Letters
Author Affiliations: Institute of Neurology, Catholic University, Rome, Italy. Corresponding Author: Assunta Bianco, MD, Institute of Neurology, Department of Geriatrics, Neurosciences and Orthopaedics, Catholic University, School of Medicine A. Gemelli, Largo Agostino Gemelli 8, 00168 Rome, Italy ([email protected]). Conflict of Interest Disclosures: None reported. 1. Cohen M, Maillart E, Tourbah A, et al; Club Francophone de la Sclérose en Plaques Investigators. Switching from natalizumab to fingolimod in multiple sclerosis: a French prospective study. JAMA Neurol. 2014;71(4):436-441. 2. de Seze J, Ongagna JC, Collongues N, et al; Alsacep Network. Reduction of the washout time between natalizumab and fingolimod. Mult Scler. 2013;19(9): 1248. 3. Stüve O, Cravens PD, Frohman EM, et al. Immunologic, clinical, and radiologic status 14 months after cessation of natalizumab therapy. Neurology. 2009;72 (5):396-401. 4. Kahan BD, Karlix JL, Ferguson RM, et al. Pharmacodynamics, pharmacokinetics, and safety of multiple doses of FTY720 in stable renal transplant patients: a multicenter, randomized, placebo-controlled, phase I study. Transplantation. 2003;76(7):1079-1084.
In Reply We read with attention comments from Bianco et al regarding the ENIGM (Enquête Nationale sur I’Introduction du Fingolimod en Relais au Natalizumab) study. In our statistical analysis, the main outcome was the presence of clinical disease reactivation (occurrence of at least 1 relapse) during the switching period. We first analyzed the washout then the fingolimod initiation period during a 6-month follow-up.1 Regarding washout, our results revealed an important reduction of disease reactivation rates for patients with washout duration shorter than 3 months (odds ratio, 0.23; P < .01). This result seems highly significant both in univariate and multivariate analyses. Regarding initiation of fingolimod, 230 patients reached the 6-month follow-up end point when the analysis was conducted. However, among patients who had not reached this end point, some had already relapsed and that is why the result (20%) was reported among the whole cohort. Furthermore, statistical analysis for this period was conducted comparing all patients who experienced at least 1 relapse while taking fingolimod compared with the patients who reached 6-month follow-up without any relapse. We did not collect either data about multiple recurrences nor the precise time to first relapse in our study. Finally, Bianco et al suggested that a randomized intervention study could give more relevant results about the safety and efficacy of switching from natalizumab to fingolimod. We would like to underline the results of the TOFINGO Study2 that were presented at the 2013 European Committee for Treatment and Research in Multiple Sclerosis Annual Meeting. The TOFINGO Study was a rater- and patient-blind, randomized study that compared the safety and efficacy of 3 different washout durations (8, 12, or 16 weeks) in a cohort of 142 patients. The main outcome was the presence of radiologic signs of disease reactivation and follow-up duration during fingolimod treatment of 32 weeks. The results showed that the patients in the 16-week washout group had a significantly higher risk for disease reactivation compared with the 2 other groups. No statistical difference was found
between 8-week and 12-week washout regimens either in efficacy or toxicity. Those results, which were not available at the time of submission of our article, are fairly similar to our findings in the ENIGM study. Mikael Cohen, MD Christine Lebrun, MD, PhD Author Affiliations: Department of Neurology, University Hospital of Nice, Nice, France. Corresponding Author: Mikael Cohen, MD, Department of Neurology, University Hospital of Nice, 30 Voie Romaine, 06000 Nice, France (cohen.m @chu-nice.fr). Conflict of Interest Disclosures: None reported. 1. Cohen M, Maillart E, Tourbah A, et al; Club Francophone de la Sclérose en Plaques Investigators. Switching from natalizumab to fingolimod in multiple sclerosis: a French prospective study. JAMA Neurol. 2014;71(4):436-441. 2. Kappos L, Radue EW, Comi G, et al. Disease control and safety in relapsing-remitting multiple sclerosis (RRMS) patients switching from natalizumab to fingolimod: a 32-week, rater- and patient-blind, randomized, parallel-group study (TOFINGO). Abstract No. 167. Paper presented at the 2013 European Committee for Treatment and Research in Multiple Sclerosis Annual Meeting; October 2-5, 2013; Copenhagen, Denmark.
Tau, S-100 Calcium-Binding Protein B, and NeuronSpecific Enolase as Biomarkers of Concussion To the Editor That the Quanterix platform was able to detect elevated levels of tau at subfentamole concentrations after sports-related concussion is indeed an exciting development in the article by Shahim and colleagues.1 However, the conclusion made by Shahim et al,1 and by the accompanying editorial,2 that S-100 calcium-binding protein B (S-100B) and neuron-specific enolase (NSE) lack use as diagnostic markers is flawed for several reasons. Shahim et al1 compared postconcussion marker concentrations in 1 subset of athletes with preinjury concentrations in an independent subset from the same ice hockey league, preventing the authors from uncovering significant subjectspecific marker differences. High variation in normal brain structure and function can obscure small but significant changes when groups, rather than individuals, are analyzed. This realization has led to the discovery of concussionrelated changes in cognitive function, cortical activation, and white matter integrity.3 Indeed, Kiechle et al4 previously demonstrated the markedly enhanced diagnostic value of S-100B when postinjury values were compared with baseline values for each athlete. Additionally, there is no biologic rationale for combining marker values from the 4 postinjury time intervals studied (1, 12, 36, and 144 hours). The axonal injury events reflected by changes in the levels of tau, S-100B, and NSE vary from hour to hour postinjury. The lack of a statistical increase in this temporally aggregated postinjury metric was used in the accompanying editorial to cast “serious doubt” on the usefulness of S-100B and an NSE as concussion biomarkers.2 In fact, Shahim et al1 reported that both S-100B and tau were significantly elevated acutely after concussion, which is arguably the most important time for making diagnostic decisions in prehospital, emergency department, playing field, and battlefield settings.
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Letters
Finally, the authors’ reasoning that S-100B and NSE were not sensitive markers of concussion because of increased levels observed after a “friendly game” of hockey is inherently flawed. Player-to-player contact is not prohibited during typical friendly games. Although no concussions were reported, any physical contact between players could have resulted in occult brain trauma, a widely reported observation in the context of football and soccer.5 Without an independent, gold-standard measure of brain injury, it is not possible to conclude with any certainty that elevations in biomarker levels after friendly games were not due to occult brain injury. While tau may have future value as a biomarker of concussion, the assertion that S-100B and NSE have little diagnostic value is not supported by the observations by Shahim et al.1 Jeffrey J. Bazarian, MD, MPH Kian Merchant-Borna, MPH Author Affiliations: Department of Emergency Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York. Corresponding Author: Jeffrey J. Bazarian, MD, MPH, Department of Emergency Medicine, University of Rochester School of Medicine and Dentistry, 265 Elmwood Ave, Rochester, NY 14642 ([email protected]). Conflict of Interest Disclosures: Dr Bazarian has a patent pending titled, “Method of Diagnosing Mild Traumatic Brain Injury.” Dr Bazarian serves as a consultant for Banyan Biomarkers, Roche Diagnostics. No other disclosures were reported. 1. Shahim P, Tegner Y, Wilson DH, et al. Blood biomarkers for brain injury in concussed professional ice hockey players [published online March 13, 2014]. JAMA Neurol. doi:10.1001/jamaneurol.2014.36. 2. Gatson J, Diaz-Arrastia R. Tau as a biomarker of concussion [published online March 13, 2014]. JAMA Neurol. doi:10.1001/jamaneurol.2014.443. 3. Bazarian JJ, Zhu T, Blyth B, Borrino A, Zhong J. Subject-specific changes in brain white matter on diffusion tensor imaging after sports-related concussion. Magn Reson Imaging. 2012;30(2):171-180. 4. Kiechle K, Bazarian JJ, Merchant-Borna K, et al. Subject-specific increases in serum S-100B distinguish sports-related concussion from sports-related exertion. PLoS One. 2014;9(1):e84977.
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creases we observed after a friendly game. In agreement, several studies have found increased serum levels of S-100B in the absence of head injury in soccer players, marathon runners, and patients with peripheral trauma. 3-5 Neuronspecific enolase is also released in the blood by hemolysis, which may be a serious source of error in some cases. Finally, only 5 of the 28 concussed ice hockey players had S-100B elevations above the cutpoint suggested by Undén et al6 in their consensus statement on guidelines for the initial management of mTBI. The criticism by Bazarian and Merchant-Borna that we compared postconcussion data with preseason values of 2 complete teams (ie, not the preconcussion samples from the same individuals who experienced concussion and therefore perhaps missed interesting intraindividual changes in the biomarkers) is in our minds a very minor weakness of our study. The common (and rational) way to use fluid biomarkers is to compare with a reference group. In a clinical situation, Bazarian and Merchant-Borna will never have access to preconcussion samples from patients. A clinically useful biomarker simply has to be good enough to provide meaningful data also in the absence of such samples. Moreover, an important aspect of interpreting biomarker results is taking into account the dynamic changes in the biomarker levels following the injury (eg, compare the clinical use of troponins in the diagnosis of myocardial infarction). In our study, we noticed an increase and fall in the levels of T-tau, which correlated with the postconcussive symptoms, whereas NSE and S-100B displayed no such, or less clear, dynamics. Taken together, all these data suggest that S-100B and NSE are quite insensitive biomarkers for mTBI and clearly inferior to tau. However, we agree that we should continue analyzing these biomarkers head to head also in future studies of candidate blood biomarkers for mTBI, in which additional biomarkers (eg, neurofilament light and spectrin breakdown products) should be assessed because we still do not have the optimal biomarker at hand.
5. Koerte IK, Ertl-Wagner B, Reiser M, Zafonte R, Shenton ME. White matter integrity in the brains of professional soccer players without a symptomatic concussion. JAMA. 2012;308(18):1859-1861.
Pashtun Shahim, MD Kaj Blennow, MD, PhD Henrik Zetterberg, MD, PhD
In Reply We thank Bazarian and Merchant-Borna for their comment on our article,1 suggesting that we should have interpreted the S-100 calcium-binding protein B (S-100B) and neuron-specific enolase (NSE) data in our study more positively than we did. We wish to clarify that we maintain our conclusion about the limited diagnostic value of S-100B and NSE in the context of mild traumatic brain injury (mTBI) for the following reasons: (1) the magnitude of the biomarker changes following concussion was higher for T-tau than for S-100B and NSE, (2) the levels of S-100B and NSE, but not T-tau, increased after a friendly game without concussion compared with baseline samples from the same individuals, and (3) postconcussion T-tau levels were more strongly associated with concussion severity than S-100B and NSE. An additional drawback with S-100B and NSE is that both of these proteins are expressed in extracerebral tissues,2 which may explain the in-
Author Affiliations: Clinical Neurochemistry Laboratory, Institute of Neuroscience and Physiology, Sahlgrenska Academy at University of Gothenburg, Sahlgrenska University Hospital, Mölndal, Sweden (Shahim, Blennow, Zetterberg); Reta Lila Weston Laboratories, Department of Molecular Neuroscience, University College London Institute of Neurology, London, England (Zetterberg). Corresponding Author: Pashtun Shahim, MD, Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, S-431 80 Mölndal, Sweden ([email protected]). Conflict of Interest Disclosures: Drs Blennow and Zetterberg are listed as coinventors on a US patent application for plasma tau as a brain injury marker. Dr Blennow has served on advisory boards for Eli Lilly, Kyowa Kirin Pharma, Pfizer, and Roche. No other disclosures were reported. 1. Shahim P, Tegner Y, Wilson DH, et al. Blood biomarkers for brain injury in concussed professional ice hockey players [published online March 13, 2014]. JAMA Neurol. doi:10.1001/jamaneurol.2014.36. 2. Anderson RE, Hansson LO, Nilsson O, Dijlai-Merzoug R, Settergren G. High serum S100B levels for trauma patients without head injuries. Neurosurgery. 2001;48(6):1255-1258, discussion 1258-1260.
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Copyright 2014 American Medical Association. All rights reserved.
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3. Routsi C, Stamataki E, Nanas S, et al. Increased levels of serum S100B protein in critically ill patients without brain injury. Shock. 2006;26(1):20-24. 4. Stålnacke BM, Ohlsson A, Tegner Y, Sojka P. Serum concentrations of two biochemical markers of brain tissue damage S-100B and neurone specific enolase are increased in elite female soccer players after a competitive game. Br J Sports Med. 2006;40(4):313-316.
6. Undén J, Ingebrigtsen T, Romner B; Scandinavian Neurotrauma Committee (SNC). Scandinavian guidelines for initial management of minimal, mild and moderate head injuries in adults: an evidence and consensus-based update. BMC Med. 2013;11:50.
5. Hasselblatt M, Mooren FC, von Ahsen N, et al. Serum S100beta increases in marathon runners reflect extracranial release rather than glial damage. Neurology. 2004;62(9):1634-1636.
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Copyright 2014 American Medical Association. All rights reserved.
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927
Author Affiliations: Institute of Neurology, Catholic University, Rome, Italy. Corresponding Author: Assunta Bianco, MD, Institute of Neurology, Department of Geriatrics, Neurosciences and Orthopaedics, Catholic University, School of Medicine A. Gemelli, Largo Agostino Gemelli 8, 00168 Rome, Italy ([email protected]). Conflict of Interest Disclosures: None reported. 1. Cohen M, Maillart E, Tourbah A, et al; Club Francophone de la Sclérose en Plaques Investigators. Switching from natalizumab to fingolimod in multiple sclerosis: a French prospective study. JAMA Neurol. 2014;71(4):436-441. 2. de Seze J, Ongagna JC, Collongues N, et al; Alsacep Network. Reduction of the washout time between natalizumab and fingolimod. Mult Scler. 2013;19(9): 1248. 3. Stüve O, Cravens PD, Frohman EM, et al. Immunologic, clinical, and radiologic status 14 months after cessation of natalizumab therapy. Neurology. 2009;72 (5):396-401. 4. Kahan BD, Karlix JL, Ferguson RM, et al. Pharmacodynamics, pharmacokinetics, and safety of multiple doses of FTY720 in stable renal transplant patients: a multicenter, randomized, placebo-controlled, phase I study. Transplantation. 2003;76(7):1079-1084.
In Reply We read with attention comments from Bianco et al regarding the ENIGM (Enquête Nationale sur I’Introduction du Fingolimod en Relais au Natalizumab) study. In our statistical analysis, the main outcome was the presence of clinical disease reactivation (occurrence of at least 1 relapse) during the switching period. We first analyzed the washout then the fingolimod initiation period during a 6-month follow-up.1 Regarding washout, our results revealed an important reduction of disease reactivation rates for patients with washout duration shorter than 3 months (odds ratio, 0.23; P < .01). This result seems highly significant both in univariate and multivariate analyses. Regarding initiation of fingolimod, 230 patients reached the 6-month follow-up end point when the analysis was conducted. However, among patients who had not reached this end point, some had already relapsed and that is why the result (20%) was reported among the whole cohort. Furthermore, statistical analysis for this period was conducted comparing all patients who experienced at least 1 relapse while taking fingolimod compared with the patients who reached 6-month follow-up without any relapse. We did not collect either data about multiple recurrences nor the precise time to first relapse in our study. Finally, Bianco et al suggested that a randomized intervention study could give more relevant results about the safety and efficacy of switching from natalizumab to fingolimod. We would like to underline the results of the TOFINGO Study2 that were presented at the 2013 European Committee for Treatment and Research in Multiple Sclerosis Annual Meeting. The TOFINGO Study was a rater- and patient-blind, randomized study that compared the safety and efficacy of 3 different washout durations (8, 12, or 16 weeks) in a cohort of 142 patients. The main outcome was the presence of radiologic signs of disease reactivation and follow-up duration during fingolimod treatment of 32 weeks. The results showed that the patients in the 16-week washout group had a significantly higher risk for disease reactivation compared with the 2 other groups. No statistical difference was found
between 8-week and 12-week washout regimens either in efficacy or toxicity. Those results, which were not available at the time of submission of our article, are fairly similar to our findings in the ENIGM study. Mikael Cohen, MD Christine Lebrun, MD, PhD Author Affiliations: Department of Neurology, University Hospital of Nice, Nice, France. Corresponding Author: Mikael Cohen, MD, Department of Neurology, University Hospital of Nice, 30 Voie Romaine, 06000 Nice, France (cohen.m @chu-nice.fr). Conflict of Interest Disclosures: None reported. 1. Cohen M, Maillart E, Tourbah A, et al; Club Francophone de la Sclérose en Plaques Investigators. Switching from natalizumab to fingolimod in multiple sclerosis: a French prospective study. JAMA Neurol. 2014;71(4):436-441. 2. Kappos L, Radue EW, Comi G, et al. Disease control and safety in relapsing-remitting multiple sclerosis (RRMS) patients switching from natalizumab to fingolimod: a 32-week, rater- and patient-blind, randomized, parallel-group study (TOFINGO). Abstract No. 167. Paper presented at the 2013 European Committee for Treatment and Research in Multiple Sclerosis Annual Meeting; October 2-5, 2013; Copenhagen, Denmark.
Tau, S-100 Calcium-Binding Protein B, and NeuronSpecific Enolase as Biomarkers of Concussion To the Editor That the Quanterix platform was able to detect elevated levels of tau at subfentamole concentrations after sports-related concussion is indeed an exciting development in the article by Shahim and colleagues.1 However, the conclusion made by Shahim et al,1 and by the accompanying editorial,2 that S-100 calcium-binding protein B (S-100B) and neuron-specific enolase (NSE) lack use as diagnostic markers is flawed for several reasons. Shahim et al1 compared postconcussion marker concentrations in 1 subset of athletes with preinjury concentrations in an independent subset from the same ice hockey league, preventing the authors from uncovering significant subjectspecific marker differences. High variation in normal brain structure and function can obscure small but significant changes when groups, rather than individuals, are analyzed. This realization has led to the discovery of concussionrelated changes in cognitive function, cortical activation, and white matter integrity.3 Indeed, Kiechle et al4 previously demonstrated the markedly enhanced diagnostic value of S-100B when postinjury values were compared with baseline values for each athlete. Additionally, there is no biologic rationale for combining marker values from the 4 postinjury time intervals studied (1, 12, 36, and 144 hours). The axonal injury events reflected by changes in the levels of tau, S-100B, and NSE vary from hour to hour postinjury. The lack of a statistical increase in this temporally aggregated postinjury metric was used in the accompanying editorial to cast “serious doubt” on the usefulness of S-100B and an NSE as concussion biomarkers.2 In fact, Shahim et al1 reported that both S-100B and tau were significantly elevated acutely after concussion, which is arguably the most important time for making diagnostic decisions in prehospital, emergency department, playing field, and battlefield settings.
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Copyright 2014 American Medical Association. All rights reserved.
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925
Letters
Finally, the authors’ reasoning that S-100B and NSE were not sensitive markers of concussion because of increased levels observed after a “friendly game” of hockey is inherently flawed. Player-to-player contact is not prohibited during typical friendly games. Although no concussions were reported, any physical contact between players could have resulted in occult brain trauma, a widely reported observation in the context of football and soccer.5 Without an independent, gold-standard measure of brain injury, it is not possible to conclude with any certainty that elevations in biomarker levels after friendly games were not due to occult brain injury. While tau may have future value as a biomarker of concussion, the assertion that S-100B and NSE have little diagnostic value is not supported by the observations by Shahim et al.1 Jeffrey J. Bazarian, MD, MPH Kian Merchant-Borna, MPH Author Affiliations: Department of Emergency Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York. Corresponding Author: Jeffrey J. Bazarian, MD, MPH, Department of Emergency Medicine, University of Rochester School of Medicine and Dentistry, 265 Elmwood Ave, Rochester, NY 14642 ([email protected]). Conflict of Interest Disclosures: Dr Bazarian has a patent pending titled, “Method of Diagnosing Mild Traumatic Brain Injury.” Dr Bazarian serves as a consultant for Banyan Biomarkers, Roche Diagnostics. No other disclosures were reported. 1. Shahim P, Tegner Y, Wilson DH, et al. Blood biomarkers for brain injury in concussed professional ice hockey players [published online March 13, 2014]. JAMA Neurol. doi:10.1001/jamaneurol.2014.36. 2. Gatson J, Diaz-Arrastia R. Tau as a biomarker of concussion [published online March 13, 2014]. JAMA Neurol. doi:10.1001/jamaneurol.2014.443. 3. Bazarian JJ, Zhu T, Blyth B, Borrino A, Zhong J. Subject-specific changes in brain white matter on diffusion tensor imaging after sports-related concussion. Magn Reson Imaging. 2012;30(2):171-180. 4. Kiechle K, Bazarian JJ, Merchant-Borna K, et al. Subject-specific increases in serum S-100B distinguish sports-related concussion from sports-related exertion. PLoS One. 2014;9(1):e84977.
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creases we observed after a friendly game. In agreement, several studies have found increased serum levels of S-100B in the absence of head injury in soccer players, marathon runners, and patients with peripheral trauma. 3-5 Neuronspecific enolase is also released in the blood by hemolysis, which may be a serious source of error in some cases. Finally, only 5 of the 28 concussed ice hockey players had S-100B elevations above the cutpoint suggested by Undén et al6 in their consensus statement on guidelines for the initial management of mTBI. The criticism by Bazarian and Merchant-Borna that we compared postconcussion data with preseason values of 2 complete teams (ie, not the preconcussion samples from the same individuals who experienced concussion and therefore perhaps missed interesting intraindividual changes in the biomarkers) is in our minds a very minor weakness of our study. The common (and rational) way to use fluid biomarkers is to compare with a reference group. In a clinical situation, Bazarian and Merchant-Borna will never have access to preconcussion samples from patients. A clinically useful biomarker simply has to be good enough to provide meaningful data also in the absence of such samples. Moreover, an important aspect of interpreting biomarker results is taking into account the dynamic changes in the biomarker levels following the injury (eg, compare the clinical use of troponins in the diagnosis of myocardial infarction). In our study, we noticed an increase and fall in the levels of T-tau, which correlated with the postconcussive symptoms, whereas NSE and S-100B displayed no such, or less clear, dynamics. Taken together, all these data suggest that S-100B and NSE are quite insensitive biomarkers for mTBI and clearly inferior to tau. However, we agree that we should continue analyzing these biomarkers head to head also in future studies of candidate blood biomarkers for mTBI, in which additional biomarkers (eg, neurofilament light and spectrin breakdown products) should be assessed because we still do not have the optimal biomarker at hand.
5. Koerte IK, Ertl-Wagner B, Reiser M, Zafonte R, Shenton ME. White matter integrity in the brains of professional soccer players without a symptomatic concussion. JAMA. 2012;308(18):1859-1861.
Pashtun Shahim, MD Kaj Blennow, MD, PhD Henrik Zetterberg, MD, PhD
In Reply We thank Bazarian and Merchant-Borna for their comment on our article,1 suggesting that we should have interpreted the S-100 calcium-binding protein B (S-100B) and neuron-specific enolase (NSE) data in our study more positively than we did. We wish to clarify that we maintain our conclusion about the limited diagnostic value of S-100B and NSE in the context of mild traumatic brain injury (mTBI) for the following reasons: (1) the magnitude of the biomarker changes following concussion was higher for T-tau than for S-100B and NSE, (2) the levels of S-100B and NSE, but not T-tau, increased after a friendly game without concussion compared with baseline samples from the same individuals, and (3) postconcussion T-tau levels were more strongly associated with concussion severity than S-100B and NSE. An additional drawback with S-100B and NSE is that both of these proteins are expressed in extracerebral tissues,2 which may explain the in-
Author Affiliations: Clinical Neurochemistry Laboratory, Institute of Neuroscience and Physiology, Sahlgrenska Academy at University of Gothenburg, Sahlgrenska University Hospital, Mölndal, Sweden (Shahim, Blennow, Zetterberg); Reta Lila Weston Laboratories, Department of Molecular Neuroscience, University College London Institute of Neurology, London, England (Zetterberg). Corresponding Author: Pashtun Shahim, MD, Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, S-431 80 Mölndal, Sweden ([email protected]). Conflict of Interest Disclosures: Drs Blennow and Zetterberg are listed as coinventors on a US patent application for plasma tau as a brain injury marker. Dr Blennow has served on advisory boards for Eli Lilly, Kyowa Kirin Pharma, Pfizer, and Roche. No other disclosures were reported. 1. Shahim P, Tegner Y, Wilson DH, et al. Blood biomarkers for brain injury in concussed professional ice hockey players [published online March 13, 2014]. JAMA Neurol. doi:10.1001/jamaneurol.2014.36. 2. Anderson RE, Hansson LO, Nilsson O, Dijlai-Merzoug R, Settergren G. High serum S100B levels for trauma patients without head injuries. Neurosurgery. 2001;48(6):1255-1258, discussion 1258-1260.
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3. Routsi C, Stamataki E, Nanas S, et al. Increased levels of serum S100B protein in critically ill patients without brain injury. Shock. 2006;26(1):20-24. 4. Stålnacke BM, Ohlsson A, Tegner Y, Sojka P. Serum concentrations of two biochemical markers of brain tissue damage S-100B and neurone specific enolase are increased in elite female soccer players after a competitive game. Br J Sports Med. 2006;40(4):313-316.
6. Undén J, Ingebrigtsen T, Romner B; Scandinavian Neurotrauma Committee (SNC). Scandinavian guidelines for initial management of minimal, mild and moderate head injuries in adults: an evidence and consensus-based update. BMC Med. 2013;11:50.
5. Hasselblatt M, Mooren FC, von Ahsen N, et al. Serum S100beta increases in marathon runners reflect extracranial release rather than glial damage. Neurology. 2004;62(9):1634-1636.
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