Hyperexcitability phase

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Re: Hyperexcitability phase

Postby misterjuanperalta on January 10th, 2015, 4:35 pm

Intrinsic hyperexcitability... detrimental or beneficial?

Our results show that only the S-type motoneurons display an intrinsic hyperexcitability in mSOD1 neonates. We further confirmed that the motoneurons displaying hyperexcitability were *** resistant thanks to the expression pattern of MMP9 (Kaplan et al., 2014). On the other hand, F-type motoneurons vulnerable in ***, are not hyperexcitable. We can therefore conclude that, contrary to the standard hypothesis (Ilieva et al., 2009), intrinsic hyperexcitabilty is not an early event that triggers degeneration of the motoneurons.

Source: http://elifesciences.org/content/3/e04046
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Re: Hyperexcitability phase

Postby joycecaroll on January 10th, 2015, 4:54 pm

misterjuanperalta wrote:Intrinsic hyperexcitability... detrimental or beneficial?

Our results show that only the S-type motoneurons display an intrinsic hyperexcitability in mSOD1 neonates. We further confirmed that the motoneurons displaying hyperexcitability were *** resistant thanks to the expression pattern of MMP9 (Kaplan et al., 2014). On the other hand, F-type motoneurons vulnerable in ***, are not hyperexcitable. We can therefore conclude that, contrary to the standard hypothesis (Ilieva et al., 2009), intrinsic hyperexcitabilty is not an early event that triggers degeneration of the motoneurons.

Source: http://elifesciences.org/content/3/e04046


Where did you find this? Is it new?
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Re: Hyperexcitability phase

Postby misterjuanperalta on January 10th, 2015, 5:47 pm

Last edited by misterjuanperalta on January 10th, 2015, 8:55 pm, edited 2 times in total.
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Re: Hyperexcitability phase

Postby leaflea on January 10th, 2015, 7:35 pm

okay, truthfully this is over my head, but from what I can read, this is ONLY good news, nothing scary in here at all! And it is HOT off the press. Great find, MisterJuan!! I'd love to have LittleLost or others weigh in to how this relates to Eisen et al. To me, this gives explanation as to why twitching is not an early sign of anything bad. Emma, you can relax more now, as can we all.
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Re: Hyperexcitability phase

Postby Little Lost on January 14th, 2015, 11:03 am

Leaflea. Sorry for delay in answering but been away. Thanks for the question about how this study fits in with the others.

Bit of background first then I will give my opinion on the study, though others may disagree.

Before I go on let me say for the 100th time what is meant by the " hyperexcitabiliy stage in ALS. " It is a phenomenon that has absolutley nothing to do with BFS, it has NOTHING to do with the 6.7% study either, and it has nothing to do with peripheral hyperexcitability cases on here....it has to do with the progression of ALS established disease.etc etc.

It is a phenomenon seen in ALS patients and is a symptom DOWNSTREAM of their diagnosis, not prediagnosis.

It was studied by Prof Cav and others. They noted that in ALS patients whose upper limbs were affected, an EMG of their remaining strong lower limbs(TA), would still detect abnormality such as increased jitter and fasciculation before clinical weakness in that muscle developed by about 6 months. It is almost like a way of mapping its progression and their hope was it could be a prognostic factor. ( let the patient know how long they had until lower limb failure). This they called the hyperexcitability phase just before onward spread of disease. Other studies have backed this up including one in which stem cells from ALS patients at various points in disease were differentiated into neurons and electrically studied.

For those that keep asking over and over please please read the email.....the.hyperexcitability phase talked about here is in post diagnosis ALS patients, probably as part of the damage already done. In fact their pool of bfs sufferes with peripheral hyperexcitability were used as control healthy subjects. Therefore the statement in that paper of "fasciculation before weakness ". has been misinterpreted over and over on here ever since the paper was published almost 2 years ago.

To those doing this please stop, and reread what has been written at length in previous posts, because your bias interpretation of the studies are harmful. I understand some people have health anxiety, but there comes a point of silliness, you cant walk into a packed building and shout " FIRE" because someone is smoking 10 streets away. Health anxiety or not you have to get hold of your facts. Using facts is like trying to construct a jigsaw from random pieces, you just get a load of *beep* unless they are put together in the right order i.e. like saying with nine women pregnant, you can get a baby in a month.

So now to the paper mentioned in this thread. Agsin these are just my views. Look at its title and break it up. ( note motor_neuron interchangable with moto_neuron ie both are a neuron with motor function).

Quote"
Early intrinsic hyperexcitability .........does not contribute to motoneuron degeneration .......... in amyotrophic lateral sclerosis

Félix LeroyCorresponding Author, Boris Lamotte d'Incamps, Rebecca D Imhoff-Manuel, Daniel Zytnicki

So at no point does it say there is NO hyperexcitability phase in ALS. It is not asking or challenging or disagreeing with Eisen and all the others. Instead the study is asking the next logical question.... Is this hyperexcitability phase:

a) contributing to the neurotoxicity and death of the motor neurons in ALS, hence increasing progression rate in the patients

b) or of no consequence, and just a byproduct of the disease and not contributing to the neuron degeneration.

c)or controversially is the hyperexcitability of the neurons protecting them from damage during ALS spreading.

The main reason I feel for driving the study was to explore the first option, was hyperexcitability phase DIRECTLY pathological in ALS through a process called excitotoxicity. "Excitotoxicity is the pathological process by which nerve cells are damaged and killed by excessive stimulation by neurotransmitters such as glutamate".

So the process of excitotoxicity goes something like this....

Step 1.a neurotransmitter glutamate sits on cell.

Step 2......this causes a thing called depolarisation of neuron cell membrane......., this means that sodium can flow out of neuron cell ...........and as a consequence the calcium concentrations inside the cell begin to build. ( like a seesaw when sodium gets low, calcium gets high vice versa).

Step 3....Anyway this high calcium level activates all the cell machinery inside and all the signaling, .....basically neuron goes absolutely nuts starts to fire randomly..makes things it shouldnt...even tries to migrate and turn into other cells....its gone totally cookoo.

Step4 : this " turn everything on behaviour uses up all the cells energy, it gets super tired, it gets exhausted...byproducts and toxins build up.....MAKE IT STOP shouts the poor neuron, but it doesn't and instead cell starts to become damaged, neuron dies, loss of neurons. Epileptic fits is one example of this overstimulation.

( note glutamate excitotoxicity does not occur in bfs, our neurons don't die, we are more likley to have ( intrinsically or aquired ), slightly unstable neuron cell membranes or sodium channels, antibodies against the channels. Etc. The fact is we don't get cell death through our hyperexcitability, we just twitch and recover as our emgs do not progress to losses.

So back to the study. The group took a mouse model of ALS and recorded changes in two types of motor neutrons called F and S. They deduced that the hyperexcitability occurred in the S- type ( which are spared in ALS). Thst is why they say. Quote " we conclude that early intrinsic hyperexcitability does not contribute to motoneuron degeneration. ". The paper then goes on to state that because the S-type are protected perhaps their intrinsic hyperexcitability is actually protecting them rather than being excitotoxic.

If true this is disappointing news for ALS patients, because if the hyperexcitability phase had been proven to directly contribute to ALS degeneration we have licences drugs for epilepsy which can control excitotoxicity. They may have held a potential to slow down or halt the damage to neurons by stopping the excitotoxicity.......but since the hyperexcitability phase doesn't contribute to disease progression, what is the point of trying this approach. If this study is to be believed that avenue is dead.

Ah but here is where good and bad science research comes in. I personally feel this paper has too many drawbacks to throw out the possibility of a clinical trial of above mentioned drugs. Mainly it uses one mouse model with only one gene mutated. In reality ALS is probably the end product of various genes, environmental, hormonal and pathogen interactions. i.e many roads lead there and this study examines only one. The study would have been better using humans, but where not possible more realistic nervous systems can be studied in zebra fish etc. Mouse models of ALS have been credited as a reason for slow progress in ALS research. Really the title should be

Early intrinsic hyperexcitability does not contribute to motoneuron degeneration in the mSOD1model of ALS.

Lastly this is published on elife, on which the jury is out on how stringent its checking procedures are.

Quote " this desire to be quick may lead eLife to cut corners and accept poor studies for publication. The fact that, unlike paper journals, eLife has no restrictions on the number of papers it can publish monthly only compounds the temptation to publish anything in order to establish eLife as a publishing titan. Indeed, eLife’s current initial acceptance rate is 30%, meaning that a quarter of the manuscripts submitted to eLife are passed on to reviewers and, most likely, eventually published. The journal Science, by comparison, accepts fewer than 6% of its submissions.

Anyway just my thoughts.

Bottom line as all others have said " the hyperexcitability phase " discussed in these papers is to do with ALS patients. Just as a headache in migraine does not have the same physiological bases as a headache in brain cancer. Now go beat yourself up with a feather duster it will be more productive than spending anymore time reading my rubbish. Said "rubbish " because I will get beeped out if I say *beep*......ah see what I mean....crap.


Let it go .......pleeeeeeeeeeeeeaaaaaaaaaaaaasssssssssssssssseeeeeeeeeeeeee. See even my words have fas fas fasci fasciculations now.
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Re: Hyperexcitability phase

Postby joycecaroll on January 14th, 2015, 12:24 pm

LittleLost, you are truly amazing. Your post's are always so well written and wise. I read your PM's almost everyday to help keep what's left of my sanity. Thank you so much.

I truly trust Twitchydoc and he's been talking a lot about this phase. The way I see it, the possibility of this phase is is the energy to my anxiety at this point, and that's why I want to understand the subject fully. As I mentioned before, I'm finding it hard to research this my self, and that's why I turn to you and Twitchydoc. In an obsessive manner, I know.

I would like to ask two questions:
1. Ok, so the hyperexcitability phase does not occour pre diagnosis. Does that mean fasciculations can not come before weakness in the beginning of ALS?
2. IF there still is a 7 months waiting period after fasciculation onset, what am I suppoused to wait for? Weakness or EMG changes?

Anyway, once again, thank you for taking the time to explain the hyperexcitability phase. It's very reassuring.
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Re: Hyperexcitability phase

Postby garym on January 14th, 2015, 5:46 pm

joycecaroll wrote:2. IF there still is a 7 months waiting period after fasciculation onset, what am I suppoused to wait for? Weakness or EMG changes?


First, thanks Helen for the very informative response. You are a real asset to this site and I want to show my appreciation for you. You are truly appreciated!

Now, I'll try to answer this for you.....don't wait for anything! get on with your life because you have a benign condition. As for your question, emg changes will precede noticeable/clinical weakness but since you can't stay continuously connected to a machine, weakness would start to manifest itself and would be obvious IF you had als, which you don't. So don't wait 7 months, enjoy everyday even if you fasciculate....enough really bad stuff happens to people than to worry about obscure, rare possibilities. My mother-in-law just got dx'd with stage 4 melanoma. After watching my mother die of cancer 3 years ago and now having this with my wife's mother, it really puts the needless/useless worry here in perspective.

take care,
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Re: Hyperexcitability phase

Postby Little Lost on January 14th, 2015, 6:06 pm

Edit sorry Gary just read your post as I was in middle of posting this. Your advice to Joyce much better than mine, but had banged a reply out anyway.

Hi Joyce,

so in answer to your questions 1 and 2.

1). There is no relationship between the 2 topics. This thread and the studies mentioned are about " hyperexcitability in established ALS patients" and NOT about "fasciculations preceding ALS." They are both different stages of the disease. I am not being awkward. Look...... lets say we are examining a detailed study about what type of trees dogs prefer to pee under. We get our hypothesis, we design suitable experiments to test, and we carry out our detailed study....we conclude dogs like to pee under oak trees. We can then guess why we get this result, so perhaps being larger the oak trees offer more shelter, or the wood holds the scent more etc etc. These are fair questions related to our dog tree study. What we CANT do is extrapolate or deduce anything about how cats pee near trees. Different species, different subject. So when you are trying to marry what happens in established ALS with what happens before it begins, it can't be done.

So your question about fasciculations preceding weakness has been discussed at length by people on this forum more knowledgeable than me on that particular topic. There are pages and pages, on it. I only have 3 points to say on this well trod subject.

a) It has been reported very occassionally, but mostly along with some sort of clinical problems and obviously not enough for fasciculations to be a statistically reliable early biomarker of ALS/ MNDs.

b) On the other side of the coin I can also read reports of clean emgs done on patients for gardening accidents, or car crash injury, who just by sheer coincidence months later start display ALS symptoms. These provides the rare paired emg I.e. before symptoms and one after symptoms on the same patient, and not one fasciculation recorded in the preclinical stage. Should I therefore conclude the abscence of fasciculations preceeds ALS onset. See how easy it is to create associations.

C) lastly the information and certainty you crave is not there. We are physiological systems made of different genes and exposed to different environments. There is too much variability to ever get certainty. The closest we can get is statistically significant trends and there will always be exceptions due to our different genotypes etc.

So in answer to question 2. In the hyperexcitability stage of ALS emg changes occur 3 to 6 months before more typical ALS emg findings come in. Which results in 6 to 12 months before significant weakness ( longest recorded was 18 months)....... But you are not in a hyperexcitability phase, not with a clean clinical. As Prof Cav says in his email to us when he described this phase...... there were profound changes in every other muscle he tested. Joyce ask yourself if you were really in the hyperexcitability stage which remember Prof Cav described in profound ALS patients.....how did you pass your clinical.

None of these time limits apply to you. The glass slipper doesn't fit so stop trying to squeeze your foot into it, you are only hurting yourself more. We all worry, it is hell to be caught in the fear especially initially, but try to hold onto a bit of logic. As long as you have that, the logic grows and it gets easier.

Take care


PS sorry just read your post Gary was submitting as you submitted, and I am so sorry about your mother in law. Your advice is spot on, and we don't need a science article to tell us that, or analyse why it is important. You will be a good nurse Joyce cause you will relate to your patients anxiety, keep going.
Last edited by Little Lost on January 14th, 2015, 6:14 pm, edited 2 times in total.
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Re: Hyperexcitability phase

Postby J4son on January 14th, 2015, 6:10 pm

There is also an empirical way of looking at things. I mean to see and check what is going on the ground and draw a conclusion from it. More than 5000 members are registered on this site. Some of them have seen GP's but most have seen neurologists and many in the best ALS clinics in the world: Europe, France, UK, Germany, The U.S (Mayo etc.) I don't remember someone being told by those specialists that they should wait a certain amount of time because of a hyper-excitability phase. On the other hand none of those 5000 members here diagnosed with BFS went to develop ALS. If a hyperexcitability phase before the onset of symptoms was something so common, then we should have seen hundreds of people here developing MND with time. But no one did... Zero percent...
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Re: Hyperexcitability phase

Postby garym on January 14th, 2015, 10:00 pm

Little Lost wrote:Edit sorry Gary just read your post as I was in middle of posting this.


no worries Helen.
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Re: Hyperexcitability phase

Postby TwitchyDoc on January 15th, 2015, 3:38 am

J4Ason: You are missing some key facts. Hyperexcitability ALWAYS occurs prior to neurodegeneration, it is a natural physiological event. In MND, this phase usually lasts (according to MND experts) weeks, rarely months. This is what is Joyce so obsessed about and I am happy she trust me and turn on me when she feels the need.
Again, the comprehensive paper about PNH posted somewhere in this thread would really help you to understand. There is nothing particulary scary, it is just neurophysiology.
But I cannot not comment on that fallacy that out of 5000 members 0 developed anything. We know about a few MND cases and we have no idea whether these 4 000 memebers are fine. We have no idea and hence you cannot say that. I remember a lady who came here with swallowing issues, tongue fasciculations and pathologic findings on swallowing study - clearly that was by no means BFS..
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Re: Hyperexcitability phase

Postby joycecaroll on January 15th, 2015, 4:20 am

TwitchyDoc wrote:J4Ason: You are missing some key facts. Hyperexcitability ALWAYS occurs prior to neurodegeneration, it is a natural physiological event. In MND, this phase usually lasts (according to MND experts) weeks, rarely months. This is what is Joyce so obsessed about and I am happy she trust me and turn on me when she feels the need.
Again, the comprehensive paper about PNH posted somewhere in this thread would really help you to understand. There is nothing particulary scary, it is just neurophysiology.
But I cannot not comment on that fallacy that out of 5000 members 0 developed anything. We know about a few MND cases and we have no idea whether these 4 000 memebers are fine. We have no idea and hence you cannot say that. I remember a lady who came here with swallowing issues, tongue fasciculations and pathologic findings on swallowing study - clearly that was by no means BFS..



Ok so let's see If I get this. I read all your PM's to me, and together with above post this is what I gather:

1. Something should have shown on my EMG 6 weeks after fasciculation onset, whas it hyperexcitability caused by ALS? Only in rare cases is EMG on the affected body part clean, but usually this manifest with clean UMN signs?
2. It's been 7 months now since fasciculation onset on my tongue, so there is a really small risk of it being mnd at this point?
3. With ALS, fasciculations are more or less always present, even in the hyperexcitability phase?
4. Bulbar is rapid, so I should have noticed something by now?
5. Clean EMG with ALS usually exists with UMN signs, such as spastic speach
6. Benign tongue fasciculations have not been studied, so the answers are not really out there

Also:
Is it worrisome that no neuro ever checked my bulbar reflexes? They only looked at my tongue, had me move it from side to side.

I'm looking for what's most realistic. I know nothing is 100 % sure, but as a neuropatholgist with extensive knowledge in ALS, would you agree above facts are understod correctly on my part? Meaning, the risk of ALS can never be excluded, but the time having passed, no other bulbar symptoms and the non persistence nature of my fasciculations points away from ALS?
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Re: Hyperexcitability phase

Postby TwitchyDoc on January 15th, 2015, 4:25 am

Joyce, yes, you got it right.

Recently I was discussing with Martin Turner, quite a big shot amongst neurologists, he agreed with me that tongue fasciculations are affected by something we call "refferal bias" - meaning that physicians tend to correlate them with malignant causes only because they only see patients reffered to them with other problems. He admitted that writing "never benign" in his book was not correct and I am happy for that.

As for the reflexes, usually only jaw jerk is checked (tapping on the chin) or snout/sucking reflexes.

UMN involvement of the tongue would manifest as slowness of side-to-side movement, so that is another thing you can exclude.

All in all, stop worrying about that ;)
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Re: Hyperexcitability phase

Postby joycecaroll on January 15th, 2015, 4:38 am

TwitchyDoc wrote:Joyce, yes, you got it right.

Recently I was discussing with Martin Turner, quite a big shot amongst neurologists, he agreed with me that tongue fasciculations are affected by something we call "refferal bias" - meaning that physicians tend to correlate them with malignant causes only because they only see patients reffered to them with other problems. He admitted that writing "never benign" in his book was not correct and I am happy for that.

As for the reflexes, usually only jaw jerk is checked (tapping on the chin) or snout/sucking reflexes.

UMN involvement of the tongue would manifest as slowness of side-to-side movement, so that is another thing you can exclude.

All in all, stop worrying about that ;)


Thank you so much Docen. I know I've said it before, bit you thoughts mean the world to me. Thank you for all this time you've been here for me. Priceless.

I want to say the same thing to you Helen. As mentioned before, I keep all your PM's close. You guys are such good people.

I know I'm obsessive and talking sence to me is like talking sence to a wall. You guys still took the time to do this, and I'm so grateful.
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Re: Hyperexcitability phase

Postby leaflea on January 15th, 2015, 9:41 am

I LOVE that a big shot neuro "took it back" -- he admitted to probably carelessly writing something false which has unwittingly given fear to so many (tongue fasics never benign). This should be in lights! They need to be careful with their words. And we cannot take each one so literally. One should NEVER use the words "never" and "always" actually. Just this week my neuro said I will never have ALS (if my EMG is clean on 2/11) and guess what? He lost credibility with me over those stupid words. All of us would like to hear those words but we know there are no guarantees. Don't patronize me. (He said he is going to give me an extra painful EMG on 2/11 and smiled - so I am fearing it even more. I may cancel it. Then I wonder, is he a sadist? Is that why he is an ALS doctor? I mean really...if someone ever liked to watch someone suffer...)

Helen, I hope you teach. If not, you should consider it. Your illustrations are THE BEST and they just roll off your tongue (pardon the pun). It would be fun to be a student in your classroom.

It makes sense, hyperexcitability happening within the context of an ALS diagnosis or post diagnosis...I remember reading over a year ago when I was poking around on the wrong forum, a wife said her husband would always have twitching in an area before weakness. It scared me silly!!! But it was out of context. Within the context of the studies that have received so much speculation and angst around here, it makes sense... the hyperexcitability phase in ALS patients is ongoing. The woman's husband had been diagnosed with ALS already for a while and she could see this pattern in hindsight. He started twitching AFTER getting ALS, and before NEW areas of weakness. The anxiety I could have saved myself by a. never going there, and b. having this knowledge and understanding for context.
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Re: Hyperexcitability phase

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