CNS Drugs

, Volume 25, Issue 2, pp 145–155 | Cite as

Rapid Improvement of Chronic Stroke Deficits after Perispinal Etanercept

Three Consecutive Cases
Short Communication

Abstract

Background: Thrombolytic therapy reduces stroke size and disability by reperfusion and salvage of ischaemic penumbra. Emerging evidence suggests that retrieved penumbra may be the site of ongoing inflammatory pathology that includes extensive microglial activation. Microglial activation may be associated with excessive levels of tumour necrosis factor (TNF) and resultant neurotoxicity. Etanercept, a potent biologic TNF antagonist, reduces microglial activation in experimental models and has been therapeutically effective in models of brain and neuronal injury. Perispinal administration of etanercept, previously reported to be beneficial for the treatment of Alzheimer’s disease, may facilitate delivery of etanercept into the brain.

Objective: The objective of this report is to document the initial clinical response to perispinal etanercept in the first chronic stroke cohort so treated.

Methods: Three consecutive patients with stable and persistent chronic neurological deficits due to strokes that had failed to resolve despite previous treatment and rehabilitation were evaluated at an outpatient clinic. They were treated off-label with perispinal etanercept as part of the clinic’s practice of medicine.

Results: All three patients had chronic hemiparesis, in addition to other stroke deficits. Their stroke distributions were right middle cerebral artery (MCA), brainstem (medulla) and left MCA. The two patients with MCA strokes had both received acute thrombolytic therapy. Each of the three patients was treated with an initial dose of perispinal etanercept 13, 35 and 36 months following their acute stroke, respectively. Significant clinical improvement following perispinal etanercept administration was observed in all patients. Onset of clinical response was evident within 10 minutes of perispinal injection in all patients. Improvements in hemiparesis, gait, hand function, hemi-sensory deficits, spatial perception, speech, cognition and behaviour were noted among the patients treated. Each patient received a second perispinal etanercept dose at 22–26 days after the first dose that was followed by additional clinical improvement.

Conclusions: Open-label administration of perispinal etanercept resulted in rapid neurological improvement in three consecutive patients with chronic neurological dysfunction due to strokes occurring 13–36 months earlier. These results suggest that stroke may result in chronic TNF-mediated pathophysiology that may be amenable to therapeutic intervention long after the acute event. Randomized clinical trials of perispinal etanercept for selected patients with chronic neurological dysfunction following stroke are indicated.

Notes

Acknowledgements

No sources of funding were used to study the use of etanercept in this series of patients, or to prepare this manuscript. The author has multiple issued and pending US and foreign patents detailing methods of use of etanercept for neurological indications, including perispinal etanercept for stroke, including, but not limited to, US patents 6419944, 6537549, 6982089, 7214658 and7629311 and Australian patent 758523, all assigned to TACT IP, LLC. The author has received royalties from licensees to these patents.

References

  1. 1.
    Baron JC, von Kummer R, del Zoppo GJ. Treatment of acute ischemic stroke: challenging the concept of a rigid and universal time window. Stroke 1995 Dec; 26(12): 2219–21PubMedCrossRefGoogle Scholar
  2. 2.
    Back T. Pathophysiology of the ischemic penumbra: revision of a concept. Cell Mol Neurobiol 1998 Dec; 18(6): 621–38PubMedCrossRefGoogle Scholar
  3. 3.
    Baron JC, Marchal G. Ischemic core and penumbra in human stroke. Stroke 1999 May; 30(5): 1150–3PubMedCrossRefGoogle Scholar
  4. 4.
    Baron JC. Stroke research in the modern era: images versus dogmas. Cerebrovasc Dis 2005; 20(3): 154–63PubMedCrossRefGoogle Scholar
  5. 5.
    Hughes JL, Beech JS, Jones PS, et al. Mapping selective neuronal loss and microglial activation in the salvaged neocortical penumbra in the rat. Neuroimage 2010 Jan 1; 49(1): 19–31PubMedCrossRefGoogle Scholar
  6. 6.
    Price CJ, Wang D, Menon DK, et al. Intrinsic activated microglia map to the peri-infarct zone in the subacute phase of ischemic stroke. Stroke 2006 Jul; 37(7): 1749–53PubMedCrossRefGoogle Scholar
  7. 7.
    Kaushal V, Schlichter LC. Mechanisms of microglia-mediated neurotoxicity in a new model of the stroke penumbra. J Neurosci 2008 Feb 27; 28(9): 2221–30PubMedCrossRefGoogle Scholar
  8. 8.
    Baron JC. How healthy is the acutely reperfused ischemic penumbra? Cerebrovasc Dis 2005; 20 Suppl. 2: 25–31PubMedCrossRefGoogle Scholar
  9. 9.
    Goodman JC, Robertson CS, Grossman RG, et al. Elevation of tumor necrosis factor in head injury. J Neuroimmunol 1990 Dec; 30(2–3): 213–7PubMedCrossRefGoogle Scholar
  10. 10.
    Gregersen R, Lambertsen K, Finsen B. Microglia and macrophages are the major source of tumor necrosis factor in permanent middle cerebral artery occlusion in mice. J Cereb Blood Flow Metab 2000 Jan; 20(1): 53–65PubMedCrossRefGoogle Scholar
  11. 11.
    Genovese T, Mazzon E, Crisafulli C, et al. Immunomodulatory effects of etanercept in an experimental model of spinal cord injury. J Pharmacol Exp Ther 2006 Mar; 316(3): 1006–16PubMedCrossRefGoogle Scholar
  12. 12.
    Zaremba J, Skrobanski P, Losy J. Tumour necrosis factor-alpha is increased in the cerebrospinal fluid and serum of ischaemic stroke patients and correlates with the volume of evolving brain infarct. Biomed Pharmacother 2001 Jun; 55(5): 258–63PubMedCrossRefGoogle Scholar
  13. 13.
    Walberer M, Dennin MA, Simard ML, et al. Dynamics of neuroinflammation in the macrosphere model of arterio-arterial embolic focal ischemia: an approximation to human stroke patterns. Exp Transl Stroke Med 2010 Dec 20; 2(1): 22PubMedCrossRefGoogle Scholar
  14. 14.
    Pearse DD, Pereira FC, Stolyarova A, et al. Inhibition of tumour necrosis factor-alpha by antisense targeting produces immunophenotypical and morphological changes in injury-activated microglia and macrophages. Eur J Neurosci 2004 Dec; 20(12): 3387–96PubMedCrossRefGoogle Scholar
  15. 15.
    Marchand F, Tsantoulas C, Singh D, et al. Effects of etanercept and minocycline in a rat model of spinal cord injury. Eur J Pain 2009 Aug; 13(7): 673–81PubMedCrossRefGoogle Scholar
  16. 16.
    Shen CH, Tsai RY, Shih MS, et al. Etanercept restores the antinociceptive effect of morphine and suppresses spinal neuroinflammation in morphine-tolerant rats. Anesth Analg. Epub 2010 Nov 16Google Scholar
  17. 17.
    Chio CC, Lin JW, Chang MW, et al. Therapeutic evaluation of etanercept in a model of traumatic brain injury. J Neuro-chem 2010 Nov; 115(4): 921–9Google Scholar
  18. 18.
    Kato K, Liu H, Kikuchi S, et al. Immediate anti-tumor necrosis factor-alpha (etanercept) therapy enhances axonal regeneration after sciatic nerve crush. J Neurosci Res 2010 Feb 1; 88(2): 360–8PubMedCrossRefGoogle Scholar
  19. 19.
    Tobinick E. Perispinal etanercept for neuroinflammatory disorders. Drug Discov Today 2009 Feb; 14(3–4): 168–77PubMedCrossRefGoogle Scholar
  20. 20.
    Tobinick E. Tumour necrosis factor modulation for treatment of Alzheimer’s disease: rationale and current evidence. CNS Drugs 2009 Sep 1; 23(9): 713–25PubMedCrossRefGoogle Scholar
  21. 21.
    Tobinick E. Perispinal etanercept: a new therapeutic paradigm in neurology. Expert Rev Neurother 2010 Jun; 10(6): 985–1002PubMedCrossRefGoogle Scholar
  22. 22.
    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: 28PubMedCrossRefGoogle Scholar
  23. 23.
    Tobinick EL, Gross H. Rapid improvement in verbal fluency and aphasia following perispinal etanercept in Alzheimer’s disease. BMC Neurol 2008; 8: 27PubMedCrossRefGoogle Scholar
  24. 24.
    Tobinick EL, Gross H. Rapid cognitive improvement in Alzheimer’s disease following perispinal etanercept administration. J Neuroinflammation 2008; 5: 2PubMedCrossRefGoogle Scholar
  25. 25.
    Tobinick E. Perispinal etanercept for treatment of Alzheimer’s disease. Curr Alzheimer Res 2007 Dec; 4(5): 550–2PubMedCrossRefGoogle Scholar
  26. 26.
    Griffin WS. Perispinal etanercept: potential as an Alzheimer therapeutic. J Neuroinflammation 2008; 5: 3PubMedCrossRefGoogle Scholar
  27. 27.
    Immonen RJ, Kharatishvili I, Niskanen JP, et al. Distinct MRI pattern in lesional and perilesional area after traumatic brain injury in rat: 11 months follow-up. Exp Neurol 2009 Jan; 215(1): 29–40PubMedCrossRefGoogle Scholar
  28. 28.
    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 2010 Nov; 51(11): 1788–95PubMedCrossRefGoogle Scholar
  29. 29.
    Batson OV. The vertebral vein system: Caldwell lecture, 1956. Am J Roentgenol Radium Ther Nucl Med 1957 Aug; 78(2): 195–212PubMedGoogle Scholar
  30. 30.
    Tobinick E, Vega CP. The cerebrospinal venous system: anatomy, physiology, and clinical implications. Med Gen Med 2006; 8(1): 53CrossRefGoogle Scholar
  31. 31.
    Folstein MF, Folstein SE, McHugh PR. “Mini-mental state”: a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975 Nov; 12(3): 189–98PubMedCrossRefGoogle Scholar
  32. 32.
    Nasreddine ZS, Phillips NA, Bedirian V, et al. The Montreal Cognitive Assessment, MoCA: a brief screening tool for mild cognitive impairment. J Am Geriatr Soc 2005 Apr; 53(4): 695–9PubMedCrossRefGoogle Scholar
  33. 33.
    Smith T, Gildeh N, Holmes C. The Montreal Cognitive Assessment: validity and utility in a memory clinic setting. Can J Psychiatry 2007 May; 52(5): 329–32PubMedGoogle Scholar
  34. 34.
    Wade DT, Wood VA, Heller A, et al. Walking after stroke: measurement and recovery over the first 3 months. Scand J Rehabil Med 1987; 19(1): 25–30PubMedGoogle Scholar
  35. 35.
    Atkinson HH, Rosano C, Simonsick EM, et al. Cognitive function, gait speed decline, and comorbidities: the health, aging and body composition study. J Gerontol A Biol Sci Med Sci 2007 Aug; 62(8): 844–50PubMedCrossRefGoogle Scholar
  36. 36.
    Purser JL, Pieper CF, Poole C, et al. Trajectories of leg strength and gait speed among sedentary older adults: longitudinal pattern of dose response. J Gerontol A Biol Sci Med Sci 2003 Dec; 58(12): M1125–34PubMedCrossRefGoogle Scholar
  37. 37.
    Galasko D, Bennett D, Sano M, et al. An inventory to assess activities of daily living for clinical trials in Alzheimer’s disease: the Alzheimer’s Disease Cooperative Study. Alzheimer Dis Assoc Disord 1997; 11 Suppl. 2: S33–9PubMedCrossRefGoogle Scholar
  38. 38.
    Jorgensen HS, Nakayama H, Raaschou HO, et al. Recovery of walking function in stroke patients: the Copenhagen Stroke Study. Arch Phys Med Rehabil 1995 Jan; 76(1): 27–32PubMedCrossRefGoogle Scholar
  39. 39.
    Friedman PJ. Gait recovery after hemiplegic stroke. Int Disabil Stud 1990 Jul–Sep; 12(3): 119–22PubMedCrossRefGoogle Scholar
  40. 40.
    Lechan RM, Fekete C. Infundibular tanycytes as modulators of neuroendocrine function: hypothetical role in the regulation of the thyroid and gonadal axis. Acta Biomed 2007; 78 Suppl. 1: 84–98PubMedGoogle Scholar
  41. 41.
    Zhang LC, Zeng YM, Ting J, et al. The distributions and signaling directions of the cerebrospinal fluid contacting neurons in the parenchyma of a rat brain. Brain Res 2003 Oct 31; 989(1): 1–8PubMedCrossRefGoogle Scholar
  42. 42.
    Nadeau S, Rivest S. Effects of circulating tumor necrosis factor on the neuronal activity and expression of the genes encoding the tumor necrosis factor receptors (p55 and p75) in the rat brain: a view from the blood-brain barrier. Neuroscience 1999; 93(4): 1449–64PubMedCrossRefGoogle Scholar
  43. 43.
    Kang YM, He RL, Yang LM, et al. Brain tumour necrosis factor-alpha modulates neurotransmitters in hypothalamic paraventricular nucleus in heart failure. Cardiovasc Res 2009 Sep 1; 83(4): 737–46PubMedCrossRefGoogle Scholar
  44. 44.
    Beattie MS, Ferguson AR, Bresnahan JC. AMPA-receptor trafficking and injury-induced cell death. Eur J Neurosci 2010 Jul; 32(2): 290–7PubMedCrossRefGoogle Scholar
  45. 45.
    Buchhave P, Zetterberg H, Blennow K, et al. Soluble TNF receptors are associated with Abeta metabolism and conversion to dementia in subjects with mild cognitive impairment. Neurobiol Aging 2010 Nov; 31(11): 1877–84PubMedCrossRefGoogle Scholar
  46. 46.
    Chen YM, Chen HH, Lan JL, et al. Improvement of cognition, a potential benefit of anti-TNF therapy in elderly patients with rheumatoid arthritis. Joint Bone Spine 2010 Jul; 77(4): 366–7PubMedCrossRefGoogle Scholar
  47. 47.
    Clark IA, Alleva LM, Vissel B. The roles of TNF in brain dysfunction and disease. Pharmacol Ther 2010 Dec; 128(3): 519–48PubMedCrossRefGoogle Scholar
  48. 48.
    Elfferich MD, Nelemans PJ, Ponds RW, et al. Everyday cognitive failure in sarcoidosis: the prevalence and the effect of anti-TNF-alpha treatment. Respiration 2010; 80(3): 212–9PubMedCrossRefGoogle Scholar
  49. 49.
    Menza M, Dobkin RD, Marin H, et al. The role of inflammatory cytokines in cognition and other non-motor symptoms of Parkinson’s disease. Psychosomatics 2010 Nov; 51(6): 474–9PubMedGoogle Scholar
  50. 50.
    Park KM, Bowers WJ. Tumor necrosis factor-alpha mediated signaling in neuronal homeostasis and dysfunction. Cell Signal 2010 Jul; 22(7): 977–83PubMedCrossRefGoogle Scholar
  51. 51.
    Sarajarvi T, Helisalmi S, Antikainen L, et al. An association study of 21 potential Alzheimer’s disease risk genes in a Finnish population. J Alzheimers Dis 2010; 21(3): 763–7PubMedGoogle Scholar
  52. 52.
    Shi J, Shen W, Chen J, et al. Anti-TNF-alpha reduces amyloid plaques and tau phosphorylation and induces CD 11c-positive dendritic-like cells in the APP/PS1 transgenic mouse brain. Brain Res 2011 Jan 12; 1368: 239–47PubMedCrossRefGoogle Scholar
  53. 53.
    Terrando N, Monaco C, Ma D, et al. Tumor necrosis factor-alpha triggers a cytokine cascade yielding postoperative cognitive decline. Proc Natl Acad Sci U S A 2010 Nov 23; 107(47): 20518–22PubMedCrossRefGoogle Scholar
  54. 54.
    Tweedie D, Sambamurti K, Greig NH. TNF-alpha inhibition as a treatment strategy for neurodegenerative disorders: new drug candidates and targets. Curr Alzheimer Res 2007 Sep; 4(4): 378–85PubMedCrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2011

Authors and Affiliations

  1. 1.Institute for Neurological Research, a private medical group, inc.Los AngelesUSA

Personalised recommendations