Puzzle Pieces Coming Together
“There have been some things that have really helped me … to move my thinking forward….The picture is coming together.” Dr.. Bateman from a talk at OFFER
Take the pieces of a big puzzle – piece a few together, scatter some of the rest on the floor, and then throw the box and the rest of the pieces away – and that’s what we’ve had with Chronic Fatigue Syndrome. We’ve had a few pieces of the puzzle, some of which fit together (and some of which didn’t appear to) but nowhere has the broad outline of the puzzle – the disease – been apparent.
Dr. Lucinda Bateman thinks that’s changing. In a videotaped talk for OFFER she stated she believes the broad outlines of the ME/CFS puzzle are now visible, and as they continue to become more visible we’ll be able to fill in the pieces of the puzzle faster and faster.
Two events helped Dr. Bateman come to this conclusion.
IOM Committee – One was being on the IOM committee. The IOM committee was a great opportunity, she said, to be around really smart people who are really good at what they do – working together to solve a problem that no one has been able to solve. Reading and summarizing two hundred ME/CFS abstracts for that group really got her mind cranking. (The IOM committee appears to be looking at all the literature. Ron Davis, another member, has also been poring over hundreds of papers.)
Stanford Symposium and IACFS/ME Conference – Those mental gears the IOM work began turning shifted into high gear for Dr. Bateman at the Stanford Symposium and the IACFS/ME Conference in March of this year. For the first time widely ranging research findings began to mesh for her; the puzzle outlines were becoming more apparent. She believes she now knows where the root of the disease is.
A Modern Medical Mystery: Exposing the Weaknesses in Modern Medicine
First, though, she asked how disabling illnesses such as ME/CFS and Fibromyalgia which affect 5 to 10 million people a year in the US could still be such a medical mystery?
She turned that question on its head by simply asking, “What kind of illnesses should our very advanced medical system have difficulty dealing with? That is, what kinds of illnesses is it weak in?”
Viruses: Viruses, of course, have played a huge role in our medical history. Formerly they were major killers and causes of disability. Now, unless you have HIV/AIDS or are a transplant patient, viruses are almost like an afterthought in the medical world.
Dr. Bateman noted there are not many drugs for viruses and not a lot of tests for them. The medical system generally starts focusing on viruses only when people are about to die from them.
(Kristin Loomis of the HHV6 Foundation has noted that the medical community in the U.S. is very reluctant to view viruses as causal factors in disease. Even in idiopoathic heart problems where a viral etiology seems likely biopsies are not done in the U.S..)
Immune system: We have a rudimentary understanding of the immune system.
Endocrine system: We’re good at the basics, but we have little understanding of how endocrine problems originate in the hypothalamus and pituitary (as they appear to do in ME/CFS). She noted that when she tried to do more extensive workups she found that (a) endocrinologists don’t do most of the tests in the textbooks, and (b) the tests they do are not adequately covered by the insurance companies.
(Stopping there, of course puts the cause of the problem into a black box. The difference between having an adrenal problem and a hypothalamus problem is immense; one is a glandular issue and the other gets you looking at the brain.)
The Three Biggies in Chronic Fatigue Syndrome
Next she talked about the three big factors in ME/CFS are autoimmunity, the brain (neuroinflammation/neuroendocrine), and the autonomic nervous system
Next, Dr. Bateman used Dr. Rose’s IACFS/ME talk on autoimmunity to dig deeper. When Dr. Rose, who is often called the “father of autoimmunity”, laid out a description of autoimmunity, this description, Dr. Bateman felt fit ME/CFS just fine.
Substituting the words ‘ME/CFS’ for ‘autoimmune disorder’ came out like this”
“ME/CFS and FM can strike any part of the body and any organ and symptoms vary widely and diagnosis and treatment are often difficult. Another problem is that ME/CFS and FM are allocated in different medical specialties. … This compartmentalization has hampered communication among physicians and researchers interested in autoimmune disorders.”
Dr. Bateman argued that of the three types of evidence for an autoimmune disorder laid out by Dr. Rose (direct, indirect, and circumstantial), ME/CFS and FM meet the circumstantial evidence criteria of being an autoimmune disorder.
Then she went down Dr. Rose’s list of typical features: environmental trigger, unusually high rate of genetic predisposition, endocrine involvement, and ‘others’, and checked them off one by one.
Environmental trigger to the disease – Almost all the environmental triggers known to kick off autoimmune disorders (viruses, bacteria, stress, and pollutants) have been associated with disease onset in ME/CFS.
Genetic Predisposition – Rates of genetic predisposition to ME/CFS and FM appear to be very high relative to other diseases (perhaps even higher than in autoimmune disorders). A Utah ME/CFS study found 2.5 times the risk of getting ME/CFS in first degree relatives.
The HLA genes control how we recognize pathogens, and HLA gene abnormalities tend to show up in rheumatologic autoimmune disorders as such lupus, rheumatoid arthritis, MS, and narcolepsy that share a ‘soft boundary’ with ME/CFS; i.e., these are disorders ME/CFS is often misdiagnosed as. HLA gene abnormalities have been found in ME/CFS studies.
Autoimmune disorders tend to flock together in the same person; Dr. Bateman can point to increased rates of autoimmune thyroiditis, celiac disease, and Sjogren’s Syndrome found in her ME/CFS practice.
Dr. Bateman on the Puzzle Pieces Coming Together For ME/CFS
Gender and Hormones – Females predominate in autoimmune illnesses as they do in ME/CFS, and men with ME/CFS tend to have low testosterone. Plus, the most common time of onset is when hormonal fluctuations are at their greatest: during early adulthood and during menopause. Hormones definitely play a role in ME/CFS.
A Systemic “Autoimmune Disorder” - Dr. Bateman highlighted lupus, an autoimmune disease that can attack – and this is the important part – every organ in your body. Lupus can do this because the autoantibodies associated with it attack the nucleus of cells. The nuclei in the cells of an ME/CFS patient are not getting attacked by autoantibodies – something else is going on – but ME/CFS is similar in that it is a systemic disorder which affects many parts of the body.
If it’s not the nuclei what is it then? Dr. Bateman noted that autoimmune disorders have been found for virtually every organ in the body except for one: the central nervous system.
A few diseases (multiple sclerosis, Parkinson’s, narcolepsy, dementia) come close, but the medical profession isn’t sure if the destruction found in the brain in those diseases is caused by an autoimmune process or something else.
What is ME/CFS? It’s an autoimmune-like condition of the central nervous system. Next we learn why Dr. Bateman believes the central nervous system is key.
“Lots of things happened in my brain [during the conference] to make connections and put those puzzle pieces together.”
A lot of things clicked in Dr. Bateman’s brain about ME/CFS as she watched the presentations on the brain at the Stanford Symposium.
Evidence for problems in the brain has been growing, she noted. Brain blood flows are low, serotonin and dopamine often get dysregulated, inflammation in the thymus and amygdala may be present, and the recent neuroinflammation study from Japan found widespread evidence of inflammation in the brain. Importantly, the more inflammation they found the more fatigued the person was.
“The Sleeping Brain”
The Zinns‘ studies in the Stanford Symposium really put matters into focus for Dr. Bateman. They were good-sized (100 person) studies.
First they found reduced frequencies of peak alpha brain waves across more than 50% of the frontal cortex (the entire frontal and side parts of the upper brain) – a huge part of the brain. That was, Dr. Bateman said, “a little bit troubling”. Since these brain waves regulate our awake/sleep states, reduced alpha frequencies essentially mean people with ME/CFS aren’t as ‘awake’ as healthy people.
The Zinn’s also found increased delta waves in ME/CFS patients when they were awake. Given the fact that delta waves are usually only seen when we’re asleep, this is a “little troubling” as well and could go far to explain the fatigue present in this disorder.
It was a double brain-wave whammy for people with ME/CFS: the brain waves that signal that one is awake and active were down, and those that that signal one is asleep were up – when they were awake!
Mark Zinn noted these findings could produce pain and fatigue, poor coordination and balance, slowed and more difficult movement, hypersensitivity, and poor working memory.
ME/CFS to him looked like inflammation of the lower parts of the brain, e.g., limbic encephalitis – something that could cause slowing of the entire brain. Dr. Bateman noted an earlier 600+ person Harvard study was able to use EEG readings to accurately predict who had ME/CFS and who did not, and smaller studies using MRI, SPECT, or PET scans have provided ample evidence of brain problems.
(The remarkable thing about the 600 person plus EEG study was that it was able to differentiate between ME/CFS, healthy controls, depressed and ‘people with fatigue’).
She also mentioned that Rhomberg tests were frequently positive in this disorder.
(The positive Rhomberg test results are a fascinating subject. Decades ago Dr. Cheney asserted Rhomberg tests should be part of the diagnostic protocol for ME/CFS, but you’ll never see them as part of a diagnostic workup for ME/CFS suggested by the CDC or the Mayo Clinic. A positive Rhomberg test, however, makes perfect sense given Zinn’s finding. (The puzzle pieces are coming together…))
The Big Picture Emerging
Dr. Bateman then took a step back and looked at the brain from the top down.
First there’s the frontal cortex, then the limbic area, then the brain stem and the spinal cord. Going deeper into the brain, Dr. Bateman focused on the thalamus, the hypothalamus and the pituitary. These control the hormones and much of the autonomic nervous system.
The Japanese study provided preliminary evidence for inflammation in limbic regions (cingulate cortex, hippocampus, amygdala, thalamus, midbrain, and pon) of the brain. The Zinns believe limbic encephalitis (inflammation) is present.
What if that inflammation, Dr. Bateman asked, reached the lowest part of the brain where the hormones are produced? You’d probably have problems with the hormones. In fact, you’d probably have the problems with hormones that have shown up in ME/CFS.
She checked off those hormones that at least some evidence suggests are ‘off’ in ME/CFS and/or FM:
- Corticotrophin releasing hormone (CRH) – hypothalamus uses CRH to tell the pituitary to release ACTH
- Growth hormone – particularly in FM
- Thyroid hormone – at least a third of her patients are hypothyroid – an astonishingly high number. Some of it, but probably not a lot, judging from the way she talked, could be due to inappropriate thyroid supplementation. Something else (autoimmunity/neuroinflammation/?) is apparently hitting the thyroid hard in ME/CFS.
- LH and FSH (?) – regulate the ovaries and testicles, and a CDC paper shows almost every gynecological problem you can have is more common in ME/CFS. Also, ME/CFS patients’ symptoms tend to get better during pregnancy, and hormone replacement therapy tends to help in ME/CFS.
- Vasopressin – helps you retain water and constrict your blood vessels; without it you would have low blood volume and problems standing … ”Sound familiar?” she said.
- Oxytocin – oxytocin deficiency makes you prone to depression, anxiety, social isolation, and sleep problems.
Sympathetic Nervous System – Then there’s the autonomic nervous system. Inflammation in the lower brain could mess up the SNS in two ways; by affecting the thalamus (inflamed in the Japanese study) or by affecting the SNS neurons that exit just below the base of the brain.
Inflammation in either area could disrupt the ANS causing the sympathetic overdrive that produces racing heart rates, arrhythmias, and difficulty sleeping and resting. (Heart rate variability studies also show sympathetic overdrive in ME/CFS. Dr. Martinez-Lavin believes the sympathetic overdrive in both disorders begins in the thalamus.)
The Big Picture – an Inflamed Brain
Calling neuroinflammation in the brain the equivalent of autoimmunity in the body, and stating that we know the microglia are activated in ME/CFS, Dr. Bateman proposed that inflammation in the core of the brain ( limbic encephalitis) causes a cascade of problems going both ways – up into the cortex and down into the hypothalamus, thalamus, and pituitary and the autonomic nervous system.
This could cause all the major symptoms in ME/CFS and FM.
Dr. Bateman believes we have enough data to describe two subsets in ME/CFS:
An infectious onset group that develops autoimmune antibodies to the receptors that control the heart rate and blood pressure; i.e., the POTS patients.
She sees this a lot in kids. This group doesn’t have a lot of cognitive issues; instead they have problems standing, sleeping, anxiety from excess epinephrine (a.k.a. adrenaline), are deconditioned (because they have trouble standing), and are in pain due to stress and disturbed sleep. The work on this group, she thinks, is going to go fast, and that group tends to get better anyway. They’re clearly easier to treat right now.
She talked about one young man whose mother has ME/CFS and who developed full-blown POTS after coming down with West Nile Virus. By compensating for his POTS (he wears full-length body stockings) he’s able to work and even exercise. He’s no longer deconditioned and his depression and brain fog have disappeared.
It’s not perfect – he has to pace himself – but he’s highly functional, and it’s all from treating the symptoms of his POTS.
His POTS is by no means resolved! It’s likely as bad at it ever was, but ways have been found to compensate for it. He’s being kept functional by the medical profession. With the autoimmunity work going on it’s possible that his POTS will be solved.
- Problems Standing? Studies Suggest Autoimmunity Causes Orthostatic Intolerance: Implications For Chronic Fatigue Syndrome
These patients – a larger group – have widespread inflammation in the brain causing fatigue, reduced functioning, orthostatic problems (but not nearly as severe as in the first group), problems with sleep, cognition, and neuroendocrine problems. This group is much more complex but the problems are becoming clearer and clearer, and as they do we’ll get more assistance from the research community and better and bigger studies devoted to solving this ‘medical mystery’.
Dr. Bateman ended the presentation with a big smile and said, “Is that cool or what?” She’s clearly excited by what’s showing up in ME/CFS research. She believes the work done at Columbia, Harvard, Dr. Klimas’s group in Florida, and Stanford, etc., is going to create a base that’s going to draw in researchers from other fields.
Do her discoveries change how she interacts with patients? They don’t change the treatment options available at this point, but they do two things: they validate the treatments that do work because now they can see why they do, and the fact that clear causal pathways are showing up should really provide hope that we’re on the right track.
A follow up question asked if healthy relationships, optimistic outlooks, etc., are helpful? Dr. Bateman said yes, stating that stress, sleep deprivation, etc., all makes this illness worse. Ask yourself, she said, if adding anxiety to your sympathetic overdrive would be a good thing or not. That’s why meditation, accepting your illness, and doing things that slow your heart rate and the sympathetic overdrive present, can give your body a respite and help you feel better. It’s good! And she looks forward to real treatments being developed.
She believes some people do wind up with ME/CFS because they were on overdrive from the get-go (presumably the ‘burnout’ patients) but most don’t fit this pattern. The people with ‘burnout’ (my word, not hers), she said, are easier to treat. She believes that milder, easier to treat fibromyalgia is stress related, and she noted that she herself gets ‘fibromyalgia-ey’ (my word, not hers). If she’s doing too much, not exercising enough, etc., she starts getting stiff and has more aches and pain. Those stress-related symptoms go away when she gets rest, exercises, and maintains her diet.
Dr. Bateman also wonders if early intervention might be very helpful. If you could catch this disease early – within the first six months – how many problems could be prevented? In my case I wonder about that. Things got set for me pretty quickly. While there have been ups and downs – notably with chemical sensitivities which flared enormously at some point – the core of the disease (an inability to exercise, a strange ‘arousal’, etc.) was pretty much set early on. Of course many people develop other co-morbidities that cause further distress and undoubtedly worsen the original condition.
With regard to that other subset – the bigger subset with neuroinflammation – Dr. Bateman said there are treatments that work for other neuroinflammatory and autoimmune disorders such as MS. They’re not perfect, but they can provide years of a relatively normal lifestyle for some. Some people with ME/CFS get well on Ampligen. It’s going to take for this complicated group, but she’s optimistic.
- Next Up: Seeds of Hope From Dr. Bateman and OFFER’s Big Move
- For more on Dr. Bateman