CNS Drugs

, Volume 28, Issue 12, pp 1207–1213 | Cite as

Authors’ Reply to Whitlock: Perispinal Etanercept for Post-Stroke Neurological and Cognitive Dysfunction: Scientific Rationale and Current Evidence

  • Tracey A. Ignatowski
  • Robert N. Spengler
  • Edward Tobinick
Open Access
Letter to the Editor


Neuropathic Pain Etanercept Escitalopram Certolizumab Pegol Neurological Improvement 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

The authors of this article have each been involved, over the course of more than a decade, in the basic science and/or clinical investigation of tumor necrosis factor (TNF) mechanisms involving the brain, i.e. in neuroinflammation research [1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16]. One of the aims of our 2014 review was to bring together the increasing scientific evidence, from multiple fields of investigation and multiple academic centers that support a central role of neuroinflammation in the pathogenesis of post-stroke neurological dysfunction [17]. In 2014, neuroinflammation has emerged as an area of increased international research interest, with intense interest in Europe and a new neurology journal devoted to this specific field [18, 19, 20].

Novel scientific discoveries, synthesized with previous scientific evidence, provide a framework for the scientific rationale underlying the rapid effects of perispinal etanercept on brain pathology [9, 13, 16, 21, 22, 23, 24, 25, 26, 27, 28]. This framework includes the discovery, in 2011, through the use of functional magnetic resonance imaging (fMRI), that within 24 h after neutralization of TNF by systemic intravenous administration of infliximab, nociceptive activity in the thalamus and somatosenoric cortex, as well as activation of the limbic system, was blocked [22]. In 2013, a single systemic subcutaneous dose of another biologic TNF inhibitor, certolizumab pegol, was found to produce a rapid decrease in disease-related fMRI brain activity in rheumatoid arthritis patients, which preceded both clinical and structural responses to the drug [28]. Just this week it was reported that a single dose of an antidepressant, the selective serotonin reuptake inhibitor escitalopram, dramatically alters functional connectivity throughout the whole brain in healthy subjects within 3 hours of the dose [23]. The rapid and profound effect that antidepressant drugs have on the production of TNF in the brain was first demonstrated by Ignatowski and Spengler in 1994 [29]. Antidepressant administration (desipramine) to rats prevented neuron-associated TNF production, as demonstrated by staining for TNF in the locus coeruleus and hippocampus [30]. This was demonstrated to occur within 24 h after drug administration [29, 30]. These findings, along with the scientific evidence previously considered in our 2014 review, demonstrate that rapid effects of perispinal etanercept are entirely compatible with brain physiology as it is understood today [9, 13, 14, 16, 17, 21, 23, 25, 26, 27, 31, 32, 33, 34, 35, 36, 37].

Whitlock has written a letter commenting on our 2014 review [38], which begins with a misconception regarding the well-known criteria that Sir Austin Bradford Hill originally developed to facilitate evaluation of causality [38, 39]. We utilized the Hill criteria in our 2014 review [17]. Contrary to the assertion of Whitlock, expert opinion supports use of the Bradford Hill criteria as one method to assist in the evaluation of the strength of evidence supporting therapeutic causality [40, 41, 42, 43]. This modification of the Hill criteria for therapeutic evaluation was not the authors’ invention; rather, this use of the Hill criteria was suggested by central figures in the evidence-based medicine paradigm (Howick and Glasziou) and others [40, 41, 42, 43, 44]. As Williams observed in 2001:

The narrow definition of epidemiology is the study of the distribution of diseases in a population. The broader definition—an inductive science of biological inferences derived from observations—is more appropriate when relating EBM principals to clinical decision making … . The use of Bradford-Hill Criteria enhances evidence-based recommendations [42].

Explicit consideration of the Bradford Hill criteria may facilitate appreciation of the scientific rationale and evidence regarding pathophysiology underlying innovative therapeutic decision making [17, 40, 41, 43, 45].

Randomized clinical trial (RCT) evidence is essential for regulatory approval but RCTs that involve innovative methods of drug delivery may only be possible with direct involvement of the drug manufacturer [46]. A blind insistence that the RCT constitutes the only valid form of evidence, as Whitlock suggests, does a disservice to science and the public [40, 41, 43, 47, 48, 49, 50, 51, 52]. The discovery of a new use of an existing drug often begins with an initial observation made in the course of clinical practice when utilizing the drug off-label [53, 54]. Evidence development commonly involves open-label observational studies; this was the case for the first approved indication of the biologic TNF inhibitors [55]. Rigorous observational studies, including case studies and case series, are a classical approach that may provide early evidence for therapeutic effectiveness before formal RCTs are conducted [40, 41, 42, 43, 44, 47, 48, 49, 50, 53, 56, 57, 58]. It is not scientifically justifiable to ignore the valid evidence contained in observational studies when evaluating therapeutic interventions, particularly for emerging indications [41, 43, 44, 45, 47, 49, 50, 51, 56, 57, 58, 59, 60]. As multiple authors have stated:

Sometimes the effect of a medical intervention is so surprisingly strong, against the background knowledge of ‘usual prognosis’, that a case report or case series suffices to convince [57].

Case reports and case series have their own role in the progress of medical science. They permit discovery of new diseases and unexpected effects (adverse or beneficial) as well as the study of mechanisms, and they play an important role in medical education. Case reports and series have a high sensitivity for detecting novelty and therefore remain one of the cornerstones of medical progress; they provide many new ideas in medicine [58].

Given that randomized, controlled trials have not and often cannot be done for many clinical interventions, much of the clinical care provided in neurology (and all other specialties in medicine) would necessarily be considered unsubstantiated, if observational studies are discounted from consideration … the popular belief that randomized, controlled trials inherently produce gold standard results, and that all observational studies are inferior, does a disservice to patient care, clinical investigation, and education of health care professionals [49].

As recently restated in an opinion viewpoint published in JAMA Neurology, “… over-reliance on RCTs is similar to resting all of health care evidence on a one-legged stool” [41, 47]. The authors concluded:

“Most health care decisions, especially by clinicians and patients, are based on incomplete evidence. This process could be improved with better access to transparent, credible, and concise yet complete summaries of the available evidence and its strength, whether or not it is conclusive and whether or not it includes RCTs” [47].

Authorities in the field of evidence-based medicine have specifically addressed the fact that some treatments have effects that are “… so dramatic that randomised trials are unnecessary [43]. Each of the authors has personally observed the unmistakable rapid neurological improvement produced by perispinal etanercept in patients with chronic, stable, baseline neurological dysfunction [8, 9, 10, 24, 26, 27, 32, 61]. The distinctive pattern of neurological improvement that often ensues following perispinal etanercept injection, documented in published digital video and written format, provides striking scientific evidence of a therapeutic effect [32, 62].1 These results are supported by a diverse variety of additional clinical and basic science studies that have specifically utilized etanercept as a therapeutic agent [8, 9, 10, 11, 12, 14, 17, 21, 24, 25, 26, 27, 32, 61, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78]. Our recent review presents a detailed overview of the scientific evidence that supports the mechanistic reasoning utilized [17, 45, 48]. There are no gaps in the pathophysiological mechanisms discussed; the inferential chain is complete [17, 48]. The published, peer-reviewed perispinal etanercept scientific literature provides more than a decade of scientific support that includes detailed case studies documenting rapid and sustained neurological improvement in patients with neurological dysfunction that had long been unchanged prior to perispinal etanercept administration [8, 9, 10, 11, 12, 13, 14, 16, 24, 25, 26, 27, 32, 61, 74, 75, 76, 79, 80, 81, 82].

These case reports are not isolated cases. Rather these results have been replicated, confirmed and extended [17, 25, 26, 32]. Four years of clinical experience with many additional patients with chronic brain dysfunction after stroke, intracerebral hemorrhage, and acquired brain injury has followed the documented pattern of statistically significant improvements in motor impairment, cognition, psychological/behavioural function, aphasia and pain following perispinal etanercept injection reported in the 629-patient study of 2012 [17, 25, 26, 32]. Moreover, since publication of the 2012 study [26], the peer-reviewed medical literature has provided further basic science and clinical support for the scientific rationale [6, 7, 17, 21, 26, 31, 32, 33, 34, 35, 36, 37, 47, 59, 63, 65, 66, 67, 69, 71, 75, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120]. As Lei et. al. and Kathirvelu and Carmichael stated in 2013 and 2014, respectively:

Antagonism of pro-inflammatory cytokines by specific antibodies represents a compelling therapeutic strategy to improve neurological outcome in patients after intracerebral hemorrhage [107].

With direct blood extravasation into brain, secondary inflammation is a substantial feature. Drugs which reduce neuroinflammation enhance functional recovery [94].

As a noted authority in the field of TNF and brain dysfunction has written:

… the years-long interval between the stroke event and rapid clinical improvement described in these patients is consistent with experimental evidence that TNF generation persists in the CSF for very much longer (10 months plus) than in the serum (gone in 6 h)…. In this report each patient’s pre-treatment state provided an internal control. In practice, these individual pre-treatment comparisons are highly valid, since the likelihood of rapid spontaneous return of function is remote this long after the stroke event. Moreover, since no two stroke outcomes are the same, such internal controls allow precise before and after clinical comparison in a phenotypically heterogeneous condition [121].

There are now multiple, reported RCTs of etanercept for neurological indications that have shown etanercept to be superior to placebo [64, 65, 66, 69, 71]. The character, magnitude and reproducibility of patient recovery documented following perispinal etanercept for chronic post-stroke neurological dysfunction is unequivocal evidence of a therapeutic effect [8, 9, 12, 17, 24, 25, 26, 27, 32, 74].

Whitlock further errs in his analogy comparing the effects of opiates and etanercept for neuropathic pain [38]. Exerting physiological effects that are distinct from those produced by opiates, TNF blockade using etanercept for treatment of neuropathic pain is a disease-modifying therapy that directly addresses a fundamental cause of the disorder, i.e. excess TNF [1, 63, 67, 68, 70, 72, 73, 77, 78, 84]. The authors each reported favorable effects of TNF blockade for the treatment of neuropathic pain, beginning more than a decade ago [1, 11, 12, 76]. To date, there are four favorable double-blind, randomized controlled trials of etanercept for sciatica and other forms of spinal neuropathic pain that have been completed [64, 65, 69, 71]. In addition, the basic science evidence supporting a therapeutic, disease-modifying effect of etanercept for the treatment of neuropathic pain continues to increase [1, 63, 67, 68, 70, 72, 73, 77, 78, 84]. It is of significant interest that recent evidence suggests that the early analgesic effects of biologic TNF inhibitors in patients with rheumatoid arthritis may be directly mediated, not peripherally but rather by rapid brain effects of the biologic TNF inhibitor [22].

The rapid and dramatic neurological improvement repeatedly observed after perispinal etanercept administration in patients with chronic, post-stroke neurological dysfunction cannot be scientifically attributed to a placebo response, as Whitlock seems to suggest [1, 6, 8, 9, 10, 14, 16, 17, 21, 22, 24, 25, 26, 27, 32, 36, 38, 41, 43, 44, 47, 56, 66, 75, 100, 118, 121, 122, 123, 124]. In fact, a recent Cochrane review concluded:

There was no evidence that placebo interventions in general have clinically important effects [124].

Placebo effects do not produce the life-changing neurological improvements that have been documented and observed by each of the authors and others following perispinal etanercept injection [14, 25, 26, 32, 43]. In view of the distinctive character, quality and reproducibility of the clinical data, and the basic science evidence that supports the entire inferential chain, it would be a systematic error to deny the published, peer-reviewed evidence and characterize the reported clinical results of perispinal etanercept for post-stroke neurological dysfunction as anything less than a therapeutic breakthrough [8, 9, 10, 11, 12, 14, 17, 21, 24, 25, 26, 27, 32, 48, 61, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78]. Those scientists who have recognized TNF antagonism for this indication as a “compelling therapeutic strategy”[107] are exactly in line with the guidance to “translate best neuroscience, including animal and human studies, into poststroke recovery research and clinical care” that is the published consensus recommendation of world stroke leaders [125].

Etanercept is providing billions of dollars of yearly income to its manufacturers. These drug manufacturers are the only entities that possess the combination of regulatory expertise and financial capability necessary to achieve regulatory approval for these essential novel therapeutic indications. The strength of the emerging evidence argues for joint industry–government–academic cooperation to facilitate overcoming the substantial translational barriers that exist for such an innovative therapeutic approach.



Acknowledgments and Conflict Disclosure

Edward Tobinick has multiple issued and pending US and foreign patents, assigned to TACT IP, LLC, which claim methods of use of etanercept for the treatment of neurological disorders, including, but not limited to, US patents 6419944, 6537549, 6982089, 7214658, 7629311, 8119127, 8236306 and 8349323, all assigned to TACT IP, LLC; and Australian patent 758523. Dr. Tobinick is the founder of the Institute of Neurological Recovery (INR), a group of medical practices that utilize perispinal etanercept as a therapeutic modality, and also train physicians; he is also the CEO of TACT IP, LLC. Tracey Ignatowski and Robert Spengler have been expert witnesses for the INR. Tracey Ignatowski and Robert Spengler’s professional activities include their work as Co-Directors of Neuroscience at NanoAxis, LLC, a company formed to foster the commercial development of products and applications in the field of nanomedicine, which include novel methods of inhibiting TNF. This article represents the authors’ own work in which NanoAxis, LLC, was not involved. No funding was received for this letter.


  1. 1.
    Ignatowski TA, Covey WC, Knight PR, Severin CM, Nickola TJ, Spengler RN. Brain-derived TNFalpha mediates neuropathic pain. Brain Res. 1999;841(1–2):70–7.PubMedGoogle Scholar
  2. 2.
    Covey WC, Ignatowski TA, Knight PR, Spengler RN. Brain-derived TNFalpha: involvement in neuroplastic changes implicated in the conscious perception of persistent pain. Brain Res. 2000;859(1):113–22.PubMedGoogle Scholar
  3. 3.
    Covey WC, Ignatowski TA, Renauld AE, Knight PR, Nader ND, Spengler RN. Expression of neuron-associated tumor necrosis factor alpha in the brain is increased during persistent pain. Reg Anesth Pain Med. 2002;27(4):357–66.PubMedGoogle Scholar
  4. 4.
    Reynolds JL, Ignatowski TA, Spengler RN. Effect of tumor necrosis factor-alpha on the reciprocal G-protein-induced regulation of norepinephrine release by the alpha2-adrenergic receptor. J Neurosci Res. 2005;79(6):779–87.PubMedGoogle Scholar
  5. 5.
    Ignatowski TA, Spengler RN. Cytokines in synaptic function. In: Berczi I, Szentivanyi A, editors. Cytokines and the brain. NeuroImmune biology. Vol 6. Amsterdam: Elsevier; 2008. p. 111–43.Google Scholar
  6. 6.
    Martuscello RT, Spengler RN, Bonoiu AC, Davidson BA, Helinski J, Ding H, et al. Increasing TNF levels solely in the rat hippocampus produces persistent pain-like symptoms. Pain. 2012;153(9):1871–82.PubMedCentralPubMedGoogle Scholar
  7. 7.
    Ignatowski TA, Gerard BA, Bonoiu AC, Mahajan S, Knight PR, Davidson BA, et al., editors. Reduction of tumor necrosis factor (TNF) in the hippocampus alleviates neuropathic pain perception. Proceedings of the 4th International Congress on Neuropathic Pain; 2013. pp 29–35.Google Scholar
  8. 8.
    Tobinick E, Gross H, Weinberger A, Cohen H. TNF-alpha modulation for treatment of Alzheimer’s disease: a 6-month pilot study. Med Gen Med. 2006;8(2):25.Google Scholar
  9. 9.
    Tobinick EL, Gross H. Rapid improvement in verbal fluency and aphasia following perispinal etanercept in Alzheimer’s disease. BMC Neurol. 2008;8:27.PubMedCentralPubMedGoogle Scholar
  10. 10.
    Tobinick EL, Chen K, Chen X. Rapid intracerebroventricular delivery of Cu-DOTA-etanercept after peripheral administration demonstrated by PET imaging. BMC Res Notes. 2009;2:28.PubMedCentralPubMedGoogle Scholar
  11. 11.
    Tobinick EL, Britschgi-Davoodifar S. Perispinal TNF-alpha inhibition for discogenic pain. Swiss Med Wkly. 2003;133(11–12):170–7.PubMedGoogle Scholar
  12. 12.
    Tobinick E, Davoodifar S. Efficacy of etanercept delivered by perispinal administration for chronic back and/or neck disc-related pain: a study of clinical observations in 143 patients. Curr Med Res Opin. 2004;20(7):1075–85.PubMedGoogle Scholar
  13. 13.
    Tobinick E. Perispinal etanercept for treatment of Alzheimer’s disease. Curr Alzheimer Res. 2007;4(5):550–2.PubMedGoogle Scholar
  14. 14.
    Griffin WS. Perispinal etanercept: potential as an Alzheimer therapeutic. J Neuroinflamm. 2008;5:3.Google Scholar
  15. 15.
    Maudsley S, Chadwick W. Progressive and unconventional pharmacotherapeutic approaches to Alzheimer’s disease therapy. Curr Alzheimer Res. 2012;9(1):1–4.PubMedGoogle Scholar
  16. 16.
    Tobinick E. Deciphering the physiology underlying the rapid clinical effects of perispinal etanercept in Alzheimer’s disease. Curr Alzheimer Res. 2012;9(1):99–109.PubMedGoogle Scholar
  17. 17.
    Ignatowski TA, Spengler RN, Dhandapani KM, Folkersma H, Butterworth RF, Tobinick E. Perispinal etanercept for post-stroke neurological and cognitive dysfunction: scientific rationale and current evidence. CNS Drugs. 2014;28(8):679–97.PubMedCentralPubMedGoogle Scholar
  18. 18.
    Mohammadi D. INMiND: getting to the bottom of neuroinflammation. Lancet Neurol. 2013;12(12):1135–6.PubMedGoogle Scholar
  19. 19.
    NEURON. Call for proposals for “European Research Projects on Neuroinflammation”, NEURON. 2014. Accessed 9 Oct 2014.
  20. 20.
    Ransohoff R. Call for papers: Neurology: Neuroimmunology and Neuroinflammation, a new neurology journal. Neurology. 2014;82:648–9.Google Scholar
  21. 21.
    Camara ML, Corrigan F, Jaehne EJ, Jawahar MC, Anscomb H, Baune BT. Effects of centrally administered etanercept on behaviour, microglia and astrocytes in mice following a peripheral immune challenge. Neuropsychopharmacology. 2014;. doi: 10.1038/npp.2014.199.PubMedGoogle Scholar
  22. 22.
    Hess A, Axmann R, Rech J, Finzel S, Heindl C, Kreitz S, et al. Blockade of TNF-alpha rapidly inhibits pain responses in the central nervous system. Proc Natl Acad Sci USA. 2011;108(9):3731–6.PubMedCentralPubMedGoogle Scholar
  23. 23.
    Schaefer A, Burmann I, Regenthal R, Arelin K, Barth C, Pampel A, et al. Serotonergic modulation of intrinsic functional connectivity. Cur Biol. 2014. doi: 10.1016/j.cub.2014.08.024.
  24. 24.
    Tobinick E. Perispinal etanercept: a new therapeutic paradigm in neurology. Expert Rev Neurother. 2010;10(6):985–1002.PubMedGoogle Scholar
  25. 25.
    Tobinick E. Rapid improvement of chronic stroke deficits after perispinal etanercept: three consecutive cases. CNS Drugs. 2011;25(2):145–55.PubMedGoogle Scholar
  26. 26.
    Tobinick E, Kim NM, Reyzin G, Rodriguez-Romanacce H, Depuy V. Selective TNF inhibition for chronic stroke and traumatic brain injury : an observational study involving 629 consecutive patients treated with perispinal etanercept. CNS Drugs. 2012;26(12):1051–70.PubMedGoogle Scholar
  27. 27.
    Tobinick EL, Gross H. Rapid cognitive improvement in Alzheimer’s disease following perispinal etanercept administration. J Neuroinflamm. 2008;5:2.Google Scholar
  28. 28.
    Rech J, Hess A, Finzel S, Kreitz S, Sergeeva M, Englbrecht M, et al. Association of brain functional magnetic resonance activity with response to tumor necrosis factor inhibition in rheumatoid arthritis. Arthritis Rheum. 2013;65(2):325–33.PubMedGoogle Scholar
  29. 29.
    Ignatowski TA, Spengler RN. Tumor necrosis factor-alpha: presynaptic sensitivity is modified after antidepressant drug administration. Brain Res. 1994;665(2):293–9.PubMedGoogle Scholar
  30. 30.
    Ignatowski TA, Noble BK, Wright JR, Gorfien JL, Heffner RR, Spengler RN. Neuronal-associated tumor necrosis factor (TNF alpha): its role in noradrenergic functioning and modification of its expression following antidepressant drug administration. J Neuroimmunol. 1997;79(1):84–90.PubMedGoogle Scholar
  31. 31.
    Vezzani A. Epilepsy and inflammation in the brain: overview and pathophysiology. Epilepsy Curr. 2014;14(1 Suppl):3–7.PubMedCentralPubMedGoogle Scholar
  32. 32.
    Tobinick E, Rodriguez-Romanacce H, Levine A, Ignatowski TA, Spengler RN. Immediate neurological recovery following perispinal etanercept years after brain injury. Clin Drug Investig. 2014;34(5):361–6.PubMedGoogle Scholar
  33. 33.
    Sedger LM, McDermott MF. TNF and TNF-receptors: from mediators of cell death and inflammation to therapeutic giants—past, present and future. Cytokine Growth Factor Rev. 2014;. doi: 10.1016/j.cytogfr.2014.07.016.Google Scholar
  34. 34.
    Pribiag H, Stellwagen D. Neuroimmune regulation of homeostatic synaptic plasticity. Neuropharmacology. 2014;78:13–22.PubMedGoogle Scholar
  35. 35.
    Olmos G, Llado J. Tumor necrosis factor alpha: a link between neuroinflammation and excitotoxicity. Mediat inflamm. 2014;2014:861231.Google Scholar
  36. 36.
    Cheng X, Shen Y, Li R. Targeting TNF: a therapeutic strategy for Alzheimer’s disease. Drug Discov Today. 2014;. doi: 10.1016/j.drudis.2014.06.029.Google Scholar
  37. 37.
    Santello M, Volterra A. TNF-alpha in synaptic function: switching gears. Trends Neurosci. 2012;35(10):638–47.PubMedGoogle Scholar
  38. 38.
    Whitlock DR. Comment on: “Perispinal etanercept for post-stroke neurological and cognitive dysfunction: scientific rationale and current evidence”. CNS Drugs. 2014. doi: 10.1007/s40263-014-0211-1.
  39. 39.
    Hill AB. The environment and disease: association or causation? Proc R Soc Med. 1965;58:295–300.PubMedCentralPubMedGoogle Scholar
  40. 40.
    Howick J, Glasziou P, Aronson JK. The evolution of evidence hierarchies: what can Bradford Hill’s ‘guidelines for causation’ contribute? J R Soc Med. 2009;102(5):186–94.PubMedCentralPubMedGoogle Scholar
  41. 41.
    Kaplan BJ, Giesbrecht G, Shannon S, McLeod K. Evaluating treatments in health care: the instability of a one-legged stool. BMC Med Res Methodol. 2011;11:65.PubMedCentralPubMedGoogle Scholar
  42. 42.
    Williams JK. Understanding evidence-based medicine: a primer. Am J Obstet Gynecol. 2001;185(2):275–8.PubMedGoogle Scholar
  43. 43.
    Glasziou P, Chalmers I, Rawlins M, McCulloch P. When are randomised trials unnecessary? Picking signal from noise. BMJ. 2007;334(7589):349–51.PubMedCentralPubMedGoogle Scholar
  44. 44.
    OCEBM Levels of Evidence Working Group. The Oxford 2011 levels of evidence. Oxford Centre for Evidence-Based Medicine. 2011. Accessed 9 Oct 2014.
  45. 45.
    Baeten D, van Hagen PM. Use of TNF blockers and other targeted therapies in rare refractory immune-mediated inflammatory diseases: evidence-based or rational? Ann Rheum Dis. 2010;69(12):2067–73.PubMedGoogle Scholar
  46. 46.
    US FDA. Guidance for clinical investigators, spon`sors, and IRBs. Investigational new drug applications (INDs)—determining whether human research studies can be conducted without an IND. 2013. Accessed 9 Oct 2014.
  47. 47.
    Dacks PA, Bennett DA, Fillit HM. Evidence needs to be translated, whether or not it is complete. JAMA Neurol. 2014;71(2):137–8.PubMedGoogle Scholar
  48. 48.
    Howick J, Glasziou P, Aronson JK. Evidence-based mechanistic reasoning. J R Soc Med. 2010;103(11):433–41.PubMedCentralPubMedGoogle Scholar
  49. 49.
    Concato J. Observational versus experimental studies: what’s the evidence for a hierarchy? NeuroRx. 2004;1(3):341–7.PubMedCentralPubMedGoogle Scholar
  50. 50.
    Concato J, Shah N, Horwitz RI. Randomized, controlled trials, observational studies, and the hierarchy of research designs. N Engl J Med. 2000;342(25):1887–92.PubMedCentralPubMedGoogle Scholar
  51. 51.
    Trudeau DL. The value of observational studies in neurotherapy. J Neurother. 2001;4(3):1–4.Google Scholar
  52. 52.
    Grossman J, Mackenzie FJ. The randomized controlled trial: gold standard, or merely standard? Perspect Biol Med. 2005;48(4):516–34.PubMedGoogle Scholar
  53. 53.
    Demonaco HJ, Ali A, Hippel E. The major role of clinicians in the discovery of off-label drug therapies. Pharmacotherapy. 2006;26(3):323–32.PubMedGoogle Scholar
  54. 54.
    Tobinick EL. The value of drug repositioning in the current pharmaceutical market. Drug News Perspect. 2009;22(2):119–25.PubMedGoogle Scholar
  55. 55.
    Elliott MJ, Maini RN, Feldmann M, Long-Fox A, Charles P, Bijl H, et al. Repeated therapy with monoclonal antibody to tumour necrosis factor alpha (cA2) in patients with rheumatoid arthritis. Lancet. 1994;344(8930):1125–7.PubMedGoogle Scholar
  56. 56.
    Sackett DL, Rosenberg WM, Gray JA, Haynes RB, Richardson WS. Evidence based medicine: what it is and what it isn’t. BMJ. 1996;312(7023):71–2.PubMedCentralPubMedGoogle Scholar
  57. 57.
    Vandenbroucke JP. Case reports in an evidence-based world. J R Soc Med. 1999;92(4):159–63.PubMedCentralPubMedGoogle Scholar
  58. 58.
    Vandenbroucke JP. In defense of case reports and case series. Ann Intern Med. 2001;134(4):330–4.PubMedGoogle Scholar
  59. 59.
    Kiene H, Hamre HJ, Kienle GS. In support of clinical case reports: a system of causality assessment. Glob Adv Health Med. 2013;2(2):64–75.PubMedCentralPubMedGoogle Scholar
  60. 60.
    Smith GC, Pell JP. Parachute use to prevent death and major trauma related to gravitational challenge: systematic review of randomised controlled trials. BMJ. 2003;327(7429):1459–61.PubMedCentralPubMedGoogle Scholar
  61. 61.
    Tobinick E. Perispinal etanercept produces rapid improvement in primary progressive aphasia: identification of a novel, rapidly reversible TNF-mediated pathophysiologic mechanism. Medscape J Med. 2008;10(6):135.PubMedCentralPubMedGoogle Scholar
  62. 62.
    Tobinick E, Rodriguez-Romanacce H, Levine A, Ignatowski TA, Spengler RN. Immediate neurological recovery following perispinal etanercept years after brain injury. Clin Drug Invest 2014; 34(5):361-66.Google Scholar
  63. 63.
    Coelho SC, Bastos-Pereira AL, Fraga D, Chichorro JG, Zampronio AR. Etanercept reduces thermal and mechanical orofacial hyperalgesia following inflammation and neuropathic injury. Eur J Pain. 2014;18(7):957–67.PubMedGoogle Scholar
  64. 64.
    Cohen SP, Bogduk N, Dragovich A, Buckenmaier CC 3rd, Griffith S, Kurihara C, et al. Randomized, double-blind, placebo-controlled, dose-response, and preclinical safety study of transforaminal epidural etanercept for the treatment of sciatica. Anesthesiology. 2009;110(5):1116–26.PubMedGoogle Scholar
  65. 65.
    Freeman BJ, Ludbrook GL, Hall S, Cousins M, Mitchell B, Jaros M, et al. Randomized, double-blind, placebo-controlled, trial of transforaminal epidural etanercept for the treatment of symptomatic lumbar disc herniation. Spine. 2013;38(23):1986–94.PubMedGoogle Scholar
  66. 66.
    Holmes C, Butchart J, Wolfe L, Davies L, Dodge S, Lewsey I, et al. The safety and tolerability of etanercept in Alzheimer’s disease (STEADI-09): a phase II double blind randomised placebo controlled trial 2014. Copenhagen: Alzheimer’s Association International Conference; 2014.Google Scholar
  67. 67.
    Iwatsuki K, Arai T, Ota H, Kato S, Natsume T, Kurimoto S, et al. Targeting anti-inflammatory treatment can ameliorate injury-induced neuropathic pain. PloS One. 2013;8(2):e57721.PubMedCentralPubMedGoogle Scholar
  68. 68.
    Kato K, Kikuchi S, Shubayev VI, Myers RR. Distribution and tumor necrosis factor-alpha isoform binding specificity of locally administered etanercept into injured and uninjured rat sciatic nerve. Neuroscience. 2009;160(2):492–500.PubMedGoogle Scholar
  69. 69.
    Ohtori S, Miyagi M, Eguchi Y, Inoue G, Orita S, Ochiai N, et al. Epidural administration of spinal nerves with the tumor necrosis factor-alpha inhibitor, etanercept, compared with dexamethasone for treatment of sciatica in patients with lumbar spinal stenosis: a prospective randomized study. Spine. 2012;37(6):439–44.PubMedGoogle Scholar
  70. 70.
    Olmarker K, Rydevik B. Selective inhibition of tumor necrosis factor-alpha prevents nucleus pulposus-induced thrombus formation, intraneural edema, and reduction of nerve conduction velocity: possible implications for future pharmacologic treatment strategies of sciatica. Spine. 2001;26(8):863–9.PubMedGoogle Scholar
  71. 71.
    Sainoh T, Orita S, Yamauchi K, Suzuki M, Sakuma Y, Kubota G, et al. Intradiscal administration of tumor necrosis factor-alpha inhibitor, etanercept, clinically improves intractable discogenic low back pain. Glob Spine J. 2014. doi: 10.1055/s-0034-1376544.
  72. 72.
    Shen CH, Tsai RY, Shih MS, Lin SL, Tai YH, Chien CC, et al. Etanercept restores the antinociceptive effect of morphine and suppresses spinal neuroinflammation in morphine-tolerant rats. Anesth Analg. 2011;112(2):454–9.PubMedGoogle Scholar
  73. 73.
    Sommer C, Schafers M, Marziniak M, Toyka KV. Etanercept reduces hyperalgesia in experimental painful neuropathy. J Peripher Nerv Syst. 2001;6(2):67–72.PubMedGoogle Scholar
  74. 74.
    Tobinick E. Perispinal etanercept for neuroinflammatory disorders. Drug Discov Today. 2009;14(3–4):168–77.PubMedGoogle Scholar
  75. 75.
    Tobinick E. Author’s reply to Page. “Selective TNF inhibition for chronic stroke and traumatic brain injury: an observational study involving 629 consecutive patients treated with perispinal etanercept”. CNS Drugs. 2013;27(5):399–402.PubMedGoogle Scholar
  76. 76.
    Tobinick EL. Targeted etanercept for discogenic neck pain: uncontrolled, open-label results in two adults. Clin Ther. 2003;25(4):1211–8.PubMedGoogle Scholar
  77. 77.
    Watanabe K, Yabuki S, Sekiguchi M, Kikuchi S, Konno S. Etanercept attenuates pain-related behavior following compression of the dorsal root ganglion in the rat. Eur Spine J. 2011;20(11):1877–84.PubMedCentralPubMedGoogle Scholar
  78. 78.
    Zanella JM, Burright EN, Hildebrand K, Hobot C, Cox M, Christoferson L, et al. Effect of etanercept, a tumor necrosis factor-alpha inhibitor, on neuropathic pain in the rat chronic constriction injury model. Spine. 2008;33(3):227–34.PubMedGoogle Scholar
  79. 79.
    Tobinick EL. Targeted etanercept for treatment-refractory pain due to bone metastasis: two case reports. Clin Ther. 2003;25(8):2279–88.PubMedGoogle Scholar
  80. 80.
    Tobinick E, Vega CP. The cerebrospinal venous system: anatomy, physiology, and clinical implications. Med Gen Med. 2006;8(1):53.Google Scholar
  81. 81.
    Tobinick E. Tumour necrosis factor modulation for treatment of Alzheimer’s disease: rationale and current evidence. CNS Drugs. 2009;23(9):713–25.PubMedGoogle Scholar
  82. 82.
    Ignatowski TA, Spengler RN, Dhandapani KM, Folkersma H, Butterworth RF, Tobinick E. Perispinal etanercept for post-stroke neurological and cognitive dysfunction: scientific rationale and current evidence. CNS Drugs. 2014.Google Scholar
  83. 83.
    Ye J, Jiang R, Cui M, Zhu B, Sun L, Wang Y, et al. Etanercept reduces neuroinflammation and lethality in mouse model of Japanese encephalitis. J Infect Dis. 2014;210(6):875-89.Google Scholar
  84. 84.
    Winkelstein BA, Allen KD, Setton LA. Chapter 19: intervertebral disc herniation: pathophysiology and emerging therapies. In: Shapiro IM, Risbud MV, editors. The intervertebral disc. Wien: Springer; 2014.Google Scholar
  85. 85.
    Wilcox KS, Vezzani A. Does brain inflammation mediate pathological outcomes in epilepsy? Adv Exp Med Biol. 2014;813:169-83.Google Scholar
  86. 86.
    Wang K, Liu B, Ma J. Research progress in traumatic brain penumbra. Chin Med J. 2014;127(10):1964–8.PubMedGoogle Scholar
  87. 87.
    Walters ET. Neuroinflammatory contributions to pain after SCI: roles for central glial mechanisms and nociceptor-mediated host defense. Exp Neurol. 2014;258C:48–61.Google Scholar
  88. 88.
    Viviani B, Boraso M, Marchetti N, Marinovich M. Perspectives on neuroinflammation and excitotoxicity: a neurotoxic conspiracy? Neurotoxicology. 2014;43:10-20.Google Scholar
  89. 89.
    Topdag M, Iseri M, Topdag DO, Kokturk S, Ozturk M, Iseri P. The effect of etanercept and methylprednisolone on functional recovery of the facial nerve after crush injury. Otol Neurotol. 2014;35(7):1277-83.Google Scholar
  90. 90.
    Sun Q, Hampel H, Blennow K, Lista S, Levey A, Tang B, et al. Increased plasma TACE activity in subjects with mild cognitive impairment and patients with Alzheimer’s disease. J Alzheimer’s Dis. 2014;41(3):877–86.Google Scholar
  91. 91.
    Siniscalchi A, Gallelli L, Malferrari G, Pirritano D, Serra R, Santangelo E, et al. Cerebral stroke injury: the role of cytokines and brain inflammation. J Basic Clin Physiol Pharmacol. 2014;25(2):131-7.Google Scholar
  92. 92.
    Ohtori S, Inoue G, Miyagi M, Takahashi K. Pathomechanisms of discogenic low back pain in humans and animal models. Spine J. 2014;. doi: 10.1016/j.spinee.2013.07.490.PubMedGoogle Scholar
  93. 93.
    Najem D, Bamji-Mirza M, Chang N, Liu QY, Zhang W. Insulin resistance, neuroinflammation, and Alzheimer’s disease. Rev Neurosci. 2014;25(4):509-25.Google Scholar
  94. 94.
    Kathirvelu B, Carmichael ST. Intracerebral hemorrhage in mouse models: therapeutic interventions and functional recovery. Metab Brain Dis. 2014;. doi: 10.1007/s11011-014-9559-7.PubMedGoogle Scholar
  95. 95.
    Griessenauer CJ, Raborn J, Foreman P, Shoja MM, Loukas M, Tubbs RS. Venous drainage of the spine and spinal cord: a comprehensive review of its history, embryology, anatomy, physiology, and pathology. Clin Anat. 2014;. doi: 10.1002/ca.22354.Google Scholar
  96. 96.
    Gisondi P, Sala F, Alessandrini F, Avesani V, Zoccatelli G, Beltramello A, et al. Mild cognitive impairment in patients with moderate to severe chronic plaque psoriasis. Dermatology. 2014;228(1):78–85.PubMedGoogle Scholar
  97. 97.
    Ferreira ST, Clarke JR, Bomfim TR, De Felice FG. Inflammation, defective insulin signaling, and neuronal dysfunction in Alzheimer’s disease. Alzheimer’s dement J Alzheimer’s Assoc. 2014;10(1S):S76–83.Google Scholar
  98. 98.
    Faingold CL. Network control mechanisms: cellular inputs, neuroactive substances, and synaptic changes. In: Faingold CL, Blumenfeld H, editors. Neuronal networks in brain function. CNS Disorders, and Therapeutics: Elsevier; 2014.Google Scholar
  99. 99.
    Ekici MA, Uysal O, Cikriklar HI, Ozbek Z, Turgut Cosan D, Baydemir C, et al. Effect of etanercept and lithium chloride on preventing secondary tissue damage in rats with experimental diffuse severe brain injury. Eur Rev Med Pharmacol Sci. 2014;18(1):10–27.Google Scholar
  100. 100.
    Detrait ER, Danis B, Lamberty Y, Foerch P. Peripheral administration of an anti-TNF-alpha receptor fusion protein counteracts the amyloid induced elevation of hippocampal TNF-alpha levels and memory deficits in mice. Neurochem Int. 2014;. doi: 10.1016/j.neuint.2014.04.001.PubMedGoogle Scholar
  101. 101.
    Yoshiyama Y, Lee VM, Trojanowski JQ. Therapeutic strategies for tau mediated neurodegeneration. J Neurol Neurosurg Psychiatry. 2013;84(7):784–95.PubMedCentralPubMedGoogle Scholar
  102. 102.
    Works MG, Koenig JB, Sapolsky RM. Soluble TNF receptor 1-secreting ex vivo-derived dendritic cells reduce injury after stroke. J Cereb Blood Flow Metab. 2013;33(9):1376-85.Google Scholar
  103. 103.
    Waters RJ, Murray GD, Teasdale GM, Stewart J, Day I, Lee RJ, et al. Cytokine gene polymorphisms and outcome after traumatic brain injury. J Neurotrauma. 2013;30(20):1710–6.PubMedCentralPubMedGoogle Scholar
  104. 104.
    Swardfager W, Winer DA, Herrmann N, Winer S, Lanctot KL. Interleukin-17 in post-stroke neurodegeneration. Neurosci Biobehav Rev. 2013;37(3):436–47.PubMedGoogle Scholar
  105. 105.
    Shi X, Zhou W, Huang H, Zhu H, Zhou P, Zhu H, et al. Inhibition of the inflammatory cytokine tumor necrosis factor-alpha with etanercept provides protection against lethal H1N1 influenza infection in mice. Critical Care. 2013;17(6):R301.PubMedCentralPubMedGoogle Scholar
  106. 106.
    Miller ZA, Rankin KP, Graff-Radford NR, Takada LT, Sturm VE, Cleveland CM, et al. TDP-43 frontotemporal lobar degeneration and autoimmune disease. J Neurol Neurosurg Psychiatry. 2013;84(9):956–62.PubMedGoogle Scholar
  107. 107.
    Lei B, Dawson HN, Roulhac-Wilson B, Wang H, Laskowitz DT, James ML. Tumor necrosis factor alpha antagonism improves neurological recovery in murine intracerebral hemorrhage. J Neuroinflamm. 2013;10(1):103.Google Scholar
  108. 108.
    Kaufman EL, Carl A. Biochemistry of back pain. Open Spine J. 2013;5:12–8.Google Scholar
  109. 109.
    Johnson VE, Stewart JE, Begbie FD, Trojanowski JQ, Smith DH, Stewart W. Inflammation and white matter degeneration persist for years after a single traumatic brain injury. Brain. 2013;136(Pt 1):28–42.PubMedCentralPubMedGoogle Scholar
  110. 110.
    Furst DE, Fleischman R, Kalden J, Kavanaugh A, Sieper J, Mease P, et al. Documentation of off-label use of biologics in rheumatoid arthritis. Ann Rheum Dis. 2013;72(Suppl 2):ii35–51.Google Scholar
  111. 111.
    Efrati S, Fishlev G, Bechor Y, Volkov O, Bergan J, Kliakhandler K, et al. Hyperbaric oxygen induces late neuroplasticity in post stroke patients: randomized, prospective trial. PloS One. 2013;8(1):e53716.PubMedCentralPubMedGoogle Scholar
  112. 112.
    Clark IA, Vissel B. Treatment implications of the altered cytokine-insulin axis in neurodegenerative disease. Biochem Pharmacol. 2013;86(7):862–71.PubMedGoogle Scholar
  113. 113.
    Chio CC, Chang CH, Wang CC, Cheong CU, Chao CM, Cheng BC, et al. Etanercept attenuates traumatic brain injury in rats by reducing early microglial expression of tumor necrosis factor-alpha. BMC Neurosci. 2013;14(1):33.PubMedCentralPubMedGoogle Scholar
  114. 114.
    Cheong CU, Chang CP, Chao CM, Cheng BC, Yang CZ, Chio CC. Etanercept attenuates traumatic brain injury in rats by reducing brain TNF-alpha contents and by stimulating newly formed neurogenesis. Mediat Inflamm. 2013;2013:620837.Google Scholar
  115. 115.
    Butterworth RF. The liver-brain axis in liver failure: neuroinflammation and encephalopathy. Nature Rev Gastroenterol Hepatol. 2013;10(9):522–8.Google Scholar
  116. 116.
    Brambilla L, Martorana F, Rossi D. Astrocyte signaling and neurodegeneration: new insights into CNS disorders. Prion. 2013;7(1):28–36.PubMedCentralPubMedGoogle Scholar
  117. 117.
    Boivin N, Menasria R, Piret J, Rivest S, Boivin G. The combination of valacyclovir with an anti-TNF alpha antibody (etanercept) increases survival rate compared to antiviral therapy alone in a murine model of herpes simplex virus encephalitis. Antivir Res. 2013;100(3):649–53.PubMedGoogle Scholar
  118. 118.
    Blaylock RL. Immunology primer for neurosurgeons and neurologists part 2: innate brain immunity. Surg Neurol Int. 2013;4:118.PubMedCentralPubMedGoogle Scholar
  119. 119.
    Bai L, Song N, Yu J, Tan L, Shen Y, Xie J, et al. Elevated plasma levels of soluble TNFRs and TACE activity in Alzheimer’s disease patients of northern Han Chinese descent. Curr Alzheimer Res. 2013;10(1):57–62.PubMedGoogle Scholar
  120. 120.
    Williams M, Coyle JT. Historical perspectives on the discovery and development of drugs to treat neurological disorders. In: Barrett JE, Coyle JT, Williams M, editors. Translational neuroscience: applications in psychiatry, neurology, and neurodevelopmental disorders. New York: Cambridge University Press; 2012. p. 129–48.Google Scholar
  121. 121.
    Clark I. New hope for survivors of stroke and traumatic brain injury. CNS Drugs. 2012;26(12):1071–2.PubMedGoogle Scholar
  122. 122.
    Clark I, Atwood C, Bowen R, Paz-Filho G, Vissel B. Tumor necrosis factor-induced cerebral insulin resistance in Alzheimer’s disease links numerous treatment rationales. Pharmacol Rev. 2012;64(4):1004–26.PubMedGoogle Scholar
  123. 123.
    Hrobjartsson A, Gotzsche PC. Is the placebo powerless? An analysis of clinical trials comparing placebo with no treatment. N Engl J Med. 2001;344(21):1594–602.PubMedGoogle Scholar
  124. 124.
    Hrobjartsson A, Gotzsche PC. Placebo interventions for all clinical conditions. Cochrane Database Syst Rev. 2010;(1):CD003974.Google Scholar
  125. 125.
    Hachinski V, Donnan GA, Gorelick PB, Hacke W, Cramer SC, Kaste M, et al. Stroke: working toward a prioritized world agenda. Stroke. 2010;41(6):1084–99.PubMedCentralPubMedGoogle Scholar

Copyright information

© The Author(s) 2014

Open AccessThis article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.

Authors and Affiliations

  • Tracey A. Ignatowski
    • 1
  • Robert N. Spengler
    • 2
  • Edward Tobinick
    • 3
  1. 1.Department of Pathology and Anatomical Sciences and Program for NeuroscienceSchool of Medicine and Biomedical Sciences, The State University of New YorkBuffaloUSA
  2. 2.NanoAxis, LLCClarenceUSA
  3. 3.Institute of Neurological RecoveryBoca RatonUSA

Personalised recommendations