A new breakthrough in the understanding of traumatic brain injury


The INR has made a stunning discovery: that chronic brain dysfunction may respond to therapeutic intervention, even years after the initial injury. Please see: Selective TNF Inhibition for Chronic Stroke and Traumatic Brain Injury – An Observational Study Involving 629 Consecutive Patients Treated With Perispinal Etanercept. Edward Tobinick MD, Nancy M. Kim, Gary Reyzin, Helen Rodriguez-Romanacce and Venita DePuy. CNS Drugs. 2012 26(12). Results can vary, and more than one dose may be necessary for optimal benefit, but these results represent a new breakthrough in the understanding of the neurological basis of chronic brain dysfunction following TBI.


Consultation for TBI at the INR

Patients who have experienced TBI often have weakness or decreased sensation in one or more extremities, cognitive or speech difficulties, or other neurological problems that can last for years. Consultation with an INR physician following hospital discharge is encouraged, even if the brain injury has occurred years before. Please call the INR (310) 479-0107 (California) or, in Florida (561) 353-9707 for further information.

Inflammation mediated by the inflammatory cytokine TNF contributes to neurological dysfunction following TBI [1-4]. Basic science studies suggest that TBI may result in progressive neurologic injury during the first year [5-8]. Etanercept has demonstrated favorable results in published scientific studies of TBI in animal models [4,9]. Etanercept has also demonstrated favorable effects for other types of neurologic injury in both human studies and basic science models [10-12].

What is Traumatic Brain Injury?

Traumatic brain injury (TBI), a form of acquired brain injury, occurs when a sudden trauma causes damage to the brain. TBI can result when the head suddenly and violently hits an object, or when an object pierces the skull and enters brain tissue.  Symptoms of a TBI can be mild, moderate, or severe, depending on the extent of the damage to the brain.   A person with a mild TBI may remain conscious or may experience a loss of consciousness for a few seconds or minutes. Other symptoms of mild TBI include headache, confusion, lightheadedness, dizziness, blurred vision or tired eyes, ringing in the ears, bad taste in the mouth, fatigue or lethargy, a change in sleep patterns, behavioral or mood changes, and trouble with memory, concentration, attention, or thinking.  A person with a moderate or severe TBI may show these same symptoms, but may also have a headache that gets worse or does not go away, repeated vomiting or nausea, convulsions or seizures, an inability to awaken from sleep, dilation of one or both pupils of the eyes, slurred speech, weakness or numbness in the extremities, loss of coordination, and increased confusion, restlessness, or agitation.

Chronic TBI should be distinguished from acute TBI. Adverse residual neurological and brain effects from TBI occurring years before can continue. These chronic adverse effects can include difficulties with attention, concentration, planning, calculation, reading, vision, hearing, balance and motor activities such as walking or use of hands or limbs.


  1.   Knoblach SM, Fan L, Faden AI. Early neuronal expression of tumor necrosis factor-alpha after experimental brain injury contributes to neurological impairment. J Neuroimmunol, 95(1-2), 115-125 (1999).
  2.  Goodman JC, Robertson CS, Grossman RG, Narayan RK. Elevation of tumor necrosis factor in head injury. J Neuroimmunol, 30(2-3), 213-217 (1990).
  3. Shohami E, Bass R, Wallach D, Yamin A, Gallily R. Inhibition of tumor necrosis factor alpha (TNFalpha) activity in rat brain is associated with cerebroprotection after closed head injury. J Cereb Blood Flow Metab, 16(3), 378-384 (1996).
  4.  Chio CC, Lin JW, Chang MW, Wang CC, Yang CZ, Chang CP. Therapeutic evaluation of etanercept in a model of traumatic brain injuryJ Neurochem,  (2010). 
  5. Bouilleret V, Cardamone L, Liu YR, Fang K, Myers DE, O’Brien TJ. Progressive brain changes on serial manganese-enhanced MRI following traumatic brain injury in the rat. J Neurotrauma, 26(11), 1999-2013 (2009).
  6. Bramlett HM, Dietrich WD. Quantitative structural changes in white and gray matter 1 year following traumatic brain injury in rats. Acta Neuropathol, 103(6), 607-614 (2002).
  7.  Liu YR, Cardamone L, Hogan RE et al. Progressive metabolic and structural cerebral perturbations after traumatic brain injury: an in vivo imaging study in the rat. J Nucl Med, 51(11), 1788-1795 (2010).
  8. Rodriguez-Paez AC, Brunschwig JP, Bramlett HM. Light and electron microscopic assessment of progressive atrophy following moderate traumatic brain injury in the rat. Acta Neuropathol, 109(6), 603-616 (2005).
  9.  Campbell SJ, Jiang Y, Davis AE et al. Immunomodulatory effects of etanercept in a model of brain injury act through attenuation of the acute-phase response. J Neurochem, 103(6), 2245-2255 (2007).
  10.  Cohen SP, Bogduk N, Dragovich A et al. Randomized, double-blind, placebo-controlled, dose-response, and preclinical safety study of transforaminal epidural etanercept for the treatment of sciatica. Anesthesiology, 110(5), 1116-1126 (2009).
  11.  Dinomais M, Stana L, Egon G, Richard I, Menei P. Significant recovery of motor function in a patient with complete T7 paraplegia receiving etanercept. J Rehabil Med, 41(4), 286-288 (2009).
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2012 Scientific Citations to INR Publications

The following are selected publications that have cited scientific publications of the INR® in 2012:

1. Belarbi, K., et al., TNF-alpha protein synthesis inhibitor restores neuronal function and reverses cognitive deficits induced by chronic neuroinflammation. J Neuroinflammation, 2012. 9: p. 23.

2. Bomfim, T.R., et al., An anti-diabetes agent protects the mouse brain from defective insulin signaling caused by Alzheimer’s disease- associated Abeta oligomers. J Clin Invest, 2012. 122(4): p. 1339-53.

3. Butchart, J. and C. Holmes, Systemic and central immunity in Alzheimer’s disease: therapeutic implications. CNS Neurosci Ther, 2012. 18(1): p. 64-76.

4. Cereda, C., et al., The Role of TNF-alpha in ALS: New Hypostheses for Future Therapeutic Approaches, in Amyotrophic Lateral Sclerosis, M.H. Maurer, Editor. 2012, InTech. p. 413-436.

5. Clark, I., et al., Tumor necrosis factor-induced cerebral insulin resistance in Alzheimer’s disease links numerous treatment rationales. Pharmacol Rev, 2012. 64(4): p. 1004-26.

6. Dhawan, G. and C.K. Combs, Inhibition of Src kinase activity attenuates amyloid associated microgliosis in a murine model of Alzheimer’s disease. J Neuroinflammation, 2012. 9: p. 117.

7. Drent, M., E.E. Lower, and J. De Vries, Sarcoidosis-associated fatigue. Eur Respir J, 2012. 40(1): p. 255-63.

8. Ferraccioli, G., et al., Rheumatoid Arthritis and Alzheimer Disease: Possible Cellular and Molecular Links. Gerontology and Geriatric, 2012. 1(1).

9. Gabbita, S.P., et al., Early intervention with a small molecule inhibitor for tumor necrosis factor-alpha prevents cognitive deficits in a triple transgenic mouse model of Alzheimer’s disease. J Neuroinflammation, 2012. 9: p. 99.

10. Gruber, H.E., et al., Genome-wide analysis of pain-, nerve- and neurotrophin -related gene expression in the degenerating human annulus. Mol Pain, 2012. 8(1): p. 63.

11. Hojlund, J., et al., Effect of head rotation on cerebral blood velocity in the prone position. Anesthesiol Res Pract, 2012. 2012: p. 647258.

12. Ingles-Esteve, J., et al., Inhibition of specific NF-kappaB activity contributes to the tumor suppressor function of 14-3-3sigma in breast cancer. PLoS One, 2012. 7(5): p. e38347.

13. Jiang, T., J.T. Yu, and L. Tan, Novel disease-modifying therapies for Alzheimer’s disease. J Alzheimers Dis, 2012. 31(3): p. 475-92.

14. Krishnadas, R. and J. Cavanagh, Depression: an inflammatory illness? J Neurol Neurosurg Psychiatry, 2012. 83(5): p. 495-502.

15. Landoni, V.I., et al., Shiga toxin 1 induces on lipopolysaccharide-treated astrocytes the release of tumor necrosis factor-alpha that alter brain-like endothelium integrity. PLoS Pathog, 2012. 8(3): p. e1002632.

16. Lauterbach, E.C., Psychotropic drug effects on gene transcriptomics relevant to Alzheimer disease. Alzheimer Dis Assoc Disord, 2012. 26(1): p. 1-7.

17. Lima, A. and F. Antunes, Intervention of Physical Medicine and Rehabilitation in Failed Back Surgery Syndrome. Journal of Regional Anaesthesia and Pain Management, 2012. 68: p. 29-30.

18. Maccioni, R.B., et al., In Search of Therapeutic Solutions for Alzheimer’s Disease, in When Things Go Wrong–Diseases and Disorders of the Human Brain, T. Mantamadiotis, Editor. 2012, InTech. p. 125-.

19. Matias-Guiu, J.A. and R. Garcia-Ramos, Primary progressive aphasia: from syndrome to disease. Neurologia, 2012.

20. Montgomery, S.L. and W.J. Bowers, Tumor Necrosis Factor-alpha and the Roles it Plays in Homeostatic and Degenerative Processes Within the Central Nervous System. Journal of Neuroimmune Pharmacology, 2012. 7(1): p. 42-59.

21. Ooi, L., et al., New drugs under development for Alzheimer’s disease, in Advances in Alzheimer’s Disease Management, S. Gauthier and P. Rosa-Neto, Editors. 2012. p. 58-67.

22. Ramesh, V., et al., Disrupted sleep without sleep curtailment induces sleepiness and cognitive dysfunction via the tumor necrosis factor-alpha pathway. J Neuroinflammation, 2012. 9.

23. Santello, M. and A. Volterra, TNF-alpha in synaptic function: switching gears. Trends Neurosci, 2012. 35(10): p. 638-47.

24. Singh, P.L., et al., Current therapeutic strategies for inflammation following traumatic spinal cord injury. Neural Regeneration Research, 2012. 7(23): p. 1812-1821.

25. Steele, M.L. and S.R. Robinson, Reactive astrocytes give neurons less support: implications for Alzheimer’s disease. Neurobiol Aging, 2012. 33(2): p. 423 e1-13.

26. Stringer, M.D., et al., The vertebral venous plexuses: the internal veins are muscular and external veins have valves. Clin Anat, 2012. 25(5): p. 609-18.

27. Tweedie, D., et al., Tumor necrosis factor-alpha synthesis inhibitor 3,6′-dithiothalidomide attenuates markers of inflammation, Alzheimer pathology and behavioral deficits in animal models of neuroinflammation and Alzheimer’s disease. J Neuroinflammation, 2012. 9: p. 106.

28. Wilcock, D.M., Neuroinflammation in the aging down syndrome brain; lessons from Alzheimer’s disease. Curr Gerontol Geriatr Res, 2012. 2012: p. 170276.

29. Woodward, M.C., Drug treatments in development for Alzheimer’s disease. Journal of Pharmacy Practice and Research, 2012. 42(1): p. 58-65.

30. Yoshiyama, Y., V.M. Lee, and J.Q. Trojanowski, Therapeutic strategies for tau mediated neurodegeneration. J Neurol Neurosurg Psychiatry, 2012.