The anatomy and physiology of the cerebrospinal venous system, a unique, bi-directional vascular pathway, remains little known in the general medical community, despite recognition in multiple neurosurgical and anatomical publications. The external vertebral venous plexus drains into, and is a component of, the cerebrospinal venous system (Fig. Perispinal injection of etanercept is designed to facilitate selective delivery of etanercept to the central nervous system, as drugs administered posterior to the spine are absorbed into the external vertebral venous plexus (Fig. Perispinal administration of etanercept for treatment of brain disorders involves needle injection overlying the spine superficial (external) to the ligamentum flavum. This difficulty in reaching the brain in therapeutic concentrations when administered systemically is consistent with other studies documenting limited (0.1–0.6 %) penetration of large molecules into the brain when administered systemically. Its use to deliver etanercept for treatment of post-stroke neurological dysfunction is necessitated by the fact that etanercept has difficulty in traversing the blood–brain barrier (BBB) in therapeutically effective concentration when administered systemically, due in large part to its high molecular weight (150,000 Da). Perispinal administration is a novel method of drug delivery. The etanercept stroke studies are previously published studies of the senior author and colleagues. Perispinal etanercept for this indication has been explored clinically nearly exclusively by the senior author, his colleagues, and a small group of independent physicians who have trained in the perispinal etanercept treatment method. Perispinal etanercept for post-stroke neurological dysfunction was invented and pioneered by the senior author. The 20 etanercept post-stroke studies are designated herein as ‘the etanercept stroke studies’. Perispinal etanercept produced rapid improvement in a variety of chronic post-stroke neurological dysfunctions (Table 1). Statistically significant improvements in neurological and cognitive function and reduction in pain were noted in the stroke cohort. The study included 617 consecutive patients treated a mean of 42 months following stroke (‘the 617-patient stroke cohort’), and 12 patients following traumatic brain injury (TBI). In December 2012, an observational study of 629 patients treated off-label with perispinal etanercept was published. Each patient received a second perispinal etanercept dose at 22–26 days after the first, which was followed by additional improvement. Onset of clinical response was evident within 10 min of the etanercept dose in each patient. #Intacept 50 mg injection price series#In February 2011, rapid improvement in cognition improvement in chronic neurological dysfunction and reduction in chronic, intractable post-stroke pain was noted among a series of three patients treated off-label 13, 25, and 36 months after stroke with a single dose of etanercept, administered by perispinal injection. The world stroke research community recognizes the urgent need for improved stroke treatments. Current drug treatments are grossly inadequate. Post-stroke disability represents a major public health problem throughout the world. 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. 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. 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. Recent observational studies have reported rapid and sustained improvement in chronic post-stroke neurological and cognitive dysfunction following perispinal administration of etanercept. Activated microglia release TNF, which mediates neurotoxicity in the stroke penumbra. Brain imaging has demonstrated chronic intracerebral microglial activation and neuroinflammation following stroke and other forms of acute brain injury. Etanercept is a recombinant therapeutic that neutralizes pathologic levels of TNF. TNF plays an important role both in modulating synaptic function and in the pathogenesis of neuropathic pain. 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.
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