Paraneoplastic Syndromes

[Valentijn]

For those who didn't follow part of the discussion above, here is what we were talking about with the acronym LEMS: Lambert-Eaton Myasthenic Syndrome.

Probably easy to distinguish from ME based on "Weakness is often relieved temporarily after exertion or physical exercise." But a reasonable candidate for people without PEM who are nonetheless very sick and disabled.

 

[Sidereal]

Probably easy to distinguish from ME based on "Weakness is often relieved temporarily after exertion or physical exercise." But a reasonable candidate for people without PEM who are nonetheless very sick and disabled.

Right. This also seems like the polar opposite of what you see in ME:

On neurological examination, the weakness demonstrated with normal testing of power is often less severe than would be expected on the basis of the symptoms. Strength improves further with repeated testing, e.g. improvement of power on repeated hand grip (a phenomenon known as "Lambert's sign"). At rest, reflexes are typically reduced; with muscle use, reflex strength increases. This is a characteristic feature of LEMS.

Personally, my muscle power is normal when I'm rested. As I exert myself, strength gets worse and worse. As for reflexes, mine are increased.

 

[anciendaze]

Probably easy to distinguish from ME based on "Weakness is often relieved temporarily after exertion or physical exercise." But a reasonable candidate for people without PEM who are nonetheless very sick and disabled.

This is an example of how sloppy diagnostic criteria can muddle research. These patients do not have normal fatigue, but it differs dramatically from ME-patient PEM. I am sure there are patients without uncontrolled neoplasms who do not have the severe autoimmune response seen in textbook cases. These could easily end up in a CFS cohort. If these respond to a therapy which ME patients do not this could move group means to indicate some positive effect which would be entirely spurious in talking about ME patients.

 

[Gingergrrl]

Thank you guys (every single one of you who is helping me with this) and I have been in appts and tests all day with another full day tomorrow and we are extending our stay for an additional night. I can't post any details right now, it's way too difficult on my iPhone but will once we get home on Sat night or Sun. Am so appreciative of Stanford who is figuring all this out and if this treatment ends up working (long term) it will save my life.

It's weird to be quoting myself but wanted to use this thread to let everyone know that I had a productive trip with several consults and medical tests and got home safely last night. Am not well enough to post more details right now but will as soon as I can. Many people sent me PM's and hoping to reply to those soon, too.

@anciendaze I definitely want to follow-up with you re: paraneoplastic syndromes and get your feedback on a few things. Also, my book arrived "The girl on the 6th floor" but haven't started reading it yet.

 

[Gingergrrl]

Probably easy to distinguish from ME based on "Weakness is often relieved temporarily after exertion or physical exercise." But a reasonable candidate for people without PEM who are nonetheless very sick and disabled.

I will be seeing a Neuromuscular doc to have an EMG to test for LEMS but I truly suspect that I do not have it. LEMS usually has the antibody called "P/Q type calcium channel Ab" which I am negative for and I am positive for the "N-type Calcium Channel Ab" which is less common in LEMS (but still correlates.) It sadly also correlates with small cell lung cancer which I am in the process of also trying to rule out.

The other reason I suspect I do not have LEMS is that my muscle weakness, especially my lung weakness, is not improved in any way by exertion (which is known as the Lambert's Sign.) If I continue to exert myself when I cannot breathe, I am gasping for air with chest pain and the further I push, the worse it gets. Also, LEMS typically begins with leg weakness and my legs and lower body are strong vs. my lungs, arms and upper body are weak. But we feel it is worth it to have the EMG in case I have some atypical form.

Will give a more general update in next post.

 

[Gingergrrl]

I wasn't sure where to post this update but this thread on paraneoplastic syndromes (PNS) seemed like the most appropriate place. Am still trying to catch up on PM's and wanted to update those I have not had a chance to respond to yet. Am also hoping this info might help others as I believe there must be others out there like me who have an ME/CFS type illness but remain diagnostically unclear.

Long story short, I tested positive for two rare antibodies: Anti GAD65 Ab, and N-type Calcium Channel Ab. My doctors feel both correlate to my extreme lung weakness/restriction and shortness of breath (which is by far my #1 worst symptom and has been progressive and life altering.) I went to Stanford for autonomic testing which confirmed that I have POTS (which I already knew) and also revealed that I have autonomic neuropathy and abnormal sweating to my feet (which I did not know.)

But more important than the autonomic testing, they ran blood tests which were sent to Mayo Clinic. One of these tests was the PAVAL panel which checks for auto-antibodies which relate to paraneoplastic syndromes (which was a new concept for me.) @anciendaze can explain this better than I can (and hoping he will correct me if I explain this wrong!) but these syndromes are the link between autoimmune diseases and cancer. One such disease is LEMS (which as I posted above, I most likely do not have) but also links highly with small cell lung cancer. Another example is Myasthenia Gravis (which I do not have) but links highly with thymus cancer (thymoma.)

Often the paraneoplastic symptoms appear before the cancer and can be brain/encephalitis symptoms or even dysautonomia. Sometimes the auto-antibodies knock out the cancer in a very early stage so it is never discovered and sometimes there is no cancer. But the auto-antibodies increase the risk and in my case where I am so symptomatic, we are going to try to knock them out either with plasmapheresis, IVIG or possibly immunosuppressants (but these are risky b/c they can actually increase your cancer risk.)

I've had some preliminary tests and am waiting to discuss with the docs but my lung cat scan from Oct 2015 (from a different hospital) was not as high resolution quality as I was told. Plus it was six months ago so we needed to do another one which I did last week. It showed two types of nodules in my lungs but they are tiny (3mm or under) and one of them correlates with mold exposure which I had for 2-3 years at a severe level. I will discussing with the lung doctor what they might mean but my understanding is that they are too small to identify beyond "non-specific" and we just watch and wait.

We also tested to make sure I do not have pulmonary hypertension or blood clots in my lungs and while I do not yet have 100% confirmation on this, it appears that I do not. But the two antibodies are affecting the neuromuscular junctions and the ability to push the calcium ion across the synapse. The calcium itself is there but it is being blocked by the auto-antibody which is attacking the calcium channel and it's functioning. The other antibody GAD65 is more vague and confusing to me but I think it is blocking the conversion of glutamate to GABA which can also affect my lung functioning.

Lastly I am trying a new med called pentoxifylline to see if it helps improve blood perfusion to my lungs. On my V/Q scan we think the mismatch is b/c blood is not getting to the apex/top of lungs due to dysautonomia/POTS and these antibodies. (All of this is paraphrased and interpreted by me who lacks any science background and nothing is a direct quote from my doctors.)

I had reached the point that ME/CFS was a wastebasket diagnosis for me and there were no more treatments to try. I feel so grateful that these antibodies have been identified, as well as the lung cancer risk that correlates with one of them so it can be monitored. And there is now a proposed treatment that could reduce or eliminate the antibodies and potentially improve my breathing and muscle weakness. I know it could not work, but am willing to take the risk as my QOL is so low.

Hope this helps someone out there and the timing was uncanny that someone started a thread on paraneoplastic syndromes as I was dealing with all of this!

 

[wastwater]

does this have something in common with the book brain on fire think that was anti nmda

 

[Gingergrrl]

does this have something in common with the book brain on fire think that was anti nmda

No idea and am not familiar with the book but maybe someone else is?

 

[anciendaze]

One minor correction: the neurotransmitter crossing the synapse at neuromuscular junctions is acetylcholine. The calcium-channel problem is on the presynaptic nerve cell. People can also have problems with sodium or potassium channels on nerve cells, and both are necessary for electrical nerve impulses. These problems are amazingly specific. If you look at the nerve under an optical microscope you will not see them unless the problem is so severe it causes structural changes in the nervous system, and by that time there may not be much anyone can do about it.

I wouldn't be too concerned about labels. This may not be paraneoplastic in some narrow sense, but your immune system doesn't depend on medical labels. There is no question, however, that you have some kind of immune response causing trouble. Your immune system is responding as if something is a threat to life, like cancer. At this point I'm guessing this is a false alarm caused by mycotoxins from mold, and, believe me, there are some nasty ones. Your MCAS doctor should have some experience with this.

You have one advantage over many on this forum, though it may not seem like an advantage. There is no question you have suffered life-altering changes and life-threatening episodes. Your problems have been progressive, so far, and there is evidence of neuropathy. This is enough to convince doctors to try a real intervention. For others the idea that we can spend the rest of our lives housebound or bedbound is considered reasonable management of a mysterious condition. As long as your doctors are reasonably prudent, and check if interventions are causing harm, they have a good chance of improving your situation.

 

[jimells]

For others the idea that we can spend the rest of our lives housebound or bedbound is considered reasonable management of a mysterious condition.

Funny you should write this today. Just an hour ago I was thinking that the attitude of my current doctors is that as long as they keep me alive, they have done their job. Naturally, I reject this attitude.

 

[Gingergrrl]

One minor correction: the neurotransmitter crossing the synapse at neuromuscular junctions is acetylcholine. The calcium-channel problem is on the presynaptic nerve cell.

Thank you for correcting that and I was worried that I would not explain it correctly and want to reiterate that everything I wrote in this post is from my non-sciency brain and never a direct quote from my doctors! So, it sounds like the calcium channel blocking antibody is on the pre-synaptic side of the nerve cell vs. in the synapse and am hoping I can remember that!

I wouldn't be too concerned about labels. This may not be paraneoplastic in some narrow sense, but your immune system doesn't depend on medical labels. There is no question, however, that you have some kind of immune response causing trouble. Your immune system is responding as if something is a threat to life, like cancer.

I agree but labels do help me to understand things a bit better and allow me to research what I am potentially dealing with. But I agree that there is no question anymore that my immune system is in chaos or hyper-drive responding as if there is a threat to life, like cancer, which is why I need to knock out these pathogenic antibodies sooner rather than later if I can.

At this point I'm guessing this is a false alarm caused by mycotoxins from mold, and, believe me, there are some nasty ones. Your MCAS doctor should have some experience with this.

I am not certain that it is due to mold alone but that b/c my immune system was already weakened by mono and then a second virus, that breathing in toxic mold for 2-3 years only made the problem a million times worse. My MCAS Doctor actually does not know a lot about mold but I have an excellent mold doc. These are the two I tried for six mos to get them to speak to each other but finally gave up.

You have one advantage over many on this forum, though it may not seem like an advantage. There is no question you have suffered life-altering changes and life-threatening episodes. Your problems have been progressive, so far, and there is evidence of neuropathy. This is enough to convince doctors to try a real intervention.

Agreed that now that these antibodies have been found, and I have searched for three years to find my current set of doctors, that I am finally in a position that something is being offered to me that could help.

For others the idea that we can spend the rest of our lives housebound or bedbound is considered reasonable management of a mysterious condition.

This is absolutely not acceptable or okay for anyone and the doctors/society who view it this way should be ashamed of themselves.

As long as your doctors are reasonably prudent, and check if interventions are causing harm, they have a good chance of improving your situation.

This is what I am praying for... first that I will have the opportunity to start the treatment and that all the risks will be monitored b/c I have extra risks with severe MCAS that those without MCAS do not have. Am trying to be cautiously optimistic at this point.

You have helped me a great deal in explaining and understanding things and I really appreciate it.

 

[wastwater]

I did have a burst of high potassium measured in my blood around ebv acute onset
I saw something about potassium leak channels too ,not sure what they do.
Encephalitis society UK have some good bits on there site.

 

[anciendaze]

Potassium channel defects feature large in the collection of channelopathies which produce periodic paralysis. This is a heterogenous collection of rare problems with ion channels, mostly inherited, but there are questions about why some have fairly late onset after development is pretty much over. One curious correlation is that the genetic diseases are also considered connective tissue disorders, though not always due to the same molecules.

 

[anciendaze]

Just as an illustration of the extremely specific nature of many channelopathies, I'm going to describe the way in which a calcium-channel defect affects neuromuscular junctions in more detail, with some historical background.

At one time there were lots of electrical analogies for neurological problems in which nerves were simply thought of as wires which happened to have unusually slow conduction speeds. The synapses connecting them were not considered as important as the neurons, and neurotransmitters were almost as boring as solder in electrical circuits. No reputable neurologist is going to make that mistake today. There are so many neurotransmitters known new ones get combinations of letters and numbers instead of names, and a great deal of complex activity is known to take place around synapses.

The first discovered neurotransmitter was acetylcholine, which carries nerve impulses across neuromuscular junctions. This happens to be where part of the problem reported by Gingergrrl is taking place.

After the prehistory of neurology, when we only knew about acetylcholine as a neurotransmitter, there was a period when people thought we might get by with understanding about 3 or 4 neurotransmitters. No such luck.

You can find some accounts of neurotransmitter problems talking about biosynthesis of a particular one, and presumed shortages of same. I'll tell you right now that most such explanations are wrong, and increasing supplies of chemical precursors for particular neurotransmitters typically fails to benefit patients. Part of the problem is that other biochemical mechanisms compensate for changes due to over- or under-supply of precursors. This kind of homeostasis is necessary for nerves to function in a changing biochemical milieu, so you don't go crazy every time you eat. We still don't understand why some drugs which change biochemical concentrations in hours take days or weeks to produce changes in symptoms.

In fact synapses do a great deal of recycling of neurotransmitters. Molecules which fit receptors on the post-synaptic side send a signal, then are released. They can bounce around the synaptic cleft until they either hit a receptor or are picked up in vesicles on the pre-synaptic side. Vesicles are like little bags of chemicals formed inside nerve cells when they pick up enough molecules of the right sort at the presynaptic surface. These start out tiny, but are combined by fusion until they are big enough to be released into the synaptic cleft again. Those calcium channels are necessary for the fusion of vesicles preceding release of a burst of neurotransmitters contained in them.

Using an optical microscope you can just about see the gap between neurons called the synaptic cleft. Vesicles within neurons are harder to see, and the calcium channels responsible for fusion of vesicles are invisible.

This is only one role for calcium channels in the nervous system, out of many. Calcium channels are only one class of ion channels. Most ions of alkali metals or alkaline earth metals have specific classes of ion channels with physiological significance. Generally speaking, ion channels are simpler than receptors for really complicated molecules like serotonin, norepinephrine, dopamine, NMDA or GABA.

There is a serious mismatch between the complexity of these biochemical problems and medical understanding of the resulting conditions.

 

[Gingergrrl]

The first discovered neurotransmitter was acetylcholine, which carries nerve impulses across neuromuscular junctions. This happens to be where part of the problem reported by Gingergrrl is taking place.

Can I hire you as a consultant to my doctors LOL? I am going to re-read your above post several times to try to grasp it better. How does the acetylcholine relate or connect to the calcium ions not being pushed through the junction fast enough. Is acetylcholine also being blocked by the N-type calcium channel antibody in addition to the calcium being blocked?

 

[anciendaze]

Can I hire you as a consultant to my doctors LOL? I am going to re-read your above post several times to try to grasp it better. How does the acetylcholine relate or connect to the calcium ions not being pushed through the junction fast enough. Is acetylcholine also being blocked by the N-type calcium channel antibody in addition to the calcium being blocked?

Nobody who knows me well has accused me of being a medical expert. I do have a peculiar memory. This doesn't prevent me from being wrong. There are a lot of medical situations where nobody really knows what is happening inside "those damn patients".

The calcium channels are active when small vesicles containing acetylcholine fuse to form larger vesicles, and when large vesicles fuse with the presynaptic membrane to release acetylcholine. This takes place inside the presynaptic neuron, and there is no particular evidence that calcium ions cross the synaptic cleft. Simple blood tests for calcium are not going to say much of anything about this. The action takes place inside individual nerve cells.

Normal functioning neuromuscular junctions go through this whole sequence of events rapidly when an electrical impulse arrives in the presynaptic neuron. This causes release of significant numbers of acetylcholine molecules into the synaptic gap, some of which are picked up in receptors on the post-synaptic side. When enough of these have docked with receptors there are chemical changes in the post-synaptic neuron which trigger an electrical impulse. Normal muscle function requires a stream of impulses at many neuromuscular junctions to produce a large contraction of muscle fibers.

You do this all the time, but you didn't even know you were doing anything so complicated, did you?

 

[Gingergrrl]

Nobody who knows me well has accused me of being a medical expert.

I would LOL...

There are a lot of medical situations where nobody really knows what is happening inside "those damn patients".

Agreed.

You do this all the time, but you didn't even know you were doing anything so complicated, did you?

I read everything you have written on this topic but it is still too complex for my brain to grasp. Would it be correct to say that the N-type calcium channel antibody (what I have) is preventing the calcium ions from crossing from the pre-synaptic side of the nerve to the post-synaptic side b/c the antibody is blocking this action from happening? And this in turn is weakening my muscles? Therefore we need to find a way to get rid of these pathogenic antibodies which will hopefully increases my muscle strength in particular in my lungs. (And I have even less of an understanding of what the anti GAD65 Ab's are doing!)

 

[anciendaze]

...
I read everything you have written on this topic but it is still too complex for my brain to grasp. Would it be correct to say that the N-type calcium channel antibody (what I have) is preventing the calcium ions from crossing from the pre-synaptic side of the nerve to the post-synaptic side b/c the antibody is blocking this action from happening? And this in turn is weakening my muscles? Therefore we need to find a way to get rid of these pathogenic antibodies which will hopefully increases my muscle strength in particular in my lungs. (And I have even less of an understanding of what the anti GAD65 Ab's are doing!)

You're not there yet.

The calcium ions don't cross the synaptic gap. They are involved in actions inside the nerve on the presynaptic side which allow it to release a burst of acetylcholine molecules from vesicles inside the nerve, which acetylcholine molecules then cross the gap and reach specialized receptors on the postsynaptic side. This is only one of many actions involving N-type calcium channels, but it is the most important when it comes to triggering contractions of muscles.

Don't feel too bad about not understanding the GAD65 antibodies, unless these directly damage the pancreas and cause type 1 diabetes it is hard to pin down specific actions. About all I can say is that this affects synapses using the GABA neurotransmitter, which show up all over the place. This likely has something important to do with your autonomic problems and dietary troubles.

This is actually progress. We now have treatable causes for problems with both autonomic function and neuromuscular junctions. The trick will be to reverse these problems without doing great violence to other immune functions. Prudent practice will be a series of experiments without irreversible effects. Each time something works you should feel better in a reasonably short time. Doctors who approach subtle problems looking for a "bigger hammer" should be avoided. A single intervention which has the potential to cure you instantly would also have the potential to make you worse, and in your current condition it wouldn't take much more to really clobber you.

 

[Gingergrrl]

You're not there yet.

I figured ... and most probably never will be. Would love to understand the science behind all of this but more than anything just want the opportunity to try the treatment which is currently at a standstill until my doctor calls to get me an urgent appt at the local doctor here. Otherwise I wait another month in limbo.

The calcium ions don't cross the synaptic gap. They are involved in actions inside the nerve on the presynaptic side which allow it to release a burst of acetylcholine molecules from vesicles inside the nerve, which acetylcholine molecules then cross the gap and reach specialized receptors on the postsynaptic side. This is only one of many actions involving N-type calcium channels, but it is the most important when it comes to triggering contractions of muscles.

I thought the calcium ions try to cross the synapse but the antibodies blocked them? But it sounds like you are saying that the calcium ions remain on the pre-synaptic side but are blocked from allowing the burst of Ach molecules to cross the gap to the post-synaptic side. Is this right? Do you think this is happening in others with ME/CFS who have not had the PAVAL (paraneoplasatic panel) test or that I am just a rare freak of nature?

Don't feel too bad about not understanding the GAD65 antibodies, unless these directly damage the pancreas and cause type 1 diabetes it is hard to pin down specific actions. About all I can say is that this affects synapses using the GABA neurotransmitter, which show up all over the place. This likely has something important to do with your autonomic problems and dietary troubles.

I definitely do not have diabetes (been screened by my Endo many times) so the anti GAD65 Ab's are doing something else in my case. More likely affecting the GABA neurotransmitter like you said and relating to my autonomic issues (or maybe lung muscle weakness?) When you say they could relate to my dietary troubles, do you mean to the MCAS/allergic reactions (or something different?)

This is actually progress. We now have treatable causes for problems with both autonomic function and neuromuscular junctions. The trick will be to reverse these problems without doing great violence to other immune functions. Prudent practice will be a series of experiments without irreversible effects. Each time something works you should feel better in a reasonably short time. Doctors who approach subtle problems looking for a "bigger hammer" should be avoided. A single intervention which has the potential to cure you instantly would also have the potential to make you worse, and in your current condition it wouldn't take much more to really clobber you.

I bolded part of your quote and would love to learn more what you mean re: finding a treatment that could reverse these problems (autonomic function and neuromuscular weakness) without doing great violence to other immune functions or causing irreversible effects .

I agree that in my current condition, some interventions could kill me and I need to make the right choice but so far nothing concrete is even being offered to me. They want me to have an EMG to rule out LEMS (which both myself and the doc does not think I have) and I agree to this plan but first appt is not for another month unless they can get me in sooner (which they can but requires them to make a phone call which so far they have not made.)

You said each time something works, I should feel better in a reasonably short period of time. Were you thinking of IVIG or something different? If something improved my breathing even 5%, I would know it immediately. Right now if food is hot, I do not even have the lung strength to blow on it to cool it off. It is insane how weak my lung capacity is right now. It shocks me every day but I somehow just adapt to it.

 

[anciendaze]

This exchange is getting more like a PM, where we should probably continue.

I don't really know how to get medical professionals to move faster, other than via emergency departments, which you will want to avoid if possible. You should have a local doctor to take over your case, and follow up on the findings you have. At present the problem is not that your doctors are taking things easy, it is that you are in limbo where no one is responsible for what happens next. Some professional has to be responsible for the treatments you need.

Once you have that new doctor I'd say IVIG is a reasonable intervention with limited risk. It may not work, but it is unlikely to precipitate a crisis. If it fails, you still have the option of plasmaphaeresis, even before you get to B-cell depletion experiments. (I don't think your concerns about exchanging "good plasma" are relevant if the preceding treatment did not produce improvement. However, if you feel strongly about it you might go directly for plasmaphaeresis.) If a doctor who is responsible for you feels you are still sinking after trying these standard interventions, then there is a good case to be made for quasi-experimental treatment when the alternative is grim.

This is what happened in the case of Rebecca2z. She has a diagnosis of EDS, but I don't think that played a major role in the decision to try Rituximab. It was just that her condition was bad and deteriorating, and her doctors were out of good traditional options. Since patients who had similar conditions had improved, and there were published reports of improvement, and no other options were promising, this was a typical justification for off-label quasi-experimental use of an existing approved medication. Her life was at risk, she was aware of the risks, and the option of doing nothing was unacceptable.