New hope for stroke recovery: Post-Stroke perispinal injection of etanercept. Myth or fact?

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I was unaware of the off label injection of etanercept (Enebrel) for stroke until a patient  asked me if I knew anything about it! I had heard about its clinical application in autoimmune disease such as Rheumatoid arthritis (RA) but never heard of its use in stroke. etanercept is a tumor necrosis factor (TNF) inhibitor works by blocking these cytokines and in return dampens the inflammatory cascade. In Ischemic events, TNF is released by microglia and macrophages, and contributes to the volume of the infarct (1). There has been a number of studies suggesting the efficacy of this treatment:  Wang et al in 2013 investigated the effect of TNF inhibitors on animal models with TBI and their results showed a decrease in inflammatory levels and down regulation in RNA transcription of protein kinase(2). Belarbi et al, evaluated the therapeutic potential of a novel analog of thalidomide DT, an agent with an anti TNF alpha activity in a model of chronic neuroinflammation in animal models and saw  decreased pro-inflammatory cytokines levels in the hippocampus(3). There are at least 3 more animal model studies out there with promising results, indicating that TNF inhibitors decrease or stop neuroinflammatory processes  following a stroke or trauma. At last, in a large observational study Tobinick et al observed 629 consecutive patients (617 following stroke and 12 following TBI) and noted that etanercept therapy significantly attenuated TBI-induced cerebral ischemia, neurological motor deficits and significant improvement in motor and sensory  impairment, spasticity, motor improvement, cognition, aphasia and behavioural/psychological functions(4) the author also provided the following list of benefits:

 1.Published, peer-reviewed reports of improvement in cognition in humans following the use of etanerceptor TNF antibodies by independent academic sources other than the present authors.

2. Favourable results of etanercept and other recombinant TNF inhibitors in animal models of stroke, traumatic brain injury,  Alzheimer’s  disease,  and neuropathic pain.

3.Published, peer-reviewed reports of rapid, significant, and sustained neurological and clinical improvement following  perispinal etanercept in patients with chronic neurological dysfunction following stroke, traumatic brain injury, Alzheimer’s disease, sciatica, and other forms of spinal pain.

4.Positron emission tomographic imaging data, and the data from direct pathological examination of brain tissue demonstrating chronic microglial activation in the brain following stroke and traumatic brain injury in humans that may last for years after a single brain injury.

5.Etanercept demonstrated the ability to reduce microglial activation in multiple experimental   models, including in models of brain injury.

6.Known effects of TNF on synaptic function.

7.Known rapid  effects of  TNF on  neuronal and synaptic function.

8.Recognition   in   the   scientific   community   of   the therapeutic potential of perispinal etanercept for the treatment of neurological disorders, as indicated by scientific citation.

9.Four randomized, clinical trials reporting favourable effects   of   etanercept   for   spinal   neuropathic pain supporting  earlier reports  of the  effectiveness   of perispinal etanercept for these indications.

10.A known anatomic pathway for carriage of etanercept following perispinal injection, the

Vertebral-venous-plexus

Is it safe after all?

According to multiple peer reviewed analyses it would be difficult to deny the efficacy of etanercept and its TNF inhibitory effects, but is it safe to be used in stroke population? this is what Enbrel listed on their website as possible side effects of etanercept(keep in mid that they are selling this medication mainly for the treatment of rheumatoid arthritis):

 

ENBREL is a medicine that affects your immune system. ENBREL can lower the ability of your immune system to fight infections. Serious infections have happened in patients taking ENBREL. These infections include tuberculosis (TB) and infections caused by viruses, fungi, or bacteria that have spread throughout the body. Some patients have died from these infections. Your doctor should test you for TB before you take ENBREL and monitor you closely for TB before, during, and after ENBREL treatment, even if you have tested negative for TB.There have been some cases of unusual cancers reported in children and teenage patients who started using tumor necrosis factor (TNF) blockers before 18 years of age. Also, for children, teenagers, and adults taking TNF blockers, including ENBREL, the chances of getting lymphoma or other cancers may increase. Patients with RA or psoriasis may be more likely to get lymphoma.

  • Infections, new or worsening of infections you already have
  • Hepatitis B can become active if you have had it before
  • Nervous system problems such as multiple sclerosis, seizures, or inflammation of eye nerves
  • Blood problems (some fatal)
  • Heart failure, new or worsening heart failure you already have
  • Psoriasis, new or worsening psoriasis you already have
  • Allergic reactions, with symptoms that include a severe rash, a swollen face, or trouble breathing
  • Immune reactions, including a lupus-like syndrome, lymphoma (a type of cancer) and other cancers, and autoimmune hepatitis
– See more at: https://www.enbrel.com/support/side-effects-safety-information/#sthash.xedi5JcP.dpuf

Conclusion:

Asprin took 16 years to become the standard of care in heart attack management from the day its efficacy was proved, on the other hand Mast trousers were standard of care in the 70’s . We also had the Edinburgh  phrenological society which was a legitimate scientific society back then. so the moral of the story is that  according to the available research and anecdotal evidence etanrecpet appears to work. on the hand the institute of neurological recovery  says that 1 out of 5 patients receiving etanercept does not show any improvements.  Links to patients success stories and procedures are added to the bottom of this article and you can see some  patients claim that they improved drastically and some with minimal improvements. I have talked to 2 patients who received the treatment and  they saw minimal improvements afterwards. At this point more information is required to draw a definitive conclusion about the efficacy of this treatment and possible long term side effects of the off label use of etanercept in stroke patients.

****There is also a  practice advisory from the American Academy of Neurology against the use of etanercept for stroke which came out in June 2016:

For adult patients with post-stroke disability, does etanercept administered by any route (compared with no etanercept or placebo) improve functional status?

Level U : Clinicians should counsel patients considering etanercept for treatment of post-stroke disability that there is insufficient evidence to determine its effectiveness and that the treatment may be associated with adverse outcomes and high cost (As of this writing, the cost of a 25-mg vial of etanercept is about $440 in US currency plus additional costs).

Links:

1:http://www.abc.net.au/news/2016-05-23/hopes-ama-will-pass-new-stroke-treatment/7436406

2:

 

References:

1.Tobinick E, Rodriguez-Romanacce H, Levine A, Ignatowski

TA, Spen-gler, RN. Immediate neurological recovery following perispinal etanercept

years after brain injury.Clin Drug Investig. 2014;34(5):361–366.

2.Belarbi K, Jopson T, Tweedie D, et al. TNF-α protein synthesis inhibitor

restores neuronal function and reverses cognitive deficits induced by

chronic neuroinflammation.J Neuroinflammation. 2012;9:23.

3.Wang YX, You Q, Su WL, et al. Ruan CPA study on inhibition of

inflammation via p75TNFR signaling pathway activation in mice with

traumatic brain injury.J Surg Res. 2013;182(1):127–133.

4.Tobinick E, Kim NM, Reyzin G, Rodriguez-Romanacce H, DePuy V.

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):1051–1070.

 

 

 

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