Perispinal injection of a TNF blocker directed to the brain of rats alleviates the sensory and affective components of chronic constriction injury-induced neuropathic pain.

Neuropathic pain is chronic pain that follows nerve injury, mediated in the brain by elevated levels of the inflammatory protein tumor necrosis factor-alpha (TNF). We have shown that peripheral nerve injury increases TNF in the hippocampus/pain perception region, which regulates neuropathic pain symptoms. In this study we assessed pain sensation and perception subsequent to specific targeting of brain-TNF (via TNF antibody) administered through a novel subcutaneous perispinal route. Neuropathic pain was induced in Sprague-Dawley rats via chronic constriction injury (CCI), and thermal hyperalgesia was monitored for 10 days post-surgery. On day 8 following CCI and sensory pain behavior testing, rats were randomized to receive perispinal injection of TNF antibody or control IgG isotype antibody. Pain perception was assessed using conditioned place preference (CPP) to the analgesic, amitriptyline. CCI-rats receiving the perispinal injection of TNF antibody had significantly decreased CCI-induced thermal hyperalgesia the following day, and did not form an amitriptyline-induced CPP, whereas CCI-rats receiving perispinal IgG antibody experienced pain alleviation only in conjunction with i.p. amitriptyline and did form an amitriptyline-induced CPP. The specific targeting of brain TNF via perispinal delivery alleviates thermal hyperalgesia and positively influences the affective component of pain. PERSPECTIVE: This study presents a novel route of drug administration to target central TNF for treatment of neuropathic pain. Targeting central TNF through perispinal drug delivery could potentially be a more efficient and sustained method to treat patients with neuropathic pain.

Perispinal etanercept stroke trial design: PESTO and beyond.

INTRODUCTION: Perispinal etanercept (PSE) is an innovative treatment designed to improve stroke recovery by addressing chronic post-stroke neuroinflammation. Basic science evidence, randomized clinical trial (RCT) evidence and 14 years of favorable clinical experience support the use of PSE to treat chronic stroke. This article provides guidance for the design of future PSE RCTs in accordance with current FDA recommendations. AREAS COVERED: Scientific background and essential elements of PSE RCT design. EXPERT OPINION: Intimate familiarity with PSE, its novel method of drug delivery, and the characteristics of ideal enriched study populations are necessary for those designing future PSE stroke trials. The design elements needed to enable a PSE RCT to generate valid results include a suitable research question; a homogeneous study population selected using a prospective enrichment strategy; a primary outcome measure responsive to the neurological improvements that result from PSE; trialists with expertise in perispinal delivery; optimal etanercept dosing; and steps taken to minimize the number of placebo responders. RCTs failing to incorporate these elements, such as the PESTO trial, are incapable of reaching reliable conclusions regarding PSE efficacy. SF-36 has not been validated in PSE trials and is unsuitable for use as a primary outcome measure in PSE RCTs.

Rapid improvement in severe long COVID following perispinal etanercept.

BACKGROUND: This study aimed to describe the neurological improvements in a patient with severe long COVID brain dysfunction following perispinal etanercept administration. Perispinal administration of etanercept, a novel method designed to enhance its brain delivery via carriage in the cerebrospinal venous system, has previously been shown to reduce chronic neurological dysfunction after stroke. Etanercept is a recombinant biologic that is capable of ameliorating two components of neuroinflammation: microglial activation and the excess bioactivity of tumor necrosis factor (TNF), a proinflammatory cytokine that is a key neuromodulator in the brain. Optimal synaptic and brain network function require physiological levels of TNF. Neuroinflammation, including brain microglial activation and excess central TNF, can be a consequence of stroke or peripheral infection, including infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes COVID-19. METHODS: Standardized, validated measures, including the Montreal Cognitive Assessment, Beck Depression Index-II (BDI-II), Fatigue Assessment Scale, Controlled Oral Word Association Test, Trail Making Tests, Timed Finger-to-Nose Test, 20 m Self-Paced Walk Test, 5 Times Sit-to-Stand Test and Grip Strength measured with a Jamar Dynamometer were used to quantitate changes in cognition, depression, fatigue and neurological function after a single 25 mg perispinal etanercept dose in a patient with severe long COVID of 12 months duration. RESULTS: Following perispinal etanercept administration there was immediate neurological improvement. At 24 h, there were remarkable reductions in chronic post-COVID-19 fatigue and depression, and significant measurable improvements in cognition, executive function, phonemic verbal fluency, balance, gait, upper limb coordination and grip strength. Cognition, depression and fatigue were examined at 29 days; each remained substantially improved. CONCLUSION: Perispinal etanercept is a promising treatment for the chronic neurologic dysfunction that may persist after resolution of acute COVID-19, including chronic cognitive dysfunction, fatigue, and depression. These results suggest that long COVID brain neuroinflammation is a potentially reversible pathology and viable treatment target. In view of the increasing unmet medical need, clinical trials of perispinal etanercept for long COVID are urgently necessary. The robust results of the present case suggest that perispinal etanercept clinical trials studying long COVID populations with severe fatigue, depression and cognitive dysfunction may have improved ability to detect a treatment effect. Positron emission tomographic methods that image brain microglial activation and measurements of cerebrospinal fluid proinflammatory cytokines may be useful for patient selection and correlation with treatment effects, as well as provide insight into the underlying pathophysiology.

The value of drug repositioning in the current pharmaceutical market.

Drug repositioning is the process of developing new indications for existing drugs or biologics. Increasing interest in drug repositioning has occurred due to sustained high failure rates and costs involved in attempts to bring new drugs to market. It has been estimated that it may cost more than USD 800 million to develop a new drug de novo. In addition, due to regulatory requirements regarding safety, efficacy and quality, the time required to develop a new drug de novo has been estimated to be 10 to 17 years. De novo drug discovery has failed to efficiently supply pharmaceutical company pipelines. A rational approach to drug repositioning may include a cross-disciplinary focus on the elucidation of the mechanisms of disease, allowing matching of disease pathways with appropriately targeted therapeutic agents. Repurposed drugs or biologics have the advantage of decreased development costs and decreased time to launch due to previously collected pharmacokinetic, toxicology and safety data. For these reasons, repurposing should be a primary strategy in drug discovery for every broadly focused, research-based pharmaceutical company.

Rapid cognitive improvement in Alzheimer's disease following perispinal etanercept administration.

Substantial basic science and clinical evidence suggests that excess tumor necrosis factor-alpha (TNF-alpha) is centrally involved in the pathogenesis of Alzheimer's disease. In addition to its pro-inflammatory functions, TNF-alpha has recently been recognized to be a gliotransmitter that regulates synaptic function in neural networks. TNF-alpha has also recently been shown to mediate the disruption in synaptic memory mechanisms, which is caused by beta-amyloid and beta-amyloid oligomers. The efficacy of etanercept, a biologic antagonist of TNF-alpha, delivered by perispinal administration, for treatment of Alzheimer's disease over a period of six months has been previously reported in a pilot study. This report details rapid cognitive improvement, beginning within minutes, using this same anti-TNF treatment modality, in a patient with late-onset Alzheimer's disease. Rapid cognitive improvement following perispinal etanercept may be related to amelioration of the effects of excess TNF-alpha on synaptic mechanisms in Alzheimer's disease and provides a promising area for additional investigation and therapeutic intervention.

Rapid improvement in verbal fluency and aphasia following perispinal etanercept in Alzheimer's disease.

BACKGROUND: Recent clinical studies point to rapid and sustained clinical, cognitive, and behavioral improvement in both Alzheimer's disease and primary progressive aphasia following weekly perispinal administration of etanercept, a TNF-alpha inhibitor that acts by blocking the binding of this cytokine to its receptors. This outcome is concordant with recent basic science studies suggesting that TNF-alpha functions in vivo as a gliotransmitter that regulates synaptic function in the brain. We hypothesized that perispinal etanercept had the potential to improve verbal function in Alzheimer's disease, so we included several standarized measures of verbal ability to evaluate language skills in a clinical trial of perispinal etanercept for Alzheimer's disease. METHODS: This was a prospective, single-center, open-label, pilot study, in which 12 patients with mild-to-severe Alzheimer's disease were administered etanercept, 25-50 mg, weekly by perispinal administration for six months. Two additional case studies are presented. RESULTS: Two-tailed, paired t-tests were conducted comparing baseline performance to 6-month performance on all neuropsychological measures. Test batteries included the California Verbal Learning Test-Second Edition, Adult Version; Logical Memory I and II(WMS-LM-II) from the Wechsler Memory Scale-Abbreviated; the Comprehensive Trail Making Test (TMT); Boston Naming Test; and letter(FAS) and category verbal fluency. All measures revealed a significant effect except for the Boston Naming Test and the TMT-4, with WMS-LM-II being marginally significant at p = .05. The FAS test for letter fluency was most highly significant with a p < 0.0007. In addition, rapid improvement in verbal fluency and aphasia in two patients with dementia, beginning minutes after perispinal etanercept administration, is documented. CONCLUSION: In combination with the previously reported results of perispinal etanercept in Alzheimer's disease and primary progressive aphasia, these results further argue that larger scale studies of this therapeutic intervention, including Phase 3 trials, are warranted in dementias. In addition, these results may provide insight into the basic pathophysiologic mechanisms underlying Alzheimer's disease and related forms of dementia, and suggest the existence of novel, rapidly reversible, TNF-mediated pathophysiologic mechanisms in Alzheimer's disease which are worthy of further investigation.

Perispinal etanercept for treatment of Alzheimer's disease.

BACKGROUND: Increasing basic science and clinical evidence implicates inflammatory processes and resulting glial activation in the pathogenesis of Alzheimer's Disease. Excess TNF-alpha, a cytokine with pleotropic effects in the CNS, has been suggested to be involved in the pathogenesis of AD. In addition to its pro-inflammatory effects, TNF-alpha affects synaptic transmission; and glutamate, NMDA, and amyloid pathways. More specifically, TNF-alpha, produced by glia, has been shown to affect both synaptic strength and to mediate synaptic scaling, a homeostatic mechanism important to the control of neural networks. A recently published small, open-label pilot study suggested that inhibition of the inflammatory cytokine TNF-alpha utilizing the perispinal administration of etanercept may lead to sustained cognitive improvement for six months in patients with mild, moderate, and severe Alzheimer's disease. RESULTS: Continued open-label clinical experience with this new treatment modality, now for more than two years, suggests that weekly maintenance treatment with perispinal etanercept may have a sustained positive effect. In addition, rapid clinical improvement, within minutes of dosing, has been observed on a repeated basis in multiple patients. DISCUSSION: It is hypothesized that perispinal administration of etanercept may enable rapid delivery to the CNS via the cerebrospinal venous system, resulting in improvement in synaptic mechanisms which have been dysregulated by excess TNF-alpha. TNF-alpha modulation in Alzheimer's disease may also act by influencing glutamate, NMDA, amyloid and other inflammatory pathways. Methods of perispinal administration, as described in the pilot study, may prove useful for delivering other therapeutics, particularly large molecules, to the CNS. Further study in randomized, placebo-controlled clinical trials and in basic science studies is merited.

The cerebrospinal venous system: anatomy, physiology, and clinical implications.

There is substantial anatomical and functional continuity between the veins, venous sinuses, and venous plexuses of the brain and the spine. The term "cerebrospinal venous system" (CSVS) is proposed to emphasize this continuity, which is further enhanced by the general lack of venous valves in this network. The first of the two main divisions of this system, the intracranial veins, includes the cortical veins, the dural sinuses, the cavernous sinuses, and the ophthalmic veins. The second main division, the vertebral venous system (VVS), includes the vertebral venous plexuses which course along the entire length of the spine. The intracranial veins richly anastomose with the VVS in the suboccipital region. Caudally, the CSVS freely communicates with the sacral and pelvic veins and the prostatic venous plexus. The CSVS constitutes a unique, large-capacity, valveless venous network in which flow is bidirectional. The CSVS plays important roles in the regulation of intracranial pressure with changes in posture, and in venous outflow from the brain. In addition, the CSVS provides a direct vascular route for the spread of tumor, infection, or emboli among its different components in either direction.

TNF-alpha modulation for treatment of Alzheimer's disease: a 6-month pilot study.

CONTEXT: Current pharmacologic treatments for Alzheimer's disease (AD) do not prevent long-term clinical deterioration. Tumor necrosis factor (TNF)-alpha, a proinflammatory cytokine, has been implicated in the pathogenesis of AD. OBJECTIVE: To investigate the use of a biologic TNF-alpha inhibitor, etanercept was given by perispinal extrathecal administration for the treatment of AD. METHODS: This was a prospective, single-center, open-label, pilot (proof-of-concept) study, in which 15 patients with mild-to-severe AD were treated for 6 months. We administered etanercept, 25-50 mg, once weekly by perispinal administration. Main outcome measures included the Mini-Mental State Examination (MMSE), the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog), and the Severe Impairment Battery (SIB). RESULTS: The average age of our patient population was 76.7. The mean baseline MMSE was 18.2 (n = 15); the mean baseline ADAS-Cog was 20.8 (n = 11); and the mean baseline SIB was 62.5 (n = 5). There was significant improvement with treatment, as measured by all of the primary efficacy variables, through 6 months: MMSE increased by 2.13 -/+ 2.23, ADAS-Cog improved (decreased) by 5.48 -/+ 5.08, and SIB increased by 16.6 -/+ 14.52. CONCLUSION: An increasing amount of basic science and clinical evidence implicates inflammatory processes and resulting glial activation in the pathogenesis of AD. This small, open-label pilot study suggests that inhibition of the inflammatory cytokine TNF-alpha may hold promise as a potential approach to AD treatment. Further study in randomized, placebo-controlled clinical trials is merited.

Perispinal Delivery of CNS Drugs.

Perispinal injection is a novel emerging method of drug delivery to the central nervous system (CNS). Physiological barriers prevent macromolecules from efficiently penetrating into the CNS after systemic administration. Perispinal injection is designed to use the cerebrospinal venous system (CSVS) to enhance delivery of drugs to the CNS. It delivers a substance into the anatomic area posterior to the ligamentum flavum, an anatomic region drained by the external vertebral venous plexus (EVVP), a division of the CSVS. Blood within the EVVP communicates with the deeper venous plexuses of the CSVS. The anatomical basis for this method originates in the detailed studies of the CSVS published in 1819 by the French anatomist Gilbert Breschet. By the turn of the century, Breschet's findings were nearly forgotten, until rediscovered by American anatomist Oscar Batson in 1940. Batson confirmed the unique, linear, bidirectional and retrograde flow of blood between the spinal and cerebral divisions of the CSVS, made possible by the absence of venous valves. Recently, additional supporting evidence was discovered in the publications of American neurologist Corning. Analysis suggests that Corning's famous first use of cocaine for spinal anesthesia in 1885 was in fact based on Breschet's anatomical findings, and accomplished by perispinal injection. The therapeutic potential of perispinal injection for CNS disorders is highlighted by the rapid neurological improvement in patients with otherwise intractable neuroinflammatory disorders that may ensue following perispinal etanercept administration. Perispinal delivery merits intense investigation as a new method of enhanced delivery of macromolecules to the CNS and related structures.

Targeted etanercept for discogenic neck pain: uncontrolled, open-label results in two adults.

BACKGROUND: Etanercept, a recombinant biologic anti-tumor necrosis factor (TNF)-alpha therapeutic, is approved for the treatment of certain autoimmune arthritides by subcutaneous (SC) injection. TNF-alpha has been suggested to play a central role in neuropathic pain and neuronal damage associated with intervertebral disc herniation. Directed local administration of etanercept, in anatomic proximity to the site of disc and neuronal abnormality, may result in an enhanced therapeutic response. OBJECTIVE: This study reviews findings from 2 patients with chronic, severe, discogenic cervical pain who were treated with a targeted cervical injection of etanercept with the objective of obtaining relief from their treatment-resistant pain. METHODS: In this uncontrolled, open-label study, the case histories of 2 patients (1 woman and 1 man) presenting with a history of chronic neck pain refractory to various treatments are reviewed. Both patients were treated with etanercept 25 mg by SC injection to the cervical region (case 1) or the posterior neck overlying the spine (case 2). RESULTS: Both patients experienced almost complete pain relief as assessed subjectively. In case 1, the Oswestry score decreased from 58 before treatment to 6 one day following treatment. In addition, 1 day after treatment the patient reported a subjective assessment of 98% pain improvement, 100% sensory improvement, and 100% weakness improvement. She has remained asymptomatic for >1 year. In case 2, the Oswestry score decreased from 44 before treatment to 4 two months after treatment. The patient reported 100% pain relief and 90% sensory improvement 1 day after treatment. At 8-month follow-up, pain improvement continued to be 100% and sensory improvements was 75%. CONCLUSIONS: Etanercept, delivered by targeted SC injection, may be of benefit for selected patients with resistant pain associated with cervical disc disease. Further study of this new treatment modality is warranted.

Targeted etanercept for treatment-refractory pain due to bone metastasis: two case reports.

BACKGROUND: Parallel bodies of research suggest both a central role for osteoclasts in tumor-induced destruction of bone and the ability of biologic tumor necrosis factor-alpha (TNF-alpha) antagonists to attenuate the osteoclast-mediated bone destruction that accompanies a variety of nonmalignant disorders. Additional studies have implicated TNF-alpha in the promotion of osteoclast-mediated malignant osteolysis and the pathogenesis of neuropathic pain. TNF-alpha antagonists have the potential to interfere in both processes. OBJECTIVE: This article reviews the cases of 2 patients with treatment-refractory pain due to cancer metastases to bone who were given targeted injections of the biologic anti-TNF agent etanercept based on its potential to interfere directly with both malignant activation of osteoclasts and neuropathic pain. METHODS: One patient had a diagnosis of non-small cell lung cancer and the other had a diagnosis of breast cancer. Both presented with treatment-refractory pain due to bone metastases. The 2 patients received etanercept 25 mg by targeted SC injection in anatomic proximity to the site of spinal metastasis for relief of their treatment-refractory pain. RESULTS: Both patients experienced rapid, substantial, and sustained relief of chronic refractory pain at the treatment site after targeted administration of etanercept. Symptomatic improvement was correlated with objective measures of improvement, including weight gain in 1 patient and decreased uptake of radioactive tracer at the targeted site on positron emission tomography in the other. CONCLUSIONS: Etanercept delivered by targeted SC injection may be of clinical benefit in selected patients with treatment-refractory pain caused by bone metastases. Clinical trials are needed to define the potential benefit of biologic TNF-alpha antagonists in the treatment and prevention of malignant osteolysis.

Efficacy of etanercept delivered by perispinal administration for chronic back and/or neck disc-related pain: a study of clinical observations in 143 patients.

OBJECTIVE: Documentation of the clinical results obtained utilizing perispinal etanercept off-label for treatment-refractory back and neck pain in a clinical practice setting. RESEARCH DESIGN AND METHODS: The medical charts of all patients who were treated with etanercept for back or neck pain at a single private medical clinic in 2003 were reviewed retrospectively. Patients were treated if they had disc-related pain which was chronic, treatment-refractory, present every day for at least 8 h, and of moderate or severe intensity. Patients with active infection, demyelinating disease, uncontrolled diabetes, lymphoma or immunosuppression were excluded from treatment with etanercept. Etanercept 25 mg was administered by subcutaneous injection directly overlying the spine. Visual Analogue Scales (VAS, 0-10 cm) for intensity of pain, sensory disturbance, and weakness prior to and 20 min, 1 day, 1 week, 2 weeks, and 1 month after treatment were completed. Inclusion criteria for analysis required baseline and treatment VAS data. MAIN OUTCOME MEASURES: Before and after treatment VAS comparisons for intensity of pain, sensory disturbance, and weakness. RESULTS: 143 charts out of 204 met the inclusion VAS criteria. The 143 patients had a mean age of 55.8 +/- 14, duration of pain of 9.8 +/- 11 years, and an initial Oswestry Disability Index of 42.8 +/- 18, with 83% having back pain, 61% sciatica, and 33% neck pain. 30% had previous spinal surgery, and 69% had previously received epidural steroid injections (mean 3.0 +/- 3). The patients received a mean of 2.3 +/- 0.7 doses of perispinal etanercept separated by a mean interval of 13.6 +/- 16.3 days. The mean VAS intensity of pain, sensory disturbance, and weakness were significantly reduced after perispinal etanercept at 20 min, 1 day, 1 week, 2 weeks, and 1 month with a p < 0.0001 at each time interval for the first dose in this patient population. CONCLUSIONS: Perispinal etanercept is a new treatment modality which can lead to significant clinical improvement in selected patients with chronic, treatment-refractory disc-related pain. Generalizability of the present study results is limited by the open-label, uncontrolled methodology employed. Based on this and other accumulating recent studies, etanercept may be useful for both acute and chronic disc-related pain. Further study of this new treatment modality utilizing double-blind placebo controlled methodology is indicated. NOTE: This treatment method is protected by multiple patents awarded to Edward Tobinick MD, including U. S. patents 6 015 557; 6 177 077; 6 419 944; 6 537 549 and Australian patent 758 523.

Perispinal TNF-alpha inhibition for discogenic pain.

OBJECTIVE: To examine the potential of etanercept, a biological inhibitor of tumour necrosis factor-alpha (TNF), delivered by perispinal administration, for the treatment of pain associated with intervertebral disc disease. METHODS: Charts from 20 selected patients treated at our private clinic by perispinal delivery of etanercept 25 mg for severe, chronic, treatment-resistant discogenic pain were reviewed. Therapeutic benefit was assessed clinically and was documented by changes in a validated pain instrument, the Oswestry Disability Index. The patients were treated off-label with etanercept as part of our usual practice of medicine. Five detailed case reports are presented, including three additional patients. RESULTS: Rapid, substantial and sustained clinical pain reduction was documented in this selected group of patients. The cohort of 20 patients had a mean age of 56.5 and mean duration of pain of 116 months. Nine of the patients had undergone previous spinal surgery; 17 had received an epidural steroid injection or injections (mean 3.2). This group of patients received a mean of 1.8 doses (range 1-5, median 1.0) of etanercept during the observation period. The mean length of follow-up was 230 days. Clinical improvement was confirmed by a decrease in the calculated Oswestry Disability Index from a mean of 54.85 +/- 12.5 at baseline, improving to 17.2 +/- 15.3 (p <0.003) at 24 days and ending at 9.8 +/- 13 (p <0.003) at 230 days. CONCLUSIONS: TNF inhibition by etanercept delivered by perispinal administration may offer clinical benefit for patients with chronic, treatment-resistant discogenic pain. Further study of this new treatment modality is warranted.

Perispinal etanercept for post-stroke neurological and cognitive dysfunction: scientific rationale and current evidence.

There is increasing recognition of the involvement of the immune signaling molecule, tumor necrosis factor (TNF), in the pathophysiology of stroke and chronic brain dysfunction. TNF plays an important role both in modulating synaptic function and in the pathogenesis of neuropathic pain. Etanercept is a recombinant therapeutic that neutralizes pathologic levels of TNF. Brain imaging has demonstrated chronic intracerebral microglial activation and neuroinflammation following stroke and other forms of acute brain injury. Activated microglia release TNF, which mediates neurotoxicity in the stroke penumbra. Recent observational studies have reported rapid and sustained improvement in chronic post-stroke neurological and cognitive dysfunction following perispinal administration of etanercept. The biological plausibility of these results is supported by independent evidence demonstrating reduction in cognitive dysfunction, neuropathic pain, and microglial activation following the use of etanercept, as well as multiple studies reporting improvement in stroke outcome and cognitive impairment following therapeutic strategies designed to inhibit TNF. The causal association between etanercept treatment and reduction in post-stroke disability satisfy all of the Bradford Hill Criteria: strength of the association; consistency; specificity; temporality; biological gradient; biological plausibility; coherence; experimental evidence; and analogy. Recognition that chronic microglial activation and pathologic TNF concentration are targets that may be therapeutically addressed for years following stroke and other forms of acute brain injury provides an exciting new direction for research and treatment.

Immediate neurological recovery following perispinal etanercept years after brain injury.

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.