A reader wrote today the following

“I know this will and does seem like an excuse to anyone who hasn’t suffered from CFS / Lyme and related illnesses, but I’ve been feeling so depressed and so tired and so dumb the last six plus months that following a complex protocol feels impossible. I don’t know if depression or total lack of motivation is something you’ve dealt with personally, but I would truly appreciate any advice you have. I’m hoping that if I can get some relief in that area that I will feel motivated and less defeated and more clear when trying to start and follow a protocol. “

This is not unfamiliar to people dealing with CFS patients. A lot of the problems stem from the decrease of executive function coupled with difficulty processing information. If you go to any CFS forum, you will hear dozen of opinions often with concerns about taking too much of ABC.

A classic example is concerns about taking above the recommended daily allowance (RDA). The RDA for Vitamin D is 600 IU/day but this level will never result in Vitamin D levels in the body reaching the level that has been shown to reduce symptom severity for Chronic Fatigue Syndrome and Fibromyalgia (prior post). A 2015 study found IBS quality of life improves with increase of Vitamin D. Even Doctor  Mercola states “The Institute of Medicine’s (IOM) recommended dietary allowance(RDA) for vitamin D underestimates the need by a factor of 10″ [2015] and recommend 9000 IU. Because of mal-absorption that occurs with CFS, I advocate 15,000 IU. What happens? You walk into your medical professional and tell them you are taking 9000 – 15000 IU/day and they freak out, pressuring you to reduce it to just 600 IU — because that is what is in the official literature.

Most CFS patients ends up having to make their own decisions on what to take and dosages — and with limited cognitive abilities, that is a challenge.

Dealing with Depression

This is a good point to start a list of daily supplements.

• ” evidence of decreased depression risk among women with higher intakes of vitamin B₆ from food, which was dependent on total energy intake, and among men with higher intakes of B₁₂ from food” [2015]
• “vitamin B consumption and serum vitamin B12 and folic acid levels were low …among patients with depression.” [2015]
• ” men with deficient vitamin D status were more likely to have current major depressive disorder… Associations among women were not significant” [2015]

So three vitamins should be taken daily

• Vitamin D3: 9000-15000 IU/day
• Folate (B9) – 6,000-13,000 mcg – See this post for studies.
  • “. A remarkable 81% of CFS patients experienced subjective improvement of their symptoms after treatment with folinic acid” [2006] [Full Text] [Amazon] 800 – 1600 mcg /day – The folinic acid form is biologically active, not plain folate.
• B12 – 1000 mcg/ 1 mg seems to be the effective ongoing dosage, see this post
• B6 supplementation have been reported to be problematic, I need to do more research

To Avoid: Lactobacillus Acidophilus, a recent study found that higher levels were associated with depression

To Take: See CFS Depression, Diet and the Microbiome

Confusion

Every decision that you must deal with, adds confusion. I have seen patients selecting pills to be exhausting.

One approach that I have done with people that are irregular in taking supplements is to prepare 7 zip-lock bags labelled (Monday, Tuesday, … Sunday). Sorting and selecting pills only need to be done once a week.

Combining these bags with a marker pen that writes the number of capsules from each bottle (as shown below), eliminates the decisions to be made. For many supplements (except anti-infection ones), keep taking the number specified until the bottle is empty.  Many CFSer end up with 1/2 or 3/4 filled bottle of supplements that they stop taking (which does not help a tight budget!).  When the bottle is done, consider a different one OR refill OR BOTH!

Fear

Fear is a harder item to deal with.  One resolution of not having a cure from the MDs is to simply wait until a cure is found.  Will a specific treatment make me worst?  An adverse reaction associated to something reported on a forum can result in significant fear about taking something — even when studies have found strong positive effects.

For me, when I was in relapse with CFS, I kept to items with demonstrated positive effects according to PubMed, if some one (even a MD) suggestions something contrary I asked for a pubmed article supporting their belief. If they cannot provide one, then I ignore them — End of influence.  Information from forums, while emotionally nice and supportive, are often coming from people with cognitive impairment, poor memory etc etc etc. The information actually comes with significant costs to a CFS patient — a lot of noise that can be very difficult to sort thru.

Where do you go from here?

Three vitamins should decrease depression significantly as well as improve symptoms. If you have been eating yogurt or probiotics high in L. acidophilus, you may wish to stop.

You want to simplify pill taking — do 7 days of pills and do it by only figuring out the dosages ONCE instead of every day.

Temperature in CFS is often reported as low, or very very low. This tends to be ignored by most medical professionals — they have been trained to deal with high temperatures (fever) and not low temperatures.

• “Adolescent patients with chronic fatigue syndrome have abnormal catecholaminergic-dependent thermoregulatory responses both at rest and during local skin cooling” [2007]

This is sometimes called Wilson’s Temperature Syndrome (reading Wikipedia is recommended, his model is suspect). A study on 7 CFS patients in 1998, found that the temperature was normal during the study (37C or 98.6F ) but with CFS patients having almost twice the variation of controls. This increased variability was reported again in 2001. A 1996 study found  “the CFS patients showed no significant correlation between the timing of the temperature acrophase and the melatonin onset (P < 0.5), whereas the normal significant correlation was observed in the controls (P < 0.05).”

Another blogger (Dr. Hansa) has written about temperature in CFS, so I will not repeat their material here. Cites like WebMD does cite low body temperature ((below 97.6F or 36.5C) as a common symptom which occurs in some patients. Also it is in Dr. Berne’s Symptom Checklist on Phoenix Rising.  It appears to apply only to a subset of CFS patients.

One Model

First, let us understand how body temperature works:

“Chronic stress is known to affect serotonin (5HT) neurotransmission in the brain and to alter body temperature. The body temperature is controlled in part, by the medial preoptic area (mPOA) of the hypothalamus.” [2015]

Looking at hypothalamus and “chronic fatigue syndrome”, we find over 150 articles on PubMed. On serotonin “chronic fatigue syndrome” , we find over 100 articles. Both aspects have abnormalities with CFS.

• In myalgic encephalomyelitis/chronic fatigue syndrome, increased autoimmune activity against 5-HT is associated with immuno-inflammatory pathways and bacterial translocation. [2013]
• Increased autoimmune activity against 5-HT: a key component of depression that is associated with inflammation and activation of cell-mediated immunity, and with severity and staging of depression.[2012]

No effect found The effect of ondansetron, a 5-HT3 receptor antagonist, in chronic fatigue syndrome: a randomized controlled trial.[2010] For a more detail [technical] description see this 2011 article.

Interesting, there are sexual differences with 5HT which may be connected with the difference of incidence of CFS between males and females. [2015]

• Insomnia Caused by Serotonin Depletion is Due to Hypothermia. [2015] – which has implication on sleep issues with CFS.

My Experience

I am one of those patients whose temperature decrease with increased severity of symptoms. A temperature of 95.5 F (35.3C) was not unusual. As I recovered, the temperature slowly increased. The key is to make sure that you record the temperature at the same time and in the same circumstance each day. There is daily variation in temperature as the day goes on.

The bacterial translocation as a factor does bring us back to gut bacteria dysfunction. The low temperature is a symptom that can be used to monitor you state.

I have a news feed on items dealing with CFS.  Below are interesting notes from scanning the feed:

• Myalgic encephalomyelitis, chronic fatigue syndrome: An infectious disease. [2015]
• Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is associated with pandemic influenza infection, but not with an adjuvanted pandemic influenza vaccine. [2015]

Brain

• “We did not note increased all-cause mortality in people with chronic fatigue syndrome, but our findings show a substantial increase in mortality from suicide.” [2016]
• “The spontaneous brain electrical activities in CFS patients were significantly reduced. The abnormal changes in the cerebral functions were localized at the right frontal and left occipital regions in CFS patients.” [2016] Prior SPECT studies found hypoperfusion (low oxygen) in the brain which may be the cause.
• ” differences between FMS patients and controls in the insula, amygdala, anterior/mid cingulate cortex, superior temporal gyrus, the primary and secondary somatosensory cortex, and lingual gyrus.” [2016]
• ” Our results demonstrate altered functional connectivity of several regions associated with cognitive, affective, memory, and higher cognitive function in ME/CFS patients. Connectivity to memory related brain areas (para-hippocampal gyrus) was correlated with clinical fatigue ratings, providing supporting evidence that brain network abnormalities may contribute to ME/CFS pathogenesis.” [2015]

DNA

• ” Here 442 SNPs were identified as candidates for association with ME/CFS (adjusted P-value<0.05).” [2016]
• Mitochondrial DNA variants correlate with symptoms in myalgic encephalomyelitis/chronic fatigue syndrome.[2016] “Analysis of mitochondrial genomes in ME/CFS cases indicates that individuals of a certain haplogroup or carrying specific SNPs are more likely to exhibit certain neurological, inflammatory, and/or gastrointestinal symptoms.”
• Maintenance of Chronic Fatigue Syndrome (CFS) in Young CFS Patients Is Associated with the 5-HTTLPR and SNP rs25531 A &gt; G Genotype. [2015]

Supplements And Treatment

• ” Results from this study indicated that supplemental guanidinoacetic acid can positively affect creatine metabolism and work capacity in women with CFS, yet GAA had no effect on main clinical outcomes, such as general fatigue and musculoskeletal soreness.” [2016]  – in other words, better labs, no symptom change.
• “Changes in patients who showed a clinically significant change in faecal Streptococcus after treatment[erythromycin 400 mg b.d. for 6 days] (responders; defined as post-therapy distribution<6%) were compared to participants who did not respond to treatment. In the seven responders, there was a significant increase in actigraphic total sleep time (p=0.028) from baseline to follow up, compared with non-responders…Improved vigour scores were associated with a lower Streptococcus count …  poorer mood was associated with higher Lactobacillus …. Short term antibiotic treatment appears to be insufficient to effect sustainable changes in the gut ecosystem in most CFS participants.” [2015]

Symptoms

• “FM patients had an approximately 1.40-fold risk of dry eye syndrome than those without FM.” [2016]
• “When initiating gate, 23.5% of patients with CFS looked toward the ground compared with only 2.6% of nondisabled controls. After 7 m, subjects were asked to close their eyes, and after another 7 m, they were asked, “How much is 100 minus 7?” Of the patients with CFS, 55.9% stopped walking compared with 5.3% of nondisabled controls” [2015]
• “Upon exercise challenge, there were significant changes in the abundance of major bacterial phyla in the gut in ME/CFS patients not observed in healthy controls. In addition, compared to controls clearance of bacteria from the blood was delayed in ME/CFS patients following exercise.” [2015]
• Increased Vulnerability to Pattern-Related Visual Stress in Myalgic Encephalomyelitis. [2015]
• Altered resting-state functional connectivity in women with chronic fatigue syndrome. [2015]
• Reductions in circulating levels of IL-16, IL-7 and VEGF-A in myalgic encephalomyelitis/chronic fatigue syndrome. [2016]
• Extended B-cell phenotype in patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A cross-sectional study. [2015]
• Serum Immune Proteins in Moderate and Severe Chronic Fatigue Syndrome/Myalgic Encephalomyelitis Patients.[2015]
• Cytokine inhibition in chronic fatigue syndrome patients: study protocol for a randomized controlled trial. [2015]
  • Evidence for abnormal cytokine expression in Gulf War Illness: A preliminary analysis of daily immune monitoring data. [2015]
• Frequent IgG subclass and mannose binding lectin deficiency in patients with chronic fatigue syndrome. [2015]
• Antibodies to β adrenergic and muscarinic cholinergic receptors in patients with Chronic Fatigue Syndrome. [2016]
• Longitudinal analysis of immune abnormalities in varying severities of Chronic Fatigue Syndrome/Myalgic Encephalomyelitis patients. [2015]

A reader asked my opinion on helminth theraphy for CFS? “Helminths , also commonly known as parasitic worms, are large multicellular organisms, which when mature can generally be seen with the naked eye. They are often referred to as intestinal worms …” Wikipedia. The question came from reading this article in the Guardian.

Since the goal of this blog is to get rid of a stable dysfunction microbiome — the use of intestinal worms has a conceptual logic. So, what evidence is there to support it use, either direct or indirect?

Human Studies

• “promising results from using experimental hookworm infection to reduce gluten sensitivity in celiac disease patients.” [2015]
• Experimental hookworm infection and escalating gluten challenges are associated with increased microbial richness in celiac subjects. [2015]
• Differences in the Faecal Microbiome in Schistosoma haematobium Infected Children vs. Uninfected Children. [2015]
• The microbiota and helminths: sharing the same niche in the human host. [2014]
• ” Our data show that, although hookworm infection leads to a minor increase in microbial species richness, no detectable effect is observed on community structure, diversity or relative abundance of individual bacterial species.”[2014] NOTE: This was done on HEALTHY individuals, which suggests that it may normalize unhealthy gut bacteria.
• Evaluating the role of intestinal parasites in the high rates of irritable bowel syndrome in South America: a pilot study. no significant correlation was found

Impact on Microbiome

• “a significant increase in the abosamal pH was observed in infected goats…, the infection altered the abundance of approximately 19% of the 432 species-level operational taxonomic units (OTU) detected per sample. ….A total of 30 taxa displayed a significantly different abundance between control and infected goats.”[2016]
• ” The results suggest that in clinically heathy dogs and cats, helminths and protozoa are associated with different microbiomes and possibly variable gut microbiota functions.” [2015]
• ” microbiota compositional shifts during helminth infection contribute to the multifaceted ways that helminths modulate host immunity.”  [2015]
• “Recent studies reported that the presence of helminth infection alters the composition of the bacterial intestinal microbiota and, conversely, that the presence and composition of the bacterial microbiota affect helminth colonization and persistence within mammalian hosts.” [2015]
• Suppression of inflammation by helminths: a role for the gut microbiota? [2015]
• Alteration of the rat cecal microbiome during colonization with the helminth Hymenolepis diminuta.[2015]

Bottom Line

The approach appears viable and with the right species [2014], there is a hint that it will normalize an unhealthy microbiome. I suspect that it is not a “single treatment magic silver bullet”, it should be part of a systematic plan to correct and maintain a healthy microbiome.

Explaining Chronic Fatigue Syndrome and related conditions to people (employee, friends, family, etc) who has no direct experience can be a thankless, exhausting and frustrating experience.

The root problem in explaining is the listener may not be able to relate to what is being described. Often CFSers go into whatever is a current theory or the results of dozens of tests. Some conditions, like Irritable Bowel Disease, UC, or Crohn’s are easier to explain because most people have experience food that have not agreed with them — thus they have something concrete to relate to.

I have a model of what CFS is and I am inclined to explain the model. The following is my monologue….

“My illness or disease is simple to understand but very hard to treat. As a result of an illness [even if it is due to stress, I would keep to citing illness — mentioning stress will send the listener down a different path], likely flu or some travel related bug, I became sick. I recovered from it but the symptoms returned afterwards — it is sometimes called post infection syndrome. The same thing is well documented wtih giardiasis and other infections. Many of these infections have mild symptoms or are hard to detect. With the Bergen giardiasis epidemic, they estimated 1/3 of those infected did not have symptoms severe enough to see a doctor, or were false-negative to lab tests.

There is a paper from 2010 titled “Giardiasis–why do the symptoms sometimes never stop?” which cites “disturbances in the gut mucosa“. A friend, DanB, came down with CFS after a trip to central America — I believe this is one of the best documented model of how CFS occurs.

Let me explain, when you get an infection, it changes gut bacteria. The changes are very distinct and researchers have found that they can identified many diseases by just looking at the changes in gut bacteria with 90% accuracy.  When you get over the infection, the gut bacteria should return to normal . The key word is should.  “After giardiasis enteritis at least 5% developed clinical characteristics and functional impairment comparable to previously described post-infectious fatigue syndrome.”[2012]

“Prospective studies have shown that 3% to 36% of enteric infections lead to persistent new IBS symptoms; the precise incidence depends on the infecting organism.” [2009]

Bergen, Norway is better than Incline Village!

In 2004, Bergen, Norway had a major epidemic of giardiasis and because of the national medical system, they were able to measure what actually happens and follow all of the patients through the years – something impossible in the US. They verified by lab tests that the giardiasis was successfully treated. They also found that infections of cryptosporidum parvum increased as a side effect. “One-third of the patients experienced recurring symptoms after treatment” [2009]

So 1/3 did NOT return to normal within a year.

• At 2 years: “among 82 patients with persisting abdominal symptoms elicited by the Giardia infection…We found that 66 (80.5%) of the 82 patients had symptoms consistent with irritable bowel syndrome (IBS) and 17 (24.3%) patients had functional dyspepsia (FD)” [2009]
• “Fatigue was reported by 41%, whereas 38% reported abdominal symptoms, and there was a highly significant association between these symptoms. Increasing age was a highly significant risk factor for fatigue. The symptoms were not due to chronic infection in this cohort.” at 2 years after the infection [1262 patients] [2009]
• “Patients with post-giardiasis IBS suffer very little somatic comorbidity, suggesting that the aetiology of this form of postinfective IBS is predominantly biological in origin and may thus differ from the more common, non-postinfective forms of IBS.” [2009]
• At 3 years, “The prevalence of IBS in the exposed group was 46.1%…  Chronic fatigue was reported by 46.1%” [2012]
• “A total of 58 (60%) out of 96 patients with long-lasting post-infectious fatigue after laboratory confirmed giardiasis were diagnosed with CFS … At the time of referral (mean illness duration 2.7 years) 16% reported improvement, 28% reported no change, and 57% reported progressive course with gradual worsening. ” [2012]

This outbreak, like CFS, mainly affected females “Young women have previously been reported as the predominant group infected during a waterborne giardiasis outbreak, due to elevated water consumption. Here, the demographics of those subsequently infected are described, and young women again predominate. As secondary cases were not waterborne, this cannot be attributed to drinking habits.” [2008]

In 2007, ” Both these findings subsided overtime. Increasingly, investigations could not determine a definite cause for the persistent symptoms. The very long-term post-giardiasis diarrhoea, bloating, nausea and abdominal pain documented here need further study.” and ” In conclusion, patients with Giardia-induced gastrointestinal symptoms developed both IBS and FD. They exhibited gastric hypersensitivity with lower drinking capacity and delayed gastric emptying.” [2007]

Is giardia the source of CFS?

The answer is that it can be a cause of CFS in some. There appear to be many infections that can result in post-infection fatigue syndrome.  What is striking about this epidemic is that the results matches the general population of CFS patients

• Mainly female patients (almost the same ratio of males to females – 86% female [2012])
• 80% had IBS, this is also the rate with CFS in some studies
• Symptom improvement from tetracycline or the use of live faecal flora (quasi fecal transplant) occurs in both, and with both, disappears if not maintained.
  • ” Nevertheless, short-term therapy with either antibiotics or probiotics does seem to reduce symptoms among IBS patients. It seems most likely that the benefits of antibiotic therapy are mediated through subtle and, perhaps, localized, quantitative and/or qualitative changes in the colonic flora.” [2007]

Treatment

A 2008 study on persisting symptoms after Giardia infection found that “tetracycline and folic acid for 28 days..  the improvement was significant for the T/F group…One month after treatment, in the T/F group (23.1%) .. reported global symptom improvement. Symptoms recurred in all of these, and after 1 y total symptom scores were unchanged from baseline”.

“Eighteen received treatment with rifaximin plus metronidazole (8-10 days) whereas 10 received a suspension of live faecal flora, installed into the duodenum during gastro-duodenoscopy… total customary symptom scores were barely significantly reduced (p = 0.07) after antibiotics, but were highly significantly reduced (p = 0.0009) after bacterio-therapy. However, symptom improvement following bacterio-therapy did not persist 1 year later…. High faecal excretion of fat and SCFAs suggests that intestinal malabsorption of fat and carbohydrates may play a role in the IBS-like complaints of these patients.” [2009]

Bottom Line

CFS is CFS — the triggering cause may be different, but the results are similar. Above we find that tetracyclines improved (temporarily) as did live faecal flora being implanted (think of fetal transplants). The problem is getting the gut bacteria back to normal and keeping it there until it is stable.

Articles:

• [A modern epidemic]. 2004
• Cryptosporidium parvum infections in Bergen, Norway, during an extensive outbreak of waterborne giardiasis in autumn and winter 2004. [2006]
• [Uncovering the giardiasis-outbreak in Bergen 2004]. [2007]
• Effects of albendazole/metronidazole or tetracycline/folate treatments on persisting symptoms after Giardia infection: a randomized open clinical trial. [2008]
• Persisting symptoms and duodenal inflammation related to Giardia duodenalis infection. [2007]
• Subjective health complaints and quality of life in patients with irritable bowel syndrome following Giardia lamblia infection: a case control study.[2009]
• High rate of fatigue and abdominal symptoms 2 years after an outbreak of giardiasis.[2009]
• Antibiotic or bacterial therapy in post-giardiasis irritable bowel syndrome. [2009]
• High rate of fatigue and abdominal symptoms 2 years after an outbreak of giardiasis. [2009]
• Severity of Giardia infection associated with post-infectious fatigue and abdominal symptoms two years after. [2009]
• Irritable bowel syndrome and chronic fatigue 3 years after acute giardiasis: historic cohort study. [2012]
• Chronic fatigue syndrome after Giardia enteritis: clinical characteristics, disability and long-term sickness absence. [2012]
• The impact of atopic disease on the risk of post-infectious fatigue and irritable bowel syndrome 3 years after Giardia infection. A historic cohort study. [2012]
• Immunophenotyping in post-giardiasis functional gastrointestinal disease and chronic fatigue syndrome. [2012]
• Chronic fatigue syndrome 5 years after giardiasis: differential diagnoses, characteristics and natural course. [2013]
• Irritable bowel syndrome and chronic fatigue 6 years after giardia infection: a controlled prospective cohort study. [2014]
• The relationship between irritable bowel syndrome, functional dyspepsia, chronic fatigue and overactive bladder syndrome: a controlled study 6 years after acute gastrointestinal infection. [2015]
• Perceived food intolerance and irritable bowel syndrome in a population 3 years after a giardiasis-outbreak: a historical cohort study. [2015]