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Open Access Research article

Transdermal rotigotine for the perioperative management of restless legs syndrome

Birgit Högl1*, Wolfgang H Oertel2, Erwin Schollmayer3 and Lars Bauer3

Author Affiliations

1 Department of Neurology, Innsbruck Medical University, Innsbruck, Austria

2 Department of Neurology, Philipps University, Marburg, Germany

3 UCB Biosciences GmbH, Monheim, Germany

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BMC Neurology 2012, 12:106  doi:10.1186/1471-2377-12-106

The electronic version of this article is the complete one and can be found online at: http://www.biomedcentral.com/1471-2377/12/106


Received:8 December 2011
Accepted:31 July 2012
Published:25 September 2012

© 2012 Högl et al.; licensee BioMed Central Ltd.

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Background

Immobilisation, blood loss, sleep deficiency, and (concomitant) medications during perioperative periods might lead to acute exacerbation of symptoms in patients with the restless legs syndrome (RLS). Continuous transdermal delivery of the dopamine agonist rotigotine provides stable plasma levels over 24 h and may provide RLS patients with a feasible treatment option for perioperative situations. To assess the feasibility of use of rotigotine transdermal patch for the perioperative management of moderate to severe RLS, long-term data of an open-label extension of a rotigotine dose-finding study were retrospectively reviewed.

Methods

The data of all 295 patients who had entered the 5-year study were screened independently by two reviewers for the occurrence of surgical interventions during the study period. The following data were included in this post-hoc analysis: patient age, sex, surgical intervention and outcome, duration of hospital stay, rotigotine maintenance dose at the time of surgery, rotigotine dose adjustment, and continuation/discontinuation of rotigotine treatment. All parameters were analysed descriptively. No pre-specified efficacy assessments (e.g. IRLS scores) were available for the perioperative period.

Results

During the study period, 61 surgical interventions were reported for 52 patients (median age, 63 years; 67% female); the majority of patients (85%) had one surgical intervention. The mean rotigotine maintenance dose at time of surgery was 3.1 ± 1.1 mg/24 h. For most interventions (95%), rotigotine dosing regimens were maintained during the perioperative period. Administration was temporarily suspended in one patient and permanently discontinued in another two. The majority (96%) of the patients undergoing surgery remained in the study following the perioperative period and 30 of these patients (61%) completed the 5-year study.

Conclusions

Although the data were obtained from a study which was not designed to assess rotigotine use in the perioperative setting, this post-hoc analysis suggests that treatment with rotigotine transdermal patch can be maintained during the perioperative period in the majority of patients and may allow for uninterrupted alleviation of RLS symptoms.

Trial Registration

The 5-year rotigotine extension study is registered with ClinicalTrials.gov, identifier NCT00498186.

Background

Restless legs syndrome (RLS), also known as Willis-Ekbom disease, is a common neurological disorder with substantial human and economic costs [1-3]. The disease remains underdiagnosed and also misdiagnosed in primary care [4] which recently prompted the proposal of diagnosis and treatment algorithms for primary care physicians/general practitioners by a task force sponsored by the European RLS study group [4]. RLS patients have an urge to move their legs (and sometimes arms and other body parts) during periods of rest and inactivity; this is usually accompanied or caused by unpleasant sensations in these limbs. The general circadian pattern (worsening in the evening and at night) can change as disease severity increases, and daytime symptoms develop [5].

One of the essential diagnostic criteria for RLS is the induction or exacerbation of symptoms by rest [6]; any form of immobilisation might therefore substantially increase symptom severity. Both leg discomfort and periodic leg movements indeed significantly worsened due to immobility in RLS patients but not in healthy controls [7]. Hospital stays for surgical interventions involving bed rest and possibly forced immobilisation during the postoperative period might therefore trigger or worsen symptoms in RLS patients. Additional factors potentially contributing to this exacerbation are illness- or pain-induced sleep deprivation, iron deficiency due to perioperative blood loss, and possibly the use of certain anaesthesia and concomitant medications such as neuroleptic agents, antiemetic agents with dopamine antagonistic properties, other dopamine antagonists, opioid antagonists, and some antihistamines and antidepressants [8,9]. New onset of RLS has also been reported following surgery with spinal anaesthesia. However, as lower mean corpuscular volume and haemoglobin pre-surgery were associated with new-onset RLS after surgery in this series, it cannot be excluded that iron deficiency accounted for new onset or exacerbation of RLS in that study [10]. Worsening of RLS symptoms might result in agitated patients with involuntary limb jerks during surgery, and general restlessness and major pain during recovery with ensuing postoperative complications and poor RLS symptom control for a prolonged period following surgery [11,12].

Current recommendations for perioperative RLS management suggest maintenance of RLS medication until just before surgery and resumption after surgery at full dose [13]. When using oral dopaminergic agents with a short half life, this temporary discontinuation might worsen RLS symptoms. Resuming full-dose treatment too quickly might also be problematic with dopamine agonists which require slow titration to avoid side effects. The dopamine agonist rotigotine, an efficacious and generally well tolerated treatment for RLS and Parkinson’s disease (PD) [14], might provide a suitable treatment alternative for RLS patients in the perioperative setting. Formulated in a transdermal patch, the continuous drug delivery generates stable rotigotine plasma concentrations over 24 h with once-daily application [15]. Administration of rotigotine transdermal patch may thus permit continuous alleviation of RLS symptoms in the perioperative setting. Previous studies considered rotigotine transdermal patch a feasible alternative for perioperative PD management [16,17]. Treatment was associated with good control of PD symptoms, easy switching and re-switching of regular PD medication, and a high patient acceptance [16].

In order to assess rotigotine transdermal patch for the perioperative management of RLS, long-term data of a rotigotine 5-year study were retrospectively reviewed.

Methods

Data for this post-hoc analysis were obtained from a 5-year prospective open-label study of rotigotine treatment for moderate to severe RLS (SP710, NCT00498186, [18]), which is the extension of a 6-week randomised, double-blind, placebo-controlled rotigotine dose-finding study (SP709, NCT00243217) [19]. The study design is summarised in Figure 1. Patients eligible for participating in the dose-finding study were 18–75 years of age, had met the diagnosis of idiopathic RLS based on the four essential diagnostic criteria according to the International RLS Study Group (IRLSSG [6]), and had an IRLSSG severity rating scale (IRLS [20]) sum score ≥ 15 (= at least moderate RLS); complete inclusion/exclusion criteria are described elsewhere [19]. Study completers were given the option of long-term treatment with their optimal rotigotine dose (dose range 0.5-4 mg/24 h) provided they had no ongoing serious adverse events (AEs) suspected to be related to their randomly assigned treatment in the preceding dose-finding study. They were excluded for severe application site reactions or noncompliance in the preceding double-blind study. During the open-label extension, administration of concomitant treatments was kept to a minimum. Visits were scheduled at monthly intervals during the first year and at 3-monthly intervals thereafter. Both studies were performed according to the Declaration of Helsinki and Good Clinical Practice, and were approved by a central institutional review board in Germany (Kommission für Ethik in der ärztlichen Forschung im Fachbereich Humanmedizin der Philipps-Universität Marburg) and in Austria (Ethikkommission der Medizinischen Universität Innsbruck). In Spain, review and approval was provided by the local ethics committees of the Hospital Universitario La Princesa, Madrid, of the Hospital de la Ribera, Alzira/Valencia, and of the USP Institut Universitari Dexeus, Barcelona.

thumbnailFigure 1. Design of the 5-year open-label extension study with rotigotine transdermal patch in restless legs syndrome (adapted from Oertel et al. [[19,21]]). Patients completing the double-blind study had the option of long-term treatment with their optimal dose of transdermal rotigotine (0.5-4 mg/24 h) in the open-label extension.

Written informed consent was obtained from all patients before participation.

The data of all 295 patients who had entered the open-label extension (mean age, 58.3 ± 10.1 years; median, 61 years; 66% female) were screened independently by two reviewers (ES, LB) for the occurrence of surgical interventions during the study period. They reviewed all clinical study report narratives of serious AEs and other significant AEs and crosschecked the obtained information against the Council for International Organisations of Medical Sciences (CIOMS) suspect adverse reaction report forms. In case of inconsistent data, the relevant narratives and CIOMS forms were re-examined by both reviewers in order to reach an agreement about the case.

The following data were extracted for all patients with a surgical intervention during the study period: patient age, sex, surgical intervention and outcome, duration of hospital stay, rotigotine maintenance dose at the time of surgery, rotigotine dose adjustment, and continuation/discontinuation of rotigotine treatment. All parameters were analysed descriptively. No pre-specified efficacy assessments (e.g. IRLS scores) were available for the perioperative period, i.e. before and after the surgical intervention.

Results

Surgical interventions

During the 5 year study period, 61 surgical interventions were reported for 52 patients (17.6%). These patients had a mean age of 60.4 ± 11.6 years (median, 63 years) at study entry; 67.3% were female. Table 1 lists demographics and surgery details for each patient. Forty-four patients (84.6%) had one surgical intervention; seven patients had two procedures and one patient had three interventions. The duration of patients’ hospital stay ranged from 0 to 44 days. Surgeries consisted mainly of orthopaedic (45.9%), gynaecological/urological (14.8%), and cardiovascular (13.1%) procedures (Table 2). The most frequent surgery outcome was recovered/resolved (77.1%, Figure 2). According to the very detailed case descriptions, no complications, adverse events or other surgery, RLS or medication related issues were observed. A sub-analysis of the IRLS scores at time of surgery could not be conducted in this post-hoc analysis, because data were not available; the overall study population presented with a mean IRLS score of 27.8 ± 5.9 at baseline, indicating moderate to severe RLS [21]. Although eligibility criteria of the original study stipulated the consistent use of two combined effective contraception methods (including at least one barrier method) unless sexually abstinent, one patient became pregnant and had a planned abortion. The investigator considered the abortion as not related to trial medication. The subject had been exposed to the trial medication for 607 days and was withdrawn from the study 17 days prior to the abortion.

Table 1. Characteristics of the patients included in the post-hoc analysis

Table 2. Surgical interventions during the 5-year rotigotine study

thumbnailFigure 2. Reported outcome of surgical interventions.

Rotigotine dosing during the perioperative period

The rotigotine maintenance dose at the time of surgery is listed for each patient in Table 1. The mean dose was 3.1 ± 1.1 mg rotigotine/24 h (median, 3.5 mg/24 h). For the majority of interventions (n = 58, 95.1%), rotigotine dose regimens were maintained during the perioperative period. Administration was temporarily suspended in a 49-year old female patient for leg fracture surgery. Treatment was later resumed and the patient completed the study. Two patients permanently discontinued rotigotine treatment prior to surgical intervention; a 30-year old female patient stopped rotigotine administration 17 days before her surgery due to pregnancy (study withdrawal criterion) and a 71-year old male patient withdrew in order to prepare for upcoming lipoma surgery on his right lower leg. Tumor growth had been noticed by the patient prior to the start of the study.

Study completion

In total, 50 (96.2%) of the patients undergoing surgery remained in the study following the perioperative period and 30 of these patients (61.2%) completed the 5-year study. The other 19 patients discontinued prematurely; reasons were lack of efficacy (6 patients), adverse events (4 patients, one case each of gambling, hallucinations, application site pruritus, and osteoarthritis), unsatisfactory compliance (3), major protocol violations (3), withdrawn consent (1) and others (2).

Discussion

Bed rest, forced immobilisation, pain-induced sleep deprivation, iron depletion owing to intraoperative blood loss, and medications can all exacerbate RLS symptoms during the perioperative period [9]. Additionally, the temporary discontinuation of oral RLS medication before surgery and resumption at full dose postoperatively which is currently recommended for the perioperative RLS management [13] might worsen symptoms during surgery and lead to the occurrence of side effects when re-establishing the medication postoperatively. Administration of a medication such as rotigotine transdermal patch which provides stable plasma concentrations over 24 h with once-daily application may allow an uneventful continuous management of RLS symptoms in the perioperative setting.

To investigate this hypothesis, a retrospective analysis was carried out to obtain information about the perioperative management of RLS with rotigotine transdermal patch. Data from all patients undergoing surgery during the study period were extracted from the database of a 5-year open-label rotigotine study [18]. As can be expected from a database with a median age of 61 years, surgical interventions occurred frequently [22]: nearly one fifth of all patients underwent surgery during the 5-year study period, consisting mainly of orthopaedic, gynaecological/urological, and cardiovascular procedures. Treatment with rotigotine transdermal patch could be continued throughout the perioperative period in all but 3 of these patients without a change in rotigotine maintenance dose.

Rotigotine transdermal patch might be useful in the perioperative setting for the continuous alleviation of the usual RLS symptoms experienced by the patients. Additionally, the continuous drug delivery might counteract involuntary movements during surgery or during recovery triggered by bed rest and immobilisation, illness- or pain-induced sleep deprivation, iron depletion, (concomitant) medications, or certain anaesthetics. Several case reports have described the transient occurrence of RLS and periodic limb movements with epidural or spinal anaesthesia [10,23-28] which might worsen the symptoms already present in RLS patients and might lead to interference with surgical procedures and a prolonged recovery time.

This investigation was a retrospective analysis and not a prospective study providing efficacy data such as IRLS values for the perioperative period. It should also be noted that the original study from which these data were obtained was not designed to assess the use of rotigotine transdermal patch in the perioperative setting. To our knowledge, no pharmacokinetic studies investigating interactions with medications commonly used during surgery have been conducted for rotigotine. The present post-hoc analysis can therefore only provide a first indication that administration of the patch can be continued satisfactorily in the majority of patients undergoing surgery and should be confirmed by additional studies.

Current guidelines recommend the use of oral opioid-containing medications before, during, and after surgery when dopaminergic medication is suspended or slowly being re-established [13]. In case oral administration of opioid-containing medications is not possible, parenteral routes are suggested. The rotigotine transdermal patch avoids invasive routes of administration providing an alternative to patients’ regular oral dopaminergic medication for the perioperative period. Although switching from different dopaminergic medications to the rotigotine patch has not been investigated systematically in RLS patients, overnight switching was effective and well tolerated in patients suffering from PD [29,30]. Switching and re-switching of regular antiparkinsonian medication to the patch was also considered feasible in perioperative PD management [16].

Conclusions

Although the data were obtained from a study which was not designed to assess rotigotine use in the perioperative setting, this post-hoc analysis suggests that treatment with rotigotine transdermal patch can be maintained during the perioperative period in the majority of patients and might thus permit uninterrupted alleviation of RLS symptoms. Rotigotine transdermal patch may be a feasible treatment alternative in perioperative situations where administration of oral treatments is limited, unavailable, or not applicable. Further prospective studies are clearly warranted to confirm this finding.

Competing interests

BH has been a consultant or acted on advisory boards for GSK, BI, UCB, Lundbeck, Jazz, Nycomed, Sanofi, Pfizer, Merz, Cephalon, and has been a speaker for GSK, BI, UCB, Pfizer, Cephalon,

WHO has received honoraria for consultancy and for serving on scientific advisory boards, and travel support from UCB; and honoraria for consultancy and lecture fees from Teva, Novartis, GlaxoSmithKline, Boehringer Ingelheim, Orion Pharma, and Merck Serono.

ES and LB are employees of UCB Pharma, Monheim, Germany; both receive UCB stock options.

Authors' contributions

BH participated in study conception, data interpretation, manuscript writing, and manuscript review and critique. WHO participated in data interpretation and critical revision of the manuscript. ES and LB participated in study conception, data analysis and interpretation, and critical revision of the manuscript. All authors read and approved the final manuscript.

Acknowledgements

Both the 5-year study and the current analysis which used data from this study were sponsored by UCB Pharma, Monheim, Germany. The sponsor was involved in the design of the post-hoc study, analysis and interpretation of the data, manuscript writing, and in the decision to submit the paper for publication. The authors wish to thank E. Grosselindemann (Brett Medical Writing, Bibra Lake, Australia) and B. Brett (Brett Medical Writing, Pulheim, Germany) for writing and editorial assistance which was contracted by UCB Pharma, Monheim, Germany.

References

  1. Ohayon MM, O’Hara R, Vitiello MV: Epidemiology of restless legs syndrome: a synthesis of the literature.

    Sleep Med Rev 2012, 16:283-295. PubMed Abstract | Publisher Full Text OpenURL

  2. Reinhold T, Müller-Riemenschneider F, Willich SN, Brüggenjürgen B: Economic and human costs of restless legs syndrome.

    Pharmacoeconomics 2009, 27:267-279. PubMed Abstract | Publisher Full Text OpenURL

  3. Dodel R, Happe S, Peglau I, Mayer G, Wasem J, Reese JP, Giani G, Geraedts M, Trenkwalder C, Oertel WH, Stiasny-Kolster K: Health economic burden of patients with restless legs syndrome in a German ambulatory setting.

    Pharmacoeconomics 2010, 28:381-393. PubMed Abstract | Publisher Full Text OpenURL

  4. García-Borreguero D, Stillman P, Beneš H, Buschmann H, Chaudhuri KR, Gonzalez Rodríguez VM, Högl B, Kohnen R, Monti GC, Stiasny-Kolster K, Trenkwalder C, Williams A-M, Zucconi M: Algorithms for the diagnosis and treatment of restless legs syndrome in primary care.

    BMC Neurol 2011, 11:28. PubMed Abstract | BioMed Central Full Text | PubMed Central Full Text OpenURL

  5. Trenkwalder C, Paulus W: Restless legs syndrome: pathophysiology, clinical presentation and management.

    Nat Rev Neurol 2010, 6:337-346. PubMed Abstract | Publisher Full Text OpenURL

  6. Allen RP, Picchietti D, Hening WA, Trenkwalder C, Walters AS, Montplaisir J: Restless legs syndrome: diagnostic criteria, special considerations, and epidemiology. A report from the restless legs syndrome diagnosis and epidemiology workshop at the National Institutes of Health.

    Sleep Med 2003, 4:101-119. PubMed Abstract | Publisher Full Text OpenURL

  7. Michaud M, Lavigne G, Desautels A, Poirier G, Montplaisir J: Effects of immobility on sensory and motor symptoms of restless legs syndrome.

    Mov Disord 2002, 17:112-115. PubMed Abstract | Publisher Full Text OpenURL

  8. Högl B, Gschliesser V: Management of restless legs syndrome in the hospital and during surgery. In Restless Legs Syndrome. Edited by Hening WA, Allen RP, Chokroverty S, Earley C. Saunders/Elsevier; 2009:279-283. OpenURL

  9. Högl B, Falkenstetter T: Restless legs syndrome and surgery. In Acute and Emergent Events in Sleep Disorders. Edited by Chokroverty S, Sahota P. Oxford University Press; 2010:436-443. OpenURL

  10. Högl B, Frauscher B, Seppi K, Ulmer H, Poewe W: Transient restless legs syndrome after spinal anesthesia: a prospective study.

    Neurology 2002, 59:1705-1707. PubMed Abstract | Publisher Full Text OpenURL

  11. Raux M, Karroum EG, Arnulf I: Case scenario: anesthetic implications of restless legs syndrome.

    Anesthesiology 2010, 112:1511-1517. PubMed Abstract | Publisher Full Text OpenURL

  12. Karroum EG, Raux M, Riou B, Arnulf I: Acute exacerbation of restless legs syndrome during perioperative procedures: case reports and suggested management [In French].

    Ann Fr Anesth Reanim 2010, 29:920-924. PubMed Abstract | Publisher Full Text OpenURL

  13. Restless Legs Syndrome Foundation:

    Surgery and RLS.

    http://www.rls.org/Document.Doc?id=2082 webcite

    OpenURL

  14. Boroojerdi B, Wolff H-M, Braun M, Scheller DKA: Rotigotine transdermal patch for the treatment of Parkinson’s disease and restless legs syndrome.

    Drugs Today 2010, 46:483-505. PubMed Abstract | Publisher Full Text OpenURL

  15. Elshoff J-P, Braun M, Andreas J-O, Middle M, Cawello W: Steady-state plasma concentration profile of transdermal rotigotine – an integrated analysis of three Phase 1 multiple dose studies.

    Clin Ther 2012, 34:966-978. PubMed Abstract | Publisher Full Text OpenURL

  16. Wüllner U, Kassubek J, Odin P, Schwarz M, Naumann M, Häck H-J, Boroojerdi B, Reichmann H: Transdermal rotigotine for the perioperative management of Parkinson’s disease.

    J Neural Transm 2010, 117:855-859. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  17. Korczyn AD, Reichmann H, Boroojerdi B, Häck H-J: Rotigotine transdermal system for perioperative administration.

    J Neural Transm 2007, 114:219-221. PubMed Abstract | Publisher Full Text OpenURL

  18. Oertel W, Trenkwalder C, Beneš H, Ferini-Strambi L, Högl B, Poewe W, Stiasny-Kolster K, Fichtner A, Schollmayer E, Kohnen R, García-Borreguero D: Long-term safety and efficacy of rotigotine transdermal patch for moderate-to-severe idiopathic restless legs syndrome: a 5-year open-label extension study.

    Lancet Neurol 2011, 10:710-720. PubMed Abstract | Publisher Full Text OpenURL

  19. Oertel WH, Beneš H, García-Borreguero D, Geisler P, Högl B, Saletu B, Trenkwalder C, Sommerville KW, Schollmayer E, Kohnen R, Stiasny-Kolster K: Efficacy of rotigotine transdermal system in severe restless legs syndrome: a randomized, double-blind, placebo-controlled, six-week dose-finding trial in Europe.

    Sleep Med 2008, 9:228-239. PubMed Abstract | Publisher Full Text OpenURL

  20. Walters AS, LeBrocq C, Dhar A, Hening W, Rosen R, Allen RP, Trenkwalder C: Validation of the International Restless Legs Syndrome Study Group rating scale for restless legs syndrome.

    Sleep Med 2003, 4:121-132. PubMed Abstract | Publisher Full Text OpenURL

  21. Oertel WH, Beneš H, García-Borreguero D, Geisler P, Högl B, Trenkwalder C, Tacken I, Schollmayer E, Kohnen R, Stiasny-Kolster K: One year open-label safety and efficacy trial with rotigotine transdermal patch in moderate to severe idiopathic restless legs syndrome.

    Sleep Med 2008, 9:865-873. PubMed Abstract | Publisher Full Text OpenURL

  22. National Center for Health Statistics.

    http://205.207.175.93/HDI/TableViewer/tableView.aspx?ReportId=605 webcite

    OpenURL

  23. Watanabe S, Sakai K, Ono Y, Seino H, Naito H: Alternating periodic leg movement induced by spinal anesthesia in an elderly male.

    Anesth Analg 1987, 66:1031-1032. PubMed Abstract | Publisher Full Text OpenURL

  24. Shin YK: Restless leg syndrome: unusual cause of agitation under anesthesia.

    South Med J 1987, 80:278-279. PubMed Abstract | Publisher Full Text OpenURL

  25. Ward NG: Akathisia associated with droperidol during epidural anesthesia.

    Anesthesiology 1989, 71:786-787. PubMed Abstract | Publisher Full Text OpenURL

  26. Watanabe S, Ono A, Naito H: Periodic leg movements during either epidural or spinal anesthesia in an elderly man without sleep-related (nocturnal) myoclonus.

    Sleep 1990, 13:262-266. PubMed Abstract OpenURL

  27. Moorthy SS, Dierdorf SF: Restless legs during recovery from spinal anesthesia.

    Anesth Analg 1990, 70:337. PubMed Abstract | Publisher Full Text OpenURL

  28. Martinez LP, Koza M: Anesthesia-related periodic involuntary movement in an obstetrical patient for caesarean section under epidural anesthesia: a case report.

    J Am Assoc Nurse Anesth 1997, 65:150-153. OpenURL

  29. LeWitt PA, Boroojerdi B, MacMahon D, Patton J, Jankovic J: Overnight switch from oral dopaminergic agonists to transdermal rotigotine patch in subjects with Parkinson disease.

    Clin Neuropharmacol 2007, 30:256-265. PubMed Abstract | Publisher Full Text OpenURL

  30. Kim H-J, Jeon BS, Lee WY, Lee MC, Kim JW, Kim J-M, Ahn T-B, Cho J, Chung SJ, Grieger F, Whitesides J, Boroojerdi B: Overnight switch from ropinirole to transdermal rotigotine patch in patients with Parkinson disease.

    BMC Neurol 2011, 11:100. PubMed Abstract | BioMed Central Full Text | PubMed Central Full Text OpenURL

Pre-publication history

The pre-publication history for this paper can be accessed here:

http://www.biomedcentral.com/1471-2377/12/106/prepub