Category Archives: Mood Disorders

A Tale of Recovery from Panic Disorder and OCD

Posted by on January 8, 2013 225 comments

Allison is a nutritional medicine student in Australia whose story illustrates many of our favorite themes – the importance of a healthy ancestral diet and good nourishment; the significance of infections in disease; the value of diagnostic profiling such as stool tests; and the potential value of antibiotics and fecal transplants as therapies for diseases not normally considered to be infectious. Most of all, she shows that in chronic disease, there is always ground for hope. Here’s Allison!  – Paul

When you are convinced that it is raining inside of a bus, sensing the rain drops on your skin, you know that something is very wrong. That was my experience after collapsing at work in London in July 2008, where I had moved in 2007 for the working holiday that’s so much a part of the Australian experience for many young people. After working too hard in my job, I’d picked up a virus which started off as a sore throat and then suddenly escalated to much more. I tried going back to work after two weeks at home resting, but it was to no avail. I had no energy, had trouble standing upright and was so spacey, I felt like I was on another planet – or not on any planet at all.

I’m now writing this from the safety of the other side of what can only be described as a personal hell on Earth. Four years on from that virus, and about ten years after I first started to experience post-viral fatigue episodes, I have finally been given the gift of answers as to what has wreaked so much havoc on my life. I feel incredibly lucky after all this time that the universe has given me answers, when so many people I care about in the online health groups I frequent, don’t seem to be so fortunate. I’m not particularly religious, but getting answers is akin to a miracle.

I’ll backtrack a little to 1999 at age 22 when I had a bout of glandular fever (known as “mono” in the US). I’d watched my elder brother deal with chronic fatigue syndrome in the late 1980s and knew just how bad it could be. It took me about 6 weeks to recover, but I don’t think my health was ever really the same. As a young girl, I was very sporty and academic. But as I got older and I experienced these viruses (to this day I don’t know exactly what virus they were), I was not the same healthy person. I always felt much more tired than other people and was prone to depression, stress intolerance and self-loathing. In the early 2000s, I was able to work full time and had a pretty good social life but I had odd reactions to straightforward procedures like wisdom tooth removal, root canal and vaccinations. Those dental procedures left me feeling flu-like for weeks and the Hepatitis B vaccination needed for overseas travel left me with a large grey patch of raised skin on my inner thigh.  In 2006, things started unravelling for me. After a bad relationship breakup, I picked up yet another virus and felt very dizzy and spaced out. I quickly developed severe muscle weakness and could hardly get out of bed. After about 6 weeks, I returned to work but experienced excruciating headaches and a sudden bout of claustrophobia on a train while commuting to work. In early 2007, I had a repeat of the very same thing for the same length of time. Mum would drive me to the beach for some sea air and I struggled to get my leg muscles to work so I could simply walk on the sand. When I returned to work, I resigned as it was quite a negative environment anyway – except for some of the lovely people I had the pleasure to work with. I was determined that my plans to move to London for a working holiday in mid-2007 would still hold. After “recovering” from that latest bout of post-viral fatigue, I found a contract job so I could save money for my big adventure. The only problem was that at that new job, I developed severe anxiety which left me paralysed at work and wanting to flee – almost all day, every day. My stress tolerance was non-existent. I didn’t seek help at all for the anxiety, I wish I had. Somehow, I managed to make it to the end of that contract and felt proud of myself for getting to the end of it and leaving the project in a pretty decent state for handover. With that, I took off for London.

In London, things were great for the most part but I still had anxiety at work, poor stress tolerance and was pushing myself too hard at work in a less than ideal physical environment – think cramped working conditions with not much fresh air and no air-conditioning. Welcome to modern London! I made it to December 2007 and planned a trip home to escape the London winter, but I developed a serious flu which finally subsided after several weeks but not without making me feel awful and scaring the life out of me. I did well when I was back home for three months and then returned to London again. I only lasted a couple of months before that sore throat I mentioned showed up and kicked off a whole lot of problems.

Literally overnight, I developed about thirty upsetting symptoms that were so bizarre I just couldn’t wrap my head around them. This was not the usual virus and post-viral fatigue episodes I had experienced. It was different. The worst symptoms were:

  • Severe thyroid pain that alternated between stabbing sensations and a vague feeling of pressure
  • Hot and cold body temperature fluctuations, so much so that on a 23C day in London, I could only relieve my body heat by taking a cold bath for half an hour
  • Intense muscle aching around my shoulder and neck region that was only partially helped by holding a bottle of frozen drink to the area
  • I needed to urinate every half hour and every hour overnight – that was quite unpleasant!
  • Constant crying at the drop of a hat. I would call my parents back home in Australia every day and cry. I also saw a couple of health practitioners when I was there (some were doctors, some were “alternative” practitioners such as a naturopath) and I would just constantly cry. Obviously, I was really afraid of what was happening to me, but the crying was excessive
  • I had disturbing thoughts, usually at night time, such as thinking I wanted to jump out of the window of my fifth floor apartment. I also had that very odd experience of rain inside the bus
  • The apartment building also had no lifts, so getting back up to the apartment was a real test of my will, since my legs had stopped functioning
  • I was very dizzy and mentally spaced out
  • Alcohol tolerance was non-existent. During this period, it was my birthday and one of my dear new London friends took me out and I felt so drunk on just a few sips of cider.

The doctors that I consulted during this period were not all that helpful. One was very blunt and told me I had chronic fatigue syndrome and to come back in two months for assessment for a hospital in-patient program. A neurologist I had seen in Sydney in 2007 about my excruciating headaches concluded that since an MRI showed no abnormalities, that my problems were all psychological and I should get myself some Vitamin Z, medico slang for Prozac. He also prescribed Endep for the headaches which didn’t help. Of course, being a crying mess out of frustration and fear from all of these post-viral episodes will typically make a doctor assume the whole thing has a psychological basis.

After two months of no improvement, I had to make the difficult decision to come home to Australia as it represented the best chance I would have to recover, surrounded by supportive family, friends and an environment more conducive to healing. Sorry London, but sunshine and clean air are a necessity for me! I felt like a failure but I knew it was the best choice I could make. I naively assumed I would be back in London in no time at all.

On the flight back home, I couldn’t access the sea salt I’d put in my bag that had successfully resolved the excess urination problem, so that meant I was visiting the plane bathroom every half an hour for almost the entire trip. I wonder what the passengers next to me thought! I got back home to Australia and remember feeling very, very spacey, cold and out of it. I was very relieved to be back home though without the pressures of paying for rent and looking after myself. My Mum to this day has no idea how I made it home on my own and I don’t either. I guess I was just on auto-pilot, desperate to get back home to start healing.

I had pinned all of my problems on thyroid and adrenal issues – this turned out to be partly true, but these were more symptoms of an underlying problem than an actual cause itself. It took me a while to figure that out, which unfortunately was time I could have been treating the foundations with diet and targeted supplementation. I was unable to convince any endocrinologists I’d seen that I had a thyroid problem. All the testing I had (hormone levels plus antibodies) was “normal”, though an ultrasound showed decreased vascularity. They had no explanation for the thyroid pain I had, which incidentally disappeared once I started taking selenium in London. I was diagnosed by a holistic GP with hypothyroidism based on symptoms and started on T4-containing thyroid medication. Every attempt at any medication with T4 in it, synthetic or dessicated porcine thyroid, was a disaster leaving me even worse than off the medication. I’ve been on T3-only medication for a couple of years now and do quite well on it. I was also diagnosed in 2009 with a significant imbalance between levels of zinc and copper but I didn’t understand the implications of that, nor that I’d need to monitor it for life, so I took the supplements prescribed by a GP (general practitioner – the Australian equivalent of an MD) for only three months and gave up.

In late 2009, on Christmas Eve, I was driving back home after visiting a friend and I suddenly had an overwhelming sensation of intense fear wash over me and I thought to myself “I can’t remember how to drive, I have to stop the car and get out”. Time stood still and I desperately wanted to get out of the car and lie down on the median strip. I luckily made it back home but collapsed in a pool of adrenalin. That was the start of the most intense panic attacks you can imagine, something far worse than the anxiety I’d experienced before. I couldn’t drive because the panic was so intense and then the panic was occurring almost all the time – when I was a passenger in a car, on a train, on a bus, riding an escalator in a store, even going for walks in my beloved local park on the bay. I would get a sensation of primal fear and then think I wouldn’t be able to get home safely. Panic attacks were sometimes like a sudden powerful punch to the chest – at other times like a slowly rising tsunami. Home became my safe haven, but I even developed panic attacks at home. I would dread having to leave the house and cry because I hated that this had become my life. If it wasn’t bad enough having the physical symptoms I’d dealt with for years, the panic attacks almost did me in. I could feel agoraphobia approaching quickly and I knew without any doubt that I did not want this to be my life.

Skip to 2011 and things were so bad that I felt at breaking point. I couldn’t see a way out. I was having not just panic attacks but very intrusive thoughts of jumping in front of trains. I was despairing but not suicidal, so these thoughts scared me greatly and I felt I couldn’t trust myself. It made doing normal things that people take for granted almost impossible. I somehow managed to get by with family support, learning mindfulness techniques and breathing exercises. I tried neurofeedback for many sessions and sometimes felt an improvement only to regress again. I was trying to work during this period but it was just not manageable, my sleep quality was at an all time low and I would go to work in a daze, just waiting for the panic attacks to come which they did without fail every day. Having to commute home for an hour added to the problem – thinking about trying to catch the train home in peak hour was just torture. On one occasion, I had to run off a train as it was pulling in to a crowded station as I felt incredibly claustrophobic and fearful. I had somehow managed to complete a Masters Degree in 2010 but it was a struggle to sit in class with all of this going on. I would always sit near the door and didn’t contribute as much as I would have liked during class discussions. Often when I was a passenger in the car my Mum was driving, I would actually get out of the car at traffic lights while the car was stopped because I couldn’t handle being in the car stopped at lights as time stood still for an eternity – it was torture. Trying to rationalise just didn’t work – wherever this fear was coming from, it sure didn’t respond to rational self-talk.

A doctor that I started to see out of desperation in 2011 ordered a Bioscreen test to look at the gut levels of bacterial strains deemed by the researchers who established the lab to be significant in “mystery” ailments like chronic fatigue, behavioural and mental illnesses. Lo and behold, there were a lot of problems that came up on my results – extremely high levels of particular streptococcus strains and non-existent levels of many other bacterial strains considered essential. I had virtually no digestive symptoms at all though. My doctor didn’t really explain the significance of the streptococcus result as it pertains to mental health. I took a 12-day round of erythromycin, felt no different and left that by the wayside. Shortly after, I went to see another doctor that the neurofeedback practitioner worked with and the zinc:copper imbalance came up again and was confirmed as a likely contributor to many of my symptoms. I also had very low levels of B6 according to a Metametrix  organic acids test. My dream recall was non-existent but returned with P5P and B6 supplementation, so I obviously really needed it. I also had an igG subclass deficiency which has now resolved with guided zinc supplementation. Working on the zinc:copper balance has made a big improvement to my health – my immune system is now much more resilient. I haven’t had a post-viral episode for about two years now. I also made the switch to a Paleo diet in early 2011 after getting frustrated with my lack of progress. That has given me a great foundation with which to repair my broken body.

But, I still had panic attacks and increasing agoraphobia which were preventing me from participating in life and making me despair.  I was doing mindfulness and breath work, but they were really no match for it – they helped me cope but only just. Even the mirtazapine I had been taking, which at first was a godsend, had stopped being effective, so I knew I was in trouble. I stumbled on a blog from a fellow Australian called The Power of Poo when I was looking up some information for someone about histamine. In it, the author detailed the connection between streptococcus and mental health. That was a real lightbulb moment. I took this as a sign, so went back to the doctor who had prescribed the erythromycin and asked for two more rounds to see if it would make a difference. The side effects were awful – I felt like I’d been hit by a truck. But after a few weeks, the darkness enveloping me lifted and I felt so much more calm than I’d felt in a long time. I really couldn’t believe it.

Since then, I have re-tested the levels of gut bacteria and taken a few more rounds of erythromycin when I felt the panic attacks returning. I took that to be a sign that the streptococcus was still too high – that was confirmed with the re-testing which showed the streptococcus levels had reduced, but not nearly enough. I still have some episodes of anxiety, but they are nothing compared to the panic attacks I experienced. I am able to do things I had stopped doing – I’m now able to sit through an entire film in a cinema without leaving. I can leave the house without the thought of impending doom stopping me. I am slowly returning to driving but am taking things slow. I feel that the avoidance behaviours that took hold when the panic disorder was at its height need to be addressed somehow, so I try to do some informal exposure, though this isn’t easy when such strong memories are still there. But they are just that – memories.

In 2012, I came across information about a condition that is mostly documented in children and adolescents called PANDAS. The etiology of this condition involves strep throat triggering an immune and neurological response which leads to a range of symptoms including OCD, anxiety, autoimmune complications and excess urination. Bingo! When reading about it, I was convinced that this was what had happened to me. I spoke to one of my doctors about this and he has heard of adults being diagnosed with PANDAS, though there isn’t a lot of awareness of this condition – even less so when it applies to adults and even less so in Australia. My doctor tested my strep titres and one of them was high over range and the other was high in range. This, combined with my history and symptoms was enough confirmation for me. I am considering consulting with an immunologist who recognises PANDAS, though I don’t believe I need a formal diagnosis. I know this is what had tormented me.

I’m now looking at what my options are in the long term as I really do not want to be dependent on antibiotics to keep streptococcus levels under control and endless probiotics to re-populate the bacteria that have been decimated over the years. I’m investigating faecal transplant which has been incredibly successful in Clostridium difficile infections but is not widely recognised as a treatment for much else, especially conditions that are not obvious digestive problems.

Something that I don’t understand that bothers me greatly, is that the medical profession does not currently recognise the link between gut bacteria and mental health. There is acknowledgement that bacteria can cause illnesses such as bacterial pneumonia, endocarditis and rheumatic fever, but there is a gaping hole in the area of mental health and its connection to bacteria. Enlightened health professionals are well aware of this, but the average GP is not. How many people are needlessly suffering and only getting partial relief (if that) with medications? I know from my own experience that if I didn’t get the answer to my situation, I would either be dead, sectioned in hospital or completely agoraphobic and unable to leave my house. I am one of the lucky ones. Lucky that I had a supportive family, lucky that I could get information from the Internet (which often gets an unfair rap from medical professionals) and lucky that in my country, I can access and afford the testing and treatment I need.

I thank my lucky stars every day.

How to Recognize and Fix a Brain Infection

Posted by on July 20, 2011 195 comments

I thought I’d pull up an interesting tale from the comments. It is a great illustration of what we’re trying to accomplish on this blog.

Thomas first commented here on December 31:

I just got your book from a relative for Christmas (I told them to buy me it!) and am reading through it now. Very interesting, although some of it is beyond a simple layman like me.

The part of this blog post that starts “Thus common symptoms of a bacterial infection of the brain are those of cognitive hypoglycemia and serotonin deficiency” and continues for several paragraphs describes precisely the mysterious changes I have experience over the last decade of life (I am now 33), with the one variation being that I suffer extreme fatigue rather than insomnia or restlessness. Every other sympton, including the odd mental state you mention, is a perfect match, and I experience them all to a marked degree….

I have been diagnosed with general anxiety but never depression. I do not feel sad ever, just irritable and anhedonia-ac, if I may coin a word. Anti-depressants, and I’ve tried a bunch, do absolutely nothing for me.

Brain infections are widespread – I wouldn’t be surprised if 20% of the adult population has a brain infection of mild severity – but they are hardly ever diagnosed or treated.

Fortunately, there are some symptoms that are almost universally generated by brain infections, so it’s not necessarily that difficult to diagnose them. But I think no one knows the symptoms. Infections are generally allowed to progress for decades.

One of my crucial steps forward was when I recognized that I had the cognitive symptoms of hypoglycemia when my blood sugar was normal. I could relieve the symptoms if my blood sugar became highly elevated. Thinking about why that might be led me toward the idea of bacterial infections.

Thomas went on to describe the origin of his symptoms:

I began to decline after suffering the second subdural hematoma of my life at age 20 when I was in Italy, followed by a 5 year binge on alcohol.

This was another clue. Traumatic brain injuries, such as hematomas, often initiate brain infections, because they breach the blood-brain barrier. Alcohol is also a risk factor, as I pointed out in my reply to Thomas:

Alcohol abuse depresses bacterial immunity and would be a risk factor for a brain infection: http://www.ncbi.nlm.nih.gov/pubmed/16413723, http://www.ncbi.nlm.nih.gov/pubmed/20161709. Subdural hematomas frequently show infections, e.g. http://www.ncbi.nlm.nih.gov/pubmed/20430901.

We next heard from Thomas on February 22, when he had been on our diet for 7 weeks and had just tried his first ketogenic fast:

I’ve been doing PHD for about 7 weeks now, and tried a ketogenic fast this past weekend. I ended up going 33 hours with some coconut oil and cream. It was a bit tough having to eat a bunch of oil on an empty stomach, but nothing too bad.

I can’t say there was any improvement cognitively or with anhedonia, but there seemed to me to be a pronounced calming effect after about 24 hours of fasting. I often stutter or stumble over words (again, for about 10 years now), which usually goes away only with two or three alcoholic drinks. But the speech problems stopped almost completely during the fast, which makes me thing that there is some link to anxiety and stuttering.

Positive changes in brain function during ketosis suggest that the brain isn’t functioning normally when it relies on glucose as a fuel. There are several possible causes of this, but one is a bacterial infection. Another clue.

I generally recommend getting on our diet and supplement regimen, and reaching a stable health condition, before starting antibiotics. There are several reasons for this, which I’ll elaborate on later, but briefly:

  • Antibiotics work well on a good diet but may fail on a bad diet.
  • Pathogen die-off toxins can cause significant neurological damage and this toxicity may be substantially increased on a bad diet.
  • There is considerable diagnostic value in being able to clearly discern the reaction to antibiotics. Rarely is it certain that a brain infection is bacterial, or that the antibiotic in question is the correct one. To judge whether the antibiotic is working, it’s important that health be stable and as good as possible.

I therefore recommend being on our diet and supplement regimen for 3-4 months before starting antibiotics.

Thomas seems to have followed this advice, since he has just reported starting antibiotics:

I’ve been on PHD for a few months, and about a month ago went to the low-carb therapeutic ketogenic version of the PHD. After reading some of Paul’s posts, I believe that I might have a brain infection as a result of a head injury from more than a decade ago (Paul, if you recall, my condition has a lot of similarities to the one you once had). I started taking doxycycline a few days ago, and I have already noticed pronounced improvement (whether due to the diet or the antibiotic or both) in controlling the irritability and anxiety that have plagued me for years….

I definitely feel great since making the diet changes. My blood pressure, which has been creeping upwards over the last few years to 135/80 or so, is back down to 110/70. My testosterone is 824, and I am pleased to see that I maintaining my strength in the gym despite being on a ketogenic diet.

Pronounced improvement in the first days of doxycycline is quite possible, because doxy acts as a protein synthesis inhibitor. It essentially blocks bacterial functions and switches them into a state of hibernation. The bacteria are still there, but they are not interfering with brain function as much as before.

This improvement is confirmation that Thomas has a bacterial infection of the brain. If there were no infection, he wouldn’t notice an effect from the antibiotics.

Over a period of months, the doxycycline plus ketogenic dieting should help his innate immune defenses clear the brain of most bacteria. Combination antibiotic protocols may be even more effective.

In a follow-up comment, Thomas mentioned Ben Franklin and the blessing of good health:

Thanks for the response Paul, as well as all your help. If this works, I owe you my first-born child and then some! Ben Franklin (I think it was him) might have been right about health being the greatest blessing. The improvements I’ve seen recently have done more for my well-being than anything in the last decade, and I am profoundly grateful to you for all your excellent advice.

It’s comments like this that make blogging and book writing worthwhile.

It’s probably hard for those who have never had ill health to appreciate how enjoyable it can be for those with chronic diseases to recover good health. I’ve blogged on this before (Of Recovery, Hope, and Happiness, July 13, 2010 – don’t miss Ladybug’s painting).

Thomas, antibiotics and ketogenic dieting will work, I’m pretty sure. May you come to perfect health, and always remain grateful for the many blessings that are yours.

Seth Roberts and Circadian Therapy

Posted by on March 22, 2011 80 comments

A while back I noted that hypothyroidism is a circadian rhythm disorder and that dietary steps that restore circadian rhythms, like intermittent fasting and daytime eating, should be therapeutic (“Intermittent Fasting as a Therapy for Hypothyroidism,” Dec 1, 2010).

Many other disorders besides hypothyroidism feature disturbed circadian rhythms:

  • Sleeplessness and poor sleep
  • Depression, bipolar disorder, and other psychiatric disorders
  • Dyslipidemia, metabolic syndrome and obesity.
  • Neurodegenerative disorders

Circadian rhythm disruption also suppresses immune function and increases vulnerability to infectious disease.

Restoring or strengthening circadian rhythm may be therapeutic for all of these conditions. Even for healthy people, tactics for enhancing circadian rhythms may improve health.

Which brings us to Seth Roberts.

Seth Cured a Sleep Disorder With Circadian Therapy

Seth is a well-known blogger, a Paleo dieter and psychologist, author of  The Shangri-La Diet, and a great self-experimenter.

Seth recently gave a talk that tells the history of his self-experimentation.

It turns out he suffered from disturbed sleep for many years. He experimented to find cures for 10 years; nothing worked. But then he got a lead.

When a student suggested he eat more fruit, he started eating fruit for breakfast. His sleep got worse! This was exciting to Seth because it was, in 10 years, the first thing he tried that changed his sleep.

He had the idea of trying no breakfast. It turned out that skipping breakfast improved his sleep. One of his slides:

This directly supports our idea that intermittent fasting (confining eating to an 8-hour window each day) should be therapeutic for circadian rhythm disorders such as disturbed sleep and hypothyroidism.

But what’s exciting is that Seth continued his experiments to find other ways to improve his sleep. As a psychologist, he knew that human contact controls when we sleep: people are most awake at the times they have contact with other people, and asleep when isolated.

He knew that watching TV can have effects similar to socializing. So he tried watching Jay Leno one morning. He slept very well the next night.

It turns out that looking at human faces is almost as good as real socializing. Here is Seth’s data relating mood to whether he looked at faces:

Seth also tracked his mood over the course of the day. The response of mood to seeing pictures of human faces clearly followed a circadian (24-hour) rhythm:

Another thing that relates to circadian rhythms is exercise: we normally exercise during the day and rest at night.

For a scholar, the easiest way to exercise is to stand rather than sit (for instance, by working at a standing desk). Seth tried standing 9 hours a day – and it cleared his sleep problem!

Of course, standing is not a very strenuous exercise. Seth found that if he just stood on one leg, the effect was much more intense, and he could fix his sleep problem with only minutes of one-legged standing per day.

He also found that eating more animal food improved his sleep. It’s possible that animal fat may enhance circadian rhythms more than other foods.

Conclusion

I found this fascinating – because it adds more evidence regarding the centrality of circadian rhythms in health – and exciting, because it shows that simple tactics can be therapeutic for circadian rhythm disorders.

In the hypothyroidism post, I suggested the following tactics for improving circadian rhythms:

  • Light entrainment: Get daytime sun exposure, and sleep in a totally darkened room.
  • Daytime feeding: Eat during daylight hours, so that food rhythms and light rhythms are in synch.
  • Intermittent fasting: Concentrate food intake during an 8-hour window during daylight hours, preferably the afternoon. A 16-hour fast leading to lower blood sugar and insulin levels, and the more intense hormonal response to food that results from concentration of daily calories into a short 8-hour time window, will accentuate the diurnal rhythm.
  • Adequate carb intake: Eat at least 400 “safe starch” carbohydrate calories daily during the afternoon feeding window. Relative to a very low-carb diet, this will increase daytime insulin release and, by increasing insulin sensitivity, may reduce fasting insulin levels. It will thus enhance diurnal insulin rhythm.

To these, we can add several more based on Seth’s findings:

  • Looking at human faces: If you work at a computer, keep a window up that cycles among photos of faces, or shows a video of a talk show; keep photos of your family near your screen.
  • Standing: Work at a standing desk or, failing that, get in the habit of standing on one leg rather than two.
  • Animal fat: Eat a diet high in animal fats.

These tactics cured Seth’s sleep disorder. Might these tactics also cure or greatly improve other circadian rhythm disorders – including hypothyroidism and psychiatric disorders like depression and bipolar disorder? Could looking at human faces help the obese lose weight and improve their lipid profiles?

I don’t know but I’d certainly give these techniques a try before pharmaceutical drugs. I believe these techniques deserve clinical testing as therapies for all diseases associated with disrupted circadian rhythms. I believe that they may be just as beneficial for the healthy: by improving immune function, they may delay aging and extend lifespan.

A few weeks ago, when I posted a video of Don Rumsfeld defending the use of a standing desk (the same video was later linked by John Durant and Mark Sisson), I brashly stated, “There are few single life adjustments more likely to improve your health than working at a standing desk.”

Perhaps that statement wasn’t as exaggerated as it may have seemed!

Seth’s Talk

Tryptophan Poisoning and Chronic Infections

Posted by on December 21, 2010 14 comments

On Friday I discussed a recent paper showing that a high-tryptophan diet caused mice, after 4 to 12 weeks, to start harming themselves by tearing out fur from their bellies and forepaws. The mice also developed ulcerative dermatitis – open sores on their skin. [1]

I closed with a promise that on Monday I would suggest some reasons why a high tryptophan diet might cause these diseases.

However …

C57BL/6 Mice Are Prone to Ulcerative Dermatitis

The breed of mice used in the study, C57BL/6 mice, are an inbred strain featuring some genetic mutations which make them prone to ulcerative dermatitis and compulsive behavior.

Upon looking into the literature, it seems that if you look at these mice cross-wise they get ulcerative dermatitis.

For instance, vitamin A causes ulcerative dermatitis in these mice because of mutations that impair the disposal of excess retinol:

A number of C57BL/6 (B6) substrains are commonly used by scientists for basic biomedical research. One of several B6 strain-specific background diseases is focal alopecia that may resolve or progress to severe, ulcerative dermatitis…. Four B6 substrains tested have a polymorphism in alcohol dehydrogenase 4 (Adh4) that reduces its activity and potentially affects removal of excess retinol. Using immunohistochemistry, differential expression of epithelial retinol dehydrogenase (DHRS9) was detected, which may partially explain anecdotal reports of frequency differences between B6 substrains. The combination of these 2 defects has the potential to make high dietary vitamin A levels toxic in some B6 substrains … [2]

Malnourishment seems to lead to spontaneous development of ulcerative dermatitis. The cause may be oxidative stress, since supplemental vitamin E cures the ulcerative dermatitis:

In this study, we fed a standard NIH-31 diet fortified with vitamin E to C57BL/6 mice and strains of mice with a C57BL/6 background that had spontaneously developed ulcerative dermatitis (UD)…. Of 71 mice, 32 (45%) had complete lesion re-epithelialization with hair regrowth. Complete lesion repair was not influenced by sex, age, or coat color. The average time to complete lesion repair ranged from 2 to 5 weeks, and there was no correlation with sex or coat color. The positive response to vitamin E suggests that protection from oxidative injury may play a role in the resolution of UD lesions … [3]

When scientists studying cancer applied a carcinogenic toxin to the skin of these mice, they developed not cancer but – you guessed it – ulcerative dermatitis:

In this study, heterozygous p53-deficient (p53(+/-)) mice … and wild-type (WT) litter mates were subjected to a two-stage skin carcinogenesis protocol with 7,12-dimethylbenz[a]anthracene and 12-O-tetradecanoylphorbol-13-acetate. Instead of skin carcinomas, however, the chemical treatment protocol caused ulcerous skin lesions, and 89% of mice fed ad libitum died from infection/septicemia. When WT mice were restricted to 60% of the average calorie intake of the respective ad libitum group, however, only 33% developed such lesions, and the CR mice survived twice as long on average as the ad libitum mice. [4]

It’s interesting that calorie restriction reduces the ulcerative dermatitis rate. Note that the mice went on to die of sepsis from an unknown infection; this suggests that these mice probably had some chronic pre-existing infection that was laying dormant, but emerged to become acute when the mouse was stressed by the toxins.

So far we’ve seen that malnutrition (lack of antioxidants) and exposure to toxins (vitamin A, carcionogens) can cause ulcerative dermatitis. Our three major causes of disease are malnutrition, toxins, and pathogens, so to complete our survey we should check whether infections cause ulcerative dermatitis in these mice.

Indeed they do. The most common infection in laboratory mice is fur mites, and fur mite infections induce ulcerative dermatitis in all strains of C57BL mice. [5]

Since diseases become more common with age, we shouldn’t be surprised to see that the rate of spontaneous ulcerative dermatitis rise with age in these mice:

A spontaneous, severely pruritic ulcerative dermatitis was initially observed in 33/201 (16.4%) aged C57BL/6NNia mice obtained from the National Institute of Aging. This ulcerative dermatitis also developed in 21/98 (21%) aged C57BL/6 mice in a subsequent experimental group obtained from the same source. The average age of onset in the initial group was 20 months. These animals were negative for ectoparasite infestation and primary bacterial or fungal infection. The lesions varied from acute epidermal excoriation and ulceration to chronic ulceration with marked dermal fibrosis…. The elucidation of the pathogenesis of this disease is important because of the significant percentage of animals affected … [6]

Given that there are so many possible triggers of ulcerative dermatitis in these mice, I decided to shift the topic of this post a bit, and focus on the specific possibility that chronic infections might play a role.

Lab Mice Are At Risk For Chronic Infections

As I’ve said many times, everyone gets chronic infections. The world is saturated in germs, and sooner or later the ones that can maintain persistent infections take up residence in all of us. So health is determined by the relative balance of power between immune system and pathogens, not by exposure.

Lab mice are at heightened risk for chronic infections because of their living conditions. In the case of the tryptophan-poisoned mice, here’s a description of their accommodations:

All subjects were adult (over 6 months of age) C57BL/6 mice, bred from C57BL/6J progenitors, and housed with same-sex siblings…. Lights were on a 14-10-h light-dark cycle. Mice were caged in standard shoebox cages (12.7 cm high, 433 cm2 floor area) with wire lids…. Ages ranged from 24-66 weeks of age (mean, 47 weeks). The number of mice per cage was variable, ranging from 2-4 mice per cage. [1]

These shoebox cages are small: 433 cm2 floor area translates to roughly 15 by 29 cm or 6 by 11 inches. The lid is 5 inches high. With four mice to a cage, each mouse gets a 3 by 5 inch area.

There is little room to exercise. Crowding is stressful.

Moreover, there is no natural sunlight, and therefore no vitamin D production.

All of these factors tend to impair immune function. Their casein, cornstarch, and soybean oil diets can’t be helpful to immune function either.

Cages are generally fairly closely packed in animal facilities. The mice generally cannot touch mice in adjacent cages, but respiratory pathogens and fur mites spread easily. If one mouse in a facility gets fur mites, usually all the others get infected soon afterward, and the whole room has to be quarantined.

Note also that the mice are old enough – 6 to 15 months – to have had extensive exposure to any chronic pathogens carried by either their mouse neighbors or their human handlers.

So it wouldn’t be surprising if the lab mice in this study had chronic infections.

Chlamydiae Infections in Lab Mice

C. pneumoniae is a zoonotic bacterium that crossed from reptiles to mammals about 60 million years ago and can infect both humans and animals.

Unfortunately, nobody seems to have bothered to see if C. pneumoniae is commonly present in “healthy” lab mice. However, in test tubes C. pneumoniae infects mouse brain cells just fine:

Inspired by the suggested associations between neurological diseases and infections, we determined the susceptibility of brain cells to Chlamydia pneumoniae (Cpn). Murine astrocyte (C8D1A), neuronal (NB41A3) and microglial (BV-2) cell lines were inoculated with Cpn…. Our data demonstrate that the neuronal cell line is highly sensitive to Cpn, produces viable progeny and is prone to die after infection by necrosis. Cpn tropism was similar in an astrocyte cell line, apart from the higher production of extracellular Cpn and less pronounced necrosis. In contrast, the microglial cell line is highly resistant to Cpn as the immunohistochemical signs almost completely disappeared after 24 h. Nevertheless, significant Cpn DNA amounts could be detected, suggesting Cpn persistence. [7]

So in the mouse glial cells which were most resistant, C. pneumoniae could maintain infections even if it didn’t do much. In mouse neurons and astrocytes, C. pneumoniae was able to reproduce freely and would eventually kill the cells.

In a different mouse microglial cell line, EOC-20, C. pneumoniae replicates rapidly, increasing 9-fold in 3 days. [8] So it appears that C. pneumoniae can infect all the major cell types of the mouse brain.

In humans, C. pneumoniae generally reaches the brain by first infecting the blood vessels that feed the brain. In our C57BL/6 mice, C. pneumoniae can create a vascular infection after a single dose in the nose:

In C57BL/6J mice on a nonatherogenic diet, C. pneumoniae were detected in the aorta only 2 weeks after a single intranasal inoculation in 8% of mice. The persistence of C. pneumoniae in atheromas suggests a tropism of C. pneumoniae to the lesion. [9]

Repeated inoculation of C57BL/6J mice resulted in inflammatory changes in the heart and aorta in 8 of 40 of mice … [10]

In a ranking of mouse strains in susceptibility to C. pneumoniae infection, C57BL/6 mice occupy a middle position:

The first mouse models for C. pneumoniae infection … used several mouse strains that differed in susceptibility to infection. Swiss Webster mice and NIH/S mice were highly susceptible, followed by C57BL/6 mice, whereas BALB/c mice were least susceptible. [11]

C. pneumoniae infection typically begins with a brief, mild respiratory infection that is followed by spread of the pathogen to other organs via infected white blood cells and establishment of a persistent infection:

Infection of mice with C. pneumoniae resulted in a self-limiting pneumonia [30–32,77]. Depending on the dose given, mice displayed symptoms, like dyspnea, weakness and weight loss. The symptoms reached a maximum within 2 to 4 days and rarely lasted longer than 1 week….

Isolation of viable C. pneumoniae organisms from the lungs was generally possible up to 4 weeks after infection and occasionally up to 6 weeks [31,32,42,47,49,52,54,66,72]. However, C. pneumoniae antigens and DNA were detected in the lungs for a much longer period, up to 20 weeks after infection [42]. The presence of C. pneumoniae antigens in the lungs was limited to macrophages in alveoli and bronchus-associated lymphoid tissue [63]. These findings suggested a latent persistence of the organisms, which was confirmed by reactivation of pulmonary infection using cortisone-induced immunosuppression experiments [50,51]….

C. pneumoniae infection was not limited to the respiratory tract only. Following local infection, spreading of C. pneumoniae to multiple organs throughout the body was detected by PCR and immunohistochemical staining up to 20 weeks [42]. The dissemination was probably mediated by peripheral blood monocytes as they were positive both by PCR and isolation in some studies, whereas blood plasma was negative [38,47]. [11]

Interferon Gamma and the Immune Defense Against Chlamydiae

In both humans and mice, immune defense against Chlamydiae is mediated principally by interferon gamma. Mice that lack interferon gamma or its receptor suffer prolonged severe infections:

The central role of IFN-? in clearance is evidenced by prolonged infections that occur in IFN-?, and IFN-? receptor-, deficient mice (10, 11). [12]

Infant mice exposed to Chlamydiae die within 2 weeks if they lack interferon gamma:

Importantly, infected mice deficient in IFN-gamma or IFN-gamma receptor demonstrated enhanced chlamydial dissemination, and 100% of animals died by 2 wk postchallenge. [13]

Might Chlamydia Infection Have a Connection to Compulsive Behavior and Ulcerative Dermatitis?

I started looking into these Chlamydia infection papers to see if they might explain why C57BL/6 mice given high levels of tryptophan might develop compulsive behavior and ulcerative dermatitis.

It’s possible. The logic goes like this.

First, tryptophan is crucial to Chlamydial growth; it is a precursor to niacin, the key vitamin of bacterial metabolism, and is also essential to a number of Chlamydial proteins. So a high-tryptophan diet will promote Chlamydiae infections.

Chlamydiae trigger the innate immune response mediated by interferon gamma.

So interferon gamma will be elevated in Chlamydiae-infected mice. Interestingly, the only study I found that gave interferon gamma directly to mice found that it caused ulcerative dermatitis:

Daily subcutaneous doses of 0.02, 0.2, or 2 mg/kg/d of recombinant murine interferon-gamma (rmuIFN-gamma) were given to mice on postnatal days 8 through 60 … Males given 0.2 and 2 mg/kg/d had swelling and ulcerative dermatitis around the urogenital area, which were observed after sexual contact and attributed to a bacterial infection. [14]

What about the compulsive behavior? Well, in mice one of the principal effects of interferon gamma is to stimulate the release nitric oxide (NO):

Gamma interferon (IFN-gamma)-induced effector mechanisms have potent antichlamydial activities that are critical to host defense. The most prominent and well-studied effectors are indoleamine dioxygenase (IDO) and nitric oxide (NO) synthase. The relative contributions of these mechanisms as inhibitors of chlamydial in vitro growth have been extensively studied using different host cells, induction mechanisms, and chlamydial strains with conflicting results. Here, we have undertaken a comparative analysis of cytokine- and lipopolysaccharide (LPS)-induced IDO and NO using an extensive assortment of human and murine host cells infected with human and murine chlamydial strains. Following cytokine (IFN-gamma or tumor necrosis factor alpha) and/or LPS treatment, the majority of human cell lines induced IDO but failed to produce NO. Conversely, the majority of mouse cell lines studied produced NO, not IDO. [15]

That’s interesting, because nitric oxide (NO) induces compulsive behavior in mice. A standard measure of obsessive-compulsive behavior in mice is marble burying. Nitric oxide increases marble burying:

In view of the reports that nitric oxide modulates the neurotransmitters implicated in obsessive-compulsive disorder, patients with obsessive-compulsive disorder exhibit higher plasma nitrate levels, and drugs useful in obsessive-compulsive disorder influence nitric oxide, we hypothesized that nitric oxide may have some role in obsessive-compulsive behavior. We used marble-burying behavior of mice as the animal model of obsessive-compulsive disorder, and nitric oxide levels in brain homogenate were measured using amperometric nitric oxide-selective sensor method. Intraperitoneal administration of nitric oxide enhancers … significantly increased marble-burying behavior as well as brain nitrites levels, whereas treatment with 7-nitroindazole-neuronal nitric oxide synthase inhibitor (20-40 mg/kg, i.p.) or paroxetine-selective serotonin reuptake inhibitor (5-10 mg/kg, i.p.) dose dependently attenuated marble-burying behavior and nitrites levels in brain…. In conclusion, obsessive compulsive behavior in mice appears related to nitric oxide in brain … [16]

Giving mice arginine, which raises NO levels, reverses the effect of SSRI antidepressants:

enhancement of NO synthesis by l-arginine reversed the effect of SSRI antidepressants, further demonstrating the role of NO in regulating the marble-burying behavior [17]

In rats allowed access to cocaine, blocking NO production decreased their self-administration of the drug. [18] This raises the possibility that Chlamydiae infection, leading to increase NO production, would increase self-administration of cocaine.

So if your pet mice are addicted to cocaine, maybe you should give them antibiotics!

Conclusion

Chronic infections are widespread in both humans and animals, and can have odd effects on behavior and health. Yet researchers have barely begun to detect their existence, much less trace their effects.

I don’t know whether chronic infections were involved in the apparent poisoning of C57BL/6 mice by tryptophan. But, since tryptophan is a very strong promoter of bacterial growth, and bacterial infections trigger interferon gamma and nitric oxide release which can induce ulcerative dermatitis and compulsive behavior in this breed, the possibility can’t be ruled out.

References

[1] Dufour BD et al. Nutritional up-regulation of serotonin paradoxically induces compulsive behavior. Nutr Neurosci. 2010 Dec;13(6):256-64. http://pmid.us/21040623.

[2] Sundberg JP et al. Primary Follicular Dystrophy With Scarring Dermatitis in C57BL/6 Mouse Substrains Resembles Central Centrifugal Cicatricial Alopecia in Humans. Vet Pathol. 2010 Sep 22. [Epub ahead of print]. http://pmid.us/20861494.

[3] Lawson GW et al. Vitamin E as a treatment for ulcerative dermatitis in C57BL/6 mice and strains with a C57BL/6 background. Contemp Top Lab Anim Sci. 2005 May;44(3):18-21.  http://pmid.us/15934718.

[4] Perkins SN et al. Calorie restriction reduces ulcerative dermatitis and infection-related mortality in p53-deficient and wild-type mice. J Invest Dermatol. 1998 Aug;111(2):292-6. http://pmid.us/9699732.

[5] Dawson DV et al. Genetic control of susceptibility to mite-associated ulcerative dermatitis. Lab Anim Sci. 1986 Jun;36(3):262-7. http://pmid.us/3724051.

[6] Andrews AG et al. Immune complex vasculitis with secondary ulcerative dermatitis in aged C57BL/6NNia mice. Vet Pathol. 1994 May;31(3):293-300. http://pmid.us/8053123.

 [7] Boelen E et al. Chlamydia pneumoniae infection of brain cells: an in vitro study. Neurobiol Aging. 2007 Apr;28(4):524-32. http://pmid.us/16621171.

[8] Ikejima H et al. Chlamydia pneumoniae infection of microglial cells in vitro: a model of microbial infection for neurological disease. J Med Microbiol. 2006 Jul;55(Pt 7):947-52. http://pmid.us/16772424.

[9] Moazed TC et al. Murine models of Chlamydia pneumoniae infection and atherosclerosis. J Infect Dis. 1997 Apr;175(4):883-90. http://pmid.us/9086145.

[10] Campbell LA et al. Mouse models of C. pneumoniae infection and atherosclerosis. J Infect Dis. 2000 Jun;181 Suppl 3:S508-13. http://pmid.us/10839749.

[11] de Kruif MD et al. Chlamydia pneumoniae infections in mouse models: relevance for atherosclerosis research. Cardiovasc Res. 2005 Feb 1;65(2):317-27. http://pmid.us/15639470.

[12] Kaiko GE et al. Chlamydia muridarum infection subverts dendritic cell function to promote Th2 immunity and airways hyperreactivity. J Immunol. 2008 Feb 15;180(4):2225-32. http://pmid.us/18250429.

[13] Jupelli M et al. Endogenous IFN-gamma production is induced and required for protective immunity against pulmonary chlamydial infection in neonatal mice. J Immunol. 2008 Mar 15;180(6):4148-55. http://pmid.us/18322226.

[14] Bussiere JL et al. Reproductive effects of chronic administration of murine interferon-gamma. Reprod Toxicol. 1996 Sep-Oct;10(5):379-91. http://pmid.us/8888410.

[15] Roshick C et al. Comparison of gamma interferon-mediated antichlamydial defense mechanisms in human and mouse cells. Infect Immun. 2006 Jan;74(1):225-38. http://pmid.us/16368976.

[16] Umathe SN et al. Role of nitric oxide in obsessive-compulsive behavior and its involvement in the anti-compulsive effect of paroxetine in mice. Nitric Oxide. 2009 Sep;21(2):140-7. http://pmid.us/19584001.

[17] Krass M et al. Nitric oxide is involved in the regulation of marble-burying behavior. Neurosci Lett. 2010 Aug 9;480(1):55-8. http://pmid.us/20553994.

[18] Collins SL, Kantak KM. Neuronal nitric oxide synthase inhibition decreases cocaine self-administration behavior in rats. Psychopharmacology (Berl). 2002 Feb;159(4):361-9. http://pmid.us/11823888.