR, , Moratalla, R, Activation of DREAM (Downstream Regulatory Element Antagonistic Modulator), a calcium-binding protein, reduces L-DOPA-induced dyskinesias in mice. Biol Psychiatry 2015;77(2):95–105. doi: https://doi.org/10.1016/j.biopsych.2014.03.02324857398
Favier, M, , Carcenac, C, , Drui, G and , Boulet, S, , El Mestikawy, S, , Savasta, M, High-frequency stimulation of the subthalamic nucleus modifies the expression of vesicular glutamate transporters in basal ganglia in a rat model of Parkinson’s disease. BMC Neurosci 2013;14:152. doi: https://doi.org/10.1186/1471-2202-14-15224308494
Bruet, N , Windels, F , Carcenac, C , et al. Neurochemical mechanisms induced by high frequency stimulation of the subthalamic nucleus: increase of extracellular striatal glutamate and GABA in normal and hemiparkinsonian rats. J Neuropathol Exp Neurol 2003;62(12):1228–1240. doi: https://doi.org/10.1093/jnen/62.12.122814692699
Carta, M and , Tronci, E, Serotonin system implication in L-DOPA-induced dyskinesia: from animal models to clinical investigations. Front Neurol 2014;5:78. doi: https://doi.org/10.3389/fneur.2014.0007824904522
Carta, M, , Carlsson, T and , Kirik, D, , Björklund, A, Dopamine released from 5-HT terminals is the cause of L-DOPA-induced dyskinesia in parkinsonian rats. Brain 2007;130(7):1819–1833. doi: https://doi.org/10.1093/brain/awm08217452372
Muñoz, A , Li, Q , Gardoni, F , et al. Combined 5-HT1A and 5-HT1B receptor agonists for the treatment of L-DOPA-induced dyskinesia. Brain 2008;131(12):3380–3394. doi: https://doi.org/10.1093/brain/awn23518952677
Carta, M, , Carlsson, T, , Muñoz, A , Kirik, D, , Björklund, A, Serotonin-dopamine interaction in the induction and maintenance of L-DOPA-induced dyskinesias. Prog Brain Res 2008;172:465–478. doi: https://doi.org/10.1016/S0079-6123(08)00922-918772046
Herzog, J , Pinsker, M , Wasner, M , et al. Stimulation of subthalamic fibre tracts reduces dyskinesias in STN-DBS. Mov Disord 2007;22(5):679–684. doi: https://doi.org/10.1002/mds.2138717266046
Katayama, Y, , Oshima, H, , Kano, T and , Kobayashi, K, , Fukaya, C, , Yamamoto, T, Direct effect of subthalamic nucleus stimulation on levodopa-induced peak-dose dyskinesia in patients with Parkinson’s disease. Stereotact Funct Neurosurg 2006;84:176–179. doi: https://doi.org/10.1159/00009495716905880
Deuschl, G , Herzog, J , Kleiner-Fisman, G , et al. Deep brain stimulation: postoperative issues. Mov Disord 2006;21(SUPPL. 14). doi: https://doi.org/10.1002/mds.20957
Yelnik, J , Damier, P , Bejjani, BP , et al. Functional mapping of the human globus pallidus: contrasting effect of stimulation in the internal and external pallidum in Parkinson’s disease. Neuroscience 2000;101(1):77–87. doi: https://doi.org/10.1016/S0306-4522(00)00364-X11068138
Mouton, S , Xie-Brustolin, J , Mertens, P , et al. Chorea induced by globus pallidus externus stimulation in a dystonic patient. Mov Disord 2006;21(10):1771–1773. doi: https://doi.org/10.1002/mds.2104716856144
Matsumura, M, , Tremblay, L and , Richard, H, , Filion, M, Activity of pallidal neurons in the monkey during dyskinesia induced by injection of bicuculline in the external pallidum. Neuroscience 1995;65(1):59–70. doi: https://doi.org/10.1016/0306-4522(94)00484-M7753408
Grabli, D , McCairn, K , Hirsch, EC , et al. Behavioural disorders induced by external globus pallidus dysfunction in primates: I. Behavioural study. Brain 2004;127(9):2039–2054. doi: https://doi.org/10.1093/brain/awh22015292053