title: Selective TNF inhibition for chronic stroke and traumatic brain injury: an observational study involving 629 consecutive patients treated with perispinal etanercept.
abstract: BACKGROUND
  Brain injury from stroke and traumatic brain injury (TBI) may result in a persistent neuroinflammatory response in the injury penumbra. This response may include microglial activation and excess levels of tumour necrosis factor (TNF). Previous experimental data suggest that etanercept, a selective TNF inhibitor, has the ability to ameliorate microglial activation and modulate the adverse synaptic effects of excess TNF. Perispinal administration may enhance etanercept delivery across the blood-CSF barrier.
  
  
  OBJECTIVE
  The objective of this study was to systematically examine the clinical response following perispinal administration of etanercept in a cohort of patients with chronic neurological dysfunction after stroke and TBI.
  
  
  METHODS
  After approval by an independent external institutional review board (IRB), a chart review of all patients with chronic neurological dysfunction following stroke or TBI who were treated open-label with perispinal etanercept (PSE) from November 1, 2010 to July 14, 2012 at a group medical practice was performed.
  
  
  RESULTS
  The treated cohort included 629 consecutive patients. Charts of 617 patients following stroke and 12 patients following TBI were reviewed. The mean age of the stroke patients was 65.8 years ± 13.15 (range 13-97). The mean interval between treatment with PSE and stroke was 42.0 ± 57.84 months (range 0.5-419); for TBI the mean interval was 115.2 ± 160.22 months (range 4-537). Statistically significant improvements in motor impairment, spasticity, sensory impairment, cognition, psychological/behavioural function, aphasia and pain were noted in the stroke group, with a wide variety of additional clinical improvements noted in individuals, such as reductions in pseudobulbar affect and urinary incontinence. Improvements in multiple domains were typical. Significant improvement was noted irrespective of the length of time before treatment was initiated; there was evidence of a strong treatment effect even in the subgroup of patients treated more than 10 years after stroke and TBI. In the TBI cohort, motor impairment and spasticity were statistically significantly reduced.
  
  
  CONCLUSIONS
  Irrespective of the methodological limitations, the present results provide clinical evidence that stroke and TBI may lead to a persistent and ongoing neuroinflammatory response in the brain that is amenable to therapeutic intervention by selective inhibition of TNF, even years after the acute injury.
  
  
  CONCLUSIONS
  Excess TNF contributes to chronic neurological, neuropsychiatric and clinical impairment after stroke and TBI. Perispinal administration of etanercept produces clinical improvement in patients with chronic neurological dysfunction following stroke and TBI. The therapeutic window extends beyond a decade after stroke and TBI. Randomized clinical trials will be necessary to further quantify and characterize the clinical response.
authors.affiliation: Institute of Neurological Recovery, 100 UCLA Medical Plaza, Suites 205-210, Los Angeles, CA 90095, USA. nrimed@gmail.com
authors.forename: Edward
authors.initials: E
authors.lastname: Tobinick
authors.forename: Nancy M
authors.initials: NM
authors.lastname: Kim
authors.forename: Gary
authors.initials: G
authors.lastname: Reyzin
authors.forename: Helen
authors.initials: H
authors.lastname: Rodriguez-Romanacce
authors.forename: Venita
authors.initials: V
authors.lastname: DePuy
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000627:therapeutic use*; D000925:Anticoagulants / Q000627:therapeutic use; D001930:Brain Injuries / Q000188:drug therapy*; D015331:Cohort Studies; D000068800:Etanercept; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000008:administration & dosage / Q000627:therapeutic use*; D007278:Injections, Spinal; D008297:Male; D008875:Middle Aged; D009048:Motor Skills / Q000502:physiology; D009128:Muscle Spasticity / Q000209:etiology / Q000628:therapy; D009422:Nervous System Diseases / Q000209:etiology / Q000628:therapy; D059408:Pain Management; D018124:Receptors, Tumor Necrosis Factor / Q000008:administration & dosage / Q000627:therapeutic use*; D020127:Recovery of Function; D012677:Sensation / Q000502:physiology; D020521:Stroke / Q000188:drug therapy*; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*; D016138:Walking / Q000502:physiology; D014859:Warfarin / Q000627:therapeutic use; D055815:Young Adult
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D000925:Anticoagulants; D007074:Immunoglobulin G; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D014859:Warfarin; D000068800:Etanercept