Does Very Severe ME/CFS involve a extra process: ME/CFS + X?

[Creekside]

It's really difficult to understand failures of complex interacting subsystems. I suppose there's some math to calculate the possible failure modes based on the number of potential factors and the number of potential interactions. I expect it's a rather large exponential rise. Possibly high enough to put it in the "basically impossible" category. Do you put that amount of resources in trying to solve the problem faced only by a small minority, or do you put those resources into treating the root cause of ME, which solves the problem for the majority and the minority?

 

[Jonathan Edwards]

That's a pretty convincing page of posts on a continuum, plus repeated reminders how fluctuant these phenomena are.

The only interpretation I can make at present is that it is all the same process, just varying in degree. If so, it makes me think of the cataplexy that goes with narcolepsy again - where the paralysis is very evident and very temporary.

It also reinforces my growing conviction that the basis of disability in ME/CFS is not about:
Muscle ATP
Any other intrinsic muscle processes or states
Poor blood flow, low blood volume, blood clots or any haemodynamic issues
Autonomic discharge - as an underlying cause - even if the autonomic system gets to kick off secondarily with tachydcardia etc. and maybe GI dysfunctions
Inflammation or 'endothelial dysfunction'
Generalised metabolic imbalances

It really has to be in brain structures like basal ganglia, hypothalamus or even cerebellum.
That does not exclude there being a persistently abnormal immune response upstream.

 

[lelelemonade]

My question then would be why, biologically, for some pwME the continuum takes them to such extreme incapacity, and for others it never goes that far.

To me it seems like the key difference is not immobility but the fact that some people always bounce back no matter what they do. They might crash so bad they’ll spend a month bedridden but they’ll regain their baseline eventually, while others (a majority even? based on DecodeME demographic data) have a more progressive course. I have no idea if the majority also has the potential to become very severe. My feeling is that yes, but you have to be very unlucky

 

[Maat]

I generally would agree with the above comments. I have never experienced paralysis but more like body was made of concrete and I physically could not lift any part of it.

I was diagnosed in my 40s and am now 68. I've been a severe pwME for the last 15. I've only experienced two periods where I could say the I was on the cusp of severe and very severe which included eating difficulties and general symptoms of gastroparesis, light and sound sensitivities; when I first became severe and again during the last twelve months. I'm slowly moving from soup to soft foods at the moment. I'm not malnourished, my BMI is 37.

But I've noticed during this second deterioration after 15 years of being severe) that the symptom of problems with thermoregulation has dramatically changed coinciding with being unable to keep solid food down.

That is hyperhidrosis (excessive sweating). This lasts all day and night and drips off me from head to toe. Akin to being permanently in a sauna but without the heat. It's beginning to ease of now which also coincides with me now subsequently being able to move slowly onto soft foods.

I've excluded it being linked to side effects of medication I'm on, I'm not diabetic, no heart problems and don't have POTs.

I've never seen anyone mention this extreme sweating before and I wonder if other people have experienced it and put it down to the known thermoregulation issue.

I've re-read this series of case studies

Life-Threatening Malnutrition in Very Severe ME/CFS

Life-Threatening Malnutrition in Very Severe ME/CFS - PMC

Very severe Myalgic Encephalomyelitis (ME), (also known as Chronic Fatigue Syndrome) can lead to problems with nutrition and hydration. The reasons can be an inability to swallow, severe gastrointestinal problems tolerating food or the patient being ...

pmc.ncbi.nlm.nih.gov

which Jonathan referenced in his paper.

and there's no reference to this being a significant symptom at the time.

Then I came across this

Acute Hyperhidrosis: A Clue to Underlying Autonomic Dysfunction and a Rare Neurological Disorder

Acute Hyperhidrosis: A Clue to Underlying Autonomic Dysfunction and a Rare Neurological Disorder - PMC

Acute hyperhidrosis is characterized by excessive sweating. In the absence of other symptoms, the symptoms of sweating alone are often benign and may be ignored by patients and clinicians. Rarely, hyperhidrosis may be a harbinger of an underlying ...

pmc.ncbi.nlm.nih.gov

Abstract
Acute hyperhidrosis is characterized by excessive sweating. In the absence of other symptoms, the symptoms of sweating alone are often benign and may be ignored by patients and clinicians. Rarely, hyperhidrosis may be a harbinger of an underlying severe disease. Autonomic nervous system dysfunction leading to hyperactivity of the sympathetic nervous system can result in excessive sweating. This case report is about a gentleman who presented with acute hyperhidrosis, a symptom of autonomic dysfunction, which turned out to be a relapse of anti-leucine-rich glioma-inactivated 1 (LGI1) antibody encephalitis. This case adds to the existing literature on cases of anti-LGI-1 encephalitis, a rare form of autoimmune encephalitis, and its varied clinical manifestations. It serves as a reminder to consider a wide range of differentials in patients who present with a seemingly nonspecific complaint such as excessive sweating.

It's also a symptom in Parkinson MS and Guillain-Barre syndrome

Don't know if any of this is relevant but thought I'd mention it as it doesn't seem to be discussed much.

Edit: On the NHS page on hyperhidrosis is a link to this https://www.hyperhidrosisuk.org/secondary-hyperhidrosis

There are NICE Guidelines on it, but without also paying attention to the NICE Guidelines on ME/CFS they're pointless.

 

[Felis Catus]

To me it seems like the key difference is not immobility but the fact that some people always bounce back no matter what they do. They might crash so bad they’ll spend a month bedridden but they’ll regain their baseline eventually, while others (a majority even? based on DecodeME demographic data) have a more progressive course. I have no idea if the majority also has the potential to become very severe. My feeling is that yes, but you have to be very unlucky

Yes, I find that interesting, too. I'll post my musings from another thread below.

I've been wondering why some people don't recover or don't fully recover after an episode of PEM/crash and others do.

It seems that some people keep overdoing it, keep crashing, e.g. even for years while trying to work while others deteriorate quite quickly in comparison.

Sometimes I wondered how often others experienced PEM but having been in some patient groups for years and having built relationships with other patients, I see that some people are crashing really often (in comparison to me) but they bounce back.

At some point I started thinking that the ability to bounce back is what distinguishes those who remain stable or improve from those who get worse. But what would be the underlying mechanism? Why would someone bounce back and someone else with a similar level of functionality/severity or even higher functionality wouldn't? Is there a process which basically determines one's trajectory and the patient's circumstances can only accelerate it but not change its course?

I know no one knows. Just thinking out loud.

I don't think it's about crashing soft, i.e. that if someone does just a little bit more above their threshold, just the right amount of not too much, that it leads to recovering from subsequent PEM as opposed to doing more than that. There are people who e.g. need help with food prep and putting the dishes in the dishwasher (because those activities trigger PEM) but they can go out weekly or multiple times a week for a few hours, crash each time, recover to pre-crash levels and maintain the same level of health for years. Please don't get fixated on this particular example. It's just an attempt to illustrate that some people fully recover from an activity which seems far more taxing than what they can manage without triggering PEM. And the point it that some people can keep doing it without deteriorating while others with the same or similar severity or even in better health deteriorate from seemingly smaller endeavours.

 

[wallfish]

Related discussion thread: Why does some MECFS become very severe?

 

[wallfish]

To those who describe experiences of paralysis, immobility, extreme muscle weakness: did it feel similar to what you might experience as part of a sickness response to a very bad flu? Maybe a worse or much worse version, but still the same type of feeling?

Or should I interpret paralysis as in cases of quadriplegia?

 

[neophyte32]

I keep reading accounts from people who seem to recover from crashes almost every time, whatever happens. I sometimes wonder whether this is more typical of people with mild or moderate ME/CFS, who are often said to represent roughly 75% of patients.

But for the severe and very severe group — the remaining 25%, which includes me — it can feel as though there is eventually one crash too many, or one exertion too many.

In my own case, I would almost describe it as one chemical stressor too many. I had episodes of excessive alcohol use before I realised I had ME/CFS, then poor reactions to medications such as antidepressants, and a failed stellate ganglion block. Each of these seemed to be followed by a deterioration. My most extreme crash — when I was almost completely paralysed, confined to a dark room and only able to take liquid food — happened after trying a tiny dose of Prozac.

Subjectively, it felt as though my brain had simply imploded.

More recently, I tried TUDCA and I am now in a major crash again. At this point, I am just hoping that over the next few days I will at least regain enough function to get up and go to the bathroom.

Of course, I cannot know whether these substances actually caused the deterioration, or whether they simply coincided with a system that was already extremely fragile. But from the perspective of someone with severe ME/CFS, the idea that every crash is fully reversible does not match my experience at all.

 

[neophyte32]

To those who describe experiences of paralysis, immobility, extreme muscle weakness: did it feel similar to what you might experience as part of a sickness response to a very bad flu? Maybe a worse or much worse version, but still the same type of feeling?

Or should I interpret paralysis as in cases of quadriplegia?

My worst crash, after taking antidepressants — anything that affects neurotransmitters seems to trigger an enormous crash for me — felt more like an absolutely terrible flu that lasted for a month.

Every muscle in my body was painful, and I could do virtually nothing except be fed by my wife with a spoon and use a bedside commode.

 

[ScoutB]

+1 for the experience probably being a continuum. Even at moderate there are often times when I'm so exhausted/ill feeling that eating consists of a few bites between laying down for rest breaks. I can see how a (presumably much worse) version of that, coupled with sensory intolerances and other awful sensations would make eating so difficult a person just could not keep up with their caloric needs.

Even if the experience/phenotype is a continuum, there could still be extra genes laying the groundwork for some people to get more severe than others. At least that's how I was reading it works for the genetics of neurological disorders. One person with a set of common risk variants might be on the mild end of the spectrum, while another person with a mix of common and very rare risk variants has a more severe version of what seems to be the same issue.

 

[V.R.T.]

What does the paralysis feel like for you? I’ve experienced something like paralysis only once, in a crash. Normally I’m somewhat mobile but bedridden. I woke up being unable to move my legs except for toes. Attempts to move them only caused myoclonus. They hurt a lot more than usual. There was also something wrong with my proprioception. I couldn’t tell which position my legs were in, though they weren’t numb. The “paralysis” went away along with the pain when a caregiver bent each leg at the knee and moved it around (though I also took Mestinon a few minutes earlier). He said they were unusually hot to the touch but idk if I trust that assessment. I was covered with a blanket and it was summer. I thought it could’ve been a blood clot or something though in that case it would be weird that it affected both my legs. Or maybe it was like when your leg falls asleep but 10x worse and without anything obviously constricting the blood flow. That was years ago and it never happened again.

Normally the thing that can make me immobile for hours is that any movement exacerbates symptoms and moving too much can cause additional PEM. Also, in severe crashes, I feel as though I have muscle weakness in the sense that objects whose weight I know really well suddenly feel much heavier

I experience episodes where i can't move much if at all sometimes. They're usually brief but now at severe can last an hour or two of going in and out of it. Seems to correlate with PEM from cognitive stuff.

As opposed to getting PEM type symptoms when I try to move and not being able to move much because of that.

 

[Peter T]

I've never seen anyone mention this extreme sweating before and I wonder if other people have experienced it and put it down to the known thermoregulation issue.

When at my most severe, I got very marked night sweats.

This lasted a number of years, perhaps eight. It was episodic, occurring when I was asleep, either at night or in the day, usually around once a day, so different to your experience @Maat. However it was marked, I would need to change whatever I was wearing, clothes literally dripping, and shift to a different bed.

It was not obviously temperature related, though I could wake up feeling cold from the sweat evaporating, until I got dry.

 

[Peter T]

Having relapsing and remitting ME I have been through most levels of severity at some point in the last thirty years, so I ought to be the poster boy for the continuum interpretation, and for most of the course of my ME this subjectively makes sense.

However at my most severe some aspects felt like a step change. I had a period of nearly ten years where I was on the cusp of severe and very severe. I would only get out of bed to go to the toilet or to eat cold food direct from tins; perhaps showering once every four to six weeks. Most of my symptoms though more severe had parallels with milder symptoms at different levels of severity. I did not have any gut motility issues, however two aspects felt qualitatively distinct during this period.

The first was my orthostatic intolerance: throughout my ME, I think being upright contributed to triggering PEM but of itself did not feel problematic, however during this period standing up for more than a couple of minutes saw me get dizzy and any longer could lead to fainting and added to my ongoing PEM. Now coming out of this phase standing or sitting upright of itself does not feel problematic other than contributing to any subsequent worsening of PEM.

Second was getting into a warm bath, which immediately made me feel very ill, and it would take weeks to recover from just a few minutes in the bath. Bathing to get clean was impossible, whereas showering was possible every four to six weeks, if I managed to get the water temperature right, albeit exhausting and PEM triggering. Now as I have improved to between moderate and severe I can luxuriate in a hot bath for as long as I want, a great indulgence.

 

[Lisan_Al_Ghaib_87]

I have never been very severe, nor have I ever been firmly in the severe category.

However, around two decades before my ME/CFS onset, I remember having one episode (which never happened again) of what I would describe as non-sleep paralysis, seemingly out of nowhere. It was morning, and the night before I had gone to bed without eating, even though I was a bit hungry and ehxausted after a busy day. I woke up and could not move my body at all. I experienced extreme weakness, and my body felt as if it were trapped in some kind of hardware malfunction. This continued for around 15 minutes. It was really creepy, but I decided to sleep a bit more and see if I could regain some strength ( I woke up latter normally).

I want to add that I have experienced sleep paralysis a few times in the past, and that episode was not similar at all. I was fully awake and it was too long to be just SP.

I always remember that episode because it was so unusual (and a bit scary), and I never really understood what could have caused such a dysfunction. In light of the latest discussion, it brings to mind the possibility that my brain may have had some predisposition toward this kind of dysfunction even before my ME/CFS onset.

 

[SugarSquared]

I am lucky in that I seem to be one of the people that does not trend towards deteriorating continually. I have never been severe or very severe. I would say I lowered my baseline in January 2026, but that was from mild to moderate. I've been able to go on trips where I can take a walk for 10-30 minutes outside or sit upright and socialize for multiple hours with a lessened PEM payback than when I am at home. Somehow, all that I did this summer has not lowered my baseline. It seems to only be vigorous physical activity that can do that. It doesn't sound like a road trip or a plane ride is even conceivable to those here who are severe.

I think it is both possible that many people who are severe would not be if they received adequate advice to not exercise and that some people tend towards severe no matter what they do. I would not be surprised if we have a similar set of disease variations as multiple sclerosis. Of course, ME/CFS is not MS, but I think we can draw some parallels. Looking at the National MS Society (USA), there are four types of MS:

• Clinically Isolated Syndrome (CIS): Clinically isolated syndrome (CIS) refers to a first episode of neurologic symptoms like those of MS. These symptoms vary from person to person but commonly include bladder issues, vision problems, and difficulty with coordination, balance, walking, speaking, and swallowing. CIS is considered MS when certain criteria are met.
• Relapse-Remitting MS (RRMS): Relapsing-remitting MS (RRMS) is the most common MS disease course. RRMS shows clearly defined attacks of new or increasing neurologic symptoms. These attacks are also called relapses. They are followed by periods of partial or complete recovery, or remission. About 85% of people with MS are initially diagnosed with RRMS. When the disease course progresses, it is considered to be secondary progressive MS.
• Secondary Progressive MS (SPMS): Some people diagnosed with RRMS eventually go on to have a secondary progressive MS (SPMS) course. In this course, neurologic function declines progressively and disability increases over time.Each person’s experience with SPMS is unique. In SPMS, you may have relapses, as well as periods of stability.
• Primary Progressive MS (PPMS): With PPMS, neurologic function worsens or disability accumulates as soon as symptoms appear. There are no early relapses or remissions. About 15% of people with MS are diagnosed with PPMS. Each person’s experience with PPMS is unique. PPMS can have brief periods of stability, with or without a relapse or new MRI activity. It can also have periods of increasing disability, with or without new relapses or lesions on an MRI.

I don't think CIS is relevant to us right now, but maybe we could liken it to the first episode of PEM. On its own, you can't definitely say it's ME/CFS. Sometimes you overdo it with your hike or you have a really stressful week, and it takes time to recover. Not too concerning. When you have multiple episodes of PEM, then you start looking at ME/CFS.

I would say a relapse-remitting form is the most likely form of ME/CFS. Complete recovery and remission, especially long-term, is rare, but people can have times of stability mixed in with episode of PEM. I would say I'm like that. I suspect that many people who were subjected to GET or were not given the supports to adequately pace would be milder and have a similar pattern. However, many people are pushed past their limits and into severe.

Severe ME/CFS could be likened to SPMS, but I think it's a little more complicated. It doesn't seem like it's always progressive as it is in MS. However, how people transition from RRMS to SPMS is interesting and could be comparable. From the organization's page about RRMS:

"Before approved [disease modifying therapies] were available, the transition from RRMS to secondary progressive MS (SPMS) occurred in about half of people who had been living with RRMS for 10 to 20 years. With better access to DMTs, fewer people with RRMS transition to SPMS and the transition happens later in the course of the disease."

We don't have disease modifying therapies, but we know that continually triggering PEM can worsen someone's baseline and that encouraging proper pacing can stabilize someone's baseline. Maybe those that go into severe territory cross a threshold that changes the disease pattern somehow. At the very least, it becomes a set of symptoms and severity that make mild and moderate ME/CFS almost seem like a different disease. The way that I live compared to the way that some of you live is miles apart.

But what about the people who seem to get worse no matter what they do? I think this is where the comparison becomes the most salient. There could be a kind of ME/CFS that is progressive like PPMS. SPMS and PPMS are both progressive, but there are two distinct paths to getting there.

Now, how do we go about studying this? Genetic data, as others have pointed out, could be interesting. I don't know what the questionnaire for DecodeME looked like. @Kitty said they asked if people were homebound, but I worry that might not be specific enough as I consider myself homebound but not severe. I think we already have a hint through McGrath et al. 2026 study that found that those with early-onset disease were more likely to be severe. Maybe separating cases by early-onset and late-onset would bring about genetic differences too?

The brain maturation information that @obeat mentioned is also interesting. I wonder what kind of research can be done there, neuroimaging or otherwise. There's of course the concern with doing too many tests on severe people or physically strenuous tests which makes extensive testing trickier. The brain biopsies are another avenue currently being pursued.

What other types of research could help us see if there's a progressive form of ME/CFS or if another process pushes people to being severe?

 

[Sean]

What I remember is that every movement needed extreme willpower and using my muscles felt extremely "wrong". Sometimes I laid for hours without any movement. It may be a bit comparable to the feeling of "can't move" that marijuana can produce (though far less pleasant). But at the same time, it never felt like moving was fundamentally impossible, if I really wanted to.

At my worst, I wouldn't have described it as paralysis, but I was so extremely weak that I couldn't sit up for more than a couple of minutes, if that. I couldn't hold utensils or a pen in my hand to write, couldn't hold a cup of tea, it was too heavy.

This is my experience.

I can see why some might use the term paralysis to describe it, even though it may not be literally or technically correct. For all practical purposes it might as well be at times.

Describing the experience of ME/CFS, especially at the severe end of the spectrum, strains language to its limits.

 

[obeat]

Do we know of cases of people over the age of 40 needing to be tubefed for the first time?

Or is it a phenomenon of the teens and twenties?

I accept that the process of eating can be difficult at any age when you are severe.


I had a quick look at the genes for synaptic pruning which involves complement and microglia genes. The purpose is to create a stable neural circuit.

Roll on SequenceME!!

 

[Maat]

When at my most severe, I got very marked night sweats.

This lasted a number of years, perhaps eight. It was episodic, occurring when I was asleep, either at night or in the day, usually around once a day, so different to your experience @Maat. However it was marked, I would need to change whatever I was wearing, clothes literally dripping, and shift to a different bed.

It was not obviously temperature related, though I could wake up feeling cold from the sweat evaporating, until I got dry.

Yes it's a difficult symptom to practically manage isn't it. I've been using Kylie sheets to protect whatever I'm lying on, so I only have to deal with changing dripping wet pjs.

 

[AliceLily]

I was very severe for 2 years but thankfully never got to needing tube feeding but I remember how very difficult it was to eat and the nausea amidst what felt like a hundred symptoms. I lost a stone in weight and continued to be underweight for over 10 years.

Very severe ME/CFS felt life threatening to me. I thought I had a terminal illness. At this stage it feels like you are exposed to secondary things going wrong because of how bad the ME/CFS process is. It's at full strength and threatening to get worse. I find it difficult to look back on it.

Is there anyone here who has been through very severe needing a feeding tube and has improved to severe or moderate?

 

[hummingbird95]

Apologies, I dont have the brain power to read all the responses so far. I hope to come back soon to read more in depth.

Developed mecfs around the age of 16/17, was fluctuating mild/moderate for years. The last 3/4 years have been severe, last year at times dipping towards very severe.

To me its felt like the same illness just more severe, all encompassing, unrelenting the last few years.

My paralysis episodes over a few mins, full paralysis sets in, just as its starting I can twitch/mildly clench a muscle but once its fully set in, the signal doesnt reach the muscles at all. I did realise a few months ago I still retain ability to flare nostrils but that's it. This stage last 1 hour ish. The following 3 hours Im in a near paralysis state where occassionally I can move slightly if absolutely necessary but its difficult/unreliable/my body wants to stay in one position even if uncomfortable. This usually lasts 3 hours. Ability to move normally usually comes back pretty suddenly. Episodes can start immediately after exertion or up to 6 hours later.

Had significant pem after an mri gor weeks, even with ambulance transfer and sensory minimisation. Was in semi conscious state, half aware but immense suffering 24/7. Was losing weight and regularly unable to take meds, eat, drink due to profound fatigue. Had extremely little use of hands, couldn't use cutlery, needed pill box to be opened for me, often couldn't open food packages.

I have made a significant improvement, still severe but quality of life is way better after 2 weeks of steroids, going from 25mg to 50mg topamax and slowly titrating to 10mg abilify (not medical advice but did want to share whats been helpful, first time since becoming severe ive improved)

Happy to share more if anyone has more questions

Edited later to add: unsure of how I feel that paralysis is being discussed as functional neurological disorder. To me it follows a pattern, follows exertion, follows a timescale and is part of a pem process. Happy to delve into it more though with those with more knowledge, maybe Im just misunderstanding