Perispinal Etanercept – Chronic Brain Injury
A new case report by Tobinick et al. in the May 2014 issue of Clinical Drug Investigation describes striking success with a single perispinal etanercept dose in a patient who sustained brain injury 3 years prior.
Multiple reports have shown promise for use of etanercept, a tumor necrosis factor (TNF) inhibitor, in patients with chronic neurological deficits associated with stroke, traumatic brain injury, Alzheimer’s disease, and chronic pain. Perispinal administration accesses the vertebral venous plexus and carries the medication via the cerebrospinal venous system to the brain. The rationale for etanercept use is based on evidence that TNF is involved in microglial activation, synaptic dysfunction, and neuropathic pain, while imaging has shown that chronic neuroinflammation persists for years following brain injury.
The 52-year-old patient described in this report had persistent language impairment, hemiparesis, and hemisensory disturbances over 3 years following an episode of status epilepticus, despite intensive rehabilitation therapy. After perispinal etanercept injection, coauthors Drs. Robert N. Spengler and Tracey A. Ignatowski, who study inflammatory and neuromodulatory functions of TNF, noted improvements in gait and verbal fluency within minutes. Patient continued to show improvement in all areas of prior deficit over the next 6 days, which were sustained at last follow up 6 weeks later without further medication.
While more research is needed and etanercept carries the rare potential risks of death, infection, seizures, and further injury, the experience with this patient, as well as with over 600 patients with chronic post-stroke neurological dysfunction (Tobinick, E., N.M. Kim, et al., Selective TNF Inhibition for Chronic Stroke and Traumatic Brain Injury : An Observational Study Involving 629 Consecutive Patients Treated with Perispinal Etanercept. CNS Drugs, 2012, 26(12): p. 1051-70), expands the range of neurologic injuries that can potentially be addressed with perispinal etanercept used off-label and provides hope that impaired patients can regain function years after conventional rehabilitation attempts have failed.
Source: Clin Drug Investig, 2014, 34:361-6. doi: 10.1007/s40261-014-0186-1.
Read more: Clinical Drug Investigation
Updates
A 2014 Leading Article by Tracey A Ignatowski et al. summarizes the rationale for the Perispinal Etanercept use for post-stroke neurological and cognitive dysfunction.
Key Points: Accumulating evidence suggests that chronic post-stroke intracerebral microglial activation and neuroinflammation mediated by pathologic levels of tumor necrosis factor constitute new therapeutic targets that may persist for years after stroke. Perispinal etanercept for chronic post-stroke neurological and cognitive dysfunction is an emerging treatment modality that may lead to rapid and sustained clinical improvement in this patient population.
Perispinal Administration: Perispinal administration is a novel method of drug delivery. 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).
Importantly, perispinal etanercept for post-stroke neurological and cognitive dysfunction satisfies all of Hill’s nine criteria: strength of the association; consistency; specificity; temporality; biological gradient; biological plausibility; coherence; experimental evidence; and analogy.
According to the authors, with the additional weight of recent basic science studies reporting favorable effects of etanercept in a diverse group of brain disorders, and scientists from several independent academic centers reporting favorable effects of TNF inhibition in other stroke models, now is the time to seriously consider systematic testing of perispinal etanercept for brain injury, especially in stroke. For more information, see the overview by Tracey A Ignatowski et al.
A 2017 chapter by E. Tobinick et al. in New Therapeutics for Traumatic Brain Injury recapitulates the recent evidence suggesting that etanercept, a selective TNF inhibitor, may ameliorate microglial activation; modulate the adverse synaptic effects of excess TNF; and favorably intervene in basic science models of traumatic brain injury (TBI), stroke, subarachnoid hemorrhage, and Alzheimer’s disease. Moreover, increasing clinical data suggests that perispinal etanercept (PSE) has therapeutic utility in these conditions. Thus, PSE is an emerging treatment modality for TBI.
In a 2018 Expert Review of Neurotherapeutics Edward Tobinick outlines the promise of Perispinal etanercept (PSE) in neurology.
PSE provided the first favorable clinical data regarding TNF inhibition for the following neuroinflammatory disorders: 1) Chronic spinal pain due to intervertebral disc herniation; 2) Radicular sensory dysfunction (anesthesia and paresthesia) associated with intervertebral disc herniation; 3) Radicular motor dysfunction (muscle weakness) due to intervertebral disc herniation; 4) Spinal pain due to cancer metastasis to bone: 5) Cognitive dysfunction in AD; 6) Behavioral dysfunction in AD; 7) Chronic motor impairment and spasticity due to TBI; 8) Chronic motor impairment, spasticity, sensory dysfunction, cognitive dysfunction, psychological/behavioral dysfunction, aphasia, and pain after stroke; 9) Chronic dysfunction of taste, smell, vision, and bladder function after stroke. For more information, see the 2018 Expert Review of Neurotherapeutics.
A 2020 Research Letter by Edward Tobinick presented a case report with a 59-year-old man who visited the clinic 16 years after a right middle cerebral artery stroke.
Prior to treatment, the examination revealed a left hemiparesis, left-sided spasticity, left sensory loss involving both the left upper and lower extremities, cold allodynia on the left upper extremity, cognitive dysfunction (Montreal Cognitive Assessment score = 19/30), Fatigue Assessment Scale Score of 24/50, and chronic left-sided pain (central post-stroke pain) assessed by the patient as 5/10 in severity on a 0–10 scale. Walking 20 meters took 58 s. The Five Times Sit-to-Stand test required 27 s to complete with assist from his right arm. There was prominent left hemispatial neglect, as measured by the Clock-Drawing Test.
Background: Neglect as a consequence of right brain damage has been recognized at least since J. Hughlings Jackson’s 1876 case report. It was later appreciated that impairment in brain functional connectivity and resulting brain network dysfunction (‘connectopathy’, ‘disconnection syndrome’) underlies hemispatial neglect, a common sequela of right hemispheric stroke.
After informed consent was obtained, etanercept 25 mg was administered by perispinal injection, followed by Trendelenburg positioning, as previously described. Within 10 min, the patient reported that his chronic left-sided post-stroke pain was gone. Within 30 min after etanercept administration, the patient reported a complete absence of his chronic left-sided pain, a reduction in spasticity, and improvements in gait, balance, the ability to turn to the left, and the ability to perceive the position of his left foot. A repeat Clock-Drawing Test performed 30 min after perispinal etanercept injection no longer showed left hemispatial neglect.
According to the author, the striking pattern of immediate improvement in clock drawing documented in this patient with chronic, previously intractable, central post-stroke pain, chronic post-stroke fatigue, and left hemispatial neglect is most consistent with rapid restoration of brain functional connectivity. This evidence suggests hemispatial neglect may be caused by TNF-mediated network dysfunction and impairment in functional connectivity that remains reversible, even years after stroke. This evidence also suggests that central post-stroke pain may be mediated by TNF. For more info, see the 2020 Research Letter by Edward Tobinick.
The 2022 article entitled ‘Rapid improvement in severe long COVID following perispinal etanercept’ by Edward Tobinick et al. described the neurological improvements in a patient with severe long COVID brain dysfunction following perispinal etanercept administration.
According to the authors 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. For more information and discussion, see also our news report entitled: New Evidence of the Role of Brain Immune Mechanisms in Long COVID.
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Cover Image Credit: PET images of a living rat brain following peripheral administration of 64Cu-DOTA-etanercept. The distinctive central pattern of brain distribution suggests penetration of 64Cu-DOTA-etanercept into the CSF in the lateral and third ventricles and accumulation of tracer within the choroid plexus following perispinal administration. (A) The pattern following perispinal administration is distinct from that following ventral tail vein injection. (B) Comparison of the transverse PET image following perispinal injection with section 306 from the Allen Brain atlas . CSF: Cerebrospinal fluid; DOTA: 1,4,7,10-tetraazadodecane-N,NI,NII,NIII-tetraacetic acid. From: Perispinal etanercept: A new therapeutic paradigm in neurology, by Edward Tobinick, June 2010 Expert Review of Neurotherapeutics 10(6):985-1002
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