Symptomatic Treatment: Huperzine A/B

The following is only meant for people with neurological ME as defined by the Charitè CFS/ME center in 10.1016/j.bbi.2015.09.013. They define the disease's mechanism to be mediated by adrenergic- and muscarinergic-binding subtypes of acetylcholine-receptor antibodies. Acetylcholine-receptor antibodies are commonly found in various neuromuscular diseases. The referenced paper discusses the specific subtypes and for which condition they are usually found. Unlike ME, these conditions have a longer research history and approved medical treatment options (e.g. Myasthenia Gravis (MG) 10.1016/j.ncl.2018.01.011).

A common and early neuromuscular medication with immediate effect on the acetylcholine receptors are cholinesterase inhibitors. Their goal is to enhance the acetylcholine concentration at the receptor site and thereby enhance transmission (PMID:31335056). Pyridostigmine is one of them, and I've read other users mentioning this already. They can normalize the function of the receptors if administered the right dosage. Overdosage can have critical complications, though. This is why synthetic cholinesterase inhibitors aren't available without a prescription and should not be taken without medical advice. They are not approved for ME.

The typical synthetic cholinesterase inhibitor targets muscle function. This not only affects skeletal muscles but smooth muscles as well. Smooth muscles can be found in the iris, the esophagus, the remaining gastrointestinal system, the airway, and other places where muscle tonus is maintained without cognitive stimulus. To give some context, asthma patients have high tonus in the airway smooth muscle (10.1152/japplphysiol.00950.2012). If their cholinesterase activity was inhibited, the muscle tonus would be further enhanced, amplifying the asthmatic effects. Different cholinesterase inhibitors have different effects on skeletal vs. smooth muscle tonus (10.1097/00000539-200101000-00020).

Muscle nerve endings are not the only cell type expressing acetylcholine receptors, though. All subunits associated with ME, as identified by Charitè CFS/ME center, (i.e. β2, M3, M4) serve different purposes in the brain (10.1016/j.neuron.2012.08.036). Under normal conditions, typical synthetic cholinesterase inhibitors such as Pyridostigmine don't cross the blood-brain barrier (10.1038/nm1296-1382). Their purpose is to treat neuromuscular diseases, and brain toxicity can be avoided this way regardless of dosage.

Since ME dominantly affects the brain, my question is, what alternatives exist that target the brain and avoid effects on the muscle tonus. Rationally, a substance with high blood-brain permeability will lower the dosage requirements and hence reduce potential muscle-related complications. Alzheimer's is a disease for which this assumption has been integrated into therapeutic choices (10.3892/mmr.2019.10374). The referenced paper lists different cholinesterase inhibitors and their effects in the context of Alzheimer's. Fortunately, non-synthetic options exist here. While research on flavonoids lack differentiation and depth, and Cardanol extraction from the cashew nutshell isn't unproblematic from health and ethical standpoints, Huperzine sounds like a promising nutritional choice to me.

Huperzine A is an extract from club moss plants (WebMD). Naturally, research on herbally-extracted agents is limited. Yet, the available research shows Huperzine A to have "better penetration through the blood-brain barrier, higher oral bioavailability, and longer duration of AChE inhibitory action" (10.1111/j.1745-7254.2006.00255.x). Exceeding the recommended dosage limit of 200μg b.i.d., mild side effects could be experienced with 400μg b.i.d (10.1038/aps.2012.128). As for most herbal extracts, toxicity is still an option if severely overdosed (10.32725/jab.2009.009). Huperzine A is available over the counter and isn't restricted to Alzheimer's disease therapy. Some healthy people use it just as a neuro booster. Still, be considerate before trying new things.

 

The Charité group has speculated that these antibodies might be involved in some cases ofME but we have no good evidence for that being the case and the antibody data actually make it extremely unlikely, since antibody levels are only minimally different from the normal population. So I would say nobody has 'neurological ME as defined by Charité'.

The case for this herbal extract being of any use looks very thin to me. It is presumably available because it is an extract rather than something synthesised and legal requirements tend to be less for extracts. From what I have seen on the net there is not much to suggest it is any use to anybody and can make people feel ill, as one would expect from a cholinesterase inhibitor.

 

This is more than speculation imho. Based on this evidence, they built three trial phases of Rituximab (10.1371/journal.pone.0193672). It's open to speculation why the last phase failed, of course, but the antibody test is part of their diagnostic guidelines. I personally have the typical manifestation as they describe it, i.e. all three elevated, and M4 dominantly elevated. Together with the symptomatic diagnosis of CFS, I qualify as a neurological ME patient as they describe it. They explicitly distinguish this kind of ME from the pathologically unclassifiable types of CFS. As you can read in this forum, CFS can occur with dozens of causal factors. It is a very wide spectrum that has to be filtered and if one in three patients has elevated antibodies, it can not remain unnoticed. Thymoma-association for MG isn't even reaching this number (only 15%) (10.4061/2011/474512) and yet, the thymus is integral in their guidelines. It just happens that for some, it is the causal factor, and for many others, it's not.

Nobody is implying that this could fix the disease but the assumption is that it might provide alleviation of acetylcholine-mediated symptoms. I won't describe my personal experience because I don't want to give false hope. A single experience isn't worth anything. But I think the acetylcholine metabolism shouldn't be put out of focus when it comes to therapeutic options.

Regarding the causal degree of the antibodies, it is indeed speculation because it is difficult to distinguish pathological antibody response (as known from MG) from antibody response after otherwise-induced nerve damage (as known from ANA). Pathological studies could clarify this if it was a reproducible disease. But there is yet no scientific consensus on this matter. Regardless of causality, if antibodies are measured, it confirms that nerve damage at these types of cells is occurring, and nerve damage has consequences. I hope you get my point.

There is plenty of evidence for Alzheimer's but it's all Chinese research since it is considered a Traditional Medical Herb in China and they, besides Japan, seem to be the only ones who publicly finance research on herbal medicine. But it has been approved by different journals such as Nature. I trust their peer-review.

 

@mat, you may not be aware but I am a professor of immunology and I know Carmen Scheibenbogen, Oystein Fluge and Olav Mella well. I have been involved in the investigation of B cell involvement in ME for over 5 years.

The rituximab studies in Norway have nothing to do with finding antibodies in Berlin. The antibody studies came later. The phase 3 trial of Rituximab failed because the drug has no effect. I have looked at the raw data from the Norwegian studies in detail and I can assure you this is the case.

The levels of antibody are too small to be of any clinical relevance. There is no point in having diagnostic guidelines for a test that gives almost exactly the same results in normal people. A particular individual having these antibodies means nothing. It certainly does not mean thy are causing nerve damage. At most, the finding might suggest some indirect relevance showing up as a statistical shift in a population.

Sorry, @mat but this isn't the way things are. I spent my life studying the pathogenic mechanisms of autoantibodies. The ones that are relevant stand out like a sore thumb, they are not just slightly higher than in controls. You are right that it is difficult to distinguish pathological from non-pathological antibodies in an individual - which is in fact another reason for saying what I have said above even for illnesses where antibodies are thought significant. But it is not difficult to sort clinically relevant from trivial findings. The antibody findings in ME are trivial.

These antibodies had a reputation for being very non-specific and meaningless long before they were tested in ME. I remember an authority on neuronal antibodies saying, on hearing that there were findings in ME, 'I hope you are not going to say anti-Ach receptor antibodies, which turn up everywhere'.

This matters to me because I introduced the use of rituximab in systemic autoimmune disease in 1998 and people sometimes die from being given rituximab when they shouldn't have been. You might say that is not my fault but I try to stop it happening.

 

@Trish Thanks for the references.

@Jonathan Edwards
I was not aware of your position. Patients like me certainly appreciate any effort you put into this, and I hope you will keep trying. I agree with you that Rituximab does not show an effect because this is what the trial showed. What I meant by speculation is the question of why the first phase/s didn't show this. Maybe it works only with specific subgroups. But I have no insight as you do. If you say that Rituximab is a blank wall, I trust your word.

When mentioning the referenced paper, I confused Rituximab with Charitè's new approach of antibody filtration. I thought I had read an editorial or something that linked CD20 to these antibodies, but it seems I confused it with Charitè's β2+M4 responder vs. non-responder control of Rituximab (j.bbi.2015.09.013). So a study with Rituximab in the context of these antibodies happened in Berlin in ~2015. Please correct me if I confuse things again. Regardless, the last Berlin paper is from 2018, and their antibody filtration (Immunoadsorption) still targets the β2 subunit. A great part of the study only shows that the filtration works as the filtration is supposed to and this by itself is no evidence of therapeutic success. However, they also use symptom scores as control. Regardless, I personally don't see it promising yet because I know that the season can have an influence, and considering this, it's only secondary symptoms like the sore throat that improved significantly for a subgroup.

I think we can agree that a causal role of these antibodies is unlikely given these new studies. Nevertheless, secondary symptoms can be affected. So I still see some value there. Regarding cholinesterase inhibitors, there is an additional point to make. Antibody-targeted therapy only works if the antibodies play a pathological role. If they are a physiological response, the immune system will eventually respond differently to otherwise-induced necrosis. Yet, cholinesterase inhibitors work in both cases, let it be pathological or physiological; if something causes damage to these cells, a normalizing factor can be of benefit. I won't make a claim about the significance of the benefit. But in theory, I see the potential. Your point that the antibody levels still don't seem high enough to explain significant necrosis - it is a good point. Would a titer control of a subunit be a better quantification?

Regarding the diagnostic criteria, I agree with you that a single biomarker has no value. This is why the first-mentioned study explicitly mentions plenty of different diseases and how these subunits correlate for them. I think the test can be useful to narrow down likely causes and for differential diagnosis. As a data scientist, I've observed something in medical science. That is that there is an attitude to find singular markers, singular therapies, etc. I won't go into the topic of orthomolecular medicine, but as someone who has worked on machine learning, this doesn't make sense to me. If the given markers' confidence is low and should be higher, either a piece is missing, or the model is oversimplified, but it doesn't mean the marker is wrong and that another singular marker will provide all the answers. I think the typical model of fixed reference ranges is oversimplified. The statistical value of a numerical combination of three antibody types is much greater than categorically looking at them. Especially considering that there seems to be a cluster of three subunits + M4 being dominant. This is why I would not rule out the possibility that these antibody subunits will eventually end up in a sophisticated diagnostic model.

 

The only prior trial with an interpretable numerical result is the blinded phase 2. The result of that was also negative. There was a suggestion of an effect at a different time point and phase three was undertaken to see if this was more than a chance finding. It was a chance finding. There is nothing to suggest the drug works on subgroups. Phase 3 would have come up positive even if a minority of patients were true responders.

I agree, all I think that was shown for absorption was that antibody levels went down, not that there was a benefit.

I don't understand that. If antibodies affect symptoms that is a causal role. What would 'secondary' mean? I don't think there is a 'secondary' card to play here.

Not sure what you mean by a normalising factor. We don't yet have any evidence of anything abnormal with ACh signalling.

I just don't think these antibodies are abnormal. They have been reported as associated with all sorts of illnesses. And they are pretty much as common in normal people. That is not an indication that they are of interest in lots of illnesses but that they are non-specific and of no real interest. There may be some significant antibodies hiding amongst them I one rare disease but it looks unlikely. Antibodies with lots of non-specific associations have been around for decades, like anti heat shock protein 60 antibodies. You can find them anywhere and they mean nothing.

I agree it doesn't but in real immunological research we don't work like that anyway. The analysis is much more nuanced. Which is why the idea of finding an antibody immediately indicates a cause in your favourite disease is naive. I have always worked with hugely complex models. I did not publish a mechanism for rheumatoid disease until I had 55 steps linked through a complex systems structure with clearly defined servo loops. Forget fixed reference ranges - indeed.

The problem is that so many publications in immunology are poor quality. Maybe one in fifty are worth reading.

Sorry to be a wet blanket but this is very basic quality control stuff as far as I am concerned.

 

At least for the moment. In general, subgroups seem to be difficult to identify if the pathological mechanism and the causality are not well understood.

Let's compare it with fever during an infection. Fever is a favorable physiological response during certain infections. Hyperpyrexia is when it becomes critical. But fever causes symptoms such as dehydration and a sore throat. This is what I mean by secondary. Sore throat was also on the symptom questionnaire of the antibody filtration study - completely unrelated of course. These antibodies could be a physiological response to otherwise-induced necrosis of nerve cells and meaningless, or even favorable I imagine, given rare oncological conditions. They could also play a pathological role and actually cause an unfavorable dysfunction of nerve cells. For me, the primary symptom that identifies this disease is chronic and post-exertional fatigue.

Here is where it becomes interesting because medicine traditionally classifies diseases based on symptoms but not primarily on pathological mechanisms. The referenced study showed good antibody filtration response for the sore throat. Thus, it seems that there is an association to the ß2 receptor antibodies, assuming it's not due to confounding factors, which is unclear due to the lack of a control group. Assuming the same could be said about the fatigue and most of the other symptoms. That there is an antibody that will be determined. The antibodies will be filtered and therapy will show a therapeutic success. CFS is technically cured then. However, what if it all was a physiological response to the primary disease of some kind and this is when the primary disease becomes uncontrolled. Maybe it is all secondary. Is CFS a disease or a syndrome?

By normalizing, I only mean bringing the levels back to reference ranges. Don't we have evidence because no one identified a respective subgroup or don't we have evidence because there is no evidence to be found? Only looking at the symptoms, I see overlaps with MG; exercise-induced muscle weakness, muscle pain, painful lymph nodes, sore throat, flu-like symptoms. But I think this is another topic and I will write a new post sometime. I also see reports of off-range neurohormones, where ACh signaling plays a role. Given what we know of these subunits, it's presumable rather brain-centric than muscle-related though. You must know this better than I can figure but I assume metabolic mechanisms in the brain are difficult to filter in imaging without a biopsy.