Restless Legs Syndrome, Neuropathic Pain
Conditions
Keywords
Epidural Spinal Cord Stimulation, Muscle Sympathetic Nerve Activity, Blood Flow
Brief summary
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.
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.
Interventions
DIAGNOSTIC_TESTDual-energy X-ray absorptiometry Scan
Body composition analysis will be obtained by DEXA scan.
The following labs will be obtained during the course of the study: pregnancy test (urine), glucose, insulin, catecholamine, and cholesterol (serum).
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.
OTHERContinuous 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.
OTHERPartial 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.
OTHERMicroneurography
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.
Height and weight will be obtained.
BEHAVIORALJohn Hopkins Restless Legs Severity Scale
Subjects will be administered questionnaires to evaluate RLS symptoms using John Hopkins Restless Legs Severity Scale.
BEHAVIORALContinuous Blood Pressure Diary
Subjects participating in Continuous Blood Pressure monitoring will be administered continuous blood pressure monitoring compliance diary.
Sponsors
Marshall Holland
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
NONE
Intervention model description
Subjects are assigned to one of two groups based on whether they have Restless Leg Syndrome to undergo experimental measurements that are made at each of the five measurement time points.
Eligibility
Sex/Gender
ALL
Age
18 Years to 85 Years
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Subjects With RLS Subjects with Restless Leg Syndrome that have recently undergone Spinal Cord Stimulation (SCS) Implantation for chronic pain.
Intervention: Use of epidural spinal cord stimulation.
Dual-energy X-ray absorptiometry Scan: Body composition analysis will be obtained by DEXA scan.
Laboratory Measurements: The following labs will be obtained: pregnancy test (urine), glucose, insulin, catecholamine, and cholesterol (serum).
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.
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.
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.
Anthropometric Measurements: Height and weight will be obtained.
Continuous Blood Pressure Diary: Subjects participating in Continuous Blood Pressure monitoring will be administered continuous blood pressure monitoring compliance diary. | 5 |
| Subjects Without RLS Subjects without Restless Leg Syndrome that have recently undergone Spinal Cord Stimulation (SCS) Implantation for chronic pain.
Intervention: Use of epidural spinal cord stimulation.
Dual-energy X-ray absorptiometry Scan: Body composition analysis will be obtained by DEXA scan.
Laboratory Measurements: The following labs will be obtained during the course of the study: pregnancy test (urine), glucose, insulin, catecholamine, and cholesterol (serum).
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.
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.
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.
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.
Anthropometric Measurements: Height and weight
John Hopkins Restless Legs Severity Scale | 10 |
| 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.
Intervention: Use of epidural spinal cord stimulation.
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.
Continuous Blood Pressure Diary: Subjects participating in Continuous Blood Pressure monitoring will be administered continuous blood pressure monitoring compliance diary. | 0 |
| Total | 15 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | MSNA testing not done due to nerve recording not being able to be done due to restless legs | 1 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 2 | 3 | 0 |
Baseline characteristics
| Characteristic | Subjects With RLS | Subjects Without RLS | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 1 Participants | 0 Participants | 1 Participants |
| Age, Categorical Between 18 and 65 years | 4 Participants | 10 Participants | 14 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 4 Participants | 10 Participants | 14 Participants |
| Region of Enrollment United States | 5 participants | 10 participants | 15 participants |
| Sex: Female, Male Female | 2 Participants | 7 Participants | 9 Participants |
| Sex: Female, Male Male | 3 Participants | 3 Participants | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 5 | 0 / 10 | 0 / 0 |
| other Total, other adverse events | 0 / 5 | 0 / 10 | 0 / 0 |
| serious Total, serious adverse events | 0 / 5 | 0 / 10 | 0 / 0 |
Outcome results
Primary
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
Time frame: Baseline to 60 minutes
Population: All subjects enrolled did not complete this test or the test was terminated prior to a result being collected. The peroneal nerve signal is difficult to acquire and maintain with a small electrode through the skin, sometimes it can be lost half way if the patient moves their leg. Optional Continuous BP Monitoring did not have any subjects enrolled.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Subjects With RLS | Percent Change MSNA Burst Frequency From Baseline to 60 Minutes | -29 Percent change MSNA burst frequency | Standard Deviation 1 |
| Subjects Without RLS | Percent Change MSNA Burst Frequency From Baseline to 60 Minutes | -24 Percent change MSNA burst frequency | Standard Deviation 10 |
Primary
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.
Time frame: Baseline and 1.5 Hours
Population: Not all subjects that were enrolled completed this test. Optional Continuous BP Monitoring sub-study did not have any participants enrolled.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Subjects With RLS | Response Measurement of Thoracolumbar Epidural SCS in the Femoral Artery Blood Flow | 24 percentage of change | Standard Deviation 30 |
| Subjects Without RLS | Response Measurement of Thoracolumbar Epidural SCS in the Femoral Artery Blood Flow | 22 percentage of change | Standard Deviation 14 |