In 2010 Edward Tobinick M.D., Medical Director of the Institute of Neurological Recovery,  made a stunning discovery: that the neurological status of patients following stroke or brain injury, even years after the acute event, may rapidly improve following the off-label use of perispinal etanercept. Read the Springer press release:


New hope for survivors of stroke and traumatic brain injury

Single dose of etanercept targets brain inflammation years after damage

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A new ground-breaking study about to be published in the Adis journal CNS Drugs provides clinical evidence that, for the first time, chronic neurological dysfunction from stroke or traumatic brain injury can rapidly improve following a single dose of a drug that targets brain inflammation, even years after the stroke or traumatic event.

The observational study¹ of 629 patients, conducted over the course of nearly two years, documents a diverse range of positive effects, including statistically significant rapid clinical improvement in motor impairment, spasticity, cognition, etc. in the stroke group, with a similar pattern of improvement seen in the traumatic brain injury (TBI) group. The study involved 617 patients treated an average of 42 months after stroke and 12 patients treated an average of 115 months after TBI, long after further spontaneous meaningful recovery would be expected.

The study was conducted at the Institute of Neurological Recovery (INR) in the USA.

The drug utilized was etanercept, a therapeutic that selectively binds and neutralizes an inflammatory immune molecule that may remain elevated for years following stroke. The anti-TNF fusion protein was administered utilizing a novel delivery method, invented by Edward Tobinick M.D., lead author of the study.

“These results represent a sea change in the therapeutic possibilities for stroke and TBI patients,” said Steven Ralph PhD, Associate Professor at Griffith University School of Medical Science in Australia. “Rarely do we see such a radical breakthrough in medical treatment as this for stroke. A previous example was the advance with thrombolytic therapy using drugs such as tissue plasminogen activator (t-PA) for the treatment of acute stroke with their significant impact when applied at the early stages. However, no similar treatment has existed for chronic stroke until now.”

Professor Ralph recently led a team of physicians to the INR for training in the new [drug] delivery method, prior to their initiation of randomized trials in Australia. “Our team observed, first hand, rapid clinical improvement in stroke patients following this brief office treatment,” said Professor Ralph.

In an accompanying editorial², Professor Ian Clark, a world expert on tumor necrosis factor (TNF) and brain dysfunction, discusses the science underlying the novel treatment method and clinical results. The high prevalence of chronic post-stroke and post-TBI neurological disability, with millions of individuals affected worldwide, highlights the study’s significance.


1. Selective TNF Inhibition for Chronic Stroke and Traumatic Brain Injury – An Observational Study Involving 629 Consecutive Patients…. CNS Drugs. 2012;16(12). DOI 10.1007/s40263-012-0013-2

2. Clark, I. New Hope for Survivors of Stroke and Traumatic Brain Injury. CNS Drugs. 2012;16(12). DOI 10.1007/s40263-012-0014-1 (Free Download).

Selected INR® Scientific Publications:

  • Immediate resolution of hemispatial neglect and central post-stroke pain after perispinal etanercept: case report. Tobinick, E., Clinical Drug Investigation, 2019 Oct 22, epub. 
    (Free Link to Journal Article).
  • Perispinal etanercept advances as a neurotherapeutic. Tobinick, E., Expert Review Neurotherapeutics, 2018:1-3.(Free Download).
  • Perispinal Etanercept for Traumatic Brain Injury. Edward Tobinick MD, Rodriguez-Romanacce H, Kinssies R, Kim N. Chapter 7, pp. 109-29, in New Therapeutics for Traumatic Brain Injury, KA Heidenreich, editor. Cambridge, Mass.: Academic Press. 2017. (Link to Book Chapter).
  • Selective TNF Inhibition for Chronic Stroke and Traumatic Brain Injury – An Observational Study Involving 629 Consecutive Patients Treated with Perispinal Etanercept. Edward Tobinick MD, Kim NM, Reyzin G, Rodriguez H, DePuy V. CNS Drugs. 2012 Dec;26(12):1051-70. (Link to Journal Article).
  • Perispinal Etanercept for Post-Stroke Neurological and Cognitive Dysfunction: Scientific Rationale and Current Evidence. Ignatowski TA, Spengler RN, Dhandapani KM, Folkersma H, Butterworth RF, Tobinick E. CNS Drugs, August 2014, 28(8):679-697, published online 27 May 2014. (Free Download).
  • Immediate Neurological Recovery Following Perispinal Etanercept Years After Brain Injury. Edward Tobinick MD, Rodriguez-Romanacce H, Levine A, Ignatowski TA, Spengler RN. Clin Drug Investig. 2014 May;34(5):361-6. (Link to Journal Article).
  • Studies of Selective TNF Inhibitors in the Treatment of Brain Injury From Stroke and Trauma: A Review of Evidence to Date. Tuttolomondo, A., R. Pecoraro, and A. Pinto, Drug Design, Development and Therapy, 2014(November). 8: p. 2221-2239. (Free Download).
  • Rapid Improvement of Chronic Stroke Deficits After Perispinal Etanercept: Three Consecutive Cases. Edward Tobinick MD. CNS Drugs. 2011 Feb 1; 25(2):145-155. (Link to Journal Article).
  • Perispinal Etanercept: A New Therapeutic Paradigm in Neurology. Edward Tobinick MD. Expert Review of Neurotherapeutics. 2010 Jun;10(6):985-1002. (Free Download).
  • Perispinal Etanercept: Potential as An Alzheimer Therapeutic. Griffin WS. J Neuroinflammation. 2008 Jan 10;5:3. (Free Download).
  • Rapid cognitive improvement in Alzheimer’s disease following perispinal etanercept administration. Edward Tobinick MD, Hyman Gross MD. Journal of Neuroinflammation. 2008 Jan 9;5:2. (Free Download).
  • Efficacy of etanercept delivered by perispinal administration for chronic back and/or neck disc-related pain: a study of clinical observations in 143 patients. Edward Tobinick MD, Davoodifar S. Curr Med Res Opin. 2004 Jul;20(7):1075-85. (Link to Journal Article).

Selected Additional INR Scientific Publications:

  • Perispinal etanercept advances as a neurotherapeutic. Tobinick, E., Expert Review Neurotherapeutics, 2018:1-3.(Free Download).
  • On Overcoming Barriers to Application of Neuroinflammation Research. Edward Tobinick MD, Ignatowski, T., Spengler, R. In: Abreu GEA, ed. Mechanisms of Neuroinflammation: InTechOpen; 2017. (Free Download).
  • Perispinal Delivery of CNS Drugs.  Edward Tobinick MD.  CNS Drugs, 2016;30(6):469-80. (Free Download).
  • Authors’ Reply to Whitlock: Perispinal Etanercept for Post-Stroke Neurological and Cognitive Dysfunction: Scientific Rationale and Current Evidence. Ignatowski TA, Spengler RN, Tobinick E. CNS Drugs, December 2014, 28(12):1207-13. (Free Download).
  • Deciphering the physiology underlying the rapid clinical effects of perispinal etanercept in Alzheimer’s disease. Edward Tobinick MD. Current Alzheimer Research 2012, 9:99-109. (Free Download).
  • Tumour necrosis factor modulation for treatment of Alzheimer’s disease: rationale and current evidence. Edward Tobinick MD. CNS Drugs. 2009 Sep 1;23(9):713-25. (Full Text Link).
  • The value of drug repositioning in the current pharmaceutical market. Edward Tobinick MD. Drug News Perspect. 2009 Mar;22(2):119-25. Review. (Full Text Link).
  • Rapid intracerebroventricular delivery of Cu-DOTA-etanercept after peripheral administration demonstrated by PET imaging. Edward Tobinick MD, K Chen PhD, X Chen PhD. BMC Res Notes. 2009 Feb 27;2:28. (Free Download).
  • Perispinal etanercept for neuroinflammatory disorders. Edward Tobinick MD. Drug Discovery Today. 2009 Feb;14(3-4):168-77. (Full Text Link).
  • Perispinal etanercept produces rapid improvement in primary progressive aphasia: identification of a novel, rapidly reversible TNF-mediated pathophysiologic mechanism. Edward Tobinick MD. Medscape J Med. 2008 Jun 10;10(6):135. (Full Text Link).
  • Rapid improvement in verbal fluency and aphasia following perispinal etanercept in Alzheimer’s disease. Edward Tobinick MD, H. Gross MD. BMC Neurology. 2008 Jul 21;8:27. (Free Download).
  • Re: Inflammatory markers and the risk of Alzheimer disease: the Framingham Study. Edward Tobinick MD. Neurology. 2008 Apr 1;70(14):1222-3. (Full Text Link).
  • Perispinal etanercept for treatment of Alzheimer’s disease. Edward Tobinick MD. Current Alzheimer Research. 2007 Dec;4(5):550-2. (Link to Journal Article).
  • A critique of intradiscal administration for treatment of radiculopathy. Edward Tobinick MD. Anesthesiology. 2008 Feb;108(2):334. (Link to Journal Article).
  • Spinal delivery of p38: TNF-alpha inhibitors. Edward Tobinick MD. PLoS Med. 2006 Nov;3(11):e511. (Link to Journal Article).
  • TNF-alpha modulation for treatment of Alzheimer’s disease: a 6-month pilot study. Edward Tobinick MD, Hyman Gross MD, Alan Weinberger MD, Hart Cohen MD. MedGenMed. 2006 Apr 26;8(2):25. (Full Text Link).
  • The cerebrospinal venous system: anatomy, physiology, and clinical implications. Edward Tobinick MD. MedGenMed. 2006 Feb 22;8(1):53. (Link to Journal Article).
  • Targeted etanercept for treatment-refractory pain due to bone metastasis: two case reports. Edward L. Tobinick MD. Clinical Therapeutics. 2003 Aug;25(8):2279-88. (Link to Journal Article).
 Recent publications by independent academic scientists:
  • Excess cerebral TNF causing glutamate excitotoxicity rationalizes treatment of neurodegenerative diseases and neurogenic pain by anti-TNF agentsClark, I.A. and B. Vissel. Journal of Neuroinflammation (2016) 13:236. (Free Full Text).
  • Treatment of traumatic brain injury with anti-inflammatory drugs. Bergold Peter J. Experimental Neurology 275 (Pt 3) (2016) 367-380. (Full Text Link).
  • Inflammatory Cytokine Receptor Blocade in a Rodent Model of Mild Traumatic Brain Injury. Perez-Polo JR, Rea HC, Johnson KM, Parsley MA, et. al. Journal of Neuroscience Research 94: 27-38 (2016). (Free Download).
  • Cerebral stroke injury: the role of cytokines and brain inflammation. Siniscalchi, A., Gallelli, L., Malferrari, G., Pirritano, D. et. al. J Basic Clin Physiol Pharmacy. 2014 May 1; 25(2):131-7. 2016:14(1):98-105. (Full Text Link).
  • A Neurologist’s Guide to TNF biology, and to the principles behind the therapeutic removal of excess TNF in disease. Clark IA, B Vissel. Neural Plasticity, Volume 2015, Article ID 358263, (Free Download).
  • Action of anti-TNF-alpha drugs on the progression of Alzheimer’s disease: A case report. Carlos Henrique Ferreira Camargo, FF Justus, G Uretzlaff, MRY Blood, MD Schafranski.  Dementia & Neuropsychoelogia. 9(2) April/June 2015. (Free Download).
  • Systemically administered anti-TNF therapy ameliorates functional outcomes after focal cerebral ischemia. Clausen, B., M. Degn, N. Martin, et al., J Neuroinflammation, 2014. 11(1): p. 203. (Free Download).
  • Etanercept Alleviates Early Brain Injury Following Experimental Subarachnoid Hemorrhage and the Possible Role of Tumor Necrosis Factor-alpha and c-Jun N-Terminal Kinase Pathway. Zhang, B., J. Song, X. Ma, et al., Neurochem Res, 2014. epub 2014 Dec 27. (Link to Journal Article).
  • Targeting TNF: a therapeutic strategy for Alzheimer’s disease. Cheng X, Shen Y, Li R. Drug Discovery Today. 2014:19(11):1822-7. (Full Text Link).
  • Tumor necrosis factor alpha: a link between neuroinflammation and excitotoxicity. Olmos G, Llado J. Mediators Inflamm. 2014;2014:861231. (Free Download).
  • Immunology primer for neurosurgeons and neurologists part 2: Innate brain immunity. Blaylock RL. Surg Neurol Int. 2013;4:118. (Free Download).

Additional scientific articles:

  •  The vertebral vein system. Caldwell lecture, 1956. Batson OV. Am J Roentgenol Radium Ther Nucl Med. 1957;78(2):195-212. (Link to Journal Article).
  • The craniospinal venous system. Pearce JM. Eur Neurol. 2006;56(2):136-8. (Free Full Text).
  • History of the vertebral venous plexus and the significant contributions of Breschet and Batson. Nathoo N, Caris EC, Wiener JA, Mendel E. Neurosurgery. 2011;69(5):1007-14; discussion 14. (Link to Journal Article).
  • Venous Drainage of the Spine and Spinal Cord: A Comprehensive Review of its History, Embryology, Anatomy, Physiology, and Pathology. Griessenauer CJ, Raborn J, Foreman P, Shoja MM, Loukas M, Tubbs RS. Clinical Anatomy. 2014;epub. (Link to Journal Article).
  • Randomized, Double-blind, Placebo-Controlled, Trial of Transforaminal Epidural Etanercept for the Treatment of Symptomatic Lumbar Disc Herniation.  Freeman, B.J., et. al. Spine (Phila Pa 1976), 2013. 38(23): p. 1986-94.(Link to Journal Article).
  • 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 (Phila Pa 1976), 2012. 37(6): p. 439-44. Ohtori, et. al. (Link to Journal Article).
  • Therapeutic evaluation of etanercept in a model of traumatic brain injury. Chio CC, Lin JW, Chang MW, Wang CC, Kuo JR, Yang CZ, Chang CP. J Neurochem. 2010 Nov;115(4):921-9. (Link to Journal Article).
  • Targeting TNF-Alpha to Elucidate and Ameliorate Neuroinflammation in Neurodegenerative Diseases. Frankola KA, Greig NH, Luo W, Tweedie D. CNS Neurol Disord Drug Targets. 2011 Feb 2. (Free Full Text).
  • Anti-TNF therapy in the injured spinal cord. Esposito E, Cuzzocrea S. Trends Pharmacol Sci. 2011 Feb;32(2):107-15. Epub 2010 Dec 23. (Link to Journal Article).
  • Etanercept restores the antinociceptive effect of morphine and suppresses spinal neuroinflammation in morphine-tolerant rats. Shen CH, Tsai RY, Shih MS, Lin SL, Tai YH, Chien CC, Wong CS. Anesth Analg. 2011 Feb;112(2):454-9. (Link to Journal Article).
  • Anti-TNF-alpha reduces amyloid plaques and tau phosphorylation and induces CD11c-positive dendritic-like cell in the APP/PS1 transgenic mouse brains. Shi JQ, Shen W, Chen J, Wang BR, Zhong LL, Zhu YW, Zhu HQ, Zhang QQ, Zhang YD, Xu J. Brain Res. 2011 Jan 12;1368:239-47. (Link to Journal Article).
  • Attenuation of Inflammatory Events in Human Intervertebral Disc Cells with a Tumor Necrosis Factor Antagonist. Sinclair SM, Shamji MF, Chen J, Jing L, Richardson WJ, Brown CR, Fitch RD, Setton LA. Spine (Phila Pa 1976). 2011 Jan 6. (Free Full Text).
  • Intrathecal inflammation precedes development of Alzheimer’s disease. Tarkowski E, Andreasen N, Tarkowski A, Blennow K. J Neurol Neurosurg Psychiatry. 2003 Sep;74(9):1200-5. (Free Full Text).
  • Tumor necrosis factor-alpha mediated signaling in neuronal homeostasis and dysfunction. Park KM, Bowers WJ. Cell Signal. 2010 Jul;22(7):977-83. (Free Full Text).
  • The roles of TNF in brain dysfunction and disease. Clark IA, Alleva LM, Vissel B. Pharmacol Ther. 2010 Dec;128(3):519-48. (Link to Journal Article).
  • An association study of 21 potential Alzheimer’s disease risk genes in a Finnish population. Sarajärvi T, Helisalmi S, Antikainen L, Mäkinen P, Koivisto AM, Herukka SK, Haapasalo A, Soininen H, Hiltunen M. J Alzheimers Dis. 2010;21(3):763-7. (Link to Journal Article).
  • The role of TNF-alpha signaling pathway on COX-2 upregulation and cognitive decline induced by beta-amyloid peptide. Medeiros R, Figueiredo CP, Pandolfo P, Duarte FS, Prediger RD, Passos GF, Calixto JB. Behav Brain Res. 2010 May 1;209(1):165-73. (Link to Journal Article).
  • Soluble TNF receptors are associated with A? metabolism and conversion to dementia in subjects with mild cognitive impairment. Buchhave P, Zetterberg H, Blennow K, Minthon L, Janciauskiene S, Hansson O. Neurobiol Aging. 2010 Nov;31(11):1877-84. (Link to Journal Article).
  • Inflammation and anti-inflammatory strategies for Alzheimer’s disease–a mini-review. McNaull BB, Todd S, McGuinness B, Passmore AP. Gerontology. 2010;56(1):3-14. (Free Full Text).
  • Systemic inflammation and disease progression in Alzheimer disease. Holmes C, Cunningham C, Zotova E, Woolford J, Dean C, Kerr S, Culliford D, Perry VH. Neurology. 2009 Sep 8;73(10):768-74. (Free Full Text).
  • Paths to acceptance. The advancement of scientific knowledge is an uphill struggle against ‘accepted wisdom’. Wolinsky H. EMBO Rep. 2008 May;9(5):416-8. (Free Full Text).

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