Skip to main content
SpringerLink
Log in

Immediate Neurological Recovery Following Perispinal Etanercept Years After Brain Injury

  • Case Report
  • Published:
Clinical Drug Investigation Aims and scope Submit manuscript

Abstract

Positron emission tomographic brain imaging and pathological examination have revealed that a chronic, intracerebral neuroinflammatory response lasting for years after a single brain injury may occur in humans. Evidence suggests the immune signaling molecule, tumor necrosis factor (TNF), is centrally involved in this pathology through its modulation of microglial activation, role in synaptic dysfunction, and induction of depressive symptoms and neuropathic pain. Etanercept is a recombinant TNF receptor fusion protein and potent TNF inhibitor that has been found to reduce microglial activation and neuropathic pain in multiple experimental models. We report that a single dose of perispinal etanercept produced an immediate, profound, and sustained improvement in expressive aphasia, speech apraxia, and left hemiparesis in a patient with chronic, intractable, debilitating neurological dysfunction present for more than 3 years after acute brain injury. These results indicate that acute brain injury-induced pathologic levels of TNF may provide a therapeutic target that can be addressed years after injury. Perispinal administration of etanercept is capable of producing immediate relief from brain injury-mediated neurological dysfunction.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1

References

  1. Pappata S, Levasseur M, Gunn RN, Myers R, Crouzel C, Syrota A, et al. Thalamic microglial activation in ischemic stroke detected in vivo by PET and [11C]PK1195. Neurology. 2000;55(7):1052–4.

    Article  CAS  PubMed  Google Scholar 

  2. Gentleman SM, Leclercq PD, Moyes L, Graham DI, Smith C, Griffin WS, et al. Long-term intracerebral inflammatory response after traumatic brain injury. Forensic Sci Int. 2004;146(2–3):97–104.

    Article  CAS  PubMed  Google Scholar 

  3. Gerhard A, Schwarz J, Myers R, Wise R, Banati RB. Evolution of microglial activation in patients after ischemic stroke: a [11C](R)-PK11195 PET study. Neuroimage. 2005;24(2):591–5.

    Article  PubMed  Google Scholar 

  4. Folkersma H, Boellaard R, Yaqub M, Kloet RW, Windhorst AD, Lammertsma AA, et al. Widespread and prolonged increase in (R)-(11)C-PK11195 binding after traumatic brain injury. J Nucl Med Off Publ Soc Nucl Med. 2011;52(8):1235–9.

    Google Scholar 

  5. Ramlackhansingh AF, Brooks DJ, Greenwood RJ, Bose SK, Turkheimer FE, Kinnunen KM, et al. Inflammation after trauma: microglial activation and traumatic brain injury. Ann Neurol. 2011;70(3):374–83.

    Article  PubMed  Google Scholar 

  6. 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.

    Article  PubMed Central  PubMed  Google Scholar 

  7. Tobinick E. Rapid improvement of chronic stroke deficits after perispinal etanercept: three consecutive cases. CNS Drugs. 2011;25(2):145–55.

    Article  CAS  PubMed  Google Scholar 

  8. 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.

    Article  CAS  PubMed  Google Scholar 

  9. Sommer C, Schafers M, Marziniak M, Toyka KV. Etanercept reduces hyperalgesia in experimental painful neuropathy. J Peripher Nerv Syst. 2001;6(2):67–72.

    Article  CAS  PubMed  Google Scholar 

  10. Chio CC, Lin JW, Chang MW, Wang CC, Kuo JR, Yang CZ, et al. Therapeutic evaluation of etanercept in a model of traumatic brain injury. J Neurochem. 2010;115(4):921–9.

    Article  CAS  PubMed  Google Scholar 

  11. Roh M, Zhang Y, Murakami Y, Thanos A, Lee SC, Vavvas DG, et al. Etanercept, a widely used inhibitor of tumor necrosis factor-alpha (TNF-alpha), prevents retinal ganglion cell loss in a rat model of glaucoma. PLoS One. 2012;7(7):e40065.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  12. Patterson J. F-A-S test. In: Kreutzer JS, DeLuca J, Caplan B, editors. Encyclopedia of clinical neuropsychology. New York: Springer Science + Business Media; 2011. p. 1024.

    Chapter  Google Scholar 

  13. Gagnon C, Mathieu J, Desrosiers J. Standardized finger-nose test validity for coordination assessment in an ataxic disorder. Can J Neurol Sci Le J Can Sci Neurol. 2004;31(4):484–9.

    Google Scholar 

  14. Lanzino DJ, Conner MN, Goodman KA, Kremer KH, Petkus MT, Hollman JH. Values for timed limb coordination tests in a sample of healthy older adults. Age Ageing. 2012;41(6):803–7.

    Article  PubMed  Google Scholar 

  15. Numasawa T, Ono A, Wada K, Yamasaki Y, Yokoyama T, Aburakawa S, et al. Simple foot tapping test as a quantitative objective assessment of cervical myelopathy. Spine. 2012;37(2):108–13.

    Article  PubMed  Google Scholar 

  16. Ross TP, Calhoun E, Cox T, Wenner C, Kono W, Pleasant M. The reliability and validity of qualitative scores for the Controlled Oral Word Association Test. Arch Clin Neuropsychol Off J Natl Acad Neuropsychol. 2007;22(4):475–88.

    Article  Google Scholar 

  17. Harkonen R, Harju R, Alaranta H. Accuracy of the Jamar dynamometer. J Hand Ther Off J Am Soc Hand Ther. 1993;6(4):259–62.

    Article  CAS  Google Scholar 

  18. Longwell T, Truax P. The differential effects of weekly, monthly, and bimonthly administration of the beck depression inventory-II: psychometric properties and clinical implications. Behav Ther. 2005;36:265–75.

    Article  Google Scholar 

  19. King NS, Crawford S, Wenden FJ, Moss NE, Wade DT. The Rivermead Post Concussion Symptoms Questionnaire: a measure of symptoms commonly experienced after head injury and its reliability. J Neurol. 1995;242(9):587–92.

    Article  CAS  PubMed  Google Scholar 

  20. De Simoni MG, Perego C, Ravizza T, Moneta D, Conti M, Marchesi F, et al. Inflammatory cytokines and related genes are induced in the rat hippocampus by limbic status epilepticus. Eur J Neurosci. 2000;12(7):2623–33.

    Article  PubMed  Google Scholar 

  21. Vezzani A. Epilepsy and inflammation in the brain: overview and pathophysiology. Epilepsy Currents. 2014;14(1 Suppl):3–7.

    Article  Google Scholar 

  22. Vezzani A, French J, Bartfai T, Baram TZ. The role of inflammation in epilepsy. Nat Rev Neurol. 2011;7(1):31–40.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  23. Jankowsky JL, Patterson PH. The role of cytokines and growth factors in seizures and their sequelae. Prog Neurobiol. 2001;63(2):125–49.

    Article  CAS  PubMed  Google Scholar 

  24. Plata-Salaman CR, Ilyin SE, Turrin NP, Gayle D, Flynn MC, Romanovitch AE, et al. Kindling modulates the IL-1beta system, TNF-alpha, TGF-beta1, and neuropeptide mRNAs in specific brain regions. Brain Res Mol Brain Res. 2000;75(2):248–58.

    Article  CAS  PubMed  Google Scholar 

  25. Turrin NP, Rivest S. Innate immune reaction in response to seizures: implications for the neuropathology associated with epilepsy. Neurobiol Dis. 2004;16(2):321–34.

    Article  CAS  PubMed  Google Scholar 

  26. Mraovitch S, Calando Y, Regnier A, Lamproglou I, Vicaut E. Post-seizures amygdaloallocortical microvascular lesion leading to atrophy and memory impairment. Neurobiol Dis. 2005;19(3):479–89.

    Article  CAS  PubMed  Google Scholar 

  27. Tobinick EL, Gross H. Rapid cognitive improvement in Alzheimer’s disease following perispinal etanercept administration. J Neuroinflam. 2008;5:2.

    Article  Google Scholar 

  28. Tobinick EL, Gross H. Rapid improvement in verbal fluency and aphasia following perispinal etanercept in Alzheimer’s disease. BMC Neurol. 2008;8:27.

    Article  PubMed Central  PubMed  Google Scholar 

  29. Tobinick E. Perispinal etanercept for neuroinflammatory disorders. Drug Discov Today. 2009;14(3–4):168–77.

    Article  CAS  PubMed  Google Scholar 

  30. Tobinick E. Tumour necrosis factor modulation for treatment of Alzheimer’s disease: rationale and current evidence. CNS Drugs. 2009;23(9):713–25.

    Article  CAS  PubMed  Google Scholar 

  31. Tobinick E. Perispinal etanercept: a new therapeutic paradigm in neurology. Expert Rev Neurother. 2010;10(6):985–1002.

    Article  CAS  PubMed  Google Scholar 

  32. 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.

    Article  CAS  PubMed  Google Scholar 

  33. Tobinick E. The cerebrospinal venous system: anatomy, physiology, and clinical implications. Med Gen Med. 2006;8(1):53.

    Article  Google Scholar 

  34. Nathoo N, Caris EC, Wiener JA, Mendel E. History of the vertebral venous plexus and the significant contributions of Breschet and Batson. Neurosurgery. 2011;69(5):1007–14 (discussion 14).

    PubMed  Google Scholar 

  35. Vox F, Capron AM, Kraus MF, Alexander GC, Kirschner KL. Balancing burdens and benefits: ethical issues of off-label prescription pharmaceutical use. PM R J Inj Funct Rehabil. 2013;5(10):882–9.

    Article  Google Scholar 

  36. Kerensky TA, Gottlieb AB, Yaniv S, Au SC. Etanercept: efficacy and safety for approved indications. Expert Opin Drug Saf. 2012;11(1):121–39.

    Article  CAS  PubMed  Google Scholar 

  37. 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.

    CAS  PubMed  Google Scholar 

  38. Beck JM, Azari ED. FDA, off-label use, and informed consent: debunking myths and misconceptions. Food Drug Law J. 1998;53(1):71–104.

    CAS  PubMed  Google Scholar 

  39. Guidance for off-label use of drugs. Lancet Neurol. 2008;7(4):285.

    Google Scholar 

  40. Committee on Drugs. Policy statement: off-label use of drugs in children. Pediatrics. 2014;133:563–7.

    Google Scholar 

  41. Horrobin DF. Effective clinical innovation: an ethical imperative. Lancet. 2002;359(9320):1857–8.

    Article  PubMed  Google Scholar 

  42. 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.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  43. American Psychiatric Association. The principles of medical ethics with annotations especially applicable to psychiatry. 2001st ed. Washington: American Psychiatric Association; 2001. p. 46.

    Google Scholar 

  44. Ghaemi SN, Goodwin FK. The ethics of clinical innovation in psychopharmacology: challenging traditional bioethics. Philos Ethics Humanit Med. 2007;2:26.

    Article  PubMed Central  PubMed  Google Scholar 

  45. Gray H, Holmes T. Anatomy, descriptive and surgical. 4th ed. London: Longmans, Green, and Co.; 1866.

    Google Scholar 

Download references

Acknowledgments

Dr. 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, a group of medical practices that utilize perispinal etanercept as a therapeutic modality, and also train physicians; he is also the Chief Executive Officer of TACT IP LLC. Helen Rodriguez-Romanacce and Arthur Levine are employees of the Institute of Neurological Recovery, Boca Raton, FL, USA. The professional activities of Tracey Ignatowski and Robert Spengler 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.

Author information

Authors and Affiliations

  1. Institute of Neurological Recovery, 2300 Glades Road Suite 305E, Boca Raton, FL, 33431, USA

    Edward Tobinick, Helen Rodriguez-Romanacce & Arthur Levine

  2. Department of Pathology and Anatomical Sciences, School of Medicine and Biomedical Sciences, University at Buffalo, The State University of New York, Buffalo, NY, USA

    Tracey A. Ignatowski

  3. Program for Neuroscience, School of Medicine and Biomedical Sciences, University at Buffalo, The State University of New York, 3435 Main Street, Buffalo, NY, 14214, USA

    Tracey A. Ignatowski

  4. Buffalo, NY, USA

    Robert N. Spengler

Authors
  1. Edward Tobinick
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Helen Rodriguez-Romanacce
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Arthur Levine
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Tracey A. Ignatowski
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Robert N. Spengler
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Edward Tobinick.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 283 kb)

Supplementary material 2 (MPG 56592 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Tobinick, E., Rodriguez-Romanacce, H., Levine, A. et al. Immediate Neurological Recovery Following Perispinal Etanercept Years After Brain Injury. Clin Drug Investig 34, 361–366 (2014). https://doi.org/10.1007/s40261-014-0186-1

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40261-014-0186-1

Keywords

Search

Navigation