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Deep brain stimulation (DBS) for severe restless legs syndrome: therapeutic and physiologic considerations
Accepted Manuscript Title: Deep brain stimulation (DBS) for severe restless legs syndrome: therapeutic and physiologic considerations Author: William Ondo PII: DOI: Reference:
S1389-9457(16)30015-6 http://dx.doi.org/doi: 10.1016/j.sleep.2016.04.005 SLEEP 3045
To appear in:
Sleep Medicine
Please cite this article as: William Ondo, Deep brain stimulation (DBS) for severe restless legs syndrome: therapeutic and physiologic considerations, Sleep Medicine (2016), http://dx.doi.org/doi: 10.1016/j.sleep.2016.04.005. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Deep Brain Stimulation (DBS) for Severe Restless Legs Syndrome: Therapeutic and Physiologic Considerations
William Ondo, MD
Key Words: restless legs syndrome, Globus Pallidus internus, stereotactic surgery, movement disorders
Correspondence to: William Ondo, MD 6560 Fannin Ste 1002 Houston TX 77030 [email protected]
The underlying pathophysiology of restless legs syndrome (RLS) is poorly understood. Our current understanding is based on clinical symptoms, neurophysiology studies, animal modeling, and response to pharmacotherapy, especially dopamine agonists. High frequency deep brain stimulation (DBS) and brain lesioning are commonly used to treat movement disorders including Parkinson’s disease (PD), essential tremor (ET), dystonia, Tourette’s syndrome, and less commonly other neuropsychiatric conditions.
Page 1 of 7
The most common targets include the globus pallidus internus (GPi) for PD and dystonia, the sub-thalamic nucleus (STN) for PD, and the ventralis intermedius nucleus (VIM) of the thalamus for PD and ET. [Table 1] Although the exact physiologic response to DBS is debated, high frequency stimulation (>50Hz) has a similar response to lesioning. Probably, high frequency electrical impulses exceed the relative refractory period of the axon, resulting in the inability to generate a normal action potential. In contrast, low frequency stimulation (<25Hz) can drive the cell, increasing output. Low frequency stimulation is occasionally used, mostly for the Pedunculopontine nucleus (PPN). 1 Brain lesioning, most commonly the VIM and GPi, predates DBS but has been less commonly used over the past 20 years. Head to head trials are rare but showed similar efficacy results for tremor. 2 Recent advances have allowed deep brain lesioning without actually physically penetrating the skull via both Gamma knife (targeted Cobalt 60 radiation) and focused ultrasound. Therefore the use of lesioning, which costs less, does not require intense follow-up, and doesn’t internalize hardware, may again increase. Several publications report effects on RLS symptoms in patients who were implanted or lesioned for other concurrent indications. GPi targets have been reported to improve RLS symptoms in patients when used to treat PD and dystonia in a small number of subjects. 3,4 DBS of the sub-thalamic nucleus (STN) has been reported to both improve and worsen RLS in PD patients. 5-7 DBS of the VIM did not improve concurrent RLS in nine patients when used to treat ET.8 We implanted bilateral GPi DBS in two subjects with refractory idiopathic RLS. GPi was chosen because this site was never reported to worsen RLS associated with other
Page 2 of 7
conditions. It is also the major outflow of the basal ganglia and improves both “off” features of PD (hypodopaminergic state) and drug induced dyskinesia in PD (hyperdopaminergic state). There is evidence supporting both scenarios in RLS. 9 In both cases, the GPi single cell recordings during placement were dissimilar from those seen in PD while off medications, and more consistent with recording seen in dystonia. “Normal” recordings in humans are not actually established. The first subject (onset RLS in childhood) attempted > 20 treatments for RLS, and regularly required emergency department visits for intravenous opioids and benzodiazepines. 10 Her IRLS score ranged from 38-40/40. After implantation, she initially reported more improvement in the urge to move and actual movements than the painful component of her RLS. Sleep also subjectively improved. Her power settings varied considerably (more than 20 total adjustments) but were overall fairly similar to those used in PD. At five years follow-up, she had a good, but far from complete response, which more prominently affected the urge to move and involuntary movements than the painful component. IRLS has ranged from 20 to 36. She continued on stable dose of methadone, 40mg/day but has not required emergency room visits except on one occasion when her battery had died. A second patient reported childhood onset of RLS, attempted >10 therapies and had an IRLS of 36/40 at initial visit. After 1.75 years follow-up, she reports a “50% improvement”, mostly in the painful component, although the lowest recorded IRLS (via phone) was still 26/40. She also reported vague side effects “not feeling right” and depression. Currently one side is at 2.5 V but the other only at 0.1V due to these subjective side effects. Nevertheless symptom improvement is bilateral. She remains on stable oxycodone, 25mg/day.
Page 3 of 7
Overall, both subjects reported about 50% improvement, and in hindsight would repeat the procedure, but neither had complete relief or eliminated RLS medications. My impression is that this site may have a mitigating effect but is not the primary pathophysiologic pathway for RLS. That said, these are among the most severe of RLS sufferers and failed many treatments that usually benefit patients. Implantation of other targets certainly could be considered. [Table 1] The STN is “upstream” in basal ganglia circuitry and sends most of its output to the GPi so it is unlikely to have a better RLS response, however it is a safe and well-established target. Also, when used for PD, both subjective and objective sleep improves, although PLMS do not seem to be effected. 11 Several sites are targeted for chronic pain, including the peri-aqueductal grey and ventral posterior nuclei of the thalamus. 12 These certainly could be considered for RLS. Low frequency stimulation of dopaminergic spinal tracts (A11), which are essential in the peri-aqueductal grey, could also be considered, based on hypothesized RLS pathophysiology.
Page 4 of 7
Reference: 1. Moreau C, Defebvre L, Devos D, et al. STN versus PPN-DBS for alleviating freezing of gait: toward a frequency modulation approach? Mov Disord 2009; 24(14): 2164-6. 2. Schuurman PR, Bosch DA, Merkus MP, Speelman JD. Long-term follow-up of thalamic stimulation versus thalamotomy for tremor suppression. Mov Disord 2008; 23(8): 1146-53. 3. Rye DB, DeLong MR. Amelioration of sensory limb discomfort of restless legs syndrome by pallidotomy. Ann Neurol 1999; 46(5): 800-1. 4. 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. 5. Chahine LM, Ahmed A, Sun Z. Effects of STN DBS for Parkinson's disease on restless legs syndrome and other sleep-related measures. Parkinsonism & Related Disorders 2011; 17(3): 208-11. 6. 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. 7. Driver-Dunckley E, Evidente VG, Adler CH, 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): 1134. 9. Earley CJ, Connor J, Garcia-Borreguero D, et al. Altered Brain iron homeostasis and dopaminergic function in Restless Legs Syndrome (Willis-Ekbom Disease). Sleep Med 2014; 15(11): 1288-301. 10. Ondo WG, Jankovic J, Simpson R, Jimenez-Shahed J. Globus pallidus deep brain stimulation for refractory idiopathic restless legs syndrome. Sleep Med 2012; 13(9): 1202-4. 11. Amara AW, Watts RL, Walker HC. The effects of deep brain stimulation on sleep in Parkinson's disease. Ther Adv Neurol Disord 2011; 4(1): 15-24. 12. Boccard SG, Pereira EA, Moir L, Aziz TZ, Green AL. Long-term outcomes of deep brain stimulation for neuropathic pain. Neurosurgery 2013; 72(2): 221-30; discussion 31. 13. Lim AS, Moro E, Lozano AM, et al. Selective enhancement of rapid eye movement sleep by deep brain stimulation of the human pons. Ann Neurol 2009; 66(1): 110-4. 14. Voges BR, Schmitt FC, Hamel W, et al. Deep brain stimulation of anterior nucleus thalami disrupts sleep in epilepsy patients. Epilepsia 2015; 56(8): e99-e103. 15. Kovac S, Wright MA, Eriksson SH, Zrinzo L, Matharu M, Walker MC. The effect of posterior hypothalamus region deep brain stimulation on sleep. Cephalalgia 2014; 34(3): 219-23.
Page 5 of 7
Table 1: DBS Targets TARGET
COMMON INDICATION
EFFECT ON SLEEP REPORTED WHEN USED FOR OTHER CONDITIONS
EFFECT ON RLS
Sub-thalamic nucleus (STN)
PD, OCD
Variable results reported
Globus Pallidus Internus posteroventral (GPi-PV)
PD, dystonia, TS
Improved subjective sleep Improved sleep efficiency Dec. WASO +/- Inc. REM No change PLMS Improved subjective sleep
Improves
Ventralis intermedius nucleus (VIM)
ET, PD tremor
?
No effect
Pedunculopontine nucleus (low Hz)
Gait and freezing for PD, PSP
Increases REM sleep13
?
Centromedian nucleus (CM)*
OCD
?
?
Anterior Limb Int Capsule – Nucleus Accumbens (ALICNA)
OCD
?
?
Subcallosal cingulate white matter/singulate cortex (SCC)
Depression
?
?
Ventral striatum/ventral capsule (VS/VC)
Depression
?
?
Nucleus Basalis of Meynert (NBM)
Dementia
?
?
Fornix (low Hz)
Dementia
?
?
Medial forebrain bundle (MFB)
Depression
?
?
Anterior thalamic nuc.
Seizures
Increased PSG arousals14
?
Ventral posterior lateral thalamus
Pain
?
?
Periventricular grey
Pain
?
?
Posterior hypothalamus
Cluster headache
Marked sleep disruption (N=2)15
?
Tics
Page 6 of 7
* very similar/overlap with other names in literature including: centromedianparafascicular complex (CM-PF), ventral-oral internal thalamic nucleus (VOI), substantia periventricularis (SP)
Page 7 of 7
S1389-9457(16)30015-6 http://dx.doi.org/doi: 10.1016/j.sleep.2016.04.005 SLEEP 3045
To appear in:
Sleep Medicine
Please cite this article as: William Ondo, Deep brain stimulation (DBS) for severe restless legs syndrome: therapeutic and physiologic considerations, Sleep Medicine (2016), http://dx.doi.org/doi: 10.1016/j.sleep.2016.04.005. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Deep Brain Stimulation (DBS) for Severe Restless Legs Syndrome: Therapeutic and Physiologic Considerations
William Ondo, MD
Key Words: restless legs syndrome, Globus Pallidus internus, stereotactic surgery, movement disorders
Correspondence to: William Ondo, MD 6560 Fannin Ste 1002 Houston TX 77030 [email protected]
The underlying pathophysiology of restless legs syndrome (RLS) is poorly understood. Our current understanding is based on clinical symptoms, neurophysiology studies, animal modeling, and response to pharmacotherapy, especially dopamine agonists. High frequency deep brain stimulation (DBS) and brain lesioning are commonly used to treat movement disorders including Parkinson’s disease (PD), essential tremor (ET), dystonia, Tourette’s syndrome, and less commonly other neuropsychiatric conditions.
Page 1 of 7
The most common targets include the globus pallidus internus (GPi) for PD and dystonia, the sub-thalamic nucleus (STN) for PD, and the ventralis intermedius nucleus (VIM) of the thalamus for PD and ET. [Table 1] Although the exact physiologic response to DBS is debated, high frequency stimulation (>50Hz) has a similar response to lesioning. Probably, high frequency electrical impulses exceed the relative refractory period of the axon, resulting in the inability to generate a normal action potential. In contrast, low frequency stimulation (<25Hz) can drive the cell, increasing output. Low frequency stimulation is occasionally used, mostly for the Pedunculopontine nucleus (PPN). 1 Brain lesioning, most commonly the VIM and GPi, predates DBS but has been less commonly used over the past 20 years. Head to head trials are rare but showed similar efficacy results for tremor. 2 Recent advances have allowed deep brain lesioning without actually physically penetrating the skull via both Gamma knife (targeted Cobalt 60 radiation) and focused ultrasound. Therefore the use of lesioning, which costs less, does not require intense follow-up, and doesn’t internalize hardware, may again increase. Several publications report effects on RLS symptoms in patients who were implanted or lesioned for other concurrent indications. GPi targets have been reported to improve RLS symptoms in patients when used to treat PD and dystonia in a small number of subjects. 3,4 DBS of the sub-thalamic nucleus (STN) has been reported to both improve and worsen RLS in PD patients. 5-7 DBS of the VIM did not improve concurrent RLS in nine patients when used to treat ET.8 We implanted bilateral GPi DBS in two subjects with refractory idiopathic RLS. GPi was chosen because this site was never reported to worsen RLS associated with other
Page 2 of 7
conditions. It is also the major outflow of the basal ganglia and improves both “off” features of PD (hypodopaminergic state) and drug induced dyskinesia in PD (hyperdopaminergic state). There is evidence supporting both scenarios in RLS. 9 In both cases, the GPi single cell recordings during placement were dissimilar from those seen in PD while off medications, and more consistent with recording seen in dystonia. “Normal” recordings in humans are not actually established. The first subject (onset RLS in childhood) attempted > 20 treatments for RLS, and regularly required emergency department visits for intravenous opioids and benzodiazepines. 10 Her IRLS score ranged from 38-40/40. After implantation, she initially reported more improvement in the urge to move and actual movements than the painful component of her RLS. Sleep also subjectively improved. Her power settings varied considerably (more than 20 total adjustments) but were overall fairly similar to those used in PD. At five years follow-up, she had a good, but far from complete response, which more prominently affected the urge to move and involuntary movements than the painful component. IRLS has ranged from 20 to 36. She continued on stable dose of methadone, 40mg/day but has not required emergency room visits except on one occasion when her battery had died. A second patient reported childhood onset of RLS, attempted >10 therapies and had an IRLS of 36/40 at initial visit. After 1.75 years follow-up, she reports a “50% improvement”, mostly in the painful component, although the lowest recorded IRLS (via phone) was still 26/40. She also reported vague side effects “not feeling right” and depression. Currently one side is at 2.5 V but the other only at 0.1V due to these subjective side effects. Nevertheless symptom improvement is bilateral. She remains on stable oxycodone, 25mg/day.
Page 3 of 7
Overall, both subjects reported about 50% improvement, and in hindsight would repeat the procedure, but neither had complete relief or eliminated RLS medications. My impression is that this site may have a mitigating effect but is not the primary pathophysiologic pathway for RLS. That said, these are among the most severe of RLS sufferers and failed many treatments that usually benefit patients. Implantation of other targets certainly could be considered. [Table 1] The STN is “upstream” in basal ganglia circuitry and sends most of its output to the GPi so it is unlikely to have a better RLS response, however it is a safe and well-established target. Also, when used for PD, both subjective and objective sleep improves, although PLMS do not seem to be effected. 11 Several sites are targeted for chronic pain, including the peri-aqueductal grey and ventral posterior nuclei of the thalamus. 12 These certainly could be considered for RLS. Low frequency stimulation of dopaminergic spinal tracts (A11), which are essential in the peri-aqueductal grey, could also be considered, based on hypothesized RLS pathophysiology.
Page 4 of 7
Reference: 1. Moreau C, Defebvre L, Devos D, et al. STN versus PPN-DBS for alleviating freezing of gait: toward a frequency modulation approach? Mov Disord 2009; 24(14): 2164-6. 2. Schuurman PR, Bosch DA, Merkus MP, Speelman JD. Long-term follow-up of thalamic stimulation versus thalamotomy for tremor suppression. Mov Disord 2008; 23(8): 1146-53. 3. Rye DB, DeLong MR. Amelioration of sensory limb discomfort of restless legs syndrome by pallidotomy. Ann Neurol 1999; 46(5): 800-1. 4. 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. 5. Chahine LM, Ahmed A, Sun Z. Effects of STN DBS for Parkinson's disease on restless legs syndrome and other sleep-related measures. Parkinsonism & Related Disorders 2011; 17(3): 208-11. 6. 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. 7. Driver-Dunckley E, Evidente VG, Adler CH, 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): 1134. 9. Earley CJ, Connor J, Garcia-Borreguero D, et al. Altered Brain iron homeostasis and dopaminergic function in Restless Legs Syndrome (Willis-Ekbom Disease). Sleep Med 2014; 15(11): 1288-301. 10. Ondo WG, Jankovic J, Simpson R, Jimenez-Shahed J. Globus pallidus deep brain stimulation for refractory idiopathic restless legs syndrome. Sleep Med 2012; 13(9): 1202-4. 11. Amara AW, Watts RL, Walker HC. The effects of deep brain stimulation on sleep in Parkinson's disease. Ther Adv Neurol Disord 2011; 4(1): 15-24. 12. Boccard SG, Pereira EA, Moir L, Aziz TZ, Green AL. Long-term outcomes of deep brain stimulation for neuropathic pain. Neurosurgery 2013; 72(2): 221-30; discussion 31. 13. Lim AS, Moro E, Lozano AM, et al. Selective enhancement of rapid eye movement sleep by deep brain stimulation of the human pons. Ann Neurol 2009; 66(1): 110-4. 14. Voges BR, Schmitt FC, Hamel W, et al. Deep brain stimulation of anterior nucleus thalami disrupts sleep in epilepsy patients. Epilepsia 2015; 56(8): e99-e103. 15. Kovac S, Wright MA, Eriksson SH, Zrinzo L, Matharu M, Walker MC. The effect of posterior hypothalamus region deep brain stimulation on sleep. Cephalalgia 2014; 34(3): 219-23.
Page 5 of 7
Table 1: DBS Targets TARGET
COMMON INDICATION
EFFECT ON SLEEP REPORTED WHEN USED FOR OTHER CONDITIONS
EFFECT ON RLS
Sub-thalamic nucleus (STN)
PD, OCD
Variable results reported
Globus Pallidus Internus posteroventral (GPi-PV)
PD, dystonia, TS
Improved subjective sleep Improved sleep efficiency Dec. WASO +/- Inc. REM No change PLMS Improved subjective sleep
Improves
Ventralis intermedius nucleus (VIM)
ET, PD tremor
?
No effect
Pedunculopontine nucleus (low Hz)
Gait and freezing for PD, PSP
Increases REM sleep13
?
Centromedian nucleus (CM)*
OCD
?
?
Anterior Limb Int Capsule – Nucleus Accumbens (ALICNA)
OCD
?
?
Subcallosal cingulate white matter/singulate cortex (SCC)
Depression
?
?
Ventral striatum/ventral capsule (VS/VC)
Depression
?
?
Nucleus Basalis of Meynert (NBM)
Dementia
?
?
Fornix (low Hz)
Dementia
?
?
Medial forebrain bundle (MFB)
Depression
?
?
Anterior thalamic nuc.
Seizures
Increased PSG arousals14
?
Ventral posterior lateral thalamus
Pain
?
?
Periventricular grey
Pain
?
?
Posterior hypothalamus
Cluster headache
Marked sleep disruption (N=2)15
?
Tics
Page 6 of 7
* very similar/overlap with other names in literature including: centromedianparafascicular complex (CM-PF), ventral-oral internal thalamic nucleus (VOI), substantia periventricularis (SP)
Page 7 of 7