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Globus pallidus deep brain stimulation for refractory idiopathic restless legs syndrome
Sleep Medicine 13 (2012) 1202–1204
Contents lists available at SciVerse ScienceDirect
Sleep Medicine journal homepage: www.elsevier.com/locate/sleep
Brief Communication
Globus pallidus deep brain stimulation for refractory idiopathic restless legs syndrome William G. Ondo a,⇑, Joseph Jankovic b, Richard Simpson c, Joohi Jimenez-Shahed b a
Department of Neurology, University of Texas Health Science Center at Houston, Houston, TX, United States Department of Neurology, Baylor College of Medicine, Houston, TX, United States c Department of Neurosurgery, Methodist Neuroscience Institute, Houston, TX, United States b
a r t i c l e
i n f o
Article history: Received 19 April 2012 Received in revised form 6 June 2012 Accepted 15 June 2012 Available online 18 September 2012 Keywords: Restless legs syndrome Deep brain stimulation Globus pallidus internus Neurophysiology DBS Surgery
a b s t r a c t Objective: The neuroanatomic substrate of restless legs syndrome (RLS) is unknown. Deep brain stimulation (DBS) of the globus pallidus internus (GPi) and other targets is used to treat Parkinson’s disease (PD), and RLS symptoms associated with PD have been reported to improve when GPi DBS is used in that population. We wish to test whether GPi DBS can improve idiopathic RLS. Method: We implanted bilateral GPi DBS in a subject with refractory idiopathic RLS. Results: The GPi cells recordings were dissimilar to those of PD. Clinically, the patient had a good, but far from complete, response, which more prominently affected the urge to move and involuntary movements than the painful component. Conclusion: DBS for RLS remains investigational. Ó 2012 Published by Elsevier B.V.
Dopaminergic drugs are most frequently used to treat the troublesome sensory-motor symptoms associated with restless legs syndrome (RLS) [1], but a subset of patients become refractory to medical therapy. We describe a patient with extremely severe ‘‘malignant’’ RLS who was refractory to all medical therapy but improved with deep brain stimulation (DBS). This 53 year old woman, followed at Baylor College of Medicine Movement Disorders Clinic for severe RLS since 2007, reports that she was told she had ‘‘constant leg movements’’ in her sleep as an infant, and at 8 months of age was diagnosed with ‘‘growing pains.’’ By age 10 years she can clearly recall symptoms meeting criteria for RLS (an urge to move her legs that were worse while still, improved by riding a bicycle, walking, and very hot baths as well as worsening of symptoms at night). During her mid 30s, the symptoms markedly worsened, occurred in the afternoon, and involved her arms. She was diagnosed with RLS at age 45. By this time her symptoms of constant discomfort as a result of the irresistible urge to move and the inability to be still were very severe and disabling, involving her legs, arms, and trunk. They were present chiefly at night, resulting in marked sleep deprivation, but also persisted during the daytime except for the early morning hours.
⇑ Corresponding author. Address: 6410 Fannin, Ste 1014, Houston, TX 77030, United States. Tel.: +1 832 325 7080; fax: +1 832 325 7071. E-mail address: [email protected] (W.G. Ondo). 1389-9457/$ - see front matter Ó 2012 Published by Elsevier B.V. http://dx.doi.org/10.1016/j.sleep.2012.06.007
Evaluation prior to presentation revealed ‘‘iron deficiency’’ and mild sleep apnea, for which she was prescribed continuous positive pressure, but with which she was variably compliant. Electromyography of her legs was normal. She was also diagnosed with depression and anxiety with formal neuropsychological evaluation for which she received several anti-depressants, including mirtazapine, but denied any effect of these drugs on her RLS. She never took any dopamine receptor antagonists. She has a strong family history of RLS including her mother, maternal grandmother, a son, and two young grandchildren. The patient tried a variety of medications for RLS. She initially had a good response to ropinirole but developed probable augmentation and eventually received no overall subjective benefit from several dopamine agonists. She also had no benefit from gabapentin or pregabalin. During the most recent few years she had taken various combinations of methadone and hydrocodone, which provided partial relief. She also visited emergency rooms on many occasions for other oral or intravenous opioids. The patient was poorly tolerant of oral iron and experienced no subjective benefit from 1 g of intravenous high molecular weight iron dextran. A post-infusion ferritin level was not performed. At age 53 she was receiving minimal benefit from ropinirole 24 mg/day, methadone 10–30 mg/day, and LortabÒ 20 mg/day, and was completely disabled by her severe RLS; her International RLS scale (IRLS) was 40/40. Hot water baths also partially improved her symptoms. On examination she had constant whole body movements, including rocking, bouncing,
W.G. Ondo et al. / Sleep Medicine 13 (2012) 1202–1204
and walking, which were only suppressible for 10–20 s. Her neurological examination was otherwise unremarkable. After extensive counseling and consent, the patient underwent deep brain stimulation (DBS) of the bilateral posteroventral lateral
1203
globus pallidus internus (GPi) with a Medtronic Activa RC without complication. The GPi firing pattern, obtained awake while not under influence of anesthesia, was relatively rhythmic (Fig. 1). This is in contrast to the rather asynchronous firing pattern usually seen
Fig. 1. Single cell firing patterns in GPi of a subject with RLS. There was variability within the GPi ranging from semi-rhythmic bursting to more constant patterns.
1204
W.G. Ondo et al. / Sleep Medicine 13 (2012) 1202–1204
in Gpi recordings from patients with Parkinson’s disease [2]. With initial activation and several adjustments over the next year, she reported moderate global improvement of 40%. At peak benefit she had an IRLS of 36 but a greater than 75% reduction in observed movements. Subjectively, she reported more improvement in the urge to move and actual movements than the painful component of her RLS spanning several DBS adjustments. Her settings at this point were Right: C + 1, 0 , 3.0 V, 120 ls, 120 Hz and Left: C + 2 , 4.1 V, 120 ls, 120 Hz. Over the next 2 months she reported worsening back to baseline, but upon return system interrogation demonstrated that the DBS had inadvertently been turned off. Upon reactivation she again improved more robustly. She is now 2 years post implantation and feels that the DBS has helped more than any of her medications. DBS and lesioning of the GPi have been reported to improve RLS symptoms in patients when used to treat Parkinson’s disease (PD) and dystonia [3,4]. DBS of the sub-thalamic nucleus (STN) has been reported to both improve and worsen RLS in PD patients [5–7], and DBS of the ventralis intermedius nucleus (VIM) did not improve concurrent RLS in patients when used to treat essential tremor [8]. Many of the VIM implanted subjects had idiopathic RLS as defined by a young age of onset and positive family history of RLS. To our knowledge, this the first case of DBS attempted for isolated, idiopathic RLS. RLS occurs in about 20% of Caucasians with PD, but the majority of cases present with PD prior to RLS, suggesting that RLS is one of many non-motor components of PD, and may have a different pathogenesis than idiopathic RLS [9]. In our patient, the GPi was chosen because this site most robustly improves PD associated dyskinesia, which actually resembled the hyperkinetic RLS phenotype seen in this patient, and GPi DBS was consistently reported to help RLS associated with PD. The anatomic substrate of RLS is not known. We cannot say if the benefit our patient experienced did represent a true physiological response, thus implicating GPi involve-
ment in RLS, or whether this was a placebo or other non-specific effect. However, based on 2 years follow-up of our single case, we conclude that further studies using different targets and stimulation parameters are needed before GPi DBS could be recommended for idiopathic RLS except, perhaps, as a last resort. Conflict of Interest The ICMJE Uniform Disclosure Form for Potential Conflicts of Interest associated with this article can be viewed by clicking on the following link: http://dx.doi.org/10.1016/j.sleep.2012.06.007.
References [1] Chokroverty S. Long-term management issues in restless legs syndrome. Mov Disord 2011;26:1378–85. [2] Levy R, Dostrovsky J, Lanf A, Sime E, Hutchinson W, Lozano A. Effects of apomorphine on sub-thalamic and globus pallidus internus neurons in patients with Parkinson’s disease. J Neurophysiol 2001;86:249–60. [3] Okun MS, Fernandez HH, Foote KD. Deep brain stimulation of the GPi treats restless legs syndrome associated with dystonia. Mov Disord 2005;20(4):500–1. [4] Rye DB, DeLong MR. Amelioration of sensory limb discomfort of restless legs syndrome by pallidotomy. Ann Neurol 1999;46(5):800–1. [5] Kedia S, Moro E, Tagliati M, Lang AE, Kumar R. Emergence of restless legs syndrome during subthalamic stimulation for Parkinson disease. Neurology 2004;63(12):2410–2. [6] Chahine LM, Ahmed A, Sun Z. Effects of STN DBS for Parkinson’s disease on restless legs syndrome and other sleep-related measures. Parkinsonism Relat Disord 2011;17(3):208–11. [7] Driver-Dunckley E, Evidente VG, Adler CH, Hillman R, Hernandez J, Fletcher G, et al. Restless legs syndrome in Parkinson’s disease patients may improve with subthalamic stimulation. Mov Disord 2006;21(8):1287–9. [8] Ondo W. VIM deep brain stimulation does not improve pre-existing restless legs syndrome in patients with essential tremor. Parkinsonism Relat Disord 2006;12(2):113–4. [9] Ondo WG, Vuong KD, Jankovic J. Exploring the relationship between Parkinson disease and restless legs syndrome. Arch Neurol 2002;59(3):421–4.
Contents lists available at SciVerse ScienceDirect
Sleep Medicine journal homepage: www.elsevier.com/locate/sleep
Brief Communication
Globus pallidus deep brain stimulation for refractory idiopathic restless legs syndrome William G. Ondo a,⇑, Joseph Jankovic b, Richard Simpson c, Joohi Jimenez-Shahed b a
Department of Neurology, University of Texas Health Science Center at Houston, Houston, TX, United States Department of Neurology, Baylor College of Medicine, Houston, TX, United States c Department of Neurosurgery, Methodist Neuroscience Institute, Houston, TX, United States b
a r t i c l e
i n f o
Article history: Received 19 April 2012 Received in revised form 6 June 2012 Accepted 15 June 2012 Available online 18 September 2012 Keywords: Restless legs syndrome Deep brain stimulation Globus pallidus internus Neurophysiology DBS Surgery
a b s t r a c t Objective: The neuroanatomic substrate of restless legs syndrome (RLS) is unknown. Deep brain stimulation (DBS) of the globus pallidus internus (GPi) and other targets is used to treat Parkinson’s disease (PD), and RLS symptoms associated with PD have been reported to improve when GPi DBS is used in that population. We wish to test whether GPi DBS can improve idiopathic RLS. Method: We implanted bilateral GPi DBS in a subject with refractory idiopathic RLS. Results: The GPi cells recordings were dissimilar to those of PD. Clinically, the patient had a good, but far from complete, response, which more prominently affected the urge to move and involuntary movements than the painful component. Conclusion: DBS for RLS remains investigational. Ó 2012 Published by Elsevier B.V.
Dopaminergic drugs are most frequently used to treat the troublesome sensory-motor symptoms associated with restless legs syndrome (RLS) [1], but a subset of patients become refractory to medical therapy. We describe a patient with extremely severe ‘‘malignant’’ RLS who was refractory to all medical therapy but improved with deep brain stimulation (DBS). This 53 year old woman, followed at Baylor College of Medicine Movement Disorders Clinic for severe RLS since 2007, reports that she was told she had ‘‘constant leg movements’’ in her sleep as an infant, and at 8 months of age was diagnosed with ‘‘growing pains.’’ By age 10 years she can clearly recall symptoms meeting criteria for RLS (an urge to move her legs that were worse while still, improved by riding a bicycle, walking, and very hot baths as well as worsening of symptoms at night). During her mid 30s, the symptoms markedly worsened, occurred in the afternoon, and involved her arms. She was diagnosed with RLS at age 45. By this time her symptoms of constant discomfort as a result of the irresistible urge to move and the inability to be still were very severe and disabling, involving her legs, arms, and trunk. They were present chiefly at night, resulting in marked sleep deprivation, but also persisted during the daytime except for the early morning hours.
⇑ Corresponding author. Address: 6410 Fannin, Ste 1014, Houston, TX 77030, United States. Tel.: +1 832 325 7080; fax: +1 832 325 7071. E-mail address: [email protected] (W.G. Ondo). 1389-9457/$ - see front matter Ó 2012 Published by Elsevier B.V. http://dx.doi.org/10.1016/j.sleep.2012.06.007
Evaluation prior to presentation revealed ‘‘iron deficiency’’ and mild sleep apnea, for which she was prescribed continuous positive pressure, but with which she was variably compliant. Electromyography of her legs was normal. She was also diagnosed with depression and anxiety with formal neuropsychological evaluation for which she received several anti-depressants, including mirtazapine, but denied any effect of these drugs on her RLS. She never took any dopamine receptor antagonists. She has a strong family history of RLS including her mother, maternal grandmother, a son, and two young grandchildren. The patient tried a variety of medications for RLS. She initially had a good response to ropinirole but developed probable augmentation and eventually received no overall subjective benefit from several dopamine agonists. She also had no benefit from gabapentin or pregabalin. During the most recent few years she had taken various combinations of methadone and hydrocodone, which provided partial relief. She also visited emergency rooms on many occasions for other oral or intravenous opioids. The patient was poorly tolerant of oral iron and experienced no subjective benefit from 1 g of intravenous high molecular weight iron dextran. A post-infusion ferritin level was not performed. At age 53 she was receiving minimal benefit from ropinirole 24 mg/day, methadone 10–30 mg/day, and LortabÒ 20 mg/day, and was completely disabled by her severe RLS; her International RLS scale (IRLS) was 40/40. Hot water baths also partially improved her symptoms. On examination she had constant whole body movements, including rocking, bouncing,
W.G. Ondo et al. / Sleep Medicine 13 (2012) 1202–1204
and walking, which were only suppressible for 10–20 s. Her neurological examination was otherwise unremarkable. After extensive counseling and consent, the patient underwent deep brain stimulation (DBS) of the bilateral posteroventral lateral
1203
globus pallidus internus (GPi) with a Medtronic Activa RC without complication. The GPi firing pattern, obtained awake while not under influence of anesthesia, was relatively rhythmic (Fig. 1). This is in contrast to the rather asynchronous firing pattern usually seen
Fig. 1. Single cell firing patterns in GPi of a subject with RLS. There was variability within the GPi ranging from semi-rhythmic bursting to more constant patterns.
1204
W.G. Ondo et al. / Sleep Medicine 13 (2012) 1202–1204
in Gpi recordings from patients with Parkinson’s disease [2]. With initial activation and several adjustments over the next year, she reported moderate global improvement of 40%. At peak benefit she had an IRLS of 36 but a greater than 75% reduction in observed movements. Subjectively, she reported more improvement in the urge to move and actual movements than the painful component of her RLS spanning several DBS adjustments. Her settings at this point were Right: C + 1, 0 , 3.0 V, 120 ls, 120 Hz and Left: C + 2 , 4.1 V, 120 ls, 120 Hz. Over the next 2 months she reported worsening back to baseline, but upon return system interrogation demonstrated that the DBS had inadvertently been turned off. Upon reactivation she again improved more robustly. She is now 2 years post implantation and feels that the DBS has helped more than any of her medications. DBS and lesioning of the GPi have been reported to improve RLS symptoms in patients when used to treat Parkinson’s disease (PD) and dystonia [3,4]. DBS of the sub-thalamic nucleus (STN) has been reported to both improve and worsen RLS in PD patients [5–7], and DBS of the ventralis intermedius nucleus (VIM) did not improve concurrent RLS in patients when used to treat essential tremor [8]. Many of the VIM implanted subjects had idiopathic RLS as defined by a young age of onset and positive family history of RLS. To our knowledge, this the first case of DBS attempted for isolated, idiopathic RLS. RLS occurs in about 20% of Caucasians with PD, but the majority of cases present with PD prior to RLS, suggesting that RLS is one of many non-motor components of PD, and may have a different pathogenesis than idiopathic RLS [9]. In our patient, the GPi was chosen because this site most robustly improves PD associated dyskinesia, which actually resembled the hyperkinetic RLS phenotype seen in this patient, and GPi DBS was consistently reported to help RLS associated with PD. The anatomic substrate of RLS is not known. We cannot say if the benefit our patient experienced did represent a true physiological response, thus implicating GPi involve-
ment in RLS, or whether this was a placebo or other non-specific effect. However, based on 2 years follow-up of our single case, we conclude that further studies using different targets and stimulation parameters are needed before GPi DBS could be recommended for idiopathic RLS except, perhaps, as a last resort. Conflict of Interest The ICMJE Uniform Disclosure Form for Potential Conflicts of Interest associated with this article can be viewed by clicking on the following link: http://dx.doi.org/10.1016/j.sleep.2012.06.007.
References [1] Chokroverty S. Long-term management issues in restless legs syndrome. Mov Disord 2011;26:1378–85. [2] Levy R, Dostrovsky J, Lanf A, Sime E, Hutchinson W, Lozano A. Effects of apomorphine on sub-thalamic and globus pallidus internus neurons in patients with Parkinson’s disease. J Neurophysiol 2001;86:249–60. [3] Okun MS, Fernandez HH, Foote KD. Deep brain stimulation of the GPi treats restless legs syndrome associated with dystonia. Mov Disord 2005;20(4):500–1. [4] Rye DB, DeLong MR. Amelioration of sensory limb discomfort of restless legs syndrome by pallidotomy. Ann Neurol 1999;46(5):800–1. [5] Kedia S, Moro E, Tagliati M, Lang AE, Kumar R. Emergence of restless legs syndrome during subthalamic stimulation for Parkinson disease. Neurology 2004;63(12):2410–2. [6] Chahine LM, Ahmed A, Sun Z. Effects of STN DBS for Parkinson’s disease on restless legs syndrome and other sleep-related measures. Parkinsonism Relat Disord 2011;17(3):208–11. [7] Driver-Dunckley E, Evidente VG, Adler CH, Hillman R, Hernandez J, Fletcher G, et al. Restless legs syndrome in Parkinson’s disease patients may improve with subthalamic stimulation. Mov Disord 2006;21(8):1287–9. [8] Ondo W. VIM deep brain stimulation does not improve pre-existing restless legs syndrome in patients with essential tremor. Parkinsonism Relat Disord 2006;12(2):113–4. [9] Ondo WG, Vuong KD, Jankovic J. Exploring the relationship between Parkinson disease and restless legs syndrome. Arch Neurol 2002;59(3):421–4.