Come next month, I’ll have not seen a patient for 5 years. But those questions coming in from friends and relatives can still jog this old medical brain. A couple weeks back, Ron, who’s a distant cousin, good friend, and husband of much missed Barb (1), a nurse who used to field most of his medical queries, sent me his latest. Writing for his brother, still having quite a bit of trouble after a stroke, came a link to a recent paper addressing the use of etanercept (Enbrel) in post-stroke pain (2). While very familiar with Enbrel, I was not aware of this application. To quote the South Park kids, “I learned something today” (3) and want to pass it on.
A stroke is a horrible thing. Stroke is the fifth leading cause of death in the United States and a leading cause of long-term disability. The annual incidence of stroke in the U.S. is about 795,000 (4). Whether embolic, thrombotic, or hemorrhagic (I’ll explain), that segment of brain suddenly deprived of blood flow stops sending signals to the portion of the body it controls, and there goes function. That sudden loss was so striking to the ancients who observed it, they considered it a strike from the hand of God, possibly a punishment. Several Brazilian neurologists published their contention that a clear description of stroke symptoms appears in the Old Testament, Psalm 137:5,6 (5). David writes (RSV)” 5 – If I forget you, O Jerusalem, let my right-hand wither! 6 – Let my tongue cleave to the roof of my mouth, if I do not remember you, if I do not set Jerusalem above my highest joy!”. The authors provide their neurologic version “If I forget you, oh Jerusalem, I will suffer a stroke of the left middle cerebral artery, causing motor aphasia and right hemiplegia, if I do not remember you, if I do not keep Jerusalem as my greatest joy.” They comment “Psalm 137 is a relevant contribution from Hebrew culture to the history of neurology.” Is this description of a punishment corresponding to the symptoms found in cerebrovascular stroke of the middle cerebral artery a coincidence? Or did the Hebrews know at that time that left hemiplegia may occur without aphasia, did they know of cerebral dominance about 600 years before Christ?” Interesting, to be sure, but maybe a bit too much inside baseball for what I want to communicate here. But just a few more basics. The sudden cessation of blood flow to a portion of the brain can come about from a plugging material arriving from another part of the body, like the heart in atrial fibrillation (embolic), from a clot forming in a feeding blood vessel (thrombotic), or from bleeding into the brain (hemorrhagic). “Clot-busting” interventions are fraught with hazard as they do nothing to those thrown plugs and can worsen the bleeding of a hemorrhagic. Some recovery is usually possible due to the brain’s incredible plasticity (ability to take in one part over functions handled by another). But post-stroke care still consists mainly of physical therapy. Recently, it has been understood that a stroke was followed by a fairly intense inflammatory response in the brain. Not a surprise, as our bodies respond to damage and death anywhere with inflammation to clean up the mess and start to effect repair. The brain response included high doses of tumor necrosis factor (TNF), a prime inflammatory mediator. Similar high levels of TNF in inflamed joints led to development of an agent to block its attachment to cells: etanercept, a compound that transformed my rheumatology practice (6). Getting this agent into the brain and seeing if it made a difference in poststroke patients was the focus of the paper Ron sent me. I’m glad I finally read it. Here’s my reply to Ron.
Well, Ron, getting stuck in the back of the plane for the ATL-DTW last leg of our Mexico trip last night finally gave me a chance to look this over. Had it been a manuscript sent to me for review, I would have scrawled red ink all over it and sent it back to the editor to have the authors make some major revision, but they got it into Cereus, which is not a bad journal. What they describe are the effects of injecting Enbrel (etanercept) deep enough into spine to get it into blood vessels that run right up to the brain. The justification for this is the fact that strokes bring out an inflammatory process, and tumor necrosis factor (TNF) is a major mediator in this process. Enbrel blocks the attachment of TNF to cells, and is something I used since 1998, when it first became available. It was the first “biologic” (an agent grown in living tissue rather than made in a test tube) and is remarkably effective in rheumatoid arthritis. It really transformed my practice, as patients came back happy instead of just enduring their burden ever so slightly modified by my ministrations. Many other biologics followed, all very expensive ($1000/mo and up) with a few peculiar side effects and conferring an enhanced susceptibility to infections. RA patients just inject themselves in the leg once a week. That wouldn’t work for post stroke inflammation, as TNF is too big to leave the central nervous system and Enbrel won’t cross that barrier. Hence the perispinal injection (7). That must be delivered by a doc, and I’m guessing this is a thing now. When I Googled to find difference between perispinal and intrathecal injections (intrathecal injections are a spinal tap where the drug is delivered right into the cerebrospinal fluid – some chemotherapies go this way), up popped a choice “perispinal etanercept near me”. The author’s very sloppy table did describe 4 studies where this treatment seemed to have an effect.
I even found a YouTube describing the whole process (8).
Thanks for making me dive into something I really knew very little about. Hope this helps.
Bob
My bottom line, stroke patients having troubles with pain or slow return of function should consider this therapy.
References
- Ike B. bye, Barb. WordPress 6/7/23. https://theviewfromharbal.com/2023/06/07/bye-barb/
- Joseph AM, Karas M, Jara Silva CE, Leyva M, Salam A, Sinha M, Asfaw YA, Fonseca A, Cordova S, Reyes M, Quinonez J, Ruxmohan S. The Potential Role of Etanercept in the Management of Post-stroke Pain: A Literature Review. Cureus. 2023 Mar 15;15(3):e36185. doi: 10.7759/cureus.36185.
3. I’ve learned something today – South Park. YouTube https://www.youtube.com/watch?v=mBOhUtHg6bM
4. Stroke facts. [ Feb; 2023]. 2022. https://www.cdc.gov/stroke/facts.htm
5. Resende LA, Weber SA, Bertotti MF, Agapejev S. Stroke in ancient times: a reinterpretation of Psalms 137:5,6. Arq Neuropsiquiatr. 2008 Sep;66(3A):581-3. doi: 10.1590/s0004-282×2008000400033.
6. Burness CB, Duggan ST. Etanercept (SB4): A Review in Autoimmune Inflammatory Diseases. BioDrugs. 2016 Aug;30(4):371-8. doi: 10.1007/s40259-016-0188-z. Erratum in: BioDrugs. 2016 Oct;30(5):481.
7. Tobinick EL. Perispinal Delivery of CNS Drugs. CNS Drugs. 2016 Jun;30(6):469-80. doi: 10.1007/s40263-016-0339-2.
8. Perispinal Etanercept Treatment for Stroke clinical trial – Griffith University. YouTube. https://www.youtube.com/watch?v=2dKdeAHp2K8
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