Trial Report Low Vasopressin in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, 2024, Huhmar/Bragée/Polo

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https://www.neurology.org/doi/10.1212/WNL.0000000000205761

GENERAL NEUROLOGY: NEUROIMMUNOLOGY
April 9, 2024
Free Access

Low Vasopressin in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (P4-4.006)

Helena Huhmar, Lauri Soinne, Per Sjögren, Bo Christer Bertilson, Per Hamid Ghatan, Björn Bragée, and Olli Polo
AUTHORS INFO & AFFILIATIONS
April 9, 2024 issue
102 (17_supplement_1)
https://doi.org/10.1212/WNL.0000000000205761

Abstract

Objective:
To shed light on the pathophysiology of water homeostasis in patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), classified by WHO as a neurological disease (ICD 10 code G933).

Background:
The complex symptomatology of ME/CFS includes signs suggesting abnormal water homeostasis and hypovolemia. Since many patients report polyuria-polydipsia, we conducted an observational series of plasma and urine osmolality as well as plasma levels of vasopressin (VP) in consecutive patients diagnosed with ME/CFS according to the Canadian Consensus Criteria.

Design/Methods:
Plasma and urine osmolality (P-Osm and U-Osm, respectively) and plasma VP levels were measured in 111 patients after overnight fasting and 10-hour fluid deprivation. The clinical routine also included brain MRI and blood chemistry.

Results:
Following the fluid deprivation P-Osm was above normal (>292 mOsm/kg) in 61 patients (55.0%) and U-Osm below normal (< 750 mOsm/kg) in 74 patients (66.7%). VP-levels were below the level of detection (<1.6 pg/mL) in 91 patients (82.0%). A normal level of VP in relation to their P-Osm was found in 11 patients (9.9 %). The state resembling a central type of diabetes insipidus (cDI) would in the absence of hypophyseal imaging findings and blood chemistry consistent with any other hypophyseal hormonal defect be classified as idiopathic.

Conclusions:
Our findings suggest that deficiency of vasopressin secretion is a fundamental measurable part of the disease mechanisms, which may underlie a number of symptoms in ME/CFS, including the common complaint of orthostatic intolerance.


Disclosure: Helena Huhmar has nothing to disclose. Dr. Soinne has nothing to disclose. The institution of Prof. Sjögren has received research support from Patient-led Research Collaboration, US. Prof. Sjögren has received publishing royalties from a publication relating to health care. The institution of Dr. Bertilson has received personal compensation in the range of $50,000-$99,999 for serving as a Consultant for Medect Clinical Trial AB. The institution of Dr. Bertilson has received personal compensation in the range of $50,000-$99,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Medect Clinical Trials AB. The institution of Dr. Bertilson has received research support from ME UK. Dr. Bertilson has received intellectual property interests from a discovery or technology relating to health care. Dr. Bertilson has received personal compensation in the range of $500-$4,999 for serving as a teacher with Region Stockholm. Dr. Ghatan has nothing to disclose. Dr. Bragée has nothing to disclose. Dr. Polo has nothing to disclose.

https://twitter.com/user/status/1779139275688202641
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Can't tell much from the abstract. Reading between the lines I'm guessing the cohort may just have been regular patients coming through their clinic. Which raises the question if they then treated those they found deficient in vasopressin with vasopressin, and to what effect.

Curiously, for me this phenomenon is very specific to early-phase PEM:
sudden unexplained thirst = entering mild PEM
sudden unexplained thirst + suddenly peeing like a horse every half hour = entering bad PEM
 
My first question: is a plasma osmolality above 292 abnormal after overnight fasting and a ten hour fluid deprivation? As far as I can see, plasma osmolality is high first thing in the morning, and I'm not sure that finding that over half the participants had high plasma osmolality at that time is unusual.

But, it does seem that the pairing of that with low urine osmolality is odd. I think the urine should also have been concentrated.One reference I found suggest that the morning urine concentration after a night of no water intake should be greater than 850. That two thirds of the participants had urine osmolalities of less than 750 does seem noteworthy.

hotblack said:
If plasma osmolality changes wouldn’t this potentially have all sorts of effects on other chemical processes throughout the body?
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Yes, I would have thought so.

random googling said:
As cell membranes in general are freely permeable to water, the osmolality of the extracellular fluid (ECF) is approximately equal to that of the intracellular fluid (ICF). Therefore, plasma osmolality is a guide to intracellular osmolality. This is important, as it shows that changes in ECF osmolality have a great effect on ICF osmolality — changes that can cause problems with normal cell functioning and volume.
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Ravn said:
Curiously, for me this phenomenon is very specific to early-phase PEM:
sudden unexplained thirst = entering mild PEM
sudden unexplained thirst + suddenly peeing like a horse every half hour = entering bad PEM
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I have noticed something similar - a fluid buildup, general swelling, visibly puffy face leading into PEM, and then losing that water volume is part of the resolution of the PEM. I have seen pictures of other people in PEM and also my son - they also look puffy in the face, swollen around the eyes. I think this is something that could probably be measured.
 
abstract said:
VP-levels were below the level of detection (<1.6 pg/mL) in 91 patients (82.0%). A normal level of VP in relation to their P-Osm was found in 11 patients (9.9 %).
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That's pretty remarkable. We need this finding replicated.

I found a reference saying that vasopressin levels are naturally lowest in young women, so perhaps that is relevant to sex and age differences in the prevalence of orthostatic intolerance?

The Biology of Vasopressin, 2021 has background information
 
I produced too much urine from before 2000, and benefited greatly from desmopressin. Then, recently, a while after having had some dental work including the extraction of an infected tooth, I stopped needing it.

My blood pressure also normalised, when I had been taking the beta blocker Nebivolol since 2014, and an ACE inhibitor before that.

I am almost 71, and have had ME since about 1995. No medication needed now except to help me sleep!

https://www.s4me.info/threads/diarrhoea-caused-by-too-much-desmopressin.36981/#post-521077
 
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I’ve had periods where the peeing a lot is an early phase stage, then my body suddenly decides it needs to catch up and rehydrate and after that other PEM stuff. And periods where I’ve been stuck in that state for a prolonged time, generally when very bad.
 
Hutan’s googling said said:
As cell membranes in general are freely permeable to water, the osmolality of the extracellular fluid (ECF) is approximately equal to that of the intracellular fluid (ICF). Therefore, plasma osmolality is a guide to intracellular osmolality. This is important, as it shows that changes in ECF osmolality have a great effect on ICF osmolality — changes that can cause problems with normal cell functioning and volume.
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Thanks, that’s the sort of thing I was thinking. My biology knowledge is poor and chemistry/physics better but rusty.

But if there’s changes to how things cross the cell membrane one can imagine how various systems would get upset and behave in odd ways.

As others say, interesting paper, lots of questions.
 
Could it be helpful to take some salt first thing in the morning?

https://www.sciencedirect.com/science/article/pii/S2211124721001807

Highlights
  • •
    High dietary salt increases the osmoresponsiveness of vasopressin neurons in vivo

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    Salt loading and AngII-salt both increase the mEPSC amplitude in vasopressin neurons

  • •
    AngII-salt increases glutamate release probability and overall network excitation

  • •
    Salt loading increases stiffness and intrinsic osmosensitivity of vasopressin neurons
 
With SARS-CoV-2 being associated with a loss of sense of smell and taste could a virus cause a loss of sense of thirst?
Could this be anything to do with what's being discussed in this paper?
Some pwME say they have been helped with IV saline infusions though Jonathan Edwards says just drinking water should have the same effect.
 
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I'm not sure that people with ME/CFS all pee frequently all the time and typically with low urine solute concentrations, which is what I would have expected if low vasopressin was a biomarker. I have seen Diabete Insipidus mentioned in connection with ME/CFS quite a bit, but I'm not sure that it fits.

Arginine Vasopressin Disorder (Diabetes Insipidus), 2024
Arginine vasopressin disorder is a clinical syndrome characterized by the passage of abnormally large volumes of urine (diabetes) that is dilute (hypotonic) and devoid of dissolved solutes (ie, insipid).
...
Approximately 30% to 50% of cases of AVP-D are idiopathic. These are suggested to be associated with an autoimmune etiology in most patients.[10][11][12] The autoimmune process is characterized by lymphocytic inflammation of the pituitary gland, specifically the pituitary stalk and the posterior pituitary gland. Early in its course, imaging of the gland (through an MRI pituitary gland sequence) reveals thickening or enlargement of these structures. A longitudinal study demonstrated the presence of cytoplasmic antibodies directed against vasopressin cells in patients with endocrine abnormalities.[11]
...
  • Wolfram syndrome or DIDMOAD (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness) syndrome is characterized by AVP-D, diabetes mellitus, optic atrophy, and deafness, with cognitive and psychiatric issues that may appear later in life [17]; it is inherited as an autosomal recessive trait with incomplete penetrance and involves defects in the endoplasmic reticulum. Prognosis is poor with death at a mean age of 30 years.[18][18]
...
f) Hypoxic encephalopathy
Hypoxic encephalopathy or severe ischemia (as seen with cardiopulmonary arrest or shock) can lead to diminished ADH release.[31] The severity of this defect varies, ranging from mild and asymptomatic to marked polyuria.
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I wonder if some medications that are favoured by the clinic might have caused this result? The finding of reduced vasopressin can easily be tested, and I hope it will be.

I thought the note in the 2024 paper on Arginine Vasopressin disorder I linked about severe ischemia resulting in reduced vasopressin release was interesting, given my symptom tracking suggesting times of high shock index are associated with high levels of symptoms/PEM.
 
Patienternas törst ledde forskaren till viktig upptäckt
https://www.bragee.se/patienternas-torst-ledde-till-viktig-upptackt
Auto-translate said:
Patients' thirst led researcher to important discovery
Research from Bragée on ME/CFS

Low Vasopressin in ME/CFS - an important new discovery

Helena Huhmar, Lauri Soinne, Per Sjögren, Bo Christer Bertilson, Per Hamid Ghatan, Björn Bragée and Olli Polo

Researchers at Bragée Clinics, led by Dr Helena Huhmar, a specialist in neurology, are behind a scientific study presented at an international congress in Denver, USA, and in abstract form in the prestigious journal Neurology. [...]
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