Spinal Cord Stimulation for Restless Legs Syndrome

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.

• Dual-energy X-ray absorptiometry Scan (Diagnostic test), also known as DEXA: Body composition analysis will be obtained by DEXA scan.
• Laboratory Measurements (Other): The following labs will be obtained during the course of the study: pregnancy test (urine), glucose, insulin, catecholamine, and cholesterol (serum).
• Blood Flow Measurement (Other): 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.
• Continuous Blood Pressure (Other), also known as 24-hour Ambulatory Blood Pressure Cuff: 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.
• Partial pressure of oxygen (Other): Transcutaneous recordings will be captured to measure the partial pressure of oxygen by placing monitors on the subject's chest and foot.
• Microneurography (Other): 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.
• Anthropometric Measurements (Other): Height and weight will be obtained.
• John Hopkins Restless Legs Severity Scale (Behavioral): Subjects will be administered questionnaires to evaluate RLS symptoms using John Hopkins Restless Legs Severity Scale.
• Continuous Blood Pressure Diary (Behavioral): Subjects participating in Continuous Blood Pressure monitoring will be administered continuous blood pressure monitoring compliance diary.

Primary outcomes

• Percent Change MSNA Burst Frequency From Baseline to 60 Minutes [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
• Response Measurement of Thoracolumbar Epidural SCS in the Femoral Artery Blood Flow [Baseline and 1.5 Hours]: The response will be measured by Doppler ultrasound of the femoral artery during epidural spinal cord stimulation in patients with chronic back pain.

Sex: All, ages: 18 Years to 85 Years, accepts healthy volunteers

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

Participant flow

Outcome results

• Percent Change MSNA Burst Frequency From Baseline to 60 Minutes (Primary), Mean, Percent change MSNA burst frequency: Subjects With RLS -29 +/- 1; Subjects Without RLS -24 +/- 10; Continous BP Monitoring
• Response Measurement of Thoracolumbar Epidural SCS in the Femoral Artery Blood Flow (Primary), Mean, percentage of change: Subjects With RLS 24 +/- 30; Subjects Without RLS 22 +/- 14; Continous BP Monitoring

Adverse events

Time frame: Adverse Events and Serious Adverse Events were collected during enrollment period, up to 2 months.

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• Study Protocol (PDF, 2016-07-05)
• Statistical Analysis Plan (PDF, 2023-05-10)
• Informed Consent Form (PDF, 2020-03-02)

• Marshall Holland, MD, Principal investigator, University of Iowa