Geoff’s Narration
The GIST
Three years ago, I had several discussions with a retired ME/CFS/FM doctor (who also had ME/CFS/FM) named Frank Perrino. Perrino was full of interesting ideas about these diseases, but at one point, our conversations abruptly stopped. I tried but failed to get back in touch with him for a couple of years. Finally, with the recent Tonmya approval, I decided to publish my write-up of our talks, which focused on sleep. Unfortunately, Dr. Perrino never went over this post.
After a bout of meningitis triggered a chronic fatigue condition as a child, everything changed for Frank Perrino. While the other kids played on the field, he felt like his shoes were filled with 100-pound weights. Looking back, he can remember only a couple of days when he was full of energy and the world seemed bright.
Perrino felt like he was dragging a 100 lb ball around – until he tried Xyrem.
Still, he plodded on and made it through medical school. At one point, he was diagnosed with sleep apnea and put on a CPAP machine, which helped, but not as much as he’d hoped.
Perrino was 45 years old when something happened that changed his life. While researching a new sleep compound called Xyrem, his doctor, Neil Feldman, asked him to be a human guinea pig. Feldman was worried that Xyrem would cause the sleep in people with sleep apnea to collapse, not get better, and he wanted to test the drug on Perrino first.
Instead, the opposite happened. Perrino’s fatigue, sleepiness, brain fog, and depression disappeared; his energy returned as he made a near full recovery. He’s been on Xyrem ever since.
The GIST
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Are some people with ME/CFS/FM on the narcoleptic spectrum Dr Mullington’s sleep study will provide some answers.
Three years ago, I had several discussions with a retired ME/CFS/FM doctor (who also had ME/CFS/FM) named Frank Perrino, focusing on the sleep problems in these diseases. At some point, we drifted out of touch, and Perrino did not review this post. With Tonix’s Tomnya’s approval, though, I thought it was time to publish it.
- After a bout with spinal meningitis as a child, Perrino came down with ME/CFS. Decades later, now a doctor, he tried a medication called Xyrem, which changed his life. His fatigue, sleepiness, brain fog, and depression disappeared, and his energy returned as he made a near full recovery/
- Casting about for an answer, he realized that many of his symptoms fit a diagnosis of narcolepsy. Using sleep studies and by doing extensive patient exams, Perrino came to believe that many of his ME/CFS/FM patients fit somewhere in what he called a narcoleptic spectrum.
- Perrino found that many of his patients entered into REM sleep too early, experienced dreams while going to sleep or upon wakening, some forms of sleep paralysis while awakening, and cataplexic attacks (sudden losses of muscle tone during the day, which could cause everything from falling down to slurred speech to heavy feeling muscles).
- Perinno said most of the focus in narcolepsy is on the stereotypical narcoleptic who suddenly falls asleep during the day, but believes narcolepsy has a spectrum aspect to it and that Doctors can get too tied into overly restrictive diagnostic criteria. (Because he also suffered from insomnia, he did not fit the criteria).
- Perrino recommended that ME/CFS/FM patients do the Epworth sleepiness scale test and get a multiple sleep latency test (MSLT), which is done the day following a sleep study. The MSLT assesses daytime sleepiness by determining how quickly you fall asleep after the lights are turned out.
- A positive response during the MSLT, having cataplexic attacks, and/or having low orexin levels in the spinal fluid are all diagnostic of narcolepsy.
- For years, Perrino regularly prescribed Xyrem (or GHB), which regulates the sleep/wake cycle. The drug was cheap and easy to get, and while the drug could be touchy, he reported remarkable success with it.
- After Xyrem became associated with date rape (GHB plus alcohol can cause loss of consciousness), the drug was listed as a Schedule I drug. Xyrem became approved for narcolepsy, but under restricted conditions, and after Jazz Pharmaceuticals ‘ costs skyrocketed, it became hard to get.
- Perrino’s idea that narcolepsy is a spectrum disorder is being vindicated. While narcolepsy has traditionally been divided into two categories: one with cataplexy (which includes a loss of orexin-producing neurons in the hypothalamus) and one without cataplexy, other variants have shown up.
- While some people have a complete loss of the hypocretin neurons, others show partial losses or fluctuating levels of hypocretin. It’s now recognized that the symptoms of cataplexy can range from sometimes subtle states of daytime drowsiness to abrupt falls.
- We’re about to learn more about a key narcoleptic neuropeptide called orexin-A in ME/CFS. The Open Medicine Foundation-funded study by Dr. Mullington, is the first to measure orexin-A – the substance that Xyrem enhances – in ME/CFS patients’ cerebrospinal fluid samples. (Besides the sleep/wake cycle, orexin is also involved in energy homeostasis and autonomic nervous system regulation.)
- While low orexin-a levels are not necessary for narcolepsy, Mullington’s study could uncover a narcoleptic-like subset in ME/CFS.
- That could help on the treatment end, as 26 orexin-enhancing drugs are in the pipeline and one is up for FDA approval this year. Several more are showing promising results in phase 2 studies. Orexin-enhancing drugs are clearly a growth field.
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A New Approach to ME/CFS and Fibromyalgia
Perrino subsequently became board-certified in sleep and dedicated his career to working with people who had similar symptoms, i.e., chronic fatigue syndrome (ME/CFS) and fibromyalgia, and others suffering from non-restorative sleep.
Back then, sleep medicine was in its infancy, and Perrino didn’t know why he responded so well. Casting about for an answer, he found that he mostly fit the profile for narcolepsy: he had the wild dreams, sometimes dreamt while he was awake, had daytime sleepiness, etc. He had insomnia, though, and narcoleptics weren’t believed at that time to have trouble falling asleep at night – they had trouble staying awake during the day.
Sleep studies revealed a high prevalence of alpha and delta waves during
Perrino reported that he consistently found high levels of alpha waves (blue) during sleep in his patients.
deep sleep in his ME/CFS/FM patients. While the slow and deep delta waves herald the transition to deep sleep, alpha waves shouldn’t be present at all. They indicate that the brain is more awake than asleep at precisely the time it should be enjoying its deepest sleep.
While the sleep studies were revealing, Perrino found his patients’ case histories to be quite helpful. Perrino had been mentored by an “old-school” doctor who took extensive histories and physical examinations of his patients. While they took a great deal of time, he believes his detailed and hands-on approach was highly beneficial.
“My patients taught me an awful lot. I really listened to them; when did the symptoms start, what’s happened to them over the years, family history to put a really complete picture.”
Narcolepsy
Over time, he came to believe that many people with these conditions had a sleep-wake instability similar to narcolepsy.
Some people with narcolepsy have reduced orexin-A (hypocretin) levels. Orexin-A is a neuropeptide produced in a small cluster of cells in the hypothalamus, which regulates our circadian rhythm; that is, these neurons ensure that we’re awake during daytime and asleep at night. There is damage to the neurons that produce orexin-A occurs in narcolepsy type-1 (NT-1). Interestingly, infections appear to be a common trigger of NT-1.
Low orexin levels are often found in narcolepsy. Orexin levels are being assessed in Dr. Mullington’s ME/CFS sleep study.
If orexin-A-producing neurons in the hypothalamus get damaged, the brain may be unsure if it’s time to sleep or be awake. The sleep-wake cycle goes kablooey with wakefulness signals popping up at night and sleep signals popping up during the day.
Narcoleptics tend to enter REM sleep quickly and have trouble attaining stage 3 or the deep sleep stage. The lack of deep sleep produces all sorts of problems: inflammation, reduced levels of neurochemicals like serotonin, toxin buildup, and reduced growth hormone levels.
Signs of Narcolepsy
Excessive daytime sleepiness is to narcolepsy what post-exertional malaise is to ME/CFS. You can’t have one without the other. It manifests as people feeling uncontrollably drowsy or sleepy during the day, having difficulty focusing, experiencing “sleep attacks” (suddenly falling asleep), and problems staying alert.
Vivid dreams, particularly while falling asleep or upon waking, are one sign. Another sign is something called sleep paralysis – a feeling like you can’t move a muscle upon waking. Sometimes this can be quite subtle and manifest as heaviness. Walking during sleep or doing some other automatic behavior (writing) is another sign of narcolepsy.
Cataplexy – a sudden loss of muscle tone – can manifest in several ways including from falling down, to slurred speech, to heavy feeling muscles.
A strange condition called cataplexy – which is almost unique to narcolepsy – can also occur. During cataplexy, muscle tone suddenly and temporarily drops, potentially causing the person’s knees to buckle and have them fall to the ground, their jaws to drop, their speech to become slurred, and their muscles to feel weak and heavy. Sometimes they can’t move a limb for a while. While some symptoms are dramatic (falling to the ground), it’s now recognized that other, more subtle symptoms (muscles suddenly feeling heavy) can occur.
Oddly enough, the cataplexic “fit” often occurs in response to a sudden emotional swing, like a surprise or even hearty laughter. Perrino said sometimes people don’t notice that it’s been happening until it’s brought to their attention.
Other symptoms are more general. Having your wake center activated during sleep, or having your sleep center activated during waking, will cause some very recognizable symptoms: fatigue, pain, poor attention, anxiety, and depression.
Perrino’s Results
When Perrino started, the vast majority of doctors did not believe narcolepsy or its connection to ME/CFS/FM existed. (I suspect they still don’t). Perrino, though, was getting good results with patients doctors didn’t know what to do with: people who didn’t have sleep apnea, for instance, but who clearly had sleep problems and tons of fatigue.
Perinno said most of the focus in narcolepsy is on the stereotypical narcoleptic who suddenly falls asleep during the day, but believes narcolepsy has a spectrum aspect to it and that doctors can get too tied into overly restrictive diagnostic criteria. He believed that narcolepsy can be extremely variable between individuals, and that, in his experience, it’s more likely to cause insomnia in these diseases than excessive sleep.
Dr. Perrino reported that an early entry into REM sleep was suggestive of narcolepsy.
Having had chronic fatigue for most of his life, Perinno said he was not going to ignore abnormal data just because it didn’t fit into a classic pattern. If some people didn’t meet the entire criteria for narcolepsy, but they appeared to be heading in that direction, he would try to treat it.
Over time, he reported that he’d treated over 1,000 ME/CFS and FM patients – many of whom met his criteria for narcolepsy. (Dr. Perrino is no longer practicing.) Perrino felt that many people with ME/CFS/FM do not fit the typical narcoleptic profile but have narcoleptic aspects and can be helped with narcoleptic drugs.
Perrino looked for abnormal alpha/delta patterns and an irregular pattern of the sleep stages. Stage 1 and stage 2 sleep should first alternate, and then stage 3 sleep should kick in. At around 90 minutes, a burst of REM sleep should occur. The REM should occur in 3/4 distinct stages – each one a bit longer.
If early onset REM sleep occurred at around 60 minutes, he suspected the patient had a narcoleptic profile. It might not be classical narcolepsy, but Perrino believed it was abnormal.
The Xyrem (Sodium Oxybate) Saga
That brings us to Xyrem. Perrino reported that he found Xyrem a potent but safe sleep inducer when used correctly. Since Xyrem triggers the same mechanism that the brain is using to regulate the sleep-wake cycle, it produces about as normal deep delta wave sleep as you get. Since Perrino was finding plenty of abnormal delta wave sleep in his patients, the drug seemed made for order for ME/CFS/FM. He called it an amazing product.
That worked quite well when the treatments were easily available and dirt cheap. When the standard treatment for narcolepsy/hypersomnia became very expensive, though, the criteria needed to meet the definition became more restrictive over time. Earlier in his career, for instance, a patient didn’t need a sleep study to qualify for a narcoleptic drug – all they needed were the correct symptoms.
He noted, though, that Xyrem is not an uncomplicated drug and can cause a host of side effects and be dangerous if used improperly. Overall, though, the response was excellent. For instance, he found that some patients did better on two doses, a smaller loading dose during the day and a larger dose at night. He said he was the top prescriber of the drug in the U.S. for 15 years.
From Dirt Cheap to Unaffordable
The advent of Xyrem and its subsequent listing as a date rape drug changed all that. From its humble beginnings to today, Xyrem has had an extraordinarily twisted history.
A sodium salt of γ-hydroxybutyric acid, or GHB, Xyrem, or sodium oxybate, is a natural chemical found in very small amounts in the brain. According to Wikipedia, the attempt to turn GHB into a medical drug began in the 1960s when Dr. Henri Laborit began using it to help understand GABA.
GHB was intermittently used as an antidepressant and anesthetic, and to treat alcohol addiction and narcolepsy in Europe from the 1960s onwards. The compound really took off in the 1990s, though, when it was introduced in the U.S. as a dietary supplement and marketed to bodybuilders to help with sleep and reduce weight.
Incidents of vomiting, vertigo, loss of consciousness, and date rape began popping up. (When used at high doses and in combination with alcohol, GHB can cause people to black out.)
Noting Xyrem’s use as a date rape drug, the FDA denied approval for it in fibromyalgia
In 2000, the Hillory J. Farias and Samantha Reid Date-Rape Prevention Act of 2000 designated GHB as a Schedule I drug; i.e., a drug with a high potential for abuse like heroin or cocaine (or marijuana for that matter) which cannot be used safely even under medical supervision and which has no medical uses.
Despite Congress’s affirmation that the drug had “no medical uses”, the FDA worked with Orphan Medical, a pharmaceutical company devoted to rare diseases, to test it, and approved it for use in narcolepsy in 2002. The drug came, though, with a “strict risk control strategy” to keep it from being diverted for illegal uses.
In 2004, Orphan Medical was purchased by Jazz Pharmaceuticals, which quickly got into trouble for its zeal in marketing the product to doctors. Sales representatives had apparently been touting the drug to doctors to use off-label for fibromyalgia and symptoms like fatigue, insomnia, chronic pain, depression, and others. Once a drug is given FDA approval, the drug is often used off-label for other conditions, and doctors have generally been given free rein in promoting drugs they found useful for other conditions.
In what one former FDA official called “a very, very scary development,” Dr. Peter Gleason was arrested in 2006 for promoting off-label use of Xyrem at medical meetings sponsored by Jazz Pharmaceuticals. Gleason’s controversial arrest sent a shock wave across the pharmaceutical industry and the medical profession.
Gleason said he started prescribing the drug because other sleep drugs were addictive or had severe side effects and because it worked better. Other doctors had found the drug helped with diseases like fibromyalgia and chronic fatigue syndrome.
Gleason. though, was charged with four felonies, faced $1 million in penalties and 28 years in prison, and had his finances frozen – requiring him to turn to public assistance for legal help. Four years later, at the end of his rope, Gleason pleaded guilty to a federal misdemeanor and was sentenced to a $25 fine and one year probation. His career ruined and his finances in shambles, Gleason committed suicide in 2011. A year later, the felony conviction of a sales representative, who’d been indicted with Dr. Gleason and who continued to fight the charges, was overturned.
Jazz Pharmaceuticals ended up paying $20 million in fines, but then turned to an even bigger market – fibromyalgia. (Perrino thought Jazz should have embarked on a large educational campaign to help doctors recognize the symptoms of narcolepsy.) Several seemingly successful large fibromyalgia trials occurred in the late 2000s, but the FDA rejected the application for fibromyalgia in 2010. Dr. Roland Staud, a fibromyalgia researcher, disagreed, stating that the drug improved sleep, increased slow-wave sleep duration as well as delta power, and reduced frequent night-time awakenings, pain, and fatigue.
After Xyrem became a Schedule I drug, its cost skyrocketed.
Not to worry about Jazz Pharmaceuticals, though. They were about to do really well. In 2013, Jazz Pharmaceuticals raised the price of Xyrem by 841%, earning the company a cool $569 million. Today a 180ml bottle (about 3/4 cup) costs $6,284 or about $100,000/year, giving Jazz Pharmaceuticals a nice $1.7 billion payback for selling this simple and easy-to-make compound. (Homemade black market GHB sells from $5-25).
In 2021, the FDA approved a slightly different formulation of Xyrem with less salt in it called Xywav for idiopathic hypsomnia – a condition in which people sleep for nine or more hours a day but still don’t feel refreshed.
Jazz Pharmaceuticals now has competition. Generic forms of Xyrem (Sodium Oxybate Oral Solution (0.5 g/mL – Hikma Pharmaceuticals USA Inc. and Amneal Pharmaceuticals NY LLC) came onto the US market in 2023. They carry the same black box warning and restrictions as Xyrem. While cheaper, they are still very expensive – costing about 5K a month if my numbers are correct.
Diagnosing Narcolepsy
Perrino recommends taking the Epworth sleepiness scale test and getting the multiple sleep latency test (MSLT) done during a sleep study.
The MSLT test requires that you stay at the sleep center the next day. After being kept awake for two hours, the sleep techs begin a cycle that occurs three to four times. The lights are turned off, and you’re monitored to see if you fall asleep. In narcolepsy, average sleep latency is less than 8 minutes, and REM sleep starts soon after falling asleep in at least two of the five naps (so-called “sleep onset REM periods”). This pattern is highly suggestive of narcolepsy.
Low levels of orexin-A in the cerebrospinal fluid and experiencing cataplexy are two other diagnostic criteria for narcolepsy. (One of three criteria must be met to be diagnosed with narcolepsy.)
Perrino Disappears
Perrino called ME/CFS/FM patients “extraordinarily complicated” and didn’t believe that narcolepsy is the full answer. He felt that immune dysfunction and dysautonomia are also involved.
Narcolepsy is not currently considered a comorbidity in ME/CFS/FM but its symptom overlap is high.
We were going to continue Perrino’s thoughts on those aspects of ME/CFS/FM when our communication suddenly ceased. Attempts over the next couple of years to contact him failed. I was very much surprised as he had contacted me and was quite eager to share his thoughts on these diseases.
Xyrem had been a life-saver for him personally, but when I last heard from him, he was having trouble getting the drug. I wonder if that had something to do with it.
In the end, I think what Perrino wanted most was a deeper exploration of the narcoleptic aspects of ME/CFS/FM. The careful patient histories, sleep studies, and his own and his patients’ success with Xyrem led him to believe that ME/CFS/FM patients often fell somewhere on the narcoleptic spectrum.
Narcolepsy, ME/CFS/FM, and Long COVID
While ME/CFS/FM and long COVID display similar symptoms (fatigue, unrefreshing sleep, brain fog, dysautonomia), they are considered separate diseases.
One symptom, daytime sleepiness, which is found in all three, struck me, as a sleep study I did found that once the lights were turned out during the day, I quickly fell asleep. I was characterized with severe daytime sleepiness. I do not, however, have other symptoms of narcolepsy
Perrino’s idea that narcolepsy is a spectrum disorder is being vindicated. While narcolepsy has traditionally been divided into two categories – one with cataplexy (which includes a loss of orexin-producing neurons in the hypothalamus) and one without cataplexy – other variants have shown up.
While some people have a complete loss of the hypocretin neurons, others show partial losses or fluctuating levels of hypocretin. It’s now recognized that the symptoms of cataplexy can range from sometimes subtle states of daytime drowsiness to abrupt falls.
Narcolepsy also overlaps with idiopathic hypersomnia. (One of the RECOVER Initiative’s clinical trials is on hypersomnia in long COVID.) Researchers are increasingly using the umbrella term “central disorders of hypersomnolence” to describe narcolepsy types, idiopathic hypersomnia, and related conditions as a spectrum of overlapping disorders.
Another Post-Infectious Illness?
Narcolepsy can be triggered by an infection
Research suggests that narcolepsy can also, at times, be triggered by an infection. Both streptococcal infections (strep throat), the H1N1 influenza (and vaccine), and other respiratory infections have been shown to trigger narcolepsy in susceptible people. While the data is less consistent, some evidence suggests that EBV and enteroviruses may do the same.
It’s believed the infections spark an autoimmune response that attacks the orexin-producing neurons. People with a specific HLA allele ( HLA-DQB1*0602) appear to me most at risk.
Getting Answers – the Mullington ME/CFS Sleep Study
We’re going to learn more about a key narcoleptic neuropeptide called orexin-A in ME/CFS. The Open Medicine Foundation-funded study by Dr. Mullington, who wrote a book chapter about the role orexin plays in sleep, is the first to measure orexin-A in ME/CFS patients’ cerebrospinal fluid samples.
Orexin-containing neurons project from the hypothalamus into brain regions that produce three factors – histamine, dopamine, and norepinephrine – that are important in sleep and may be major factors in ME/CFS overall. Besides the sleep/wake cycle, orexin is also involved in energy homeostasis and autonomic nervous system regulation. Additionally, because of orexin’s role in wakefulness and alertness, low orexin levels may be implicated in cognitive function.
Are some people with ME/CFS on the narcoleptic spectrum? Dr Mullington’s sleep study will provide some answers.
Some studies have found a relationship between decreased orexin levels and attention deficit hyperactivity disorder (ADHD) – a condition that may have a high comorbidity with ME/CFS. While low orexin-a levels are not necessary for narcolepsy, Mullington’s study could uncover a narcoleptic-like subset in ME/CFS. The study is moving fast – results are expected by the end of this year.
That could help on the treatment end, as 26 orexin-enhancing drugs are in the pipeline and one is up for FDA approval this year. Several more are showing promising results in phase 2 studies. Orexin-enhancing drugs are clearly a growth field.
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Interesting stuff.
Daytime sleepiness has been my major symptom over the years. I often need a nap in the afternoons.
It’s also the worst symptom by some distance for my daughter.
And overall I would say my sleep could be a lot better. Some times it is better than others.
Interesting-sounding research. Let’s see.
Cort, how accurate are oura rings for assessing sleep issues?
I think it’s fairly accurate. I also have a Garmin watch, and I’d say they track 70%? All I can is that I’m really wedded to mine. You do have to be careful not to look at a bad score and subconsciously go “I’m in real trouble” – which just ramps up my symptoms. On the other hand, sometimes when my score is better than I thought I go with that.
If I have a big task to do – say a drive somewhere or I have to break camp and I have a bad night of sleep I won’t even look at the score.
A couple of months ago my sleep was in the pits and I was so exhausted and as my sleep has improved and I’ve taken better care of myself my scores -my activity goal, my readiness and resilience scores have all gone up so I think, while there are some days that I have bad scores and feel OK and on other days I have good scores and feel lousy, in general it tracks.
Right now I’m doing continuous glucose monitoring using Stelo and Oura is able to incorporate that. Very interesting results.
After reading a previous blog I gave fluoxetine a try …. Works so well I now struggle getting up in the mornings but get plenty of sleep and feel better for it.
Hi Cort, text in the expanded Gist box is cut off at the lower end, in the middle of the line “in phase 2 studies. Orexin-enhancing drugs are clearly a growth field.” Thanks!
Dieser Artikel ist absolut wie eine Offenbarung für mich. Danach gehöre ich scheinbar zu ME/CFS/FM-Patienten, die oft irgendwo im narkoleptischen Spektrum liegen. Es ist eine ohnmächtige Müdigkeit. Nicht kontrollierbar. Was bin ich schon verhöhnt worden, meistens von Betroffenen. Ich finde mich in so vielen geschilderten Symtomen wieder. Unvorstellbar, dass es wohl anderen genauso ergeht. Manchmal ist es sehr erschreckend. Panik und Ängste, die daraus resultieren und ich nur auf Unverständnis stoße. Auf weitere Erkenntnisse bin ich sehr gespannt. Mein Leben spielt sich überwiegend in meinen Träumen ab. Sehr interessanter Artikel für mich.
Danke
Google translation
This article is absolutely like a revelation for me. Apparently, I belong to ME/CFS/FM patients who often fall somewhere within the narcoleptic spectrum. It is a powerless fatigue. Uncontrollable. I have been ridiculed so much, mostly by those affected. I recognize myself in so many described symptoms. It is unbelievable that others are experiencing it the same way. Sometimes it is very frightening. Panic and anxieties that result from this, and I only encounter misunderstanding. I am very curious about further insights. My life mainly takes place in my dreams. Very interesting article for me. Thank you
Interesting – I for example have no tiredness, but physical exhaustion and an overactive, probably hyper-alert, restless nervous system – I need sleep medication (currently a combination of L-Tryptophane, melatonine, low-dose trimipramine and 3.5 mg nicotine patch at night) or I will be awake until the early hours of morning. I also take low dose trimipramine in the early afternoon so I can rest better.)
I wanted to ask you, do you still have PEM inspite of this? I’m interested to understand if what you describe could be an add-on onto ME/CFS with PEM, or another condition resulting in constant tiredness, because it is so different from what I experience. Thank you and best wishes!
(P.S. I always get annoyed at study questionnaires that ask for tiredness or exhjaustion in the same question, because for me it is very much not the same thing! 🙂
You expressed my thoughts exactly. This doesn’t sound like my experience of ME/CFS, which never involves sleepiness, just a profound physical exhaustion and a wired up nervous system (wired and tired, they say). And yes, I am driven nuts by study questionnaires which seem to elide “exhaustion,” “sleepiness,” and even “lacking motivation” all under the category of “fatigue.” Lol. This kind of elision is simply not going to capture the experience of PEM.
Hi, I feel the same as you. The exhaustion and sleepiness is NOT the same thing. For many years I had only exhaustion in daytime, but the last years I have the add-on of extreme sleepiness at daytime many times. I did have a new heavy airway infection /virus (not Covid) 3 years ago. Or it might be from exhausted adrenals, my day-curve is very flattened and low (not Addison yet).
Many years ago when GHB was legal, I was given it by a naturopath for sleep. It was truly life changing. Now I’m on clonazepam and gabapentin for sleep, which absolutely do not do what GHB did, which was give me deep, refreshing sleep. A doctor a few years ago was willing to try me on Alcover which is used for alcohol dependency but is basically GHB I believe and it did not do the same thing. I’m not sure why, possibly a different formulation…
Sandra, I’ve been on Clonazepam for sleep as well and figure better than nothing. Was taking 1mg per night for 4 years then reduced to .5mg per night for the last year. Instead of going off completely, I’m actually increasing back to the 1mg dose this week. I tapered down to get an accurate assessment if it was truly making a difference in my life and, if not, completely taper off. However, now that I have a one year comparison, I have noticeably less energy, more brain fog, more fatigue and overall poorer quality of life. I understand the risks of this medication for the overall population but for an illness as horribly debilitating as mecfs, the benefits outweigh the risks. I’m tired of torturing myself about taking a medication I need and at the dose I need. What is your take?
Hi Cort.
My most recent version of my CFS pathology theory is that a7 Nicotinic acetylcholine receptors all through the body are dysfunctioning because of Glutamate excitotoxicity.
For short, they ate a7 nAChR’s
TRPM3 is one type (tired t-cells) of ion channel in the AChR category.
Fascinatingly, the mitochondria have a7’s as well. They are there to allow calcium buffering. Weird, right? But when a cell gets too much calcium in its cytosol, at least the mitochondria should buffer it (absorb some) because the show must go on.
My problem was that I suspected a7’s all along, but did not have the culprit.
In some big-name autoimmune diseases such as ALS, the glutamate transporter that should clear the synapse fails. EEAT2 transporter has a known autoantibody in this case.
“glutamate plays a key role through a phenomenon called glutamate excitotoxicity, where excessive glutamate accumulation in the brain and spinal cord overstimulates and damages motor neurons. This excitotoxicity is often linked to defective glutamate transporters, leading to harmful calcium influx and neuronal death.”
So I’m saying that I’m blaming this autoantibody for most all of the CFS symptoms inclusive of brain inflammation.
I had talked about the ischemic cascade in hypoxia, after which there would be glutamate excitoxicity outside the cell, resulting in too much calcium inside. Then the mitochondria get depolarized and
that breaks the electron transport chain of the Krebs Cycle.
That was cart-before-horse though. If glutamate clearance contantly fails throughout the body,
this accounts for:
-faulty blood pressure
-POTS
-alpha waves during delta phase sleep
-exhaustion and PEM
-T-cell failure to kill cells having Epstein-Barr remnants
and the list is long.
Remember, that doctor was using Xyrem to understand GABA.
Why?
I’ll tell you:
Glutamate is converted to GABA when it is time for GABA. But that’s going to fail, isnt it, if the Glutamate transporter fails. Not enough GABA.
If you ask me, not enough GABA and too much glutamate are exactly what you need to achieve non-restorative sleep. It’s that simple.
The solution would be to try to:
-increase EEAT2 transporter expression in the astrocytes
-increase GABA receptors
-take GABA for sleep
I’d like to write a blog on the
a7 nAChR in CFS and glutamate excitotoxicity.
RILUZOLE is the drug used in ALS to tone down the glutamate excitoxicity.
This is a really helpful comment. Would definitely like to see more if you write about it.
I had too high intracellular calcium / full blood calcium for over 20 years. I also react opposite to normal to GABA, it gives me anxiety, restless and no sleep.
This is extremely interesting. I do suffer from chronic insomnia and have been searching for the ideal spleeping aid that a doctor would actually agree to prescribe.
I’m in Canada. Health Canada has recently approved QUVIVIQ (daridorexant) for the management of insomnia. (Idorsia Ltd.) Rather than inducing sleep through broad inhibition of brain activity, it blocks only the activation of orexin receptors which promote wakefulness.
In other words, it does exactly the opposite of what Xyrem does. It is a dual orexin receptor antagonist acting on both orexin 1 and orexin 2. It decreases the over-active wake drive, allowing sleep to occur, without altering the proportion of sleep stages.
As I can’t seem to fall asleep for more than one or two hours at a time, I have put great hope in the med, which my doctor did accept to prescribe. I started using it a few days ago and I’m ambivalent on it’s efficacy. It doesn’t help me fall asleep. However, I seem to be able to get 5 to 6 hours of restorative sleep, starting in the middle of the night. It’s still not enough for me, but it helps somewhat with the chronic fatigue. I’m taking the pill earlier and earlier in the evening, hoping it will start working by the time I get to bed.
It costs me 100 $ a month. In Quebec, where I live, the governement reimburses a good portion of meds for seniors, which I am. However, there’s a very narrow minded public worker who has decided that they do NOT put any type of sleep aid, on the list of coverred medications. Some years ago, to bypass that, my Dr. went as far as to prescibe an antipsychotic to help me sleep. Seems to be a common practice. It’s like using a sledgehammer to push a thumb tack. Not only did it not help me get uninterrupted sleep, it made me groggy for over three days. I tried it 3 times and I told my doctor no more!
Thank you Cort, for this especially helpful information.
Cheers!
Genevieve,
Allow me to add that Melatonin will help you GET to sleep but NOT help you remain. Hops, either in beer or alone in capsules kay also help you to fall asleep and return to sleep. It has no known adverse side effect.
That said, hops can act as a pseudo-estrogen.
Thank you, Christopher,
I do use melatonin, as well a a variety of herbal remedies, but I didn’t know about hops.
Thanks for the tip.
Hi Christopher, my experience with melatonin is that a lower dose helps get to sleep, and a higher dose in addition also helps sleeping through the night. I use a combination of sleep aids though, including melatonin. So if it only helps start sleep, the dose might be too low.
JR– good point
Genevieve, was the antipsychotic Seroquel? That’s what I’m taking.
Yes Tim, it was Seroquel.
As I said, not for me.
I’m happy if it works for you. 🙂
Hi Genevieve, what works for me at least the moment is a combination of sleep aids, currently: 500mg L-Tryptophane, between 2 and 3 mg melatonine, 6 mg low dose trimipramine, plus 3.5 mg nicotine patch. (The patch used to be activating in the beginning, but after some weeks changed to being calming.) These are not very expensive. Sometimes the amount needs to be changed a bit intuitively, depending on how wired-up (or not) the nervous system has been during the day. This combination represents for me a high degree of sleep aid, at times when my ME/CFS is better I might need less, like for example no trimipramine. It’s a bit about finding the sweet spot that works but is not too much.
I currently also take another 15-20 mg of trimipramine in the afternoon to be able to rest better during the day. For me, it downregulates the nervous system with a sedating effect. Trimipramine (old-school antidepressant and H1 antihistamine I think) can be a bit tricky to combine with other medications (like other antihistamines), so drug interaction warnings should definitely be checked for this one).
With supplements, use a brand product as I’ve read that no-name brands sometimes contain no or less active ingredient. Also, I found one (German) brand of L-tryptophane worked better than the other.
I’ve also heard magnesium threonate is supposed to help with sleep, and might look into saffron, which works comparably to an antidepressant and is also supposed to help with sleep. But currently I’m okay with this combination of sleep aids.
As I said below, my experience with melatonine is that a low dose helps go to sleep, but a higher dose will also help with sleeping through the night.
I can add that with this combination, my amounts of deep sleep etc. are normal according to the fitness tracker. I don’t have data how they’d be without medication.
Genevieve,
on a different note,
While they don’t know the exact cause of narcolepsy, it is suspected to be an autoimmune disorder, but cases of it have also occurred following head trauma. That would also fit re the fact that not everyone with ME/CFS or Fibro got it after an infection, but many did. It would also fit with the many who have been exposed to mold, because mold also can cause trauma to the brain.
Head trauma also initiates an immune reaction both within the brain and systemically. Mechanical forces disrupt neurons, glia, and blood vessels, releasing danger signals that activate resident microglia and attract peripheral immune cells. This cascade of events underpins the acute inflammation and can evolve into the chronic neuroinflammation characteristic of post-concussion syndrome… very similar to ME/CFS. However, obviously not everyone with ME/CFS is prone to daytime or excess sleeping, and some are just too uncomfortable.
Good points, Hannah
I thought it was interesting that it is associated with autoimmunity. Since autoimmunity could concievably touch so many things it would great if researchers could get a better handle on it!
so true, Cort
It would help if ANY of these ideas explained why a previously healthy person can get an infection (there are other triggers) and SUDDENLY become ‘on the narcoleptic spectrum’!
For the rest of their life.
Look into the research on the Bird Flu vaccine. This answers your question entirely. Through molecular mimicry, the vaccine caused narcolepsy. Of course people with any type of flu or virus can develop hypersomnolence as well, likely through a similar autoimmune like reaction where antibodies kill orexin receptors in the brain.
https://www.science.org/content/article/why-pandemic-flu-shot-caused-narcolepsy
It might help with ONE symptom, but ME/CFS (and things like Long Covid) dump hundreds of symptoms on the poor human victim at the same time – I want to see the mechanism for that explained, because it boggles the mind unless it explains everything.
But as Cort says issues with orexin can cause downstream issues, with the autonomic nervous system etc.
As I have been saying for 15 years, the problem is in the brain. Initiated by an immune assault. Much more research on the brain please, and much less on viruses
Hi Alicia 🙂 I’m trying to find one systemic piece of damage that accounts for all the various systems. On this page there are 2 very long posts from me that address this.
One post, in the first line says “eureka moment” and in there the golden nugget is glutamate excitotocity at a7 Nicotinic Receptors.
In the second post the first line says “Muppet News Flash”. In that one I blame the same a7 nAChR’s but I get specific about the calcium influx/outflux and intracellular levels of calcium being too high. One reader responds here that she has had such levels over 20 years.
Whenever I advance my theory I try to review: does this dysregulation or damage “check all of the boxes” for all of the CFS symptoms? I argue that it does in this case. I don’t apply it here to every symptom, only big ones, but in my mind I have.
The greatest support of my theory involving a7’s is that in all influenza infections a7’s are the cell entry point and in Covid the spike protein binds to the ACE2 receptor, but the code is injected through the a7.
I welcome challenges to what I wrote on this blog page and would do my best to apply the theory to any symptom you think it does not explain.
And that would be positive, because CFS, with all its subsets seems like it has multiple causes, and a challenge is a process of elimination.
But if the theory is true, on the other hand, it should bring all of the subsets into the fold.
My theory is based on researchers, on the material that Cort synthesizes for us, and on Pub Med “Pearls” that break down large topics such as the immune system. Accepted medical sources, in other words.
Another vaccination scandal against swine flu. It was completely harmless to young people. Now, nearly 2,000 young people in Europe suffer from narcolepsy. Most received compensation. Their lives needlessly destroyed.
I didn’t even think of narcolepsy as a post-infectious illness but it turns out that at times it can be. I just added the below to the blog – thanks for the idea 🙂
“Research suggests that narcolepsy can also, at times, be triggered by an infection. Both streptococcal infections (strep throat), the H1N1 influenza (and vaccine), and other respiratory infections have been shown to trigger narcolepsy in susceptible people. While the data is less consistent, some evidence suggests that EBV and enteroviruses may do the same.
It’s believed the infections spark an autoimmune response that attacks the orexin-producing neurons. People with a specific HLA allele ( HLA-DQB1*0602) appear to me most at risk.”
Hi Cort, is it known if this Frank Perrino had PEM? (or a different fatiguing condition without PEM?) If not, could you ask him?
Because it is so different from what I experience with ME/CFS – not tiredness at all, but physical exhaustion and hyperactive nervous system needing medication to be able to go to sleep.
I think that would be an important distinction to make to better understand if we’re talking about the narcolepsy-type fatigue as an add-on to ME/CFS with PEM, or a different condition altogether which falls under a general term of “chronic fatigue” conditions, but possibly not under Chronic Fatigue Syndrom with PEM specifically.
Thank you!
Interesting to see this post. I’ve had ME/CFS for 39 years and treated with Xyrem at one point and lots of other things over the years, but only within the last month have I actually experienced times where I almost fall asleep sitting at the table or in a meeting. I actually have to get up and walk or I’ll nod off. I did have a weird reaction to antibiotics a couple of months ago but never connected the two and it never dawned on me that what I’m experiencing could be some form of narcolepsy after all these years. It’s always something new with ME/CFS!
Hi Cort. My daughter and I have both been diagnosed with Idiopathic Hypersomnia, in addition to ME/CFS and POTS. The main distinction between IH and Narcolepsy is that we didn’t enter into REM sleep during the daytime nap portion of the sleep study, despite falling asleep very quickly each time. We’ve also both tried Xywav (after jumping through many insurance hoops). Unfortunately, we couldn’t tolerate the side effects. It was very frustrating because we both noticed that our energy level increased in addition to being more alert, but the negatives out-weighed the positives. It worsened our cognitive symptoms. Our brain fog was not just worse but different. I couldn’t remember anything. I would burn dinner if I didn’t set a timer. I would drive past my exit. I couldn’t retain anything that I read. It also seemed to make our POTS symptoms worse. Our heart rates were running higher and we were more light-headed. You would expect it to do the opposite because of the salt content, but that was not the case. We also both lost weight that we couldn’t afford to lose. I’m really glad that there are other medications in the research pipeline because I really do feel that unrefreshing sleep is a major piece of the puzzle for my family. Xyrem and Xywav are far from ideal medications, however.
Wow. Narcolepsy is so far from my experience it’s not even funny. I think I’m not alone in never experiencing sleepiness as an issue in my 20+ year journey with ME/CFS and PEM. When I am sickest, I am wired and tired, unable to sleep. Otherwise, my sleep is pretty normal, as shown by my two tracking devices. PEM is a reaction to exertion. It’s really not affected by sleep. And the “fatigue” of ME/CFS is not sleepiness. Now, obviously, individual experiences will vary. I’m not saying no one experiences sleepiness with ME/CFS, but it’s definitely not what we mean when we say “fatigue.” If only.
Resonates completely. Being able to take a nap was/is a very rare gift in years of bad and inadequate sleep. However, I did/do associate naps and longer sleeps and periods of improvement.
Unfortunately, I think you’re very close to alone in your experience. Yes, PEM is looking like as good a diagnostic as any for CFS. But the primary symptom of ME/CFS is in fact fatigue to the degree of being bed bound or severely disabled by fatigue. And fatigue is defined as exhaustion that is not relieved by rest or caused by a known trigger. So, yes, for most of us fatigue and daytime sleepiness are one and the same.
DH. I’m not alone at all. My experience is a classic ME/CFS experience. I spent 5 years fully bed-bound. I am now moderate-to-severe. When I am bed-bound, it’s not because I’m “sleepy.” I’m very very ill, utterly exhausted and nearly shaking with fatigue for the first few days of a setback. My limbs are heavy, and even sitting up in bed endangers my health. But sleepiness is just not close to what I’m experiencing, and this is common misconception about the illness. This is something different. “Wired and tired” is the usual phrase for this miserable state of extreme fatigue.
I fully agree with you, very good description of how I feel when I am that tired (not that often thankfully). Not able to sit on my couch, I need to lay down. Wired and tired up to the point you feel half dead. I would so much like to sleep butI am way too tired to do so. You are right, it is not sleepiness but damn you feel bad to be so tired…
I feel the same. ME/CFS is totally not sleepiness. I can”t sleep normal. I never sleep longer then 4 a 5 hours i wake up everytime.
Although we agree that ME/CFS is no sleepiness. I wonder if Xyrem / GHB could improve our sleep. I am curious. A couple of persons seem to have a had a WOW ! effect on their sleep. Let’s see if this is possible to try it…
I don’t think so – I think there are many ME/CFS patients without daytime sleepiness, who have a combination of hyper-alert nervous system and physical exhaustion, but no tiredness (like me). I have often been told that an overalert nervous system and restlessness can be a typical ME/CFS symptom. I was rather under the opposite impression that daytime sleepiness occurs more seldom than the sleepiness type – but well, I don’t have numbers :-). So I think we can conclude that there are ME/CFS patients with and without tiredness.
I just had an eureka moment (or else a brain-f**t ….)
I have been often revisiting circadian rhythm because CFS and other autoimmune diseases have the non-restorative sleep component.
I thought it all occurred only in the Pinneal Gland of the brain, in the Suprachiasmatic Nucleus of said gland.
But recently I read that astrocytes alone have what it takes to maintain circadian rhythm. What that does is create a juxtaposition between the brain’s circadian headquarters and the astrocytes of the body. They will hopefully always cooperate, but what happens when they don’t?
Well, to review, astrocytes are also called glia, and I know you are familiar with brain inflammation (encephalomyelitis) (the E in ME) and the microglia. We have glia at every synapse between nerve and tissue, and the brain has microglia. In the body we have immunity white blood cells, but in the brain only angry microglia, when they have an invader.
So, what if your brain knows it’s time to sleep, but your body glia disagree? Would this account for alpha waves during delta phase sleep?
The circadian rhythm is complex to expain accurately, but it is a little like a the quartz clock or atomic clock, and a LOT like vinegar and baking soda, if you will. Yes, the rhythm responds to daylight and lack if it, but it’s not intelligent. It’s not a miracle nor a mystery. It’s physical. It’s in fact a chemical. A chemical reaction of which so many need to take place over 24 hours. That’s what happens in the SCN
The body is all about charge, chemical reactions, osmosis and transporters in and out if cells. No ATP, no transport, for the most part.
My older concept of circadian rhtyhm was that the sustained darkness of bed time or night as registered by the Retina would send melatonin to the SCN. And so it does. My second part of the equation was that then the SCN would tell the body to also apply melatonin, and that the effect is to turn the volume of sensations way down so that if physical stimuli were to be sent to the brainstem (reticular formation) whose job it is to decide whether alertness is warranted, the stimuli for most of the sleep would be negligibly quiet. The brainstem is a bit like ER triage in that way.
If I’m suffocating under my pillow, or my arm is numb from lying on it, then the sustained stimulus will soon count, more receptors will be express at the entry to the spine, and a louder signal will result at the brainstem. I’ll wake up as part of triage, reposition, and hopefully drift off again, and the extra receptors will be removed.
You may recall Central Sensitization, especially in Fibro. The theory is that those extra receptors are not removed. Why not?
For whatever reason, hypervigilance of the brain occurs in many diseases and syndromes. Remember that ALS is a disease, but CFS is a syndrome. A syndrome of many diseases? Probably. As opposed to one disease called CF.
And that name’s already taken.
Since the most recent medical name for ME/CFS is SEID (systemic exertion intolerance), what could possibly have made it systemic???
Meaning… either throughout the body… or maybe just throughout one system… or a few systems. Yes, I talk about a cold virus being “in my system” but i have way more than 1 system.
Central Nervous
Peripheral Nervous
Parasympathetic Nervous
Immune
Circulation
Digestive etc etc
But…
I guess my body is a supersystem
of component subsystems.
So its SEID of our supersytem.
So we have to ask what is ubiquiotius in the body and brain?
I concluded:
Glutamate /GABA excitement/silencing
Blood vessels in the RAAS (renin-angiotensin-aldosterone system)(another most-recent medical name)
of blood pressure
a7 Nicotinic Acetylcholine Receptors
are the ones I think are implicated.
How could one infection cause a syndrome? My theory is through damagw in those specific systems. And a7 receptors affect microvessels in the kidneys, which would be enough to cause dysfunction of Aldosterone… and give you low blood volume. Not to mention damage to the overarching RAAS.
But how could it affect cognition? Because both motor neurons (flexing muscles) and thinking brain cell synapses (short-term rembering plus reasoning, and long-term remembering) need
Long-Term Potentiation (sustained elevation of electrical charge),
which are both achieved with sustained Acetylcholine neurotransmitter specifically only to a7 nAChR’s.
If the a7 is the systemic comm,
and I say it is,
I think this is interesting, and you might be on to somerhing, perhaps.
Perhaps you can make a larger post/blogpost about it, supported with science? It’s an interesting train of thought, I would love to see it laid out more properly!
Thank you Tuva.
Just so that you know, everything I say is supported by science. Both studies and research, and biochemistry. And I am in no way offended.
It’s just that I know my sources and do not feel a need to prove it to me. However. I keep screenshots of articles and by searching unique phrases from them on google I can retrieve the source and record the biblio information. I have approx 10,000 screenshots on my phones.
My sources are generally: peer-reviewed research and studies on PubMed, Springerlink, Frontiersin,Sciencedirect.com, Johns Hopkins, etc, and of course Cort’s blogs.
Im not saying take my word for it though.
Suffice it to say that writing a blog article would justify to me citing my sources in a scientific way, because at blog time it is about proving (at least supporting.
Oh, I meant no offense, at all! I hope you didn’t read my comment that way, I am not a native english speaker, and sometimes the finer points may be lost in my trying to converse. I have no doubt you have science to back up! I often wish more of us patients would get to be published, because I believe our added knowledge together is immense.
I found your theory very interesting. Any explanation that can cause to a single factor is interesting, because while there is downstream and upstream-effects, figuring out where the basics go wrong in the first place is so important.
As I read a lot of scientific articles myself, trying to figure out this mess, I would like to know more, so I can add it to the ever growing catalogue of points that are connected with each other. Wish you all the best, looking forward to see more of your theory in the future!
I’m sorry Tuva, No I didnt take offense. I was worried that I would come across as defensive by describing my sources. I didnt need to use the word “offended” at all.
What you asked for is totally reasonable and fair.
No worries, Christopher, we have both meant no harm and none of us has taken any. 🙂
It is easy to become defensive in our position, most of us have, after all, had to fight hard to be heard for our knowledge and our experience.
Wishing you all the best, keep on keeping on, it will be great reading when you get it out! 🙂
Very good thinking
Agatha, I know what you mean about fatigue vs. sleepiness. Not the same!
I used to be wired but tired at night and never got refreshing sleep. But I also have had these unexplained bouts of intense daytime sleepiness much of my adult life – way longer than I’ve had ME. I remember joking that it felt like narcolepsy. Not only does it strike me in the daytime, it also prevents me from waking up easily in the morning. Sometimes it feels like a mind and body paralysis. I know from using a sleep monitor that I don’t get an appropriate quantity of deep sleep.
One thing I’ve done that has helped alleviate the wired but tired syndrome is vagal toning – calming the nervous system. I don’t sleep any deeper but at least I rarely lay wide awake for hours at night!
I’ve been diagnosed with all three – Type 1 narcolepsy, CFS, and fibromyalgia. All are real.
Some of my symptoms are vague enough and overlap. But if you believe cataplexy only occurs in Type 1 narcolepsy and PEM only occurs in CFS, then I properly have both. They are not the same. With PEM, I can be debilitated and truly exhausted, but not sleepy and not sleeping. Narcolepsy is sort of the opposite – when that’s affecting me strongly, I’m incredibly sleepy, but if not for that, I could be active.
Pyridostigmine and LDN have helped me quite a bit. Pyridostigmine is no joke and I wouldn’t recommend anyone start it without deep investigation. I felt I had run out of other options. Xyrem actually keeps me awake, makes me itch and sends my heart rate and blood pressure through the roof, so Xyrem was not a viable option for me.
This is interesting – with both you and Peggi above reporting having both the PEM + wired symptoms, and the narcolepsy-type syptom, but separate from each other, it may suggest that narcolepsy-type sleepiness may be a comorbidity to ME/CFS i.e. a subgroup of ME/CFS; and people who have narcolepsy-type sleepiness but not PEM (?) possibly a subgroup in the chronic fatigue spectrum but not a subgroup of ME/CFS specifically.
With ME/CFS, when I feel the “tipping point-of-no-return” of a big crash oncoming following overexertion, it is a sinking feeling accompanied by overactivation of the nervous system. Personally, I believe that the overactivation starts already before the crash, at the point when you push yourself over an exertion limit and the overactivation occurs to achieve the pushing.
In an acute crash, I apply 7mg nicotine patch plus 15-20 mg low dose trimipramine to tone down the nervous system, they’re my go-to crash medications. Though they do not cure me, I think they’re a help with crash recovery.
Would this viewpoint support the use of the drug Suramin?
Most definitely it’s the autonomic system, i hit my head a few weeks ago, and boy did that concussion floor me, but I came good thankfully, really important to get that morning sunlight, as much sun all day, and always say goodnight to my best friend in the sky.
Exercise to boost endorphins and all manner of somatic and vagus nerve and brain retraining, breath practice to keep the autonomic system stable. Self Love and care and awareness goes a long way too
Thanks for this article, Cort. I find it highly likely that ME/CFS and FM are on a spectrum of narcolepsy and related. My own personal experiences with FM support this and the alpha/ delta wave patterns seen in FM sleep studies. It’s such a shame about Xyrem as I think it really would have benefited FM patients based on the data. I asked my doctor for it off label after the trial data came out but they didn’t want to wade into the controversy and risk of it being a date rape drug. I hope someone picks up on this research and the ME/CFS study ongoing sounds promising.
This so hits the nail on the head for me. Right now, I am mainly bedbound and suffer with fatigue. My sleep pattern is naps of 2 to 5 hours at a time and I start off by dreaming as soon as I close my eyes. Often I wake myself up by acting out a dream. I am known to fall asleep while talking on the phone or watching tv. My head will start jerking around as I pass out.
While I was still working, over a decade ago, after many nighttime sleep studies I was finally given a daytime study. It pointed to hypersomnia. I was given a med to help me stay awake at work. It worked great, but I pushed myself too much and eventually it no longer worked. Even the highest dosage failed and I was falling asleep at my desk for a few seconds at a time, here and there. Driving home was a nightmare and I would go straight to bed. The weekends were meant for PEMing.
Sorry if this is long-winded, but I have never felt this matched a blog before. If there’s a way for people with ME/cfs and Fibro with Nacrolepsy to get some deep sleep and energy back, that would be wonderful! I’ve been sick over 30 years. Thanks for all yours work!
That article, to me, definitely shows what length a company will go to by making high profit.
They really don’t give a rats ass if one of their drugs ruins a person’s life forever
The gulf war illness folks were given at least 15 vaccines shortly before their lives were ruined.
The more thought I put into what really happened to all of us,vaccines seem to be a plausible culprit
This is extremely noteworthy in many aspects of neurological disease and sleep, anxiety, adhd. I have Long Covid and have been reinfected (7) times. I noted other than dysautonomia , mast cell activation, problems with insomnia which I have had all my life.
My daughter was diagnosed with Narcolepsy/Cataplexy in her teens and has struggled now for years with this debilitating illness. By broadening the spectrum to include a type of circadian rhythm disorder, many people could have better quality of life outcomes.
It does appear that there is a genetic predisposition to narcolepsy. I wonder if it overlaps with ME/CFS?
A 1 month-old youtube video by Jared Youngera propos of this topic:
https://youtu.be/MFlzfh34hUk
With both Heather and Peggi above reporting having both the PEM + wired symptoms, and the narcolepsy-type syptom, but separate from each other, it might possibly point to the narcolepsy-type sleepiness may be a comorbidity to ME/CFS i.e. a subgroup of ME/CFS; and people who have narcolepsy-type sleepiness but not PEM (?) possibly a subgroup in the chronic fatigue spectrum but not a subgroup of ME/CFS specifically.
Then there’s Molly below who said she only experienced sleepiness in the deepest crashes (?) but not since she started pacing, which seems different again.
For me on the other hand, overactivated nervous system (but never sleepiness) is prominent at the start of a deep crash, I think it starts even earlier at the point when I push beyond an exertion limit which is achieved by means of the body mobilising overactivation of the nervous system.
– You know, do you think someone has ever tried to stratify patients by symptom combinations into subgroups, for example with the help of AI?
I wonder for example if symptoms of severe sensory hypersensitivites are more frequent in hyperalert patients without sleepiness. (Ny the way, annoyed at questionnaires again here: As far as I remember, even the big OMF medications survey asked only for one type of hypersensitivity (smell) and lumped it together in the same question with loss of smell – not helpful for identifying subgroups.
Hehe, you could publish a paper based on this blog, counting the # of patients who replied and the different groups they represent :-).
Hi Diana.
I hear your clear message.
I agree with you.
I have been reinfected with covid (newer mutations) only 3 times.
I took a lot of immune-supporting and anti-inflammation supplements so that any damage to my body might be minimized.
My view backward is that I could protect blood vessejs and microvessels with my antioxidant supplements,
but that pelvic floor long-covid conditions that I contracted
occurred because the bladder and colon, rectum, anus muscular dysfunctions occurred anyway because:
The excretion organs are strictly separated from the rest of my bloodstream, so much that nutrients would never go to them !
That would be a waste, and my waste organs would never receive nutrients in those spaces.
The only passage would be via blood vessels, guarded by a seriously strict barrier
This is so interesting since I was diagnosed with atypical narcolepsy 20 years before I was diagnosed with ME/CFS. However, I think it was a misdiagnosis. The issue is that I only struggle with daytime sleepiness and ease falling asleep when I’m deep in the push/crash cycle, not pacing at all, and in a deep crash. Since I’ve started pacing, my PEM almost never involves sleep attacks, hypnagogic hallucinations, or even daytime sleepiness. In fact, more often that not, the problem is being wired but tired.
I can see how the overlap of symptoms, if you’re studying someone deep in a crash state, could be compelling. But I’m not convinced that these conditions are so similar. And the fact that he says “you can’t have one without the other” about PEM and daytime sleepiness/sleep attacks is just inaccurate.
Interesting theory though, and there certainly is something here.
I have had ME/CFS & FMS all my life. I also have been diagnosed with Narcolepsy w/hallucinations, & obstructive sleep apnea. I used a C-pap full time, then off & on, & have now completely stopped. I also had EBV/mono twice as a teen & as a young adult. I carry the antibodies. Another issue is my spine – ankylosis spondylitis, degeneration/Spinal Stenosis. I have read more recently that there could be a broader “spectrum” of comorbidities/conditions/other diagnoses with ME/CFS & FMS. This article was very informative & I’ll share this w/my Neurologist at my next appointment. Thank you.
I am so sorry for your suffering. I too have what you do. At 60 years old. I’m so worn out. Doctors here in Michigan are so against pain medicine, it’s crazy!
Muppet News Flash
Exactly how being on the Narcolepsy spectrum could include non-sleepy CFS
It took me a couple of days but this might patch up the controversy between CFS PLUS sleepiness
vs
CFS lacking sleepiness
I would say it’s not a Narcolepsy spectrum, though, but rather an Orexin dysfunction spectrum on which Narcolepsy is one extreme.
The following is exactly how non-sleepy CFS might be on the opposite extreme:
I have recently been posting regarding Glutamate Excitotoxicity of a7 Nicotinic Acetylcholine receptors seemingly being the systemic missing link in SEID
(aka CFS) because this occurrence in Astrocytes (aka glia and microglia)
would logically explain weak T-cells, BP issues, kidney damage and most or all CFS symptoms.
That is to say that Cort was right on in his blog about TRPM3 channels in T-cells suffering. I said its in much more than just T-cells. It’s systemic.
The key brokenness in CFS, in my theory, is calcium homeostasis failure in a7 receptors (ion channels) . Astrocytes, easily fall into this category since neurotransmitter reuptake receptors are often a7. (perhaps always)
“Orexin signaling in astrocytes is also involved in regulating brain metabolism, sleep-wake cycles, and neurological processes like cerebral ischemia. For example, orexin-A can exert neuroprotective effects by reducing astrocytic inflammation and apoptosis after brain injury. ”
But I’m saying that it’s not just the Orexin. It’s the channels.
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0095259
” Here, we found that pretreatment of astrocytes with U73122, a specific PLC inhibitor and 2-APB, the inhibitor of both IP3 receptors and SOCE, markedly suppressed orexin-A-induced increase in ERK1/2 phosphorylation and following cell migration. Thus, PLC-Ca2+ pathway via SOCs extracellular Ca2+ influx was needed for orexin-A-induced astrocytes migration.”
We know microglia in the brain are angry in CFS. Microglia are astrocytes.
—
The trick, I have found, in finding a culprit in CFS that checks ALL the boxes, (so that subsets or phenotypes shouldnt matter), is:
Sometimes the same player can have opposite effects! And if you blink, you might miss the fact that it isnt contradictory.
Eg. in skeletal muscle Acetylcholine attaches to the a7 receptor to potentiate flexing, but in smooth muscle like your irises, it causes relaxation of an already semi-tight sphincter muscle.
But what is the commonality? Theyre both using a7 channels to change the balance of calcium ions– to achieve work. And they both need to return to homeostasis quickly when done.
Bottom line:
a7 nAChR failure, which includes TRPM3 channels, cognitive cell long-term potentiation (LTP) for logic and memory, skeletal muscle cell short-term potentiation (STP) and I hope all CFSyndrome of symptoms including sleep disorder
and their excitotoxicity leading to calcium imbalance
easily includes Orexin Dysfunction.
It’s just that NT-1 narcolepsy is a lack of Orexin, while non-sleepy CFS would be an Orexin dysfunction, not necessarily incorrect production of Orexin.
Key point that was quick in one of the above quotes:
There are two types of Orexin receptor,
and #2 basically only regulates sleep/wake, while #1 participates in that–but also in– brain metabolism, energy homeostasis, dopamine function (I feel that I can keep running) (clear headedness)
and get this:
regulating autonomic functions like BREATHING and HEART RATE.
And where does Orexin receptor #2 regulate the “decision” to be alert or not? In the brainstem. (RAS reticular activatiom system)
Guess what else the RAS modulates: what stimuli actually get through to the cerebral cortex (eg. pain, which in CFS is generalized, and which in Fibro is heightened in the Fibro points, but also can ‘set the skin on fire. ‘
So what it appears has happened
(at least in my (logical process)
is that a big proportion of CFS symptoms may now have an explanation regarding Orexin and a7 receptors in the brainstem, while the remainder of the body’s lower-down symptoms may now continue to have an explanation in a7 receptors in various other astroctyes (glia)
and the whole lot dependent on calcium level dyshomeostasis
I am a very sick person. I have so many of these symptoms in this article. I have moved to Michigan from a doctor that helped me in Florida. I’m am suffering here. Please help me. For 30 years I have fought cataplexy, fibro, insomnia and pain.
according to AI, the widely available Baclofen has the same pathway of sodium oxybate (GABA B agonist).
In summary:
There’s some randomized evidence that oral baclofen can improve sleep continuity in controlled settings (healthy phase-advance model; nocturnal GERD).
But baclofen also shows respiratory risks: an RCT in healthy volunteers found destabilized breathing, and multiple clinical reports link baclofen to central sleep apnea, particularly at higher doses or with intrathecal boluses. Use caution in OSA/CSA or when respiratory control is vulnerable.
Since my teens I’ve had adverse reactions to things I ingest or inhale – MCAS or MCS who knows? A big part of my ME. I’ve had virtually no sleep for years. I recently read an article by a health journalist writing about ME. About her mother who was a medical doctor who’d had severe ME as her daughter was growing up. Her Mother was finally helped to recover by Marek Doyle. So I looked him up on the internet. He offers a lot of free advice – some interesting and well researched articles. I found this one really interesting – he says a lot of his MCAS patients have insomnia and explains how he thinks MCAS, insomnia and microglia are linked. I found it really helpful to understand how Dr Jarred Youngers research may help my own ME symptoms.
https://www.marekdoyle.com/mcas-and-sleep-how-mast-cells-mediators-can-drive-insomnia/
Interesting, but I don’t see how narcolepsy would fit with the orthostatic intolerance/low blood flow to the brain/autonomic symptoms so common in ME/CFS. I did a quick search, and there is no mention of people with narcolepsy feeling presyncope.
As Dr Perrino didn’t seem to mention PEM, perhaps his hypothesis applies to patients who have narcolepsy and have been misdiagnosed with ME/CFS, or are undiagnosed and suffering with heavy fatigue that hasn’t been categorised.
It would certainly be a useful avenue to explore either way. I look forward to the results of Dr Mullington’s study.
Argh, I misspoke. There is a connection between narcolepsy, hypocretin and the autonomic nervous system. And there is orthostatic intolerance involved.
Apologies for not searching very well before commenting.
Thanks for illuminating that! I didn’t know about the OI connection 🙂
Failing energy and consistent,sudden near-collapse is all about malfunctioning and’or destroyed Mitochondri..Disrupution and often non-exitent energy payjways and processes.
I should know…i suffer in this way these last 35 years.
ME is as much to do with Narcolepsy as flying to the moon on horseback.
Absurd!
Mitochondrial problems can show up in the seemingly unlikeliest places. For instance, they can play a role in chronic pain.
Check this out!
“Studies have demonstrated that NT1 patients have significantly elevated levels of circulating cell-free mitochondrial DNA (ccf-mtDNA) in their cerebrospinal fluid, which is a marker of mitochondrial injury and neuroinflammation. These levels also negatively correlate with CSF hypocretin-1 concentrations, linking mitochondrial dysfunction with the central pathology of NT1.”
“Primary mitochondrial diseases can present with sleep disturbances, including excessive daytime sleepiness reminiscent of narcolepsy, due to energy metabolism failure in nervous system tissue. This makes mitochondrial dysfunction a plausible contributor to sleep-wake regulation disorders in general.”
Personally I am very interested in this orexin link, and look forward to seeing where the research leads.
Here’s an article, in English, from German researchers looking at the link between orexin and long covid:
https://www.mdpi.com/2227-9059/13/3/545