Spinal Cord Stimulation for Restless Legs Syndrome

Investigating Mechanisms of Human Spinal Cord Stimulation for Purpose of Treating Restless Leg Syndrome

The overall goal of this proposed study is to evaluate the underlying mechanisms of neural control of blood flow in the lower extremities in humans with restless leg syndrome (RLS). At least 15% of the general public suffers from RLS and many more may go undiagnosed. This unfortunate disorder leads primarily to a disturbing sensation within the patient's lower extremities that requires movement for relief (1, 2). The central hypothesis of our study is that physiological changes in lower limb blood flow as a result of thoracolumbar epidural Spinal Cord Stimulation (SCS) lead to the relief of RLS.

Study Overview

• Status: Completed
• Conditions: Restless Legs Syndrome; Neuropathic Pain
• Intervention / Treatment: Diagnostic test: Dual-energy X-ray absorptiometry Scan; Other: Laboratory Measurements; Other: Blood Flow Measurement; Other: Continuous Blood Pressure; Other: Partial pressure of oxygen; Other: Microneurography; Other: Anthropometric Measurements; Behavioral: Continuous Blood Pressure Diary; Behavioral: John Hopkins Restless Legs Severity Scale

Detailed Description

Patients age 18-85 years with (n=25) and without RLS (n=25) that have recently having undergone Spinal Cord Stimulation (SCS) implantation (thoracolumbar) for chronic pain will be recruited from the Departments of Anesthesia and Neurosurgery, University of Iowa Hospitals and Clinics. The rationale for studying both RLS patients and non-RLS patients with chronic back pain is to initially test the effectiveness of Spinal Cord Stimulation (SCS) on lower limb blood flow in the absence of symptoms of RLS. In the non-RLS patients, we could determine if SCS does in fact alter limb blood flow. We hypothesize that RLS patients have altered muscle sympathetic nerve activity (MSNA) and blood flow correlating to severity of RLS symptoms, which will then be modulated by Spinal Cord Stimulation (SCS), allowing for resolution of symptoms in RLS with MSNA-mediated improvements in leg blood flow. We also hypothesize that SCS in RLS patients will reduce 24-hour ambulatory blood pressure in parallel with reductions in MSNA.

Those deemed eligible to participate will be invited for 2 visits to the Translational Vascular Physiology Laboratory in the Clinical Research Unit (CRU) of the University of Iowa Hospitals and Clinics. Each of the 2 study visits are identical except for experimental measurements that are made at each of the five measurement time points when the Spinal Cord Stimulation (SCS) unit is either on or off as described below.

Visit 1: Experimental measurements include non-invasive "gold standard" measures of limb blood flow and arterial stiffness including femoral artery blood flow via Doppler ultrasound, calf blood flow from strain gauge venous occlusion plethysmography, and arterial stiffness via pulse wave velocity using applanation tonometry. Additionally, participants will be asked to assess the current level of leg discomfort every 10 minutes while measurements are taken by the SIT test, a validated technique for assessing restless legs symptoms where patients are asked to set and rest quietly during measurement talking, moving as little as possible (3).

Visit 2: Experimental measurements include direct measures of sympathetic nerve activity using microneurography before, during and again after administration of SCS to the patient. Additionally, participants will be asked to assess the current level of leg discomfort every 10 minutes while measurements are taken by the SIT test, a validated technique for assessing restless legs symptoms where patients are asked to set and rest quietly during measurement taking, moving as little as possible (3).

Some participates may visit the laboratory for placement of a 24-hour ambulatory blood pressure cuff.

• Study Type: Interventional
• Enrollment (Actual): 15
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa Hospitals and Clinics

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 85 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Mental capacity to understand and decide to participate in the research
• Recently have undergone or are planning to undergo SCS implantation (thoracolumbar region) for chronic pain.

Exclusion Criteria:

• Peripheral vascular disease
• History of ischemic heart disease ( examples myocardial infarction, cardiac bypass surgery, coronary stent, unstable angina)
• Heart transplantation
• Renal Failure
• Congestive heart failure
• Type 1 diabetes
• Pregnancy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Subjects with RLS; Subjects with Restless Leg Syndrome that have recently undergone Spinal Cord Stimulation (SCS) Implantation for chronic pain. Subject will have received the standard of care intervention of epidural spinal cord stimulation for pain.	Diagnostic test: Dual-energy X-ray absorptiometry Scan; Body composition analysis will be obtained by DEXA scan.; Other Names: DEXA; Other: Laboratory Measurements; The following labs will be obtained during the course of the study: pregnancy test (urine), glucose, insulin, catecholamine, and cholesterol (serum).; Other: Blood Flow Measurement; The blood flow to the arm or leg may also be measured by placing an ultrasonic probe on the skin over the femoral artery of the leg and the brachial artery of the arm.; Other: Partial pressure of oxygen; Transcutaneous recordings will be captured to measure the partial pressure of oxygen by placing monitors on the subject's chest and foot.; Other: Microneurography; The sympathetic nervous system activity to the subject's leg muscles will be measured by a tiny microelectrode placed in the peroneal nerve in the leg located just below the knee on the outer part of the leg. When the nerve is located 2 tiny sterile microelectrodes will be inserted through the skin.; Other: Anthropometric Measurements; Height and weight will be obtained.; Behavioral: John Hopkins Restless Legs Severity Scale; Subjects will be administered questionnaires to evaluate RLS symptoms using John Hopkins Restless Legs Severity Scale.
Other: Subjects without RLS; Subjects without Restless Leg Syndrome that have recently undergone Spinal Cord Stimulation (SCS) Implantation for chronic pain. Subject will have received the standard of care intervention of epidural spinal cord stimulation for pain.	Diagnostic test: Dual-energy X-ray absorptiometry Scan; Body composition analysis will be obtained by DEXA scan.; Other Names: DEXA; Other: Laboratory Measurements; The following labs will be obtained during the course of the study: pregnancy test (urine), glucose, insulin, catecholamine, and cholesterol (serum).; Other: Blood Flow Measurement; The blood flow to the arm or leg may also be measured by placing an ultrasonic probe on the skin over the femoral artery of the leg and the brachial artery of the arm.; Other: Partial pressure of oxygen; Transcutaneous recordings will be captured to measure the partial pressure of oxygen by placing monitors on the subject's chest and foot.; Other: Microneurography; The sympathetic nervous system activity to the subject's leg muscles will be measured by a tiny microelectrode placed in the peroneal nerve in the leg located just below the knee on the outer part of the leg. When the nerve is located 2 tiny sterile microelectrodes will be inserted through the skin.; Other: Anthropometric Measurements; Height and weight will be obtained.
Other: Continous BP Monitoring; This arm consists of subjects from arm "Subjects with RLS", "Subjects without RLS", and the rest of the qualifying subjects undergoing continuous blood pressure portion of the study only. Subject will have received the standard of care intervention of epidural spinal cord stimulation for pain.	Other: Continuous Blood Pressure; Continuous Blood pressure cuff will worn for 2 days with spinal cord stimulator on and off (24 hour on and 24 hour off). Optional procedure.; Other Names: 24-hour Ambulatory Blood Pressure Cuff; Behavioral: Continuous Blood Pressure Diary; Subjects participating in Continuous Blood Pressure monitoring will be administered continuous blood pressure monitoring compliance diary.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent Change MSNA Burst Frequency From Baseline to 60 Minutes	Response will measured by peroneal nerve microneurography to the lower limb during epidural spinal cord stimulation in patients with chronic back pain. Percent change MSNA burst frequency from baseline to 60 minutes	Baseline to 60 minutes
Response Measurement of Thoracolumbar Epidural SCS in the Femoral Artery Blood Flow	The response will be measured by Doppler ultrasound of the femoral artery during epidural spinal cord stimulation in patients with chronic back pain.	Baseline and 1.5 Hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Thoracolumbar epidural SCS will decrease MSNA in patients with RLS.	Response will measured by peroneal nerve microneurography to the lower limb during epidural spinal cord stimulation.	1.5 Hours
Acute thoracolumbar epidural SCS will increase femoral artery blood flow in patients with RLS.	This response will be measured by Doppler ultrasound of the femoral artery.	1.5 Hours
Acute thoracolumbar epidural SCS will improve severity of clinical symptoms in patients with RLS.	Patients will report a subjective rating of 0-10 of current RLS symptoms during spinal cord stimulation.	1.5 Hours
Acute thoracolumbar epidural SCS will improve oxygenation of the foot compared to the chest.	Transcutaneous partial pressure of oxygen will be measured on patients chest and foot.	1.5 Hours

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Thoracolumbar epidural SCS will decrease 24-hour ambulatory blood pressure.	Patients will wear continuous blood pressure monitor for 48 hours with a spinal cord simulator on and off while keeping a diary of simulator use.	48 hours

Collaborators and Investigators

• Sponsor: Marshall Holland
• Investigators: Principal Investigator: Marshall Holland, MD, University of Iowa

Publications and helpful links

General Publications

• Ohayon MM, O'Hara R, Vitiello MV. Epidemiology of restless legs syndrome: a synthesis of the literature. Sleep Med Rev. 2012 Aug;16(4):283-95. doi: 10.1016/j.smrv.2011.05.002. Epub 2011 Jul 26.
• Garcia-Borreguero D, Kohnen R, Boothby L, Tzonova D, Larrosa O, Dunkl E. Validation of the Multiple Suggested Immobilization Test: A Test for the Assessment of Severity of Restless Legs Syndrome (Willis-Ekbom Disease). Sleep. 2013 Jul 1;36(7):1101-1109. doi: 10.5665/sleep.2820.
• Cameron T. Safety and efficacy of spinal cord stimulation for the treatment of chronic pain: a 20-year literature review. J Neurosurg. 2004 Mar;100(3 Suppl Spine):254-67. doi: 10.3171/spi.2004.100.3.0254.
• Wu M, Linderoth B, Foreman RD. Putative mechanisms behind effects of spinal cord stimulation on vascular diseases: a review of experimental studies. Auton Neurosci. 2008 Feb 29;138(1-2):9-23. doi: 10.1016/j.autneu.2007.11.001.
• Earley CJ. Clinical practice. Restless legs syndrome. N Engl J Med. 2003 May 22;348(21):2103-9. doi: 10.1056/NEJMcp021288. No abstract available.
• Foreman RD, Linderoth B. Neural mechanisms of spinal cord stimulation. Int Rev Neurobiol. 2012;107:87-119. doi: 10.1016/B978-0-12-404706-8.00006-1.
• Yeh P, Walters AS, Tsuang JW. Restless legs syndrome: a comprehensive overview on its epidemiology, risk factors, and treatment. Sleep Breath. 2012 Dec;16(4):987-1007. doi: 10.1007/s11325-011-0606-x. Epub 2011 Oct 26.
• Dauvilliers Y, Winkelmann J. Restless legs syndrome: update on pathogenesis. Curr Opin Pulm Med. 2013 Nov;19(6):594-600. doi: 10.1097/MCP.0b013e328365ab07.
• Garcia-Borreguero D, Kohnen R, Silber MH, Winkelman JW, Earley CJ, Hogl B, Manconi M, Montplaisir J, Inoue Y, Allen RP. The long-term treatment of restless legs syndrome/Willis-Ekbom disease: evidence-based guidelines and clinical consensus best practice guidance: a report from the International Restless Legs Syndrome Study Group. Sleep Med. 2013 Jul;14(7):675-84. doi: 10.1016/j.sleep.2013.05.016.
• Hornyak M, Scholz H, Kohnen R, Bengel J, Kassubek J, Trenkwalder C. What treatment works best for restless legs syndrome? Meta-analyses of dopaminergic and non-dopaminergic medications. Sleep Med Rev. 2014 Apr;18(2):153-64. doi: 10.1016/j.smrv.2013.03.004. Epub 2013 Jun 6. Erratum In: Sleep Med Rev. 2014 Aug;18(4):367-8.
• Walters AS, Wagner ML, Hening WA, Grasing K, Mills R, Chokroverty S, Kavey N. Successful treatment of the idiopathic restless legs syndrome in a randomized double-blind trial of oxycodone versus placebo. Sleep. 1993 Jun;16(4):327-32. doi: 10.1093/sleep/16.4.327.
• Goldberg LI. Dopamine receptors and hypertension. Physiologic and pharmacologic implications. Am J Med. 1984 Oct 5;77(4A):37-44. doi: 10.1016/s0002-9343(84)80036-4.

Study record dates

Study Major Dates

• Study Start (Actual): July 5, 2016
• Primary Completion (Actual): April 23, 2020
• Study Completion (Actual): April 23, 2020

Study Registration Dates

• First Submitted: May 15, 2018
• First Submitted That Met QC Criteria: May 15, 2018
• First Posted (Actual): May 29, 2018

Study Record Updates

• Last Update Posted (Actual): September 21, 2023
• Last Update Submitted That Met QC Criteria: August 24, 2023
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Keywords: Muscle Sympathetic Nerve Activity; Blood Flow; Epidural Spinal Cord Stimulation
• Additional Relevant MeSH Terms: Mental Disorders; Pathologic Processes; Nervous System Diseases; Sleep Disorders, Intrinsic; Dyssomnias; Sleep Wake Disorders; Pain; Neurologic Manifestations; Neurobehavioral Manifestations; Disease; Neuromuscular Diseases; Peripheral Nervous System Diseases; Dyskinesias; Psychomotor Disorders; Parasomnias; Syndrome; Psychomotor Agitation; Restless Legs Syndrome; Neuralgia
• Other Study ID Numbers: 201605777

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: Yes
• product manufactured in and exported from the U.S.: Yes