Investigating Mechanisms of Human Spinal Cord Stimulation for Purpose of Treating Restless Leg Syndrome
Phase: NA
Conditions: Restless Legs Syndrome, Neuropathic Pain
Sponsor: Marshall Holland

 
 
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Principal Investigator (PI):   
 
Marshall Holland, MD 
 
 
 
Co-Investigators:  
 
 
 
Timothy Brennan, MD 
 
 
 
 
 
 
Mark Dyken, MD 
 
 
 
 
 
 
Seth Holwerda, PhD 
 
 
 
 
 
 
Gary Pierce, PhD 
 
 
 
 
 
 
Rahul Rastogi, MD 
 
 
 
 
 
 
Saul Wilson, MD 
 
 
 
 
 
 
 
 
Title of Study:  
Investigating Mechanisms of Human Spinal Cord 
Stimulation for the Purpose of Treating Restless 
Leg syndrome 
 
Study Center:  
University of Iowa 
  
 
Estimated number of subjects:  
50 adults between the ages of 18-80  
 
 
 
 
 
 
 
 

 
 
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I. 
Introduction .......................................................................................................................... 3 
II. 
Background .......................................................................................................................... 4 
III. 
Statement of Compliance ..................................................................................................... 6 
IV. 
IRB Oversight ...................................................................................................................... 7 
V. 
Location of Study Procedures .............................................................................................. 8 
VI. 
Main Hypothesis .................................................................................................................. 9 
VII. 
Main Screening Criteria ..................................................................................................... 10 
VIII. Recruitment procedures ..................................................................................................... 11 
IX. 
Inclusion Criteria ............................................................................................................... 12 
X. 
Exclusion Criteria .............................................................................................................. 12 
XI. 
Study Procedures ............................................................................................................... 13 
XII. 
Possible Risks of the Study ................................................................................................ 15 
XIII. Adverse Event Reporting: .................................................................................................. 16 
XIV. Data Management .............................................................................................................. 18 
XV. 
Subject Safety .................................................................................................................... 19 
XVI. References .......................................................................................................................... 20 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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I. 
Introduction 
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. 
Patients aged 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. 
 
 
 
 
 
 
 
 
 
 

 
 
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II. 
Background 
Epidural spinal cord stimulation (SCS) is an exciting clinical therapy employed by a wide 
range of physicians. In the United States, the primary indication for implantation is chronic 
pain. In Europe, the primary indication is angina. Clinical observations have provided 
inferences about the underlying mechanisms evoked by (SCS) that explain its effectiveness; 
however, a gap in the literature remains in regards to the physiological mechanisms of how 
SCS works for relieving pain due to the limited number of basic science research groups 
involved in studies related to SCS. Nonetheless, the high efficacy of SCS for the treatment of 
chronic pain of the trunk and limbs continues to be highlighted in meta-analyses and 
published reviews (4, 5). 
As pain is the most common reason for implantation in the United States, there is significant 
expertise and interest in the mechanisms of SCS for relieving pain by Dr. Tim Brennan and 
Dr. Rahul Rastogi in the Department of Anesthesia. There is also great interest in further 
understanding mechanisms of spinal cord stimulation with regard to pain and motor 
behaviors within the Department of Neurosurgery, by Dr. Chandan Reddy and Dr. Marshall 
Holland. As a result of these synergistic interests, there has been a great partnership between 
the Departments of Anesthesia and Neurosurgery leading this charge, which led to recent and 
ongoing publication regarding the role of high frequency SCS performed in human patients 
here at the University of Iowa (3). 
Restless leg syndrome (RLS), also known as Willis-Ekbom disease, is a common disorder of 
periodic limb movement that affects up to 15% of the population and is characterized by a 
distressing urge to move the lower extremities during sleep or rest (4, 5). While many cases 
are able to be treated effectively by community family physicians, the more severe cases 
require expertise provided by specialized neurologists. This unfortunate disorder leads 
primarily to a disturbing sensation within the patient’s lower extremities that requires 
movement for relief (6, 7). RLS is often categorized as primary or secondary. Primary RLS is 
more likely to occur in younger people (peak age of onset approximately 20 years of age) and 
often has a strong family history with up to 60% of patients having a family member with the 
disease. The more prevalent secondary RLS develops in adulthood (peak onset of 40 years of 
age) and is typically associated with chronic disease such as iron deficiency, chronic renal 
failure, diabetes mellitus, liver disease, rheumatologic conditions, peripheral neuropathy, and 
even pregnancy. As the growth of the proportion of elderly increases, so to shall the 
prevalence of the chronic diseases that predispose the development of RLS (2). 
Treatment of this disease has proven to be highly difficult. As the understanding of its 
pathophysiology continues to be delineated there is hope that further pharmacotherapy can be 
developed (8-10). Dopamine agonists remain the mainstay of pharmacotherapy (11)and is 
well established as a peripheral vasodilator (12). Previous studies have demonstrated 
peripheral vasodilation effects of spinal cord stimulation (13, 14). We believe that there is an 
underlying common mechanism between vasodilation and symptomatic relief of RLS. This 
study provides us with a unique opportunity to not only explore a potential novel therapy, but 
also delineate the underlying neural mechanism of blood flow control that could be exploited 

 
 
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for other physiological and pathophysiological investigation. To our knowledge, this will be 
the first study to test the novel idea of using epidural SCS to treat symptoms of RLS. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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III. 
Statement of Compliance 
This study will be conducted in compliance with the protocol, Good Clinical Practice 
and the applicable Food and Drug Administration and other Department of Health 
and Human Services regulatory requirements. 
All key personnel (all individuals responsible for the design and conduct of this 
study) have completed Human Subjects Protection and Good Clinical Practice 
training. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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IV. 
IRB Oversight 
 
Human Subjects Office / IRB 
J. Andrew Bertolatus, MD 
Hardin Library, Office 105 
600 Newton Rd 
Iowa City, IA 52242 
FWA#: FWA00003007 
Voice: 319-335-6564 
Fax: 319-335-7310 
Email: irb@uiowa.edu 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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V. 
Location of Study Procedures 
 
University of Iowa  
200 Hawkins Drive 
Iowa City, Iowa 52242 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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VI. 
Main Hypothesis 
We hypothesize that epidural SCS will reduce symptoms in patients with RLS, and 
that this reduction is due to decreases in MSNA and improvement in leg blood flow. 
 
Aim 1: To determine the extent to which epidural SCS decreases MSNA and 
improves lower limb blood flow and arterial stiffness inpatients treated with 
thoracolumbar epidural SCS for chronic back pain. 
Hypothesis 1a: Thoracolumbar epidural SCS will abolish MSNA as measured by 
peroneal nerve microneurography to the lower limbs in patients with chronic back 
pain. 
Hypothesis 1b: Thoracolumbar epidural SCS will increase femoral artery blood flow 
as measured by Doppler ultrasound and calf blood flow as measured by venous 
occlusion plethysmography after SCS in patients with chronic back pain. 
Hypothesis 1c: Thoracolumbar epidural SCS will decrease leg arterial stiffness as 
measured by femoral-dorsalis pedis pulse wave velocity after SCS in patients with 
chronic back pain. 
 
Aim 2: To determine the extent to which epidural SCS decreases MSNA and 
improves leg blood flow and arterial stiffness and reduces symptoms in patients with 
RLS. 
Hypothesis 2a: Thoracolumbar epidural SCS will increase femoral artery and calf 
blood flow and reduce leg arterial stiffness inpatients with RLS. 
Hypothesis 2b: Thoracolumbar epidural SCS will improve severity of clinical 
symptoms in patients with RLS. 
 
Aim 3: To determine the extent to which SCS decreases 24-hour ambulatory blood 
pressure. 
Hypothesis 3: Thoracolumbar epidural SCS will decrease 24-hour ambulatory blood 
pressure to a greater extent in patients with RLS compared with patients without RLS. 
 
 
 
 
 
 
 
 
 
 

 
 
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VII. 
Main Screening Criteria 
Patients aged 18-85 years with and without RLS 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. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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VIII. Recruitment procedures 
Patients will be identified as potential subjects in Neurosurgery or Pain clinic. The 
potential subject will then be approached by a member of the research team to discuss 
the study. After the study is thoroughly explained and all questions are answered, the 
subject will be asked to sign a formal written consent. 
Patients will be drawn from the general pool of patients undergoing spinal cord 
stimulation for chronic pain. Of this pool for already implanted patients, those 
patients who additionally have restless leg syndrome (RLS) will serve as the 
experimental population, while those patients who do not meet criteria for RLS will 
serve as the control population. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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IX. 
Inclusion Criteria 
 
• All subjects will be between the ages of 18-85.  
• All subjects will have the mental capacity to understand and decide to 
participate in the research. 
• All subjects will recently have undergone or are planning to undergo SCS 
implantation (thoracolumbar region) for chronic pain, as defined by standard 
clinical criteria used by the UIHC Pain Clinic for neuromodulation therapy 
(having failed conservative measures, surgery, and other interventional pain 
procedures). 
 
Group 1 and 2 will be divided based on if they have Restless Leg Syndrome (n=25) 
or do not have Restless Leg Syndrome (n=25, control group). 
X. 
Exclusion Criteria 
• <18 or >85 years of age 
• Non-English speakers 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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XI. 
Study Procedures  
 
For RLS subjects will be instructed to discontinue their RLS medications 48 hours 
prior to visits #1 & #2. 
 
For Visit 1: The subject will arrive to the CRU for their appointment which will take 
4 hours. The subject will have been fasting for 8 hours, refrain from moderate or 
vigorous exercise for at least 24 hours, refrain from drinking alcohol for at least 24 
hours prior to the visit. Any female subjects will undergo a urine pregnancy test prior 
to the study beginning. If the pregnancy test is positive, the subject will no longer be 
eligible to continue with the study. DEXA scan will be done. Subject will be asked to 
wear comfortable clothes that doesn't contain any metal or reflective surfaces as this 
may skew the results. Subjects will lay on the table. The procedure will take 10-15 
minutes. An IV catheter will be placed in the subject's arm by a RN, after 20 minutes 
the nurse will draw blood from the IV catheter to measure sugar, insulin, cholesterol, 
and catecholamine. A blood pressure cuff will be placed around the subject's upper 
arm and blood pressure will be recorded 2-3 times. 3 EKG stickers will be placed on 
the subject's chest so that heart rate and rhythm can be monitored. A non-invasive 
tonometer probe will be placed on the subject's wrist, arm, neck, upper/inner thigh, 
and ankle to record the pulse at these sites. The blood flow to the subject's arm or leg 
may also be measured by placing a probe on the skin over the femoral artery of the 
leg or the brachial artery of the arm. Transcutaneous recordings will be captured to 
measure oxygen and carbon dioxide by placing monitors on the subject's chest and 
foot. Calf blood flow using venous occlusion plethysmography (VOP): VOP will be 
used to measure calf blood flow (CBF) responses to local ischemia to test 
endothelium-dependent dilation of calf resistance arteries. Briefly, subjects lie supine 
and have blood pressure cuffs (venous occlusion) placed around upper thigh and 
pediatric blood pressure cuffs around ankle. CBF will be measured by placing a 
gallium-in-silastic strain gauge around the widest part of the calf which measures 
small changes in calf volume during periodic inflation (8 secinflated:4 sec deflated) 
of upper thigh cuffs to 40 mmHg (which temporarily prevents venous outflow and 
measures arterial inflow into calf) and continuous ankle inflation of a blood pressure 
cuff to 250 mmHg. VOP is a well-established and validated technique for measuring 
limb response to ischemia in human subjects and is expressed in ml/100 ml 
tissue/min. Calf vascular conductance, to determine blood flow adjusted for mean 
arterial pressure, will be calculated as blood flow/mean arterial pressure, expressed as 
ml/min/100mmHg. If the subject is taking any morning medications, the research 
team may ask the subject to not take them in the morning but bring them with to the 
study and take at the end of the visit. At the end of visit 1, the participant will be sent 
home with a 24-hour ambulatory blood pressure monitor (AMBP) that will be worn 
for 2 days; one with the stimulator on and one with the stimulator off. 
 

 
 
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For visit 2: The subject will arrive to the CRU for their appointment which will take 4 
hours. The subject will have been fasting for 8 hours, refrain from moderate or 
vigorous exercise for at least 24 hours, refrain from drinking alcohol for at least 24 
hours prior to the visit. Any female subjects will undergo a urine pregnancy test prior 
to the study beginning. If the pregnancy test is positive, the subject will no longer be 
eligible to continue with the study. An IV catheter will be placed in the subject's arm 
by a RN, after 20 minutes the nurse will draw blood from the IV catheter to measure 
sugar, insulin, cholesterol, and catecholamine. A non-invasive tonometer probe on 
will be placed on the subject's wrist, arm, neck, upper/inner thigh, and ankle to record 
the pulse at these sites. The blood flow to the arm or leg may also be measured by 
placing a probe on the skin over the femoral artery of the leg or the brachial artery of 
the arm. Transcutaneous recordings will be captured to measure oxygen and carbon 
dioxide by placing monitors on the subject's chest and foot. The subject's heart rate 
will be measured by using an ECG and the subject's blood pressure will be monitored 
indirectly with an automatic cuff device on one of the subject's fingers. The 
sympathetic nervous system activity to the subject's leg muscles will be measured by 
a tiny microelectrode placed in a nerve in the right leg located just below the knee on 
the outer part of the leg. When the nerve is stimulated, an involuntary twitching or 
tingling sensation of the lower leg or foot will occur. The sensation will disappear 
when the stimulation is stopped. When the nerve is located 2 tiny sterile 
microelectrodes will be inserted through the skin. VOP (venous occlusion 
plethysmography) testing to measure calf blood flow. If the subject is taking any 
morning medications, the research team may ask the subject to not take them in the 
morning but bring them with to the study and take at the end of the visit. If DEXA 
scan hasn't been completed during visit 1, it will be completed during visit 2. Subject 
will be asked to wear comfortable clothes that doesn't contain any metal or reflective 
surfaces as this may skew the results. Subjects will lay on the table. The procedure 
will take 10-15 minutes. 
 
Ambulatory blood pressure cuff visit: A visit for the placement of a Continuous 
ambulatory blood pressure cuff may be added for any willing participants. A subset of 
participants will only be completing the Continuous ambulatory blood pressure cuff 
study and will sign a separate consent form. Participants will complete a diary (data 
collection sheet) while wearing the blood pressure cuff that will include time of 
activities, sleep, and time of SCS activation and deactivation. Participants will be 
given a shipping box with postage to return the blood pressure cuff and diary if 
unable to physically return to the Clinical Research Unit. The time of this visit will 
take place at the convenience of the participant. While wearing the Continuous 
ambulatory blood pressure cuff, participants will refrain from any RLS medications 
(48hours). 
 
Enrolled subjects are eligible to come back for a third unscheduled visit to complete 
study related interventions that were not completed during the scheduled two visits if 
they wish. 
 
 

 
 
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XII. 
Possible Risks of the Study 
Emotional or psychological: There are no foreseeable emotional or psychological risks 
with this study. But there is risk of inadvertent disclosure of PHI which could cause 
emotional or psychological risk. 
Physical: The nerve recording procedure (microneurography) occasionally may result in 
the leg muscles feeling tired. Also, the patient may have a pins-and-needles feeling or a 
greater sensitivity to touch in the leg. However, these side effects rarely occur and do not 
usually last more than a couple of minutes. The ambulatory blood pressure monitor may 
cause some discomfort and could potentially bruise or scratch the participant's arm, 
though this is not very common. 
The potential risk and discomfort from the blood draw may result in any of the following 
to occur slight bruising, pain, a temporary feeling of faintness, and rarely an infection at 
the site of the blood draw. 
The pulse wave velocity has no known risks associated with the use of the non-invasive 
pulse transducer, but the ECG electrodes that are used may cause minor irritation to the 
skin 
Fasting for 8 hours prior to participating in the study may cause dehydration. You will be 
encouraged to drink plenty of water, subjects may experience hunger and irritability. if 
the subject would experience nausea, vomiting, or fainting the subject will be instructed 
to stop fasting. 
Legal or social: There are no foreseeable legal or social risks with this study. 
 
 
 
 
 
 

 
 
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XIII. Adverse Event Reporting: 
 
The University of Iowa requires Investigators to collect and report to the University 
of Iowa IRB if any of the following occur: 
 
• An unanticipated problem involving risks to subjects or others is any event or 
problem that: 
1) was unexpected (in terms of nature, severity or frequency) given (a) the 
research procedures that are described in the protocol-related documents, 
such as the IRB- approved research protocol and informed consent 
document; and (b) the characteristics of the subject population being 
studied AND 
2) suggests that the research places subjects or others (those not directly 
involved in the research such as research staff or family members) at a 
greater risk of harm (including physical, psychological, economic, or 
social harm) than was previously known or recognized AND 
3) is related or possibly related to participation in the research (possibly 
related means there is a reasonable possibility that the incident, experience 
or outcome may have been caused by the procedures involved in the 
research). 
4) Serious adverse drug event (either expected or unexpected) occurring in a 
UI subject 
5) If a subject is enrolled by U/VAHCS investigators, the investigator must 
report to the UI IRB either serious adverse drug events or unexpected 
adverse drug events. By definition, these events must be associated with 
the use of the drug. 
6) An unexpected adverse drug event is any adverse drug experience 
(associated with the use of the drug), the frequency, specificity, or severity 
of which is not consistent with the current investigator brochure; or, if an 
investigator brochure is not required or available, the specificity or 
severity of which is not consistent with the risk information provided to 
the subjects and the IRB 

 
 
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• A serious adverse drug event is any adverse drug experience (associated with 
the use of the drug) occurring at any dose that results in any of the following 
outcomes: 
 
1) Death 
2) Life-threatening adverse drug experience 
3) Inpatient hospitalization or prolongation of existing hospitalization 
4) A persistent or significant disability/incapacity 
5) A congenital anomaly/birth defect 
6) Important medical events that may not result in death, be life-threatening, 
or require hospitalization may be considered a serious adverse drug event 
when, based upon appropriate medical judgment, they may jeopardize the 
patient or subject and may require medical or surgical intervention to 
prevent one of the outcomes listed above. 
• Receipt of new information 
During the course of a study, researchers may become aware of new 
information that would impact a subject’s decision to participate or continue 
participating in the research study. For example, interim analyses of data may 
identify a trend which impacts the safety of subjects or may identify early 
efficacy (benefit) of one of the interventions under study. In addition, results 
from other research studies or changes in standards of practice or care may 
affect conduct of a study and would need to be communicated to research 
subjects. 
 
• Noncompliance 
Noncompliance is a failure to follow the federal regulations with respect to 
protection of human subjects in research or failure to follow the 
determinations of the IRB with respect to conduct of the research as approved 
by the IRB. 
 
Once per year, the IRB is required to review and approve all non-exempt research 
projects at intervals appropriate to the degree of risk, but not less than once a year. 
This is called "continuing review.” Continuing review for non-exempt research is 
required to occur as long as the research remains active for long-term follow-up 
of the research subject, even when the research is permanently closed to the 
enrollment of new subjects and all subjects have completed all research-related 
interventions and to occur when the remaining research activities are limited to 
collection of private identifiable information. 
 
Adverse Event Collection: 
 

 
 
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The clinical research team is responsible for collecting and recording the research data.  
As the results are collected, all adverse events will be identified after an informed consent 
is signed by the subject or their legally authorized representative (LAR) and the 
medication is initiated.   
 
Throughout the study, during all follow-up visits, in addition to the medical chart review, 
adverse events are to be elicited by the investigator (or designate) by asking the subject 
non-leading questions. All AEs and SAEs will be reported to the principal investigator 
(PI) and the PI will determine the final relationship of the event to the investigational 
product.  
 
XIV. Data Management 
 
The following people/agencies may have access to subject data/records: 
 
• Study team 
• Federal government regulatory agencies 
• Auditing departments of the University of Iowa 
• The National Institute of Health 
 
To protect confidentiality, we will assign each subject a study ID. All records will be 
in a locked cabinet in a locked office or password protected computer system. Data 
and records will be managed as follows: 
• Paper/hard copy records (hard copy surveys, questionnaires, case report 
forms, pictures, etc.) - Whenever possible, subject identifying information will 
be blacked out on all paper or hard copy records and replaced with the 
subject's unique study identifier. Paper records will be stored in a locked file 
cabinet in the study team's locked office.  
• Electronic records (computer files, electronic databases, etc.) – All electronic 
data bases will only be accessed by the study team and available only with a 
username and password assigned to study team by the PI.  
 
 
 
 
 
 

 
 
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XV. 
Subject Safety 
 
• To minimize risks all subjects are carefully pre-screened and screened trying to 
identify any factors that could contribute to increased risk.  
• All testing is completed at University of Iowa Hospitals and Clinics by a very 
experienced and well-trained staff and monitored by the Principal Investigator. 
• All confidential information is kept in locked offices and password protected 
computers only available to study team members.  
• The participant has contact information and study team members available 24/7.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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XVI. References 
1. Ohayon MM, O'Hara R, Vitiello MV. Epidemiology of restless legs syndrome: a 
synthesis of the literature. Sleep Med Rev. Aug2012;16(4):283-295. 
2. Earley CJ. Clinical practice. Restless legs syndrome. N Engl J Med. May 22 
2003;348(21):2103-2109. 
3. 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;36(7):1101-1109. 
4. Cameron T. Safety and efficacy of spinal cord stimulation for the treatment of 
chronic pain: a 20-year literature review. J Neurosurg. Mar 2004;100(3 Suppl 
Spine):254-267. 
5. Foreman RD, Linderoth B. Neural mechanisms of spinal cord stimulation. Int Rev 
Neurobiol. 2012;107:87-119. 
6. Ohayon MM, O'Hara R, Vitiello MV. Epidemiology of restless legs syndrome: a 
synthesis of the literature. Sleep Med Rev. Aug2012;16(4):283-295. 
7. Yeh P, Walters AS, Tsuang JW. Restless legs syndrome: a comprehensive 
overview on its epidemiology, risk factors, and treatment. Sleep Breath. Dec 
2012;16(4):987-1007. 
8. Dauvilliers Y, Winkelmann J. Restless legs syndrome: update on pathogenesis. 
Curr Opin Pulm Med. Nov 2013;19(6):594-600. 
9. Garcia-Borreguero D, Kohnen R, Silber MH, et al. 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 
SyndromeStudy Group. Sleep Med. Jul 2013;14(7):675-684. 
10. 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. Apr 2014;18(2):153-164. 
11. Walters AS, Wagner ML, Hening WA, et al. Successful treatment of the 
idiopathic restless legs syndrome in a randomized double-blind trial of oxycodone 
versus placebo. Sleep. Jun 1993;16(4):327-332. 
12. Goldberg LI. Dopamine receptors and hypertension. Physiologic and 
pharmacologic implications. Am J Med. Oct 51984;77(4A):37-44. 

 
 
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13. Foreman RD, Linderoth B. Neural mechanisms of spinal cord stimulation. Int Rev 
Neurobiol. 2012;107:87-119. 
14. Wu M, Linderoth B, Foreman RD. Putative mechanisms behind effects of spinal 
cord stimulation on vascular diseases: a reviewof experimental studies. Auton 
Neurosci. Feb 29 2008;138(1-2):9-23.