Botulinum neurotoxins: from paralysis to recovery of functional neuromuscular transmission.

19
PubMed
TI
Botulinum neurotoxins: from paralysis to recovery of functional neuromuscular transmission.
AU
Meunier FA, Schiavo G, MolgóJ
SO
J Physiol Paris. 2002;96(1-2):105.

The neuromuscular junction is one of the most accessible mammalian synapses which offers a useful model to study long-term synaptic modifications occurring throughout life. It is also the natural target of botulinum neurotoxins (BoNTs) causing a selective blockade of the regulated exocytosis of acetylcholine thereby triggering a profound albeit transitory muscular paralysis. The scope of this review is to describe the principal steps implicated in botulinum toxin intoxication from the early events leading to a paralysis to the cellular response implementing an impressive synaptic remodelling culminating in the functional recovery of neuromuscular transmission. BoNT/A treatment promotes extensive sprouting emanating from intoxicated motor nerve terminals and the distal portion of motor axons. The current view is that sprouts have the ability to form functional synapses as they display a number of key proteins required for exocytosis: SNAP-25, VAMP/synaptobrevin, syntaxin-I, synaptotagmin-II, synaptophysin, and voltage-activated Na+, Ca2+ and Ca2+-activated K+ channels. Exo-endocytosis was demonstrated (using the styryl dye FM1-43) to occur only in the sprouts in vivo, at the time of functional recovery emphasising the direct role of nerve terminal outgrowth in implementing the restoration of functional neurotransmitter release (at a time when nerve stimulation again elicited muscle contraction). Interestingly, sprouts are only transitory since a second distinct phase of the rehabilitation process occurs with a return of synaptic activity to the original nerve terminals. This is accompanied by the elimination of the dispensable sprouts. The growth or elimination of these nerve processes appears to be strongly correlated with the level of synaptic activity at the parent terminal. The BoNT/A-induced extension and later removal of “functional” sprouts indicate their fundamental importance in the rehabilitation of paralysed endplates, a finding with ramifications for the vital process of nerve regeneration.
AD
Molecular NeuroPathobiology Laboratory, Imperial Cancer Research Fund, 44 Lincoln’s Inn Fields, London WC2A 3PX, UK. f.meunier@icrf.icnet.uk
PMID
11755789

f.lux to dim your monitor – really helps eyes

hi everyone, i am switching to a new computer ( yay finally !!) and havent been able to be on much. want to make a suggestion ive had for a long time and just not remember it: there is a program called ” f.lux” its a small free program you can download here https://justgetflux.com/ it is easy to install and run on windows and i think macs.

this program automatically changes the color of the light coming out of your monitor from blue to more red on the color spectrum. this wont make much sense probly but it mimics natural day/night cycles.

usually our monitor light is bright blue, like light in the day.. .this suppresses melatonin and can mess with our sleep as well as being hard on the eyes ( i cant even use a normal screen anymore i dont know how i ever did) normally at night natural light dims as the sun goes down but our monitors continue producing this bright blue light which as i said can interfere with sleep cycles, as well as just being really tough on the eyes.

you can set this program to whatever brightness works for you,and it automatically dims in the evening at sundown and then brightens in the morning according to the directions you set. you can set it really really low if you want to.. and its reeeeally saved my eyes when im using the computer especialy at night. i really recommend it for those of us with sensitive eyes (which is like most of all of us ) or those of us who use computers a lot ( probably most or all of us ) if i use a normal screen at this point i feel like my eyes are melting from the brightness !! its also good for your brain since blue light can suppress melatonin production in the brain. this is different from just dimming your monitor, it changes where the light is on the color spectrum.

seriously check it out you can find it here i really recommend it ive run it for a good year now and wouldnt be without it. just a little thing to help us with our symptoms of sensitive eyes. https://justgetflux.com/

It’s been a bad few days

I am typing this as I hold the heating pad on my chest and pray that this will pass!  Went to the GI on Friday for a check up who told me that this cannot be related to Botox.  He gave me Rantidine for the heart burn (Xantac), Xanax for severe panic attacks (because I told him about the rapid heart rate), and a low dose of another drug that is used for a hypersensitive esophagus to calm my nerves…all 3 are anticholinergic drugs, which I found out after researching on this site and online.  I have had severe stomach issues all day, and the pressure in my chest is unbearable.  Had my normal physical today with my GP and an EKG, which was normal.  That doc recommended the Xantac twice a day for the next two weeks to see what happens.  I don’t even tell these docs things anymore because does it really make a difference??  I did take a Xantac tonight just to try it….not sure it is doing a thing.  The heat seems to help.  Any other tips?  Also, taking Vit D as I am low (per blood work with the GYN  last month at my yearly physical there)–not sure it’s setting right with me.  Anyone have issues with Vit D?  Thanks for the help!

 

OK. I am getting scared.

This shaking is not going away. It is really nearly as bad as it was whenever it was that it started. It’s like an electrical wire running current through every part of my body; some parts switch on and some switch off depending on my position. When I am sitting I shake through my legs, shoulders, and arms, sometimes all the way down to my toes. Nothing I have tried makes the slightest difference, except that when I wake up in the morning it’s quiet at least for a couple hours. This is how it’s been from December onward. There are fasciculations, too. All over my body, including my trunk and back.

I can not stand it. It is either brain or nerve damage and there is no promise that it will ever get better.

The life history of a botulinum toxin molecule.

Toxicon. 2013 Jun;68:40-59. doi: 10.1016/j.toxicon.2013.02.014. Epub 2013 Mar 18.
The life history of a botulinum toxin molecule.
Simpson L1.
Author information
Abstract

There is an emerging literature describing the absorption, distribution, metabolism and elimination of botulinum toxin. This work reveals that the toxin can be absorbed by both the oral and inhalation routes. The primary mechanism for absorption is binding and transport across epithelial cells. Toxin that enters the body undergoes a distribution phase, which is quite short, and an elimination phase, which is comparatively long. During the distribution phase, botulinum toxin migrates to the peri-neuronal microcompartment in the vicinity of vulnerable cells, such as cholinergic nerve endings. Only these cells have the ability to selectively accumulate the molecule. When the toxin moves from the cell membrane to the cell interior, it undergoes programmed death. This is coincident with release of the catalytically active light chain that paralyzes transmission. Intraneuronal metabolism of light chain is via the ubiquitination-proteasome pathway. Systemic metabolism and elimination is assumed to be via the liver. The analysis of absorption, distribution, metabolism and elimination of the toxin helps to create a life history of the molecule in the body. This has many benefits, including: a) clarifying the mechanisms that underlie the disease botulism, b) providing insights for development of medical countermeasures against the toxin, and c) helping to explain the meaning of a lethal dose of toxin. It is likely that work intended to enhance understanding of the fate of botulinum toxin in the body will intensify. These efforts will include new and powerful analytic tools, such as single molecule-single cell analyses in vitro and real time, 3-dimensional pharmacokinetic studies in vivo.

Copyright © 2013 Elsevier Ltd. All rights reserved.

PMID:
23518040
[PubMed – indexed for MEDLINE]

My Update at 5 Months.

So starting this month, I have very little pain, almost none. But the tremors in my back, neck and bottom lip are almost unbearable. I can’t forget for a single second what has happened to me and no matter how hard I try not to I find myself drifting to the internet to read about *anything* that could stop it or help it.

I’ll think — if I could just…not be shaking all the time..it would be okay. I could forget this. And then I’ll start reading about stuff other people have that have the symptom of “internal tremor”. Maybe I have Lou Gehrig’s disease. Maybe I am infested with helminths. I’ve had to absolutely stop myself from buying more crap off the internet that I’m sure have nothing to do with what is really wrong.

No pain is a blessing. None. My eyes are working much much better at 5 months, almost perfect though still floaters. My stomach is wrecked; it goes from being A OK to severely troubling ( do I have tremors because of a stomach problem? Google “Tremors and Left Lower Quadrant Cramp.). But I can have a conversation with strangers in a public setting and look them in the eye. I am not “myself” but I can see them.

I gave up on swim therapy because of the bright red rash I have that will not go away. I worry it’s the pool water; I would hate to blow up the way I did a couple weeks ago into redness and swelling on the extremities. This probably means my kidney function isn’t good but I’ve lost faith that bothering to go to see any doctor is going to have any value at all. I have large lymph nodes all over, especially in my armpits. Six months ago I would have thought oh no, breast cancer! Now I think, oh, God…that stuff is in my lymphatic system.

But! The left side is coming back! I think this is why the tremor — the left side is not *all* the way back and my entire hip and psoas process has been pushed out of position. It’s weird, there are couple muscles in there that I can’t define that don’t stop me from walking but it feels *wrong*, unbalanced. That muscle I think is why my back shakes.

My neck and shoulder girdle shake too, and sometimes it’s just all over my body. I hate it. It scares me, terrifies me. Sometimes it’s there and sometimes it’s not there and I cant figure out if that means I am “better or “worse”. I’ll try to shift positions to find the weak muscle, so I know which one to work on. I feel like the shaking in a way is progress because it means that there is less paralysis; but then I’ll remember I was shaking in the beginning both ways, a tremor like this one and then a kind of scary weave, back and forth; vertigo. I wonder if that is coming back. I have pins and needles — like little raindrops — all up and down my arms that scare the hell out of me. I have no idea what it means. On the Lyme Board they say it is a sure sign of helminths. Does it mean the rest of it is coming back?

My hand dexterity is bad both left and right, now, sometimes my fingers shake over the keyboard. Is that better or worse? Sometimes they work fine, I work fine.

How poisoned am I. Will I be okay next month, next year, will this be over, how will I live. I can’t even be the “me” that was “me” for anyone else anymore.

I have been really disinterested in engaging the outside world lately. I blew off an appointment with the ENT his receptionist said he would charge me for anyway. I haven’t taken my trash out or done my laundry in a week and a half.

I’ve been trying to get *some* exercise but to be honest sometimes I’ll read what’s written here and get discouraged. Nothing that happens now really means progress. It’s just activity until the toxin is finished ruining my life, at whatever endpoint it desires. In a way, there is nothing to *do*. Most of the strategies I’ve tried have been either minimally effective or traumatic. Every day there is a new symptom and I’ll spend my evenings mentally gauging how bad is bad enough for the Emergency Room.

None of this is going to kill us, you know. It’s just suffering.

I am confused!!!

I am really scared this morning, I  am so confused!!! I was trying to read through some  posts I’ve read before on this so forgive me if it’s already been asked, I’m just in so much pain this morning I can’t concentrate!  Today I am at 12 weeks post for my 200 units in my pelvis and 10 weeks for my second round of 50 units! I have more units than anyone I’ve seen!  I was actually starting to feel a little better week before last having only about 3 bad days a week, when I found out I had a bladder infection!  Great I said I was terrified to take antibiotics, they gave me macrobid for 7 days, it was really weird I actually stopped having my bad neuropathy in my legs and just joint pain! Wow I thought I’m getting better, I could do more and started to feel normal a bit!  Then 3 days after stopping the antibiotics the burning and tingling and numbness was coming back slowly! Last night I had all my family over for my daughters birthday tried to do all I could for her birthday dinner, could feel I was getting worse, when I laid down to sleep, bam, the pain in my hips and legs were on fire, it felt worse than the beginning pain!  The night before last I took a sleeping pill but read last night about acetycholine and did not take it last night!  My question long drawn out as it is, is this normal?  Will I get better again, what happened? I know I’m early in the game, but is there hope it will get better? I am so miserable and don’t know to what to expect!  Thanks for any help!

AMA

I’m pretty new to this illness, but I’ve got an idea. Does anybody want to go over to Reddit and do an AMA about this? We could all go as a group, whoever wanted to. This problem needs some attention and I would love to get it in front of a couple million people.

” Tiny Amounts of Toxin”

One reason doctors aren’t concerned about botox injections is because the amounts used are “tiny.” But if they are so tiny, when they go systemic why have they made me so sick for so long? I understand the ideas that botulinum is the most toxic substance known to man and that it is potentially a chemical weapon. However *people with botulism* are said to make a full recovery sometimes within several weeks.

What I’m beginning to believe is that since Botox is a “polished medical product” and botulism is a naturally occurring bacterium, that we actually are getting a WHOLE LOT MORE BOTULISM THAN PEOPLE THINK. In the lab, someone can say, well we gave mice this much polished medical product and it took this much to kill them — but in life, when a person gets botulism and they eat a bacterium, you have no idea how much neurotoxin it is releasing. Maybe not so much, maybe not a lot at all. You could have more botulism in you than anyone who goes to the hospital sick from eating home canned pickles.

it’s been five months and I have not made anything close to a full recovery, in fact overall I think I’m a little bit worse. Some overt symptoms are gone but now I’m just sick, fatigued, dizzy, shaking, a little stupefied — every single day. Still haven’t regained full use of anything on the left side of my body, rashy face and swelling. My stomach is still wrecked, bladder isn’t really working right either.

According to the literature, the recovery you make at one full year is the best you will probably ever do. But that’s for botulism. It might work the same way, and it might not.

interesting movie on youtube ‘plastic surgery gone wrong’

https:// www.youtube.com/watch?v=yimrr9yS00E

(i just edited this to disable that link from showing a huge (disturbing) preview picture. thats why i put spaces in the link)

hey i just watched an interesting (if a little gross for surgery scenes) movie.. if anyone wants to waste an hour its kind of interesting. its not about botox its about other forms of plastic surgery but it talks a bit about the advertising and how it can give a misleading sense of safety… social pressure to have these kind of procedures.. and more interestingly it talks about several examples of people who had this kind of experience and then later went on to actually change laws to make practices safer. it kind of made me wonder if we were going to change any laws, what would they be?

it was interesting.

out of curiosity i went back to that website the “coalition for injectables safety” of which my dr (past president of ASAPS) is now a member… when you click the link for information on dysport, it takes you right to the ‘safety information’ at the dysport site.. (rather than, as you would expect, a commercial about how great dysport is) this is the link it takes you to: http://www.dysportusa.com/

very interestingly, it starts right out saying it can cause botulism.

it actually uses that word, and says it straight out.

i find that pretty interesting.. i wonder if this is some kind of new development or what. it definitely wasnt as easy to access that kind of information a couple of years ago.

i mean theres so still no result if you actually -do- any of the stuff is tells you to do, like tell your dr if you have any of those symptoms.. but, at least it starts right out, saying dysport can cause symptoms of botulism. i dont know maybe things -are- changing but they still seem to be changing pretty slow…

this is the first paragraph under “the most important thing you should know about dysport”:

“Spread of Toxin Effects: In some cases, the effects of Dysport and all botulinum toxin products may affect areas of the body away from the injection site. These effects can cause symptoms of a serious condition called botulism. Symptoms of botulism can happen within hours, or days to weeks after injection and may include swallowing and breathing problems, loss of strength and muscle weakness all over the body, double vision, blurred vision and drooping eyelids, hoarseness or change or loss of voice, trouble saying words clearly, or loss of bladder control. Swallowing and breathing problems can be life threatening and there have been reports of death.

The toxic effects have been reported at doses similar to those used to treat muscle spasms in the neck. Lower doses, in both approved and unapproved uses, have also caused toxic effects.”

i dont really remember them beign quite so clear about this previously. do you guys think anythign is changing here? also i was wondering.. if there is anyone in the ‘public eye’ that we coudl put pressure on to improve these kinds of practices, i was wondering if it could be this group, the coalition for injectables safety.

im not saying i think they would actually listen to us.. but i wonder if there would be any value in trying to put pressure on them or communicate with that group in some way.

edit #2: in contrast to dysport, the botox safety information, (here – http://www.botoxcosmetic.com/ ) does -not- use the word botulism… and they still claim there has not be ‘any confirmed case’ of spread of toxin. (double speak for, noone will confirm all these cases) interesting.

Botox Poisoning And Parotitis (Mumps)

I want to just put this up here because it was one of my symptoms. *Never* in my life have I had the mumps, I was vaccinated and as far as I know I was not exposed by a family member. I did not meet anybody who had or told me they had had the mumps. However somewhere deep in the literature there is a case report that links botulism to parotitis. I saw someone else who mentioned it here.

I somehow though *had* the mumps ( for 24 hours) six weeks after my injection. That was when my real symptoms started.

Just want to put it out there. I’m wondering if Moderator can add a tag just in case someone else runs across this site in the future with the same experience.

Anticholinergic Drugs

I am testing a new theory starting today.

I started a course of doxycycline a couple days ago and had a terrible reaction to it; I nearly didn’t even know I was having a reaction because I was so spaced out and depressed. One of the main symptoms was *shaking* and fasciculations which were scaring me terribly.

So I started poking around the internet and ended up realizing the the symptoms of botox poisoning are probably in theory a lot like the autoimmune disorder myasthenia gravis. Myasthenia Gravis is a condition where the body does not have enough acetylcholine receptors because they are being attacked by the immune system. Too much botox systemically causes a blockade of acetylcholine at the neuromuscular junction.

One of the things they say about botox is that it can unmask a subclinical case of myasthenia gravis. It could be that some people who breeze by here are experiencing exactly that — not all, but you never know. It’s said that if your acetylcholine receptors are 30 percent below normal ( baseline 66 percent of acetylcholine receptors active) you will have symptoms; you will be exhibiting the condition of myasthenia gravis. But even if not, let’s say you’re at 90 percent — it could be pretty uncomfortable.

Doxycycline is one of the antibiotics that people with myasthenia gravis can’t take. I stopped the doxycycline, felt a little better and by the end of the day the shaking was mostly gone. I had other symptoms, but not that, which is good because fasciculations are *upsetting*.

The issue with patients who have myasthenia gravis, and certain drugs, is that the drugs are ANTICHOLINERGIC; meaning they block acetylcholine, which makes these people get worse. Since we ourselves now do not have as much active acetylcholine, it might be that being a botox poisoning victim and having myasthenia gravis might result in the same intolerances.

Some bad ones – *antihistamines* — most of them, the worst one being Benedryl. FLEXERIL, which I was on. H2 blockers like cimetadine and ranitadine, are anticholinergic. Actually there are a ton of things MG people can’t take because it will bring about a MYASTHENIC CRISIS which usually involves a ventilator.

So what I’m going to try for the next little while is to STOP ALL ANTICHOLINERGICS. It’s actually kind of hard to figure out which ones these are because you have to read the really really fine print to figure it out. Good thing there are lots of handy lists online about this:

http://dig.pharm.uic.edu/faq/myasthenia.aspx

http://www.myasthenia.org/LinkClick.aspx?fileticket=JuFvZPPq2vg%3D

Looking at this list I have had a fair number of these things since this all started. Some made me immensely sick — immediate allergic reaction, stomach problems, eye stuff. And the shaking, which drives me crazy.

One thing that makes me think this might be a good theory is that I generally have a lot of the symptoms of anticholinergic poisoning — red face, shaking, fasciculations, reactivity in general. So I’m just going to avoid all anticholinergics to the best of my ability and see how it goes.

Food for thought :).

Red Face

Does anybody else here wake up with a red face? I haven’t had a problem with flushing in probably 20 years, but now I’m always red. I wake up with this way, and if I don’t have it in the morning it comes on as a bright hot streak down my cheeks sometime during the day. I’m wondering if this is related to the hair dye but also maybe botox.

I know I asked this once before sort of but it is SO noticeable.

Did Botox/ Dysport leave a physical mark on your skin?

Does anyone have a mark on the body that looks like a snake bite scar. I had this strange marking that appeared in the early stages of the sickness.  The mark was located on the upper left side of  the torso. It  started to fade after 18 months. It never started out as a sore or a hive. It didn’t itch or cause discomfort. It was a strange, very evident mark. My husband called it my Botox bite (even though I got Dysport :). My doctor was quite perplexed by it. The reason I ask is that my friend (an African refugee who endured so much trauma in her life) had a stroke and was subsequently given Botox in her arm a few days later to help relax the arm. She described feeling sick in the days after with flu like symptoms that didn’t dissipate. She suspected it was the Botox and blames it for impeding her recovery. I was stunned to find on her arm near her shoulder the exact same distinctive mark. It is identical to the one I had. She said it appeared a few days after the Botox. Side note: My mark and her mark were not at the injection site.

Can anyone report if they have this mark?

Mich

Possible Cure for Botox Side Effects

http://www.ncbi.nlm.nih.gov/pubmed/?term=pyridostigmine+botox

J Voice. 2014 Nov;28(6):830-4. doi: 10.1016/j.jvoice.2014.04.010. Epub 2014 Jul 5.
Pyridostigmine for reversal of severe sequelae from botulinum toxin injection.
Young DL1, Halstead LA2.
Author information
Abstract
OBJECTIVE:

Botulinum toxin is used to treat a wide range of dystonias in the head and neck. Occasionally, patients receiving laryngeal botulinum toxin experience severe dysphagia, dyspnea, or even distant and autonomic symptoms. Rarely, these patients may require hospitalization with possible intubation and placement of nasogastric tubes. Botulinum antitoxin is not readily available and ineffective once symptoms have progressed, so patients must wait until the toxin wears off over weeks to months. Pyridostigmine prevents the breakdown of acetylcholine at the neuromuscular junction, thus making more neurotransmitter available for the muscles.
STUDY DESIGN:

A retrospective case study of patients receiving botulinum toxin for dystonia in the head and neck from 1998 to 2012 who experienced adverse effects that were successfully treated with pyridostigmine.
METHODS:

Twenty cases were selected and reviewed to demonstrate how pyridostigmine was used to modulate severe dysphagia, breathiness, dyspnea, and some distant/autonomic symptoms.
RESULTS:

Pyridostigmine was well tolerated and resulted in significant symptom improvement. Only one significant adverse effect, bradycardia, occurred in a patient with severe cardiac disease.
CONCLUSIONS:

Given the safety and efficacy of this medication, pyridostigmine should be considered to modulate severe sequelae of botulinum toxin in select patients when conservative management is deemed insufficient. Also, physicians should be aware that patient complaints of symptoms at distant sites and temporally delayed from the injection may be a result of the botulinum toxin and relieved with pyridostigmine.

Copyright © 2014 The Voice Foundation. Published by Elsevier Inc. All rights reserved.
KEYWORDS:

Adverse reactions; Botox; Botulinum toxin; Pyrodostigmine; Reversal of botulinum toxin

PMID:
25008379
[PubMed – in process]

LinkOut – more resources

http://www.medicinenet.com/pyridostigmine-oral/article.htm