Jennifer Brea: I have craniocervical and atlantoaxial instability

[JenB]

In simple terms, which symptoms ought one to look out for. Thank you.

See for a symptom list: https://www.me-pedia.org/wiki/Craniocervical_instability

But I'd also read Jeff and my stories.

 

[JenB]

One possible link between weakened connective tissues and the viruses in ME/CFS that infection can up-regulate production of connective-tissue degrading enzymes. Coxsackievirus B for example ramps up production of various matrix metalloproteinases (MMPs), which is a whole family of enzymes that destroy connective tissue proteins like collagen, elastin and gelatin.

This is amazing, thank you. Please see also: https://www.me-pedia.org/wiki/Collagen (papers on EBV, HSV-1, Bartonella). Chia thinks Coxsackie has affinity for thyroid. We'll see if he finds any virus there! I do think there's a relationship between my initial infection, the cancer in my neck, and the weakening of collagen in my neck, which is the proximate cause of CCI/AAI.

If/when you have the time, please do add info on matrix metalloproteinases + Coxsackie to the collagen page (even if brief). Or share any citations you might have.

 

[perrier]

See for a symptom list: https://www.me-pedia.org/wiki/Craniocervical_instability

But I'd also read Jeff and my stories.

Dear Jen,
Thank you and Jeff for all your hard work. Merci beaucoup as we say here. I have read these symptoms over and over. I’m trying to see if there are one or two that stand apart from ME. The only one I noted was Constant Headache.

Did you have this?

And as a neck brace was used by Jen and Jeff, is it useful to purchase one and see if symptom relief results?

 

[Hip]

In simple terms, which symptoms ought one to look out for. Thank you.

In a discussion earlier this year on another thread, there was talk about using a cheap ready-made neck traction device like those shown here, which cost around $20, as a possible means of diagnosing issues like craniocervical instability and Chiari malformation.

Though on some neck traction models the maximum upward pull on the neck may not be sufficient, as Jeff pointed out that:

The over-the-door pulley traction has helped others with CCI. It didn't seem to help me much. .... I just needed more force than 20 lbs.

The model I bought though can exert a massive 20 kg (44 pounds) force — a slightly worrying amount; I don't want to pull my head off!

When I tried it on myself, I took it up to around 12 kg force, but did not notice any improvements in symptoms, at least in my short term test.

 

[Hip]

If/when you have the time, please do add info on matrix metalloproteinases + Coxsackie to the collagen page (even if brief). Or share any citations you might have.

I will definitely put it on my MEpedia to do list (which is getting quite long!).

 

[Gingergrrl]

I have a question for @JenB or @jeff_w (or anyone who might know the answer)! Have there been any cases of someone with CCI (or cervical stenosis) who had diaphragm/breathing problems when STANDING that were completely alleviated when lying flat?

I know what I am asking basically sounds like POTS but I am curious about breathing problems that are separate (or in addition to) POTS that are caused by muscle weakness affecting the lungs and diaphragm (vs. postural tachycardia and/or hypotension).

I hope this question makes sense?!

 

[JenB]

I have a question for @JenB or @jeff_w (or anyone who might know the answer)! Have there been any cases of someone with CCI (or cervical stenosis) who had diaphragm/breathing problems when STANDING that were completely alleviated when lying flat?

In theory, if it were bad enough, this could be a spinal fluid leak. Bad leaks can cause your brain to sink (think foramen magnum == drain) and actually compress the brainstem from above. Leaks always get worse with standing.

 

[outdamnspot]

See for a symptom list: https://www.me-pedia.org/wiki/Craniocervical_instability

But I'd also read Jeff and my stories.

How frequent were your headaches?

 

[Gingergrrl]

In theory, if it were bad enough, this could be a spinal fluid leak. Bad leaks can cause your brain to sink (think foramen magnum == drain) and actually compress the brainstem from above. Leaks always get worse with standing.

Thank you for sharing the video of Dr. Carroll and it sounds like he is talking about CSF leaks with chronic headaches versus CCI that could affect breathing/diaphragm muscle strength when standing (unless I misunderstood)?

@JenB From your excellent article/blog, it sounded like your breathing problems were predominantly when you were lying flat vs. standing? Or did they also occur when you were standing?

I am 99.99% certain that CCI is not my diagnosis (but lately several people from PR have asked me why I ruled it out when I had a car accident/neck injury as one of the first triggers and had cervical stenosis on an MRI around 2010)? But I ruled it out b/c I do not have headaches (outside of IVIG induced), I do not have EDS, and my severe muscle and breathing weakness 100% resolved from treatments for autoimmunity without any kind of traction, neck brace, or treatment for CCI (which would not be logical if that was the core problem).

I have the same doctor as Jeff (who is extremely familiar with these cases) but he has never at any point even mentioned this to me as a possible diagnosis to test for and he knows I have chronic neck pain. He felt the core issue, in my case, was autoimmunity (behind all of my symptoms including muscle weakness, breathing weakness, POTS, MCAS, Hashimoto's, possible LEMS, etc).

But several people have now asked me why I ruled out CCI when I'd had a car accident and neck injury so I don't want to leave any stone un-turned (in case my remission should not last). I guess I am wondering if headaches are a required symptom for this diagnosis or if neck pain and shortness of breath (in the absence of headaches) are an equal part of the diagnostics? Sorry I typed way more than I'd planned (and did not mean for this all to be directed at Jen and am just sort of thinking out loud for anyone who comes across it)!

 

[JenB]

Thank you for sharing the video of Dr. Carroll and it sounds like he is talking about CSF leaks with chronic headaches versus CCI that could affect breathing/diaphragm muscle strength when standing (unless I misunderstood)?

Sorry about that. Perhaps it was in Rowe’s video? There is a case study where someone’s brain actually descends from the top of their skull by what looks like an inch. Not everyone has a headache, but it is a common symptom. Regardless, with *any* symptom that is positional, one should strongly suspect IMHO a structural cause.

@JenB From your excellent article/blog, it sounded like your breathing problems were predominantly when you were lying flat vs. standing? Or did they also occur when you were standing?

Now this can occur no matter what position I am in if I am not wearing my collar. For the first several months, it was only while laying down. It’s still much, much worse laying down simply because when my head is resting on a pillow, I am putting direct pressure on it, causing to slide out of place (relative to the first vertebra). For a period of time, as my symptoms worsened but before I started using a thoracic extension for my brace, I had to sleep sitting up.

I am 99.99% certain that CCI is not my diagnosis (but lately several people from PR have asked me why I ruled it out when I had a car accident/neck injury as one of the first triggers and had cervical stenosis on an MRI around 2010)?

But I ruled it out b/c I do not have headaches

Neither do I. At least, I didn’t pre-thyroid surgery (at least, not since my onset). After the surgery, I’d only get the classic occipital + neck pain when moving my neck into positions that deliberately provoked symptoms for exams or imaging. But headache not a major sx for me.

I do not have EDS

Neither do I and neither does Jeff (at least by current diagnostic criteria).

and my severe muscle and breathing weakness 100% resolved from treatments for autoimmunity without any kind of traction, neck brace, or treatment for CCI (which would not be logical if that was the core problem).

This is a clue that you have another explanation for your symptoms, to be sure. However, small fibre neuropathy is extremely common in ME, EDS, fibro, etc. (for which IVIG is a treatment). I don’t think these things are mutually exclusive. The breathing problems Jeff and I had are not a common symptom of CCI/AAI.

I have the same doctor as Jeff (who is extremely familiar with these cases) but he has never at any point even mentioned this to me as a possible diagnosis to test for and he knows I have chronic neck pain.

The only way you can know for sure is if you do the imaging and consult with a surgeon. Neck pain can have many causes and if you have chronic neck pain, you should definitely get cervical imaging and consult with spine surgeons knowledgeable in different cervical conditions (not just CCI). No one can tell if you have CCI just from your case notes. You need to be physically examined and imaged.

But several people have now asked me why I ruled out CCI when I'd had a car accident and neck injury so I don't want to leave any stone un-turned (in case my remission should not last).

If you are in full remission, I wouldn’t worry about this *too* much. But if you have chronic neck pain, I’d try to find out why.

I guess I am wondering if headaches are a required symptom for this diagnosis or if neck pain and shortness of breath (in the absence of headaches) are an equal part of the diagnostics?

No, headaches are not required. (They also aren’t a required symptom of spinal fluid leaks.) I don’t think you should consider anything to be a required symptom just because it’s on a symptom list. My impression is that required symptoms are generally only a part of diagnostic criteria that are syndromes, i.e., where the pathology is unknown. With most conditions, no symptom is present in 100% of cases.

I never had shortness of breath. I stopped breathing full stop. I don’t know if you have CCI but that isn’t the most important thing. What is important is that you had an accident and now have chronic neck pain. There can be many structural reasons for this, and you should try to figure out why.

 

[frozenborderline]

Hi @Hip. I believe I had a mild case of this for a very long time (perhaps since my onset or at latest, 14-18 months later), but never associated my symptoms with my neck or my head position. It was only after the thyroidectomy that the positional nature of the symptoms (that turning my head or laying on it made everything worse) became clear. There are several papers re: general anesthesia in rheumatoid arthritis and Down Syndrome and their relationship to CCI/AAI (two communities in which this is common). Surgery is a common trigger that can make everything worse.

CCI/AAI is also *very* common in the Ehlers-Danlos Syndrome community and you'll see many cases similar to mine and Jeff's. Although, I do think the difficulty breathing is a less common symptom and is associated with more severe cases of CCI as I believe you need to have significant cranial settling to cause that particular symptom. The other diagnoses you mention that cause compression (excluding the stenosis) are also common in EDS and are all associated with faulty connective tissue: https://onlinelibrary.wiley.com/doi/full/10.1002/ajmg.c.31549

Here are some pages you might add all this new wisdom

https://www.me-pedia.org/wiki/Brainstem (would be good to have both the inflammation studies and the discussion of brainstem deformation on the same page).

https://www.me-pedia.org/wiki/Collagen (bonus if you can find any papers on enteroviruses and collagen. I could not, but haven't looked very hard).

Jen, it's very interesting to me that these symptoms started after the thyroidectomy. Do you think that this was because of the direct physical trauma of surgery, or do you think that there's a relationship between this kind of structural problem and metabolism? The reason I ask is a lot of my muscle pain symptoms improve temporarily with thyroid treatment. I wasn't a classic hypothyroid case for most of my illness but tried it despite normal TSH levels, and then got retested around the same time I started thyroid treatment and realized that my TSH levels had raised to "officially hypothyroid" levels. A lot of people here have had some symptomatic relief with thyroid treatment but I wonder if it is at all connected to collagen or structural issues...

 

[StarChild56]

@Forçe e Honra Tagging you in case you had not seen this thread yet (which we were discussing in another thread )

Thank you! No, I hadn't and I will read it now.

 

[Tammy]

I had my own experience of probable increases in connective-tissue degrading enzymes after catching my virus: about 12 to 18 months after I caught the Coxsackie B4 virus which triggered my ME/CFS, I developed a sudden-onset crêpe paper-like wrinkling of the skin all over my body, but most prominently on the top of my hand. Here is a picture I took years ago of these sudden-onset fine wrinkles on my hand:

How long did that last?

 

[Hip]

https://www.me-pedia.org/wiki/Collagen (bonus if you can find any papers on enteroviruses and collagen. I could not, but haven't looked very hard).

I woke this morning and notice you've already done a great job overnight in adding a Pathogens and collagen degradation section to the collagen MEpedia page!

I'll just post here some of the refs and info I have collected about connective-tissue / extracellular matrix destroying enzymes, in case you find these useful.


Some basic definitions

➤ Extracellular matrix (ECM) — exists in the space between the cells, and acts as scaffolding that holds the individual cells together, creating a structured tissue. This matrix consists of proteins such as collagen (the most abundant), elastin (the next most abundant), fibronectin, laminin and others.

➤ Connective tissue — one of the 4 basic types of tissue in the body (the other 3 are epithelial tissue, muscle tissue and nervous tissue). Connective tissue is the scaffolding that structurally supports and binds organs and tissues. All 4 basic tissue types possess an extracellular matrix, but the extracellular matrix is particularly rich in connective tissue.

➤ Matrix metalloproteinases (MMP) — are a family of enzymes which break down the collagen, elastin, etc proteins of the extracellular matrix.

MMPs are secreted by the body for various purposes, such as during the growth of new blood vessels, or during wound healing and tissue repair. MMPs are also secreted by the immune system in order to "hack a path" through the tissue extracellular matrix to allow immune cells in the bloodstream to travel into these tissues to fight an infection (ref: 1). But bacteria also secrete MMPs for the same purpose: to hack a path through in the host tissue, allowing the bacterial infection to invade and spread into the host.

There are around two dozen MMPs, and each one targets a specific set of ECM proteins like collagen, elastin, etc. There is a nice list of MMPs here, also a list on Wikipedia here.

Quest and Labcorp both offer tests for blood MMP-9 levels.

➤ Neutrophil elastase (also called human leukocyte elastase, or HLE) — is another enzyme which breaks down elastin, collagen, etc. It's not considered part of the MMP family as far as I am aware.

Neutrophil elastase was found elevated in ME/CFS by Kenny De Meirleir. RED Labs offer a test for elastase levels in ME/CFS patients.

KDM thought that this neutrophil elastase was responsible for cleaving RNase L, and creating the chopped up low molecular weight RNase L that has been found in ME/CFS (see KDM's book). I am not sure if this line of investigation still holds currency.

This 2012 study by Dr Maes also found polymorphonuclear leukocyte elastase (= neutrophil elastase) elevated in ME/CFS.

➤ Tissue inhibitors of metalloproteinases (TIMP) — the enzyme activity of the MMPs is inhibited when TIMP is secreted. Thus when TIMP levels are higher, the extracellular matrix-destructive effect of MMP enzymes is reduced. There are four of these inhibitors: TIMP-1 to TIMP-4.



Effect of enterovirus infection on MMP levels

Acute coxsackievirus B3 myocarditis in mice has been shown to cause elevated MMP-2 and MMP-9 in one study; and elevated MMP-2, MMP-9 and MMP-12 in another study.

Chronic coxsackievirus B3 myocarditis in mice has been shown to cause elevated MMP-2 and MMP-3 in one study (at the 28 days stage, which is the chronic infection stage).

Acute coxsackievirus B4 infection of the pancreas in mice led to elevated MMP-9 (mainly originating from macrophages and neutrophils), one study found.



Effects of manipulating of MMP levels in enterovirus infection

In acute coxsackievirus B3 myocarditis in mice, one 2008 study found that reducing MMP-9 levels (by gene knockout) led to worsened myocardial injury. So MMP-9 appears to have a protective effect against this virus, at least in acute infection.

However, the chronic non-cytolytic enterovirus infection found in ME/CFS (and chronic myocarditis) however are a different beast to acute infection, and so the protective effect of MMP-9 may not necessarily apply in chronic enterovirus infection.

A 2003 study found MMP-9 (gelatinase B) cleaves interferon beta, destroying its antiviral effect. So in this case MMP-9 is weakening the immune response.

A 2014 study found that MMP-12 (macrophage elastase) limits the antiviral immune response by destroying the interferon alpha receptor 2 binding site. This suggest that inhibiting MMP-12 may help to control coxsackievirus B infection. Though currently no MMP-12 inhibitor drugs are clinically available.



Inhibitors of MMPs

This study on multiple sclerosis patients found MMP-9 was decreased by 58% after 3 months of omega 3 fish oil supplementation at 9.6 grams per day.

This rat study found alpha lipoic acid reduced MMP-2 and MMP-9 during ischemia-reperfusion injury.

This rat study found the angiotensin II receptor blocker drug losartan and the statin drug simvastatin increased TIMP-1 and TIMP-2 (thereby inhibiting the effects of MMPs).

This human study found losartan decreased MMP-2 and MMP-9.

This study found the angiotensin-converting enzyme (ACE) inhibitor captopril inhibits serum MMP-9 in patients with Kawasaki disease.

Dr Ritchie Shoemaker uses a low amylose diet and high-dose fish oil to treat elevated MMP-9.

This study found glucosamine sulfate inhibits MMP-2 and MMP-9 expressions in human fibrosarcoma cells, probably explaining why glucosamine is effective in relieving the symptoms of osteoarthritis.

This study found azithromycin decreases MMP-9 expression in the airways of lung transplant recipients.

This in vitro study found that doxycycline inhibited MMP-13 and MMP-8 (at concentrations that were near the concentrations achieved in the serum after oral dosing).

This in vitro study found magnesium reduces MMP-2, suggesting that the beneficial effect of magnesium supplementation on the cardiac disease may be due, at least in part, to the inhibitory effect on MMPs.


There are many other supplements that inhibit MMPs in vitro: see here; but most of these supplement probably will not work in vivo when you take them orally.

(This is because it is easy to produce effects in vitro in a cell line, because you can use high concentrations of the compound. But those high concentration are often not obtainable in vivo for various reasons, such as the maximum safe oral dose, or poor bioavailability. So you need to find studies that show a drug or supplement works in vivo in humans or animals).



Is there a possible connection of MMPs to craniocervical instability, Chiari, cervical spinal stenosis or syringomyelia?

I could not find much research on this, apart from this study on rabbits, which found that MMP-9 plays an important role in creating syringomyelia in the spine, and the study suggests that the MMP-9 inhibitor doxycycline may be used to prevent and treat syringomyelia.

(Syringomyelia a fluid-filled cyst which appears within the spinal cord, and compresses the spinal nerves, which may result in ME/CFS-like symptoms. Ref: 1).

 

[Hip]

How long did that last?

The fine skin wrinkling is still present some 15 years after I first caught the virus. And not just in me: this crêpe paper-like skin wrinkling is still present in everyone who had it triggered by the virus.

That perhaps suggests the ongoing viral infection in the body is causing the immune system to continually secrete these MMP enzymes or neutrophil elastase, which is degrading the elastin etc in the skin.


In addition, one family member with my coxsackievirus B4 developed mitral valve prolapse. Coxsackievirus B infection has been found in heart valves. Mitral valve prolapse involves the ill effects of MMP-2 on the extracellular matrix of this valve. Mitral valve prolapse is not uncommon, found in around 2-3% of the population.

 

[JenB]

Mitral valve prolapse involves the ill effects of MMP-2 on the extracellular matrix of this valve. Mitral valve prolapse is not uncommon, found in around 2-3% of the population.

And is very common in EDS

 

[Diwi9]

The fine skin wrinkling is still present some 15 years after I first caught the virus. And not just in me: this crêpe paper-like skin wrinkling is still present in everyone who had it triggered by the virus.

Just want to mention that I also developed this on the back of my hands after getting sick. I tested positive for exposure to Coxsackie B4 and Echo 30 through ARUP and had been taking Equlibrant for at least six months.

 

[sb4]

Very good work @Hip !

I may look to try some of these things in future but I am not so sure about the high dose of fish oil.

Do you think taking collagen could help rebuild these structures faster than they are taken down, or perhaps provide fodder for the MMPs?

 

[Hip]

Very good work @Hip !

I may look to try some of these things in future but I am not so sure about the high dose of fish oil.

Do you think taking collagen could help rebuild these structures faster than they are taken down, or perhaps provide fodder for the MMPs?

If I remember rightly, collagen taken as a supplement is broken down in the stomach, so it may not be possible to ingest actual collagen. But there are supplements that help provide the building materials for making collagen and elastin for connective tissue repair purposes, eg: vitamin C, silica, copper, proline, xylitol.

I suspect that the inhibitors of MMPs listed above might work better though. Low-dose doxycycline 20 mg daily (sold as the drug Periostat) for example is prescribed to slow receding gums. Receding gums (periodontitis) involves the erosion of gum tissue by MMPs, as doxycycline inhibits MMPs.



Very high dose fish oil I tried myself once (for its anti-inflammatory effects on the brain, and ability to repair damaged brains). I was taking 20 ml of cod liver oil (equivalent to 4.6 grams of EPA+DHA) daily, with no side effects at all (though it did not help ME/CFS symptoms).

 

[Sandman00747]

Just want to mention that I also developed this on the back of my hands after getting sick. I tested positive for exposure to Coxsackie B4 and Echo 30 through ARUP and had been taking Equlibrant for at least six months.

I also tested positive for Coxsackie B4 at ARUP as I believe several others here have.