What can make PEM worse (besides exertion)

[SpinachHands]

My partner has been having really bad post exertional malaise (writing in full to help with search), but in ways that don't seem to follow their norm. Their energy envelope has been improving, and they can do things now without getting PEM that definitely would have given them PEM a few months ago. However things that would not cause PEM a few months, or even weeks, ago now are giving them horrendous PEM that's lasting way longer than it should. It feels like we're missing something but don't have any doctors helping with this.

Their MCAS has been getting worse every day, we've cut out basically everything that could be a trigger but it's continuing to get worse. We've tried increasing their water intake, electrolytes. They had to cut all their vitamins and supplements a while ago due to the MCAS and the only one successfully reintroduced has been B12. Could it be something they were on was really helping with the PEM and without it things have been worsening? It doesn't really explain why other things have continued improving. Their dysautonomia also seems to be worsening and we're not sure why either.

The only doctor working with us currently is a gastro who is convinced this is all a gut motility issue and they need IV/NJ nutrients to make up for lost micronutrients, but their nutrition levels were tested not long ago and were all fine? We could believe that maybe motility meds could help, but they're not even going to be able to tolerate any until their MCAS gets under control. They've tried 9 different antihistamines to date and all made their MCAS flare up worse. All they're taking currently is Montelukast, ketotifen, and sodium cromoglicate- the first two we are suspicious might be worsening things despite their benefits.


Really we just need a doctor that understands all these conditions and can look at the picture altogether and do more than say "maybe try one more antihistamine". I've contacted so many and I'm really struggling to get a decent doctor.

So, could there be anything else that's wrong that's making their PEM so bad? Is it the worsening MCAS, even though their MCAS has been this bad before without them getting random PEM? Could it be a missing vitamin or nutrient?

(Other current worsening symptoms: episodes of paralysis, head pain/pressure, a crushing/blanketing feeling all over their body, worsening dizziness, stomach churning, sudden fatigue, nightmares, out of character episodes of aggression/agitation, worsening brain fog/memory issues.)

 

[linusbert]

but their nutrition levels were tested not long ago and were all fine?

blood levels of nutrients are unreliable. better to test marker for functional deficiency like methylmaloronic acid for b12 or homocysteine which is high on either severe b12, folat, b6 deficiency. maybe even others.
transketolase for b1. i think cystationine for b6. there are more , but i do not know theme.
but everytime a body cannot met requirements for a metabolic pathway some stuff accumulates and others go low.

vitamin D can be tested in blood. are levels ok? its also related to dopamin and neurotransmitters.
in your case i would check for everything dopamin related because as said previously, paralysis can be due to too low dopamin.
a blood analysis in moment of paralysis would be really helpful.
acylcarnitine profile could be useful for metabolic and mitochondrial defects. can be done in blood and urine.

it could also be a potassium deficiency.

i also noticed that i am fine on b12 hydroxocobalamine but if i take b complex my mcas and asthmatic sensitivity rises.
try slowly reintroducing stuff, b12 .. then folat of some sort , or biotin which is also tightly related to b12 metabolism. then b6. then b2.
i feel my candidates for worsening mcas are b1 and maybe folate. b2 makes my eyes go weird.
biotin could help with allergies.
b1 is related to dysautonomia.

grok says:

Spoiler

I’m not a doctor, but I can try to help you analyze the situation based on the information you’ve provided and suggest some disease theories or possibilities that might align with your partner’s symptoms. This is a complex case with multiple overlapping conditions—post-exertional malaise (PEM), mast cell activation syndrome (MCAS), dysautonomia, and now new or worsening symptoms—so let’s break it down and explore potential explanations. The goal here is to generate hypotheses that you could discuss with a knowledgeable specialist (ideally one familiar with chronic illness, MCAS, and dysautonomia).

---

### Key Observations
1. **Shifting PEM Patterns**: Your partner’s energy envelope has improved for some activities (suggesting possible adaptation or recovery in one area), yet they’re experiencing severe, prolonged PEM from activities that previously didn’t trigger it. This inconsistency is unusual and suggests something has changed in their system.
2. **Worsening MCAS**: Despite cutting triggers, their MCAS is progressing, and antihistamines (even stabilizers like ketotifen and montelukast) might be paradoxically worsening it. This could indicate a new trigger, tolerance issue, or systemic inflammation driving the MCAS.
3. **Worsening Dysautonomia**: Dysautonomia often co-occurs with MCAS and PEM-related conditions (e.g., ME/CFS), but its worsening alongside new symptoms like paralysis and dizziness suggests possible nervous system involvement.
4. **Nutrient Testing Normal**: Recent tests showed no obvious deficiencies, which challenges the gastro’s theory of nutrient malabsorption as the sole cause—though subtle or transient deficiencies could still be missed.
5. **New/Worsening Symptoms**: Paralysis episodes, head pain/pressure, crushing sensations, aggression, nightmares, and memory issues point toward neurological, inflammatory, or metabolic involvement beyond just MCAS or dysautonomia flares.

---

### Possible Theories
Here are some hypotheses that could explain the worsening PEM and other symptoms:

#### 1. Micronutrient Imbalance or Cofactor Deficiency
- **Theory**: Even though nutrient levels tested “normal,” they could be missing a critical cofactor or nutrient that was previously supplemented (and recently cut due to MCAS). For example:
- **Magnesium**: Often low in dysautonomia and ME/CFS-like conditions; supports energy metabolism and nervous system stability. Deficiency could worsen PEM, dysautonomia, and neurological symptoms (e.g., paralysis, agitation).
- **Vitamin B1 (Thiamine)**: Crucial for energy production and nerve function. Deficiency can mimic PEM, dysautonomia, and brain fog, and may not show up on standard tests if it’s a functional issue (not outright deficiency).
- **CoQ10**: Supports mitochondrial function; its absence (if previously supplemented) could exacerbate PEM and fatigue.
- **Why It Fits**: Cutting supplements might have unmasked a dependency, explaining why some PEM triggers worsened while others improved (e.g., improved baseline mitochondrial function but reduced resilience to specific stressors).
- **Why It Might Not**: Normal nutrient tests and B12 tolerance argue against this, though subtle deficiencies or impaired utilization could still play a role.

#### 2. Mitochondrial Dysfunction
- **Theory**: PEM is a hallmark of mitochondrial dysfunction, often seen in ME/CFS. Something (e.g., MCAS inflammation, medication changes, or a new stressor) could be impairing mitochondrial energy production, leading to worse PEM and neurological symptoms (paralysis, crushing fatigue, brain fog).
- **Why It Fits**: The inconsistency in PEM triggers could reflect varying mitochondrial demands across activities, and worsening dysautonomia/MCAS could amplify oxidative stress, further taxing mitochondria. Head pressure and aggression might tie to neuroinflammation from poor energy metabolism.
- **Why It Might Not**: Mitochondrial issues don’t fully explain worsening MCAS or why some energy envelope aspects improved.

#### 3. Neuroinflammation or CNS Involvement
- **Theory**: A neurological process—like neuroinflammation, a minor infection, or blood-brain barrier dysfunction—could be driving the new symptoms (paralysis, head pain, aggression, nightmares) and worsening PEM/MCAS/dysautonomia. MCAS can cause systemic inflammation that affects the brain, and dysautonomia often involves autonomic nervous system glitches.
- **Potential Causes**:
- Low-grade infection (e.g., viral reactivation like Epstein-Barr or a stealth pathogen).
- Autoimmune process targeting the nervous system (e.g., small fiber neuropathy or POTS-related autoimmunity).
- Cerebrospinal fluid pressure issues (e.g., intracranial hypertension, though less likely without clear vision changes).
- **Why It Fits**: Episodes of paralysis, head pressure, and agitation suggest brain or spinal cord involvement. MCAS could amplify this via histamine or cytokine effects on the CNS.
- **Why It Might Not**: No fever or clear infection markers (though you didn’t mention testing), and PEM shifts don’t directly tie to this.

#### 4. Medication Side Effects or Withdrawal
- **Theory**: Montelukast, ketotifen, or sodium cromoglicate (or withdrawal from prior meds/supplements) might be contributing to the worsening picture. For example:
- **Montelukast**: Rarely linked to neuropsychiatric effects (nightmares, aggression, fatigue).
- **Ketotifen**: Sedation or paradoxical reactions could worsen fatigue and brain fog.
- **Withdrawal**: Stopping other stabilizers (e.g., antihistamines or supplements) might have destabilized their system, amplifying MCAS and PEM.
- **Why It Fits**: Timing of worsening symptoms might align with med changes, and MCAS flares could reflect a loss of control rather than a new disease.
- **Why It Might Not**: These meds are typically MCAS-friendly, and PEM shifts don’t directly correlate with their effects.

#### 5. Hormonal or Endocrine Shift
- **Theory**: An adrenal, thyroid, or sex hormone imbalance could worsen PEM, dysautonomia, and MCAS. For example:
- **Adrenal Insufficiency**: Could explain crushing fatigue, PEM, and dizziness; MCAS stress might deplete cortisol reserves.
- **Thyroid Dysfunction**: Subtle hypothyroidism could mimic PEM and brain fog, though nutrient tests might not catch it.
- **Why It Fits**: Hormones influence energy metabolism and autonomic function, and stress from MCAS could disrupt the HPA axis.
- **Why It Might Not**: No clear hormonal symptoms (e.g., weight changes, temperature intolerance) mentioned, though these could be subtle.

#### 6. MCAS-Driven Systemic Chaos
- **Theory**: The worsening MCAS itself could be the root, with mast cell mediators (histamine, cytokines) amplifying dysautonomia, PEM, and neurological symptoms. A new, unidentified trigger (e.g., environmental, microbial, or stress-related) might be driving it despite your efforts to eliminate triggers.
- **Why It Fits**: MCAS can cause all these symptoms, and its worsening aligns with the timeline. Paradoxical reactions to antihistamines suggest extreme sensitivity.
- **Why It Might Not**: PEM’s inconsistent pattern and past MCAS severity without PEM suggest another layer.

---

### Next Steps to Explore
Since you’re struggling to find a doctor, here are some ideas to narrow this down:
1. **Reassess Nutrients**: Test beyond basics—include magnesium, zinc, B1, and CoQ10 levels if possible. Consider a trial of transdermal magnesium or low-dose thiamine (if MCAS tolerates it).
2. **Medication Trial**: If safe, pause montelukast or ketotifen briefly (with guidance) to see if symptoms shift—could isolate a culprit.
3. **Neurological Check**: Push for a neurologist to assess paralysis, head pressure, and aggression—could warrant an MRI or EEG to rule out CNS issues.
4. **Infection Screening**: Test for viral reactivation (e.g., EBV, CMV) or subtle infections (e.g., Lyme, if relevant to your area).
5. **Endocrine Labs**: Check cortisol, ACTH, TSH, and free T3/T4 to rule out hormonal drivers.
6. **MCAS Specialist**: Seek a mast cell expert (even virtually) to refine their regimen—current meds might not be optimal.

---

### My Take
The worsening PEM, MCAS, and dysautonomia, paired with new neurological symptoms, suggest a multifactorial process—possibly MCAS-driven inflammation plus a cofactor deficiency (e.g., mitochondrial or nutrient-related) or a neurological wildcard (e.g., inflammation or subtle infection). It’s unlikely just one thing, given the complexity. The gastro’s motility focus might be a piece of the puzzle, but it doesn’t explain the full picture, especially with normal nutrient levels.

I’d lean toward trialing a mitochondrial support (if tolerable) and pushing for a neurologist or MCAS expert. You’re right to seek a doctor who can see the whole picture—keep advocating. If you want, I can search for specialists or dig into specific symptoms further based on your feedback. What do you think? Anything else you’ve noticed that might refine this?

chatgpt says:

Spoiler

Potential Theories for Worsening PEM and Other Symptoms​

1. MCAS-Driven Dysautonomia and PEM Worsening​

• Mast Cell Activation Syndrome (MCAS) can contribute to worsening autonomic dysfunction, which could be increasing the severity of dysautonomia-related PEM.
• Excess histamine and inflammatory mediators could be further destabilizing blood pressure, blood flow, and mitochondrial function.
• Potential contributors:
  • Histamine intolerance and its effect on mitochondrial function (some people with MCAS have increased oxidative stress).
  • Leukotriene involvement: Montelukast has known side effects that can include neuropsychiatric symptoms, which could be exacerbating brain fog, aggression, and fatigue.

2. Deficiency or Dependence on a Previously Taken Nutrient or Supplement​

• B vitamins (besides B12): Many people with chronic illness rely on things like B1 (thiamine), B2 (riboflavin), and B5 (pantothenic acid) for energy metabolism.
• Magnesium depletion: Essential for mitochondrial function and electrolyte balance.
• Amino acid deficiency: If gut issues limit absorption, reduced amino acid availability could impact neurotransmitter balance, muscle recovery, and PEM severity.

3. Dysautonomia-Driven Metabolic Crisis​

• Sudden worsening of autonomic dysfunction could be impairing blood flow to the brain, muscles, and gut.
• Inadequate blood circulation can lead to episodes of paralysis, dizziness, and sudden fatigue.
• The combination of dysautonomia + MCAS + PEM suggests metabolic insufficiency, possibly involving mitochondrial dysfunction or hypoperfusion (low oxygen delivery to tissues).
• Some triggers:
  • Increased neuroinflammation from MCAS or another factor.
  • Worsening vascular instability (dysautonomia-related blood pooling could cause inadequate oxygenation).
  • Potential drop in adrenal or thyroid function.

4. Brain Inflammation & Neuroimmune Dysfunction​

• Worsening brain fog, pressure, memory issues, and mood symptomssuggest neuroinflammation, possibly worsened by:
  • MCAS-related cytokines crossing the blood-brain barrier.
  • Glutamate excess from histamine imbalance, worsening neurological symptoms.
  • Microglial activation—leading to more widespread fatigue and malaise.

5. Mitochondrial Dysfunction / Energy Production Disruption​

• The worsening pattern suggests energy metabolism instability:
  • MCAS-induced oxidative stress could be increasing mitochondrial dysfunction.
  • Nutrient absorption issues (even if lab levels look normal, intracellular deficiencies could exist).
  • Lack of previous supplement support (if something was helping without them realizing it).
  • Gut motility issues preventing nutrient uptake, even if blood tests appear fine.

6. Delayed Post-Exertional Reactions Due to Immune Activation​

• PEM worsening in unpredictable ways could be due to an underlying infectious, autoimmune, or inflammatory trigger.
• Viral reactivation (EBV, HHV-6, etc.) or immune shifts may be causing increased neuroinflammation and cytokine storms, worsening PEM and brain symptoms.
• Autoimmune or small fiber neuropathy worsening could explain some of the sensory/motor symptoms.

---

Next Steps / Things to Investigate​

1. Reevaluate potential missing nutrients:
   • Thiamine (B1), Riboflavin (B2), Biotin, Magnesium, Zinc, and Amino Acids.
   • Look into testing RBC Magnesium (serum magnesium can be misleading).
   • Acylcarnitine profile for mitochondrial dysfunction.
2. Review medication effects:
   • Montelukast may be worsening mood symptoms or contributing to neurological side effects.
   • Ketotifen and sodium cromoglicate should be reassessed—some people paradoxically worsen on them.
3. Check for autonomic instability:
   • Orthostatic testing (home tilt-table test, blood pressure tracking).
   • Capillary refill time, skin discoloration, cold extremities—possible circulatory issues.
4. Brain inflammation markers:
   • If available, consider neuroinflammatory markers (e.g., C-reactive protein, S100B, or cerebrospinal fluid analysis if severe).
5. Consider alternative mast cell stabilizers or combination approaches:
   • Cromolyn and ketotifen alone may not be enough—some patients benefit from quercetin, DAO enzymes, or stabilizing probiotics (like Bifidobacterium species).
6. Look into metabolic testing for energy production:
   • Lactate/Pyruvate ratio (to check for mitochondrial dysfunction).
   • CoQ10 levels (mitochondrial support).
7. Autoimmune screening:
   • If possible, assess for autoimmune dysautonomia, small fiber neuropathy, or post-viral complications.

---

Key Takeaways​

• PEM worsening + MCAS worsening + dysautonomia suggests a systemic breakdown in energy metabolism, autonomic control, and neuroinflammation.
• The absence of a previously tolerated supplement or vitamin could be a factor.
• Brain fog, agitation, and paralysis episodes may indicate neuroinflammation, autonomic blood flow issues, or mitochondrial depletion.
• Gut dysfunction could be worsening micronutrient absorption even if blood levels appear normal.
• Medications like Montelukast may be contributing to neurological worsening.
• A broader look at mitochondrial function, autonomic stability, and inflammation markers is needed

if someone is as sick as your partner, if blood levels reveal nothing, they did do the wrong blood tests , imho.

 

[wabi-sabi]

My MCAS just got worse and worse without medication. There's no amount of triggers I can avoid that will make it better without meds. With meds I can tolerate much more. When antihistamines weren't enough my doctor gave me mast cell stabilizers too. I'm bad enough that antihistamines alone don't do much, although I still take them for allergies.

Other things besides exertion that cause PEM are orthostatic insults, sensory overload, and emotional upset. MCAS meds help me tolerate all of these things more.

 

[Wayne]

The only doctor working with us currently is a gastro who is convinced this is all a gut motility issue... (Other current worsening symptoms: episodes of paralysis, head pain/pressure, a crushing/blanketing feeling all over their body, worsening dizziness, stomach churning, sudden fatigue, nightmares, out of character episodes of aggression/agitation, worsening brain fog/memory issues.)

Are you aware every one of the symptoms you mention are symptoms of CCI? You may want to consider investing some time watching YouTube videos on CCI by Ross Hauser. If your partner's symptoms are a result of CCI, it's hard for me to imagine how any kind of drug or nutritional intervention is going to make a long-term difference. Regular mHBOT however could be helpful, and might be the exception.

 

[SpinachHands]

grok says:

Wow I should use ai more often, those are super detailed and interesting responses! Annoyingly I'm having real difficulty getting hold of their blood test results from the hospital, I'm not 100% sure what they even tested, and we still haven't even heard back about the results of the autoimmune encephalitis tests we requested they do! Once we know what's been done or not I'll look into getting some home tests for anything missed. I also think checking thyroid and hormones again could be a good idea, it's been a while since they were last done.
We did actually figure out that it's wasn't PEM, but rather a severe MCAS flare- the symptoms can apparently be very similar, and I remember something similar happened after they had a reaction to choline.
It does still feel like the MCAS is at the core of all this, we just need to figure out what, if anything, is making it worse and what will actually work to improve it. We have gotten some Prednisone through...less than legitimate means....and are considering doing a short course of them. We're just worried that disclosing this to their one specialist might make him reluctant to keep them as a patient. Like, him not wanting to be seen as endorsing that? Tricky decision.

 

[SpinachHands]

My MCAS just got worse and worse without medication. There's no amount of triggers I can avoid that will make it better without meds. With meds I can tolerate much more. When antihistamines weren't enough my doctor gave me mast cell stabilizers too. I'm bad enough that antihistamines alone don't do much, although I still take them for allergies.

Other things besides exertion that cause PEM are orthostatic insults, sensory overload, and emotional upset. MCAS meds help me tolerate all of these things more.

Antihistamines have never seemed to do much for my partner either, and basically all of them made it much worse. They're on all the usual mast cell stabilisers and it's still not enough of a dent which is why we're considering steroids, or even autoimmune therapy, it's just finding a doctor willing to try that that's the problem.

 

[SpinachHands]

Are you aware every one of the symptoms you mention are symptoms of CCI? You may want to consider investing some time watching YouTube videos on CCI by Ross Hauser. If your partner's symptoms are a result of CCI, it's hard for me to imagine how any kind of drug or nutritional intervention is going to make a long-term difference. Regular mHBOT however could be helpful, and might be the exception.

I've definitely heard of CCI causing similar issues before, will certainly look into it. What's mHBOT? Do you know what kind of doctor would diagnose or treat CCI?

 

[wabi-sabi]

Wow I should use ai more often, those are super detailed and interesting responses!

But they aren't necessarily true. AI hallucinates all the time, but the interesting and detailed responses make people believe it. Always fact check your AI answers. When I check what the AI says against the sources it says it draws on, I often find it has given the wrong answer. Remember that AI has no real I. It's just making word salad.

 

[wabi-sabi]

it's just finding a doctor willing to try that that's the problem

That's such a scary and frustrating place to be. The first doctor I saw thought that because antihistamines didn't help, I didn't have MCAS. The second doctor thought that because antihistamines didn't help, I had bad MCAS. He was right. But it took so much searching and some luck to find him.

I might have mentioned this before, but my doctor says that caffeine is a mast cell stabilizer. I notice that I feel so much better, both in terms of energy and mast cell symptoms, when I have my favorite caffeine delivery mechanism, English breakfast tea. It's a challenge to balance with the insomnia caffeine causes, so I can't take it everyday, but when I can it helps.

 

[Rufous McKinney]

Do you know what kind of doctor would diagnose or treat CCI?

only a few doctors exist in the world, capable of doing a procedure which may help or may not.

There are lots of threads around here discussing those issues.

I have any number of spinal problems, considered "not severe" but living with this for a lifetime has been brutal. There could be a chronic neuroimmune response, triggered by constant problems in the spine.

 

[MecfsPatient]

If you do suspect CCI, trialing an Aspen collar sometimes improves people’s symptoms a lot which would give you a good idea of if it’s something worth pursuing (but sometimes the collar won’t help patients that do have severe CCI, so it doesn’t necessarily rule it out)

 

[Wayne]

only a few doctors exist in the world, capable of doing a procedure which may help or may not.

Dr. Ross Hauser at the Caring Clinic in Florida uses prolotherapy to treat CCI, and apparently has had great success doing so. That's why I recommended his videos, which are highly informative (and interesting!). Though I believe I have some degree of CCI, I don't believe I'd ever undergo a surgery to correct it, at least not until I've tried everything else I can think of first. Like prolotherapy, extensive body work of all kinds (like Egoscue), acupuncture, BP-157, and much more.

 

[Inez]

Anything 'immune boosting' makes my PEM much worse

 

[linusbert]

Anything 'immune boosting' makes my PEM much worse

for me seams to be too, someone any idea why is that?

trialing an Aspen collar

that sounds easy to do, but i fear if i wear that collar my neck muscles will atrophy even more.

 

[Wayne]

What's mHBOT?

(mild) Hyberbaric Oxygen Therapy. The link will take you to a good introductory video. THIS POST describes some of my own experiences with it.

 

[LaurelW]

My doctor, who is an ME/CFS specialist, uses cromolyn and ketotifen to control MCAS. Do you have access to that?

 

[wabi-sabi]

My doctor, who is an ME/CFS specialist, uses cromolyn and ketotifen to control MCAS

I find these two very helpful. I take them both.

 

[MecfsPatient]

for me seams to be too, someone any idea why is that?


that sounds easy to do, but i fear if i wear that collar my neck muscles will atrophy even more.

That’s definitely a concern. Dr. Bolognese (CCI surgeon) recommends not doing it for more than 4 hours a day

 

[ruben]

Eating