Monday, April 30, 2012

1 Three Notable NIAID 2012 Research Projects On Lyme Disease

NIAID logo
The National Institute of Allergy and Infectious Disease (NIAID) is conducting some Lyme disease related research which I think readers should know about. There are a number of projects to be found on the Project Reporter web site which may be fascinating, but I took the time to select and highlight a few projects which would be of greater interest to patients suffering with Lyme disease and/or its coinfections.

PI: Skare, Jonathan

Description (by applicant):

Lyme disease, caused by the spirochetal bacterium Borrelia burgdorferi, is the leading arthropodborne infection in the United States and causes significant morbidity in endemic areas. If untreated B. burgdorferi can persistently infect individuals even though the host mounts a potent adaptive immune response such that antibodies obtained from infected patients or experimentally infected animals effectively kills in vitro cultivated B. burgdorferi. In addition, a robust cell-mediated proinflammatory response is observed that induces IL-6, IL-12 and IFN- and inhibits IL-10. Furthermore, the spirochete can resist complement killing demonstrating that this important component of the innate immune response is not sufficient to eliminate B. burgdorferi infection.

The observation that B. burgdorferi persists in such a hostile environment indicates that the spirochete is adept at evading the host immune response via mechanisms that have not been completely elucidated. One possibility is that B. burgdorferi invades host cells and survives at low levels. Recently we have determined that B. burgdorferi invade both immortalized and, more importantly, primary cells (both fibroblasts and endothelial cells) and persist as viable cells in o-culture. In addition we have preliminary data suggesting that the ability to invade host cells involves both integrin binding and Src kinase activity.

In this application we propose to further characterize the internalization of B. burgdorferi and track the fate of B. burgdorferi within thes infected cells to determine how they affect the localized host response following infection. To accomplish this we will use both in vitro correlates of invasion and intracellular survival as well as in vivo imaging of experimentally infected mice as readouts for our studies.

Specifically, we propose to:

(1) Characterize the invasion of Borrelia burgdorferi into primary fibroblasts. The working hypothesis here is that B. burgdorferi exploits invasion as an additional mechanism to avoid host clearance. Our preliminary studies demonstrate that B. burgdorferi invasion is not dependent on host fibronectin, but does involve B1 integrins other than a5B1. In this Aim we will identify the subunit that pairs with B1 to promote invasion and will also evaluate how B. burgdorferi traffics within these cells; and

(2) Determine if invasion is required for B. burgdorferi persistence in vivo. Our working hypothesis is that invasion contributes to persistence by providing an immunoprotected niche for B. burgdorferi. Since Src kinases are required for borrelial internalization in vitro, we will determine whether Src kinase inhibitors alter the infectivity potential of B. burgdorferi in vivo. In addition to standard cultivation and molecuar approaches, novel in vivo imaging will be employed to assess how the inhibitor affects colonization.

The overall goal of these studies is to determine the extent in which an intracellular locale contributes to borrelial persistence.

PUBLIC HEALTH RELEVANCE: Borrelia burgdorferi, the etiologic agent of Lyme disease, is the most common arthropod-borne infectious agent in the United States, and, as such, represents an important Public Health issue. The studies described in this application are designed to address how B. burgdorferi is able to persist effectively in infected mammals despite effective innate immune killing mechanisms and a potent adaptive immune response directed against this pathogen. The hypothesis being tested herein is that B. burgdorferi is capable of low-level intracellular survival in non-immune cells as an additional strategy to prevent borrelial host clearance.


Comment: This really begins fulfilling my wishlist, and I look forward to the imaging study videos that I hope will be made and posted online. If there is some sort of confirmation of intracellular Bb in vivo this may explain why some patients need additional antibiotics and why existing treatments may be inadequate as a matter of timing.

This next project is bound to generate discussion, as it involves the potential role of toxins in Borrelia burgdorferi. In this case, the researcher is looking for gene clusters in Borrelia burgdorferi which may create cytolysins similar to the toxins which are found in Staphylococcus aureus, Listeria monocytogenes, and Clostridium botulinum.

PI: Mitchell, Douglas

Description (by applicant):

Abstract: The 20th century witnessed several major advances in medicine. Perhaps most important were the discovery of antibiotics for bacterial infections and effective vaccines for several major viruses. Unfortunately, the creation of effective vaccines for bacteria has lagged behind analogous anti-viral strategies. Compounded with the rise in antibiotic resistance and a lack of interest from the pharmaceutical industry in pursuing novel antibiotics, we risk losing the fight against bacterial pathogens.

Described herein is an unconventional strategy to exploit bacterial toxins as both novel targets for antibacterial agents and antigens for vaccine development. To intelligently address the increasing threat posed by bacterial pathogens, more effort is needed to uncover the molecular underpinnings of virulence. Our group specializes in the use of bioinformatics, in vitro reconstitution, and genetic manipulation to identify and characterize gene clusters that are responsible for the biosynthesis of virulence-promoting cytolysins. The best-known toxin in this family is the highly modified peptide, streptolysin S (SLS, produced by Streptococcus pyogenes).

SLS production is required for the infective process, but not essential life processes. Our work has uncovered SLS-like toxins are synthesized by at least three other notorious human pathogens, including Staphylococcus aureus, Listeria monocytogenes, and Clostridium botulinum. We aim to study the potential role of the SLS-like toxin in an additional organism, Borrelia burgdorferi (Bb), which causes Lyme disease.

Although widely known, the Bb molecular mechanism of pathogenesis is inadequately defined. If the SLS-like toxin was indeed employed during Bb infections, this would represent the first demonstration of toxin utilization in this family of organisms and would prompt a major revision of borrelioses.

Because bacteria typically employ disparate pathogenic mechanisms, the conserved, SLS-like pathway provides a rare opportunity to develop more broadly applicable, yet targeted countermeasures. From our perspective, new antimicrobial strategies should directly target the pathogenic mechanism, rather than DNA replication, protein synthesis, or the cell wall. This approach holds enormous potential, as these drugs will theoretically be resistant to resistance.

This project will identify inhibitors of SLS toxin biosynthesis for the specific purpose of developing novel antibacterials. Moreover, SLS is non-immunogenic, rendering it an unfeasible candidate for vaccine development.

We have succeeded in generating attenuated variants with the anticipation that these can be used for raising toxin-neutralizing antibodies. The notion of immunizing against a bacterial toxin represents a potentially general strategy for future vaccine development.

With this proposal, we aim to not only fundamentally shift the accepted view of Bb pathogenesis, but also to challenge the paradigm that antibiotics must kill bacteria and non-immunogenic toxins are intractable vaccine candidates. These seemingly unrelated goals are actually quite intertwined. Our approach rests on the philosophy that a more complete understanding of toxin biosynthetic pathways and chemical structure can be rationally exploited to design novel therapeutics.

Public Health Relevance: Bacterial pathogens employ numerous mechanisms to evade the human immune system. We have discovered a novel strategy within the organism that causes Lyme Disease, who's pathogenesis remains largely enigmatic. A greater understanding of these processes will lay the foundation for developing the next generation of antimicrobial drugs.



Wait... I thought Radolf & co. said Borrelia burgdorferi does not produce a toxin? I know Donta patented some genes in Bb he saw as being analogous to a toxin.

Is there now evidence of newly researched genes which create a toxin in Bb? Or is this an old hypothesis which is being revisited?

Institution: NIAID
PI: Marques, Adriana

Description (by applicant):

Lyme disease is a multisystem illness caused by infection with the spirochete Borrelia burgdorferi and it is the leading vector-borne disease in the United States. Our current work addresses the following areas in Lyme disease: development of new tests and biomarkers for infection, investigation of persistence of infection with B. burgdorferi in humans, search for the cause of Southern Tick-associated Rash Illness (STARI), and investigation of the role of immune response in Lyme disease and PLDS.

One of the main problems in Lyme diagnosis has been the lack of highly specific and sensitive assays for B. burgdorferi and the lack of a test that could be used to assess response to therapy. Such assays should greatly facilitate the accurate diagnosis of Lyme disease and assessment of response to therapy in individual patients. Currently, no such test is available.

We have developed a new test using the luciferase immunoprecipitation systems (LIPSs) for profiling of the antibody responses to a panel of B. burgdorferi proteins for the diagnosis of Lyme disease. A synthetic protein consisting of a repeated antigenic peptide sequence, named VOVO, had the best diagnostic performance, similar to the C6 test (a diagnostic test using a peptide ELISA that we have helped develop and is highly sensitive and specific). The VOVO LIPS test displays a wide dynamic range of antibody detection spanning over 10,000-fold without the need for serum dilution; and offers an efficient quantitative approach for evaluation of the antibody responses in patients with Lyme disease.

Recent studies have shown that B. burgdorferi may persist in animals after antibiotic therapy and can be detected by using the natural tick vector (Ixodes scapularis) to acquire the organism through feeding. Whether this occurs in humans is unknown.

We have implemented a new clinical protocol to investigate the utility of this approach for identifying persistence of B. burgdorferi in treated human Lyme disease.

STARI is a rash similar to the rash of Lyme disease that occurs in persons residing in southeastern and south-central states and is associated with the bite of the lone star tick, Amblyomma americanum. The cause of the rash is unknown, as it is the natural course of the disease.

We have a clinical protocol to investigate the cause of STARI, and we are applying new genomic tools that identify bacteria based on species-specific sequences in the 16S rRNA ribosomal genes to the skin biopsies from patients with STARI.

Inflammatory innate immune responses are critical in the control of early disseminated infection, while adaptive immune responses are vitally important, particularly the humoral immune response, in controlling spirochete levels in tissues and resolution of Lyme arthritis in animal models. We are examining the antibody response to immunogenically dominant antigens of B. burgdorferi in PLDS patients and controls.

Further investigation of the anti-borrelia immune response may help in elucidating the pathogenic mechanism of PLDS and yield important information for future approaches to diagnosis and treatment. We have a clinical protocol in which we use DNA microarrays to characterize gene expression patterns in skin biopsies from individuals with EM, with the aim of capturing the human host response to pathogen exposure.

We are also investigating the differences in immunological response between predominantly lymphocytic meningitis and predominantly neutrophilic meningitis. Results from these studies will serve as a window into the fundamental biology of the infection.



The existence of the VOVO LIPS test is nothing new - reports on the development of this test have been around since 2010. Also, there is already information about a chronic Lyme disease xenodiagnosis study out there.

It seems like this project has a large scope - or consists of more than one project under the same umbrella. So far, no project end date has been posted for this entry.

What would be of most interest to me would be finding differences in immunological response between patients with acute Lyme disease and those with assumed PLDS - something Alaedini has already been studying.

(Side note: I thought that it was already determined that Borrelia lonestari, a relapsing fever spirochete, was the cause of STARI or Masters disease - did I miss something?)

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Friday, April 27, 2012

6 Health Matters Magazine And Lancet Anti-Science Lyme Disease Rebuttals

I wanted to point out two noteworthy online venues which are discussing Lyme disease as well as chronic Lyme disease - one article and a series of rebuttal letters which have been circulating around the Lyme disease patient community recently.

The first venue is Health Matters, an online magazine in the UK which is edited by Steve Iliffe, a professor at the University College of London, and Paul Walker,  an independent health consultant who worked for the NHS for many years.

This month, Health Matters published part one of an article by Kate Bloor on Lyme disease, "Falling Through The Gap?: Part One: Lyme Disease Prevention In The UK."

The article does not focus on the controversy around chronic Lyme disease but instead goes straight to the roots of Lyme disease by asking about which agencies and institutions in the UK are responsible for educating the public on prevention of tickborne illnesses and how well this job has been done to date.

Quoting Kate:
"Approaches that only target those in traditional high risk groups, may not reach far enough. New research shows that one in five people diagnosed with Lyme became infected either in an allotment, park or garden and one in five patients was infected abroad. These are not normally considered high risk areas or high risk activities."
Any program for prevention should be designed to reach all those groups who are found to be at risk and not some fraction of them, and should include prevention where substantial minority groups are at risk.

Kate also included this useful bit of statistical information:
"A survey of GP’s showed that 72% reported using the wrong method of tick removal, of the surveyed councils, only 7% provided information to staff, and only 7% claimed to have information for the public on their website."
From the research I've read from Russia, one of the major causes of infection from tick bites stems from improper removal of the tick. Every effort should be made to carefully remove the entire tick including the head and mandibles, without placing pressure on the tick's abdomen/gut. This will lessen the odds of contracting an infection greatly. Here, citing that 72% of doctors removed ticks incorrectly is very concerning; doctors are the front line for treatment and should be removing ticks properly nearly 100% of the time.

That regional councils would not have their own staff education and education for the public in place is also important to note, and I have to wonder how much those who have been bitten by ticks in these areas have informed the councils on their experience and requested more warnings to the public on tickborne illnesses. To me, it seems like it would require a small amount of effort and money invested in education to help prevent more people from being bitten.

The rest of the article outlines how prevention is being managed (or not) by various organizations, the educational strides being made by patient advocacy organizations such as Borreliosis and Associated Diseases Awareness UK (BADA-UK), and the need for national and local government health agencies to make tickborne illness a priority.

More here, at the link:

The second venue I want to mention is The Lancet, which has recently published a series of rebuttal letters in response to an opinion piece posted last year, "Antiscience and ethical concerns associated with advocacy of Lyme disease" (abstract only).

  • Stella Huyshe-Shires, chairperson of Lyme Disease Action, writes about how the situation Auwaerter and his coauthors outline in the US is different from that which is experienced in the UK in regards to Lyme disease prevention, education, and treatment. She focuses on patient advocacy group's drive for awareness and evidence-based medicine to treat patients, and she mentions that the British Infection Association is now collaborating with LDA (UK) and a Department of Health funded body, the James Lind Alliance, on documentation of the uncertainties in treatment and diagnosis of Lyme disease.

  • Christian Perronne, of the Infectious Diseases Department of the University of Versailles-St Quentin, France, points out the high variability and sensitivity of serological tests for Lyme disease, how tests do not account for strain varieties, and that other microbial infections may mimic that of Lyme disease. He points out that syndromes of an unknown cause should no longer be referred to as being chronic Lyme disease, and should be investigated for other microbial and non-microbial causes using an open-minded scientific approach.

  • Carl Tuttle, of Hudson, New Hampshire, USA, wrote about how his experience of Lyme disease did not seem to match that of Auwaerter's experience, given how many people he knows have suffered serious symptoms with Lyme disease that was not diagnosed early - whereas Auwaerter indicated Lyme disease is easily diagnosed and treated. He mentions the inadequacy of serological testing and how it can lead to late stage cases which went undiagnosed and untreated, and how legislation has been passed in several states which protect doctors who treat Lyme disease patients with long-term antibiotics. He asks if the IDSA is correct in its position, then why is there so much legislation being passed which protects doctors who offer long-term antibiotic treatment?

  • And lastly, Auwaerter et al offers a response to these rebuttals here:

    Auwaerter et al state that a huge percentage of patients are being improperly diagnosed with chronic Lyme disease by alternative practitioners when these patients have another condition. They point out that serological testing is reliable, and evidence that testing is unreliable would be needed by Mr. Perronne and Mr. Tuttle in order to support their position. Auwaerter et al point out that the current guidelines stand based on independent scientific review and that "Vague symptoms such as chronic pain, fatigue, and neurocognitive complaints are poorly understood by modern medicine but are the focus of this debate." (Ed: The last full paragraph of this response is as long as the previous two put together and is comprised of nothing but a list of stated possible conflicts of interest.)


While I agree with a lot of what Ms. Huyshe-Shires had to say, I would like to step away from the argument that "Lyme disease in ______ is different because it's different here".

I've heard this before, and this argument has been made to try to distance European patients from those in the US, with an underlying belief that since European strains are different, that diagnosis and treatment should be determined using European scientists and research - not that of American based IDSA. Fine, but then I will argue that since Europeans also contract Borrelia burgdorferi that they should come up with diagnostic and treatment methods for the US as well!

Scientific research to date has shown that Borreliosis is Borreliosis, whether it is caused by Borrelia burgdorferi, Borrelia afzelii, Borrelia garinii, and a number of other strains. The symptoms produced by these organisms may differ somewhat from one locale to the next, but many have the potential to cause neuroborreliosis, and indeed, even those with a most conservative view of the Lyme disease controversy have stated that there has been too much emphasis on Europe having more neuroborreliosis and different symptoms when the situation is that clinical presentations in the US have been very similar to those in the UK

Receiving an early diagnosis and treatment matters regardless of where one is in the world and which strain they have.

I can relate to Mr. Perronne's position, to some degree. I don't think this is a heterogeneous condition - nor was it from the start even if just basing it on those who have had tick bites - since a number of ticks are coinfected with pathogens other than Borrelia burgdorferi/afzelii/garinii. I think it's possible some patients have a different infection which they contracted through a tick bite or perhaps even a tick bite made them more susceptible to a new, undefined infection. More research is needed to determine why this group is heterogeneous, and to study those with a definite history of a tick bite and persisting symptoms very closely (regardless of serological test results) as their own separate group.

Mr. Tuttle's remarks reflect the fact that regardless of what side of the Lyme disease controversy you stand on, people are suffering a lot and heated debates on the state level end up weighing in on the side of the patient. Access to extended treatment is winning - whether the IDSA approves or not.

Auwaerter et al's response, to me, is predictable and to be expected. It would be appreciated if one day they were to focus more on the content of Mr. Perronne's position and join him in it by finding a way to initiate research which directly helps patients who are suffering with persisting symptoms and to stop spending an inordinate amount of time focusing on whether or not certain doctors and patients promote pseudoscientific practices and beliefs. They've already made it quite clear to The Lancet and the public what their position is.

One has to face reality here: If some alternative to current treatment practices is discovered which is safe and effective, patients will use it. In the meantime, patients who are suffering greatly will try any of a number of drugs, antibiotics, herbs, and supplements which are available in order to get well regardless of the IDSA's position on their condition and its treatment.

Whether these attempts to relieve symptoms are scientifically backed or not is irrelevant to someone who is seeking relieve pain and is nearly (if not completely) on the verge of suicide with pain. It is this human element of suffering which Auwaerter et al do not seem to want to contend with and address in a compassionate way - nor in a clinical, scientific way by either engaging in research which directly resolves the controversy or by finding the treatment of all treatments based on their own hypothesis of what causes persisting symptoms.

Patients with persisting post treatment Lyme disease symptoms have often tried mainstream approaches to treating their conditions when they were diagnosed with something other than chronic Lyme disease - only to either experience no improvement or even experience a significant worsening of their condition. The use of steroid-based drugs used for treating rheumatic conditions has been one such example of where patients with chronic Lyme disease have tried them based on an apparent diagnosis of a rheumatic condition - only to get sicker and become more symptomatic. Why is that? Someone needs to research this, too.

At some point I need to write a detailed scientifically cited response to Auwaerter et al's original letter to the Lancet instead of the rant I wrote in response to the abstract alone last year. At the time, I was too personally offended that I and my condition were equated with pseudoscience and my offense led to ranting rather than a rational, objective calling out of each point in the full text with a substantiated counterpoint of my own. 

It's difficult to be without bias. As a person suffering with the fallout from Lyme disease and Babesiosis, I cannot be completely without bias no matter how hard I try. But I can try to read the scientific arguments and research that different parties put forward and weigh them independently of how rotten I feel. It is possible, even if at times difficult. 

In the end, I genuinely want someone to just figure out what has brought me to the level of suffering I've experienced over the past several years - even if in some of that figuring out the cause turns out to differ from that which I've suspected. Fine. Just find it, and find a treatment that gets me back to my old self. 

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Wednesday, April 25, 2012

2 Strange But True Facts About Spirochetes

Image: Kilauea Volcano
by Brian Snelson

I have a few strange but true facts about spirochetes to share which you may not know. A few are ones I have shared here before  - but most are not something about which I've already written. What you read here today may surprise you...

  • Many people call Borrelia burgdorferi spirochetes Gram negative bacteria. However, Borrelia burgdorferi are not Gram-negative bacteria even if a Gram negative stain works on them:

    "Borrelia were thought to be Gram negative because of their double membrane structure, but genetic analysis places them - along with other spirochetes - into a separate eubacterial phylum. Ultrastructural molecular and biochemical studies have emphasized the wide taxonomic gap between spirochetes and Gram-negative bacteria."

    - From "The Genus Borrelia" by Melissa Caimano. Prokaryotes (2006) 7:235-293.
  • Unlike Leptospira and Brachyspira, spirochetes in the Borrelia and Treponema genera appear to have acquired Phenylalanyl-tRNA synthetase (PheRS)  genes from Archaea through horizontal gene transfer. [1] Borrelia and Treponema have Archaea genes.
  • Somewhere along the line, an ancient Spirochaeta relative picked up genes from Archaea's order, Thermococcales. Borrelia and Treponema have close affinities with Thermococcus and Pyrococcus (not depicted on tree).[1]
  •  The fascinating thing about this genetic relationship is that these genes come from organisms which are extremely thermophilic organisms. They are extremophiles - which means they can live in extreme environments. Thermophilic extremophiles thrive in hot environments such as volcanic vents and hot springs. That genes from extremophiles would end up in mesophilic organisms which thrive in lower temperatures - such as in mammalian and acarian hosts - seems surprising. The highest temperature Borrelia garinii can still grow in is around 41-42 C. That's not anywhere near the high temperatures in which one finds Archaean Thermococcales (often over 60 C, sometimes as high as 100 C).
  • This all does seem really weird. But the reason why it isn't too far fetched to see genes from extremely thermophilic organisms in moderately warm Borrelia and Treponema is more easily understood once you know more about the wide diversity found within the genus Spirochaeta in general. A number of Spirochaeta species live in extreme environments and not just in humans, animals, or ticks. For example:
    • S. halophila lives in a high salinity pond on the Sinai shore.[2]
    • S. thermophila lives in marine hot springs in New Zealand and Russia.[3]
    • S. americana lives in alkaline, hypersaline Mono Lake in California.[4]
Champagne PoolWai-O-Tapu, near Rotorua, New Zealand by Christian Mehlführer

  • When looking at a phylogenetic tree, Spirochaeta is at the base of the tree and Borrelia and Treponema branch off later. Based on this, the best assessment one can make about the gene transfer from Archaea to Spirochaeta is that the most recent common ancestor of Spirochaeta, Borrelia, and Treponema had to have been very similar to thermophilic Spirochaeta.
  • My running joke on this is to imagine a pile of thermophilic Archaea and thermophilic Spirochaeta hanging out around a hot spring together, laughing, joking, and flirting. Before you know it, horizontal gene transfer occurs, and a new form of spirochete is born. (This would make for a good Far Side comic, I just know it.)
  • As if having Borrelia acquire Archaea genes wasn't interesting enough, it's been thought that ProS prolyl-tRNA synthetase (BB402) was acquired from a eurkaryote.

  • Treponema spirochetes have a symbiotic relationship with termites. These spirochetes help termites in breaking down cellulose in wood in the termites' guts. So it isn't just ticks which have a symbiotic relationship with spirochetes - termites have one, too.[1, 5]

  • Borrelia burgdorferi survives on the equivalent of tick antifreeze in the tick's midgut inbetween tick blood feeding cycles. Borrelia burgdorferi prefers glucose when in the tick, but it will feast on glycerol instead. See:
  • Both Borrelia hermsii and Borrelia burgdorferi metabolize chitobiose and N acetyl-glucosamine, a nutrient of these spirochetes and the major constituent of chitin for the exoskeletons of ticks.[6]
  • Borrelia have most of the genes required for the enzymes which make up the mevalonate pathway - a metabolic pathway used by the bacteria for synthesis of isoprenoid precursors. Isoprenoids are very important compounds which are found in over 30,000 products from the three domains of life (Eukaryotes, Prokaryotes, and Archaea). One interesting proposal about how Borrelia has the genes required for these enzymes for this pathway is that they come from the genetic cenancestor - an ancestor which predates the split into the three domains.[7]
  • In Act II of Samuel Beckett's play, Waiting For Godot, one character, Estragon, curses at the other, Vladimir, by calling him, "Gonococcus! Spirochete!"
Spirochetes continue to hold surprises and mysteries for us all... both good and bad. Another interesting installment of strange spirochete facts could be posted here - probably not too far in the future.


1) Cheryl P Andam and J Peter Gogarten. Biased gene transfer and its implications for the concept of lineage. Biology Direct 2011, 6:47 doi:10.1186/1745-6150-6-47
2) Greenberg EP, Canale-Parola E: Spirochaeta halophila sp. n., a facultative anaerobe from a high-salinity pond. Arch Microbiol 1976, 110:185-19
3) Aksenova H, Rainey F, Janssen P, Zavarzin G, Morgan H: Spirochaeta thermophila sp. nov., an obligately anaerobic, polysaccharolytic, extremely thermophilic bacterium. Int J Syst Bacteriol 1992, 42:175-177
4) Hoover RB, Pikuta EV, Bej AK, Marsic D, Whitman WB, Tang J, Krader P: Spirochaeta americana sp. nov., a new haloalkaliphilic, obligately anaerobic spirochaete isolated from soda Mono Lake in California. Int J Syst Evol Microbiol 2003, 53:815-821.
5) Droge S, Frohlich J, Radek R, Konig H: Spirochaeta coccoides sp. nov., a novel coccoid spirochete from the hindgut of the termite Neotermes castaneus. Appl Environ Microbiol 2006, 72:392-397.
6) Tilly, K., Elias, A.F., Errett, J., Fischer, E., Iyer, R., Schwartz, I., et al. Genetics and regulation of chitobiose utilization in Borrelia burgdorferi. J Bacteriol 183: 5544–5553.
7) Jonathan Lombard and David Moreira. Origins and Early Evolution of the Mevalonate Pathway of Isoprenoid Biosynthesis in the Three Domains of Life. Mol Biol Evol  2011, 28 (1): 87-99. doi: 10.1093/molbev/msq177

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Tuesday, April 24, 2012

3 Commentary: Critical Mass In The Media On Lyme Disease

It's April, and it's already that time of year again for Lyme disease: The media has been stepping up its coverage of Lyme disease related news items in preparation for May, which is Lyme disease awareness month.

For example:
Health Department Issues Warning About Ticks (Ohio)
10 Tips To Beat The Ticks (msnbc)
Lyme Disease Is On The Rise In New Jersey And Pennsylvania
Arkansas On Track For More Tickborne Illnesses This Summer
Scientist Says Lack Of Acorns May Mean More Lyme Disease In Maine
Minnesota: State's tick season crawling to an early start
Tick bites on the rise in Central Florida, county says
Tick season gets an early start (Iowa)
It's tick season in Lake, Mendocino counties (California)

Canada has been getting in on the action:
How to prevent disease infection after research finds Lyme-carrying ticks are on the rise in Canada
Toronto: Climate change causes Mississauga infestation
Tick season is here (Kamloops)

And also the BBC in the UK:
Great outdoors? Ticks, pets and the risk of Lyme disease
Seeking to solve the Lyme disease puzzle

All these links are to articles I just grabbed off Google News in a matter of seconds. There are so many news items listed that I could not mention them all and just selected links representative of the fact that  Lyme disease is getting more attention across the United States and the northern hemisphere in general.  If I search further afield, I'm sure I could include links from France, the Netherlands, Germany, and other countries.

This year, I noticed that the news cycle has been slightly different. The media has been discussing that tick season was going to be earlier than usual and worse than usual when it was just barely into the new year. And with this has come more stern warnings to the public to protect themselves from tick bites and prevent infection.

The media has been on top of things, it seems. How about me? As someone who has suffered from Lyme disease and coinfection, I've been thinking about my own role in how to participate activities related to this year's Lyme disease awareness month.

Last May, I wrote a series of articles for The Daily Kos for Lyme disease awareness month. Time is obviously running out to decide whether or not to write again this May, and I am leaving the decision to the last minute just as I did the previous year.

I think traditionally calling attention to Lyme disease prevention in May has made sense. But I can't help but think that being aware of all tickborne infection throughout the entire year is a better approach.

One reason why is because the world is changing. Global warming and fluctuations in the ecosystem can lead to different tick breeding times and infection patterns. Local microclimates and winters which are milder on average can lead to peak cases of Lyme disease being reported in autumn and early winter - as they have been reported in California and parts of Oregon. And if Australia turns out to have its own increase in Lyme disease cases which run according to their seasons, then timing for prevention and education would differ from North America by six months.

Another reason why is that it doesn't hurt to put the message out there all year round is because more people are likely to hear it and be aware about the potential problems tick bites can bring before they are in circumstances where they are more likely to get bitten...Hopefully they won't get bitten at all.

Any month where people are going to be going outdoors and placing themselves in environments where they are likely to encounter ticks is a month where one should take the steps necessary to protect themselves from tick bites.

My own basic online version of tickborne disease prevention education
has been this page:

It has two videos - one an animation about preventing oneself from being bitten by a tick and another about how to create your own tick removal kit.

Overall, I think there is a fair amount of information available about prevention and avoidance of Lyme disease and other tickborne infections. And it's good to repeat this information and give people reminders.

The Fear of Taking It Too Far?

From my own personal perspective - after years of reading articles about the prevention and avoidance of ticks - I'm in a position where I'm trying to figure out what seems to be the opposite problem: how not to go overboard in preventing and avoiding tickborne infection.

And it is a good question: What exactly is going overboard when one has had their life changed entirely (and not in a good way) by having contracted a tickborne infection? Some people might argue there is no such thing as going overboard.

I know it's possible that some day I could be hiking and get bitten by a tick again. That concern is real. The fear behind getting another infected tick bite is real. And I have asked myself, "Do I really want to hike again?"

Hard question. But it's still difficult to say no. In terms of risk reduction, I would rather give up living with a pet than give up spending time outdoors.

I love the great outdoors, and I miss hiking and camping - two activities which put me at the most risk for tick bites. I'm not doing either these days due to fatigue, pain, and lack of stamina. But if I were to suddenly become completely well again, I would have to think twice about how I could return to these activities and remain unscathed by ticks.

There has been a sense of loss that comes from not engaging in activities I once used to do all the time.  Hiking was a walking meditation for me that worked better than sitting in a crowded room full of people doing yoga poses. And cheaper, too.

Out in the woods, I could be alone with my thoughts and close to the earth. I could get in tune with my body and push its limits without anyone watching. I could stretch my muscles, climb rocks, and see how far I could go.

Today I feel weak and broken. I miss feeling stronger. I miss being out in nature, in the elements, encountering wildlife.

I also miss sitting near a campfire, eating and drinking with friends while telling tall tales and bad jokes... It's amazing how much I took for granted that I now miss.

I've figured out that there are things I could do to ease back into the activities I love to do while lowering my risk. I could focus on cycling, swimming, sailing, canoeing, scuba, urban walks, and hiking and camping in rocky mountainous and desert areas where ticks are far less likely to be encountered. It might take more advance planning to do some of these things - but time outdoors wouldn't have to stop. Activities may just need to be modified to alleviate my concerns.

But all this is only going to happen once I am well enough and have energy enough to do these things at all.

Shifting From A Narrow Focus On Fear Of Ticks To Action On Chronic Lyme

From where I sit, I think the awareness message has to be broader than "ticks are out there, they carry nasty infections, protect yourself from their bite"... I think the message has been getting out there, little by little, that if one does get bitten that early diagnosis and treatment is crucial.

But the bigger message which has to get out is that more research on preventing and treating late stage chronic Lyme disease is needed because this is the one aspect of Lyme disease which is the most damaging (and controversial) of all.

The science needs to be brought to public light from those who are up to their ears in it. I'd like to see more researchers being interviewed and not just patients. I'd like to see doctors discussing how much - and how long - these infections can affect one's quality of life. I'd like to see various people discuss the Embers' study on national TV. I'd like to see someone have the balls to actually discuss whether or not there can be a persistent infection in Lyme disease and mention all the studies which have been done to date on both - or rather, all - sides of the fence. I'd like to see a genuine open scientific debate.

I see it as I call it, and how I see it right now is that the dialog about Lyme disease needs to be taken past the human interest story and past the public health department's annual warnings about increasing cases of tickborne infections. A good move in this direction has been discussing the impact of global warming on the spread of ticks. An even better move would be to discuss what we can do to stop the most serious impact that Lyme disease has on us, our families, and our pets in the form of chronic and persisting symptoms.

A call for more research is needed. A call for more young people to study microbiology and immunology to better understand tickborne infections is needed. A call for more surveillance in new latitudes is needed. A call for more detailed public education on Lyme disease is needed. And a call for more serious candid discussions from the media - and not just daytime TV sensationalism - is needed.

How do we get from here to there? If I have any role in this, then it's going to have to be directed towards answering this question - whether it's May or not.

Image credit: © Jarek Tuszynski / Wikimedia Commons / CC-BY-SA-3.0 & GDFL

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Wednesday, April 18, 2012

2 Father & Son Develop Drug Which Could Reduce Lyme Excitotoxin

While looking for articles and papers on neurodegeneration in Lyme disease, I came across this interesting article in the San Francisco Chronicle about a father and son team who are working on a drug to treat neurodegeneration in conditions such as Alzheimer's disease and Huntington's disease. The father, Joseph Muchowski, is a retired chemist from Swiss drug maker, Roche. The son, Paul Muchowski, is a full time investigator at the Gladstone Institute in San Francisco, California.

The article states that the drug - currently called JM6 - inhibits an enzyme, kynurenine 3-monooxygenase (KMO) that when left unchecked, allows a toxic chemical to build up in the brain. And that JM6's effect on the brain is indirect - it inhibits the KMO enzyme in the blood, setting off a chain of events that ultimately leads to a reduction in one harmful chemical in the brain and an increase in a second, preventive chemical.

I looked at this article and realized that the specific pathway mentioned - the kynurenine pathway - is said to be involved in Lyme disease. I wondered if JM6 could potentially help people suffering with Lyme disease - and in particular, suffering from neuroborreliosis. So I decided to do a little more digging on this drug and the KMO enzyme and see what I could find out.

First of all, the Gladstone Institute already has a research page for the Muchowski Lab which mentions research related to JM6 under "Project 4":

An excerpt about Project 4 states:
"Metabolites in the kynurenine pathway (KP), generated by tryptophan degradation, are thought to play an important role in neurodegenerative disorders, including Alzheimer’s and Huntington’s diseases. 
In these disorders, glutamate receptor-mediated excitotoxicity and free radical formation have been correlated with increased levels of the toxic tryptophan metabolites 3-hydroxykynurenine (3-HK) and quinolinic acid (QUIN), and decreased levels of the neuroprotective metabolite kynurenic acid (KYNA). 
In 2005 our lab reported the results from a large-scale genetic screen in yeast that identified mutations in 28 genes that suppress toxicity of mutant huntingtin (Giorgini et al., Nature Genetics, 2005). Among the most potent mutations identified in our screen was one in a gene that encodes kynurenine 3-monooxygenase (KMO), an enzyme that plays a critical role in the KP."
From there, JM6 is said to inhibit KMO in the blood, increase KYNA levels, and reduce extracellular glutamate in the brain.

In a mouse model of Alzheimer's disease, JM6 prevents spatial memory deficits, anxiety-related behavior, and synaptic loss. In another mouse model for Huntington's disease, JM6 extends life span, prevents synaptic loss, and decreases microglial activation.

"How does all this relate to Lyme disease?" you might be wondering.

Hold on, I'll get to that in a moment, because the next thing I'd like to share is that I found a patent which appears to be related to JM6:


Inventors: Paul J. Muchowski et al

In the patent, it states that a small molecule inhibitor (in this case, I would guess JM6) can work on a number of different conditions where the kynurenine pathway (KP) plays a role in its development.

Referring to page four of the patent, it lists all conditions which fall under this category:
[0054] Diseases mediated at least in part by kynurenine3-monooxygenase include those selected from the group consisting of Huntington's disease and other polyglutamine disorders such as spinocerebellar ataxias, Alzheimer's disease, Parkinson's disease, high-pressure neurological syndrome, dystonia, olivopontocerebellar atrophy, amyotrophic lateral sclerosis, multiple sclerosis, epilepsy, consequences of stroke, cerebral ischemia, hypoxia, multi-infarct dementia, consequences of cerebral trauma or damage, damage to the spinal cord, AIDS-dementia complex, viral or bacterial meningitis, general central nervous system (CNS) infections such as viral, bacterial or parasites, for example, poliomyelitis, Lyme disease (Borrelia burgdorferi infection) and malaria, cancers with cerebral localization, Tourette's syndrome, hepatic encephalopathy, systemic lupus, analgesia and opiate withdrawal symptoms, feeding behaviour, schizophrenia, chronic anxiety, depressive disorders, disorders of the developing or aged brain, diseases of addiction, diabetes, and complications thereof. The compounds of this invention may also influence synaptogenesis after brain injury. The compounds also may influence memory.
And in this patent, I found information which may indicate that this new drug, JM6, may be able to reduce quinolinic acid which has been shown to build up in the nervous system during infection with Borrelia burgdorferi.

So what is quinolinic acid? And what role does it play in Lyme disease?

Quinolinic acid (QA) is a dicarboxylic acid which has a powerful neurotoxic effect.

(Hard to believe something so simple could cause so many problems?)

Quinolinic acid is a metabolite of tryptophan which is produced by activated microglia and macrophages in the brain and binds to N-methyl-d-aspartate (NMDA) receptors in the central nervous system. (In other words, QA can be activated by the immune response.)

Some quinolinic acid is necessary for the production of NAD+ - but too much quinolinic acid and it leads to excitotoxicity. If NDMA receptors are overstimulated by too much quinolinic acid, too much calcium enters the neurons and prevents the uptake of glutamate into the synaptic vesicle. Too much glutamate leads to the death of neurons harboring these receptors.

Clinical studies have established that sustained elevations of quinolinic acid, l-kynurenine and kynurenic acid within the cerebrospinal fluid occur in patients with a broad spectrum of inflammatory diseases and correlate with markers of immune activation and interferon-gamma (IFN-γ) activity.[1]

Increased production of quinolinic acid has been demonstrated in the CSF of patients with neurologic Lyme disease (Halperin and Heyes, 1992).[2] The level of quinolinic acid, an excitotoxin and N-methyl-D aspartate (NMDA) agonist, correlated strongly with CSF leukocytosis and was noted to be greater in patients with CNS inflammation and less in Lyme encephalopathy.[3] The presence of quinolinic acid may contribute to the neurologic and cognitive deficits such as memory loss which is seen in many Lyme disease patients.

Now that you have a basic idea of what quinolinic acid is and that it may play a role in neurologic and cognitive deficits in Lyme disease, I can move on to what JM6 is supposed to do, in theory:

In mammals, tryptophan is a precursor for serontonin - but it is also metabolized via the kynurenine pathway to generate three neuroactive substances:
  1. hydroxykynurenine  (3-hydroxykrynurenine = neurotoxic)
  2. kynurenic acid  (neuroprotective)
  3. quinolinic acid  (neurotoxic)
Kynurenic acid has neuroprotective activities in vivo while 3-hydroxykynurenine and quinolinic acid are neurotoxic.

Simplified kynurenine pathway of tryptophan metabolism. IDO,
indolamine-2,3-dioxygenase; KAT, kynurenine aminotransferase; KMO,
kynurenine 3-monooxygenase or kynurenine 3-hydroxylase;
 KYNU, kynureninase; TDO, tryptophan-2,3-dioxygenase; TPH, tryptophan hydroxylase.
Image from: 
Neuropsychopharmacology 37, 939-949 (March 2012)
Studies have shown that 3-hydroxykynurenine and quinolinic acid are causative or can contribute to delayed neurological damage and both are associated with neurodegenerative disorders and psychiatric diseases.

Drugs which block 3-hydroxykynurenine and quinolinic acid synthesis and/or increase kynurenic acid formation have been created before, such as in treatment of neurological diseases and their peripheral indications (e.g. diabetes).

Kynurenine-3-monooxygenase (KMO) is an enzyme in the tryptophan degradation pathway that catalyzes the conversion of kynurenine into 3-hydroxykynurenine (which is a precursor of the neurotoxin quinolinic acid).

Drugs which act as inhibitors of KMO are of value since they block the metabolism toward quinolinic acid and at the same time, increase the formation of neuroprotective metabolite kynurenic acid.

JM6 is one of these drugs.

The Muchowski Lab writes about what JM6 might do in vivo:
"We hypothesize that the biotransformation of JM6 to Ro 61-8048 in the gut results in KMO inhibition in peripheral monocytes, causing the accumulation of both kynurenine (KYN) and KYNA in blood. Unlike KYNA, KYN is then actively transported into the brain, where it is rapidly converted by astrocytes to KYNA. KYNA released from astrocytes mediates neuroprotection, at least in part, by decreasing glutamate levels via antagonism of presynaptic α7 nicotinic acetylcholine receptors. However, at high local concentrations, KYNA might also directly block glutamate receptors to reduce excitotoxicity. Neuroprotection by JM6 might also involve a decrease in inflammation and modulation of mitochondrial function."
So there you have it - JM6 blocks KMO in monocytes. 3-hydroxykynurenine and quinolinic acid are not converted from kynurenine - so your two neurotoxins aren't there. The available kynurenine is supposed to reduce glutamate levels and also block glutamate receptors to reduce excitotoxicity. And by extension, inflammation may be decreased and mitochondrial function improved.

To learn more about JM6, check out the Gladstone Institute's published paper in Cell:

Daniel Zwilling, Shao-Yi Huang, Korrapati V. Sathyasaikumar, Francesca M. Notarangelo, Paolo Guidetti, Hui-Qiu Wu, Jason Lee, Jennifer Truong, Yaisa Andrews-Zwilling, Eric W. Hsieh, Jamie Y. Louie, Tiffany Wu, Kimberly Scearce-Levie, Christina Patrick, Anthony Adame, Flaviano Giorgini, Saliha Moussaoui, Grit Laue, Arash Rassoulpour, Gunnar Flik, Yadong Huang, Joseph M. Muchowski, Eliezer Masliah, Robert Schwarcz, and Paul J. Muchowski. Kynurenine 3-Monooxygenase Inhibition in Blood Ameliorates Neurodegeneration. Cell 145, 863–874, June 10, 2011

Full text:


1) K. Saito, S.P. Markey, M.P. Heyes. Effects of immune activation on quinolinic acid and neuroactive kynurenines in the mouse. Neuroscience. Volume 51, Issue 1, November 1992, Pages 25–39
2) Halperin, J.J., Heyes, M.P. Neuroactive kynurenines in Lyme borreliosis. Neurology 42 (1), 43–50.
3) Fallon, B.A., et al. Inflammation and central nervous system Lyme disease. Neurobiol. Dis. (2009), doi:10.1016/j.nbd.2009.11.016

Additional Resources:

  • Fuchs, D., Dotevall, L., Hagberg, L, Werner, E., Wachter, H. Kynurenine in cerebrospinal fluid of patients with Lyme neuroborreliosis. Immunology & Infectious Diseases. 1991 Vol. 1 271-74.
  • Dotevall,  L., Fuchs, D., Reibnegger, G, Wachter, H., Hagberg, G. Cerebrospinal Fluid and Serum Neopterin Levels in Patients with Lyme Neuroborreliosis. Infection 18 (1990) No. 4.
  • Gasse, T., Murr, C. Meyersbach, P., Schmutzhard, E., Wachter, H., Fuchs, D. Neopterin production and tryptophan degradation in acute Lyme neuroborreliosis versus late Lyme encephalopathy. Eur J. Clin. Chem. Clin. Biochem. 1994 Sept 32(9):685-9.
[Edited April 19, 2012: to include KP image and mention NAD+/NADH generation using quinolinic acid.]

Addendum December 2012:

Ivan Oransky of Retraction Watch has reported that Dr. Paul Muchowski has been under investigation for submitting fraudulent data to the NIH and was found to have engaged in scientific misconduct. Muchowski is now conducting research under supervision for two years, and cannot serve on any NIH committee during this time period.

See this link for more information:

How this affects the research completed on JM6 and the related patent mentioned above remains to be seen.

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Saturday, April 14, 2012

6 Commentary: On Dr. Phil, Lyme Disease, And "Faking It".

Yesterday a segment about chronic Lyme disease aired on the Dr. Phil Show. There's been much discussion about this episode online throughout the Lyme disease patient community, and so far comments by the hundreds have been posted rapid fire to Dr. Phil's web site about chronic Lyme disease.

I am in support of seeing more coverage on Lyme disease and patients with persisting symptoms, but I am not in support of seeing the angle of hypochrondria or "faking disease" being mentioned - even in passing - in relationship to Lyme disease.

The issue of whether or not a patient is faking their symptoms came up during an interview with a 25 year old model, Stephanie, who is experiencing unusual attacks and symptoms - and who has been accused of behaving this way in order to get attention.

While I do not know all the details of Stephanie's medical history, I would be one of the last people to accuse her of faking her symptoms to get attention. I say this in part because if she has suffered with these symptoms for five years* and hasn't been getting out much due to her condition - then like myself, she's probably discovered that after that period of time other people will stop inviting you to events. Some may not even visit.

Being a model equates with an active social life, attending events, and self-promotion. Getting plenty of attention lands you work. Becoming sick and spending most of your time at home kills your career and leads to isolation. There is little to gain there, and any initial sympathy which might be gained wears thin after the first several months. People will move on without you.

Having suffered the personal costs of isolation due to chronic illness myself, I have sympathy for her situation. And I am appalled that the first thing Dr. Phil would ask was not what evidence she had that she was suffering from Lyme disease - but to ask whether or not she was faking her symptoms.

While I disagreed with her method of self medicating, it is clear to me that she has been suffering. I've never experienced what she is calling seizures - however, earlier in my illness I had episodic attacks of severe pain which would cause me to curl up, wince, and yell with pain.

The pain was so intense there was nothing else I could do. It often happened when I was alone in bed and everyone else was out of the house. If someone wanted to accuse me of a payoff for my behavior, it wasn't coming.

It seems to be a running theme over time - this concept that if one is ill with a condition that is not easily understood or for which tests have not been well developed - then somehow the patient's symptoms must be "all in their head," or the patient must be "making it all up".

And that if a patient behaves in an unusual manner, accusations fly that they must be acting out, with others suggesting that "perhaps they have a psychological problem," or  "perhaps they just want attention."

I can't think of how many times I've heard these statements made about someone with certain medical conditions - usually conditions where the person physically appears normal to others at least some portion of the time, and isn't showing an overt sign of illness or injury.

Patients with a broken leg or weeping sores are not accused of hypochrondria or of "faking it". When a physical symptom is a daily constant and is taking time to heal, it's a concrete visual reminder to others that a person is not well.

But if someone has lesions on their brain, only their radiologist who took the MRI saw it. No one else can see them.

If someone has extreme fatigue, only they know what the experience is like to be feeling the heavy weight of that burden on their body all the time - while everyone else just sees them as someone who lies on a sofa or in bed all day and might judge them as being lazy.

If someone winces in pain at someone else turning on a lamp or children talking and laughing animatedly, everyone else may see them as being overly sensitive without knowing the experience of the person for whom sounds seem three times louder and light five times brighter.

People understand what they themselves have experienced, and people understand what they can see. Many people joke about using the Missouri license plate motto as their own personal mantra: Show me. They don't believe in something's existence unless they can see it or experience it firsthand.

But anyone with an ounce of scientific reasoning and logic can see that just because one cannot see something or experience it firsthand does not mean it doesn't exist. One can detect the presence of some agent or phenomenon through indirect detection. Much like antibodies in a blood test, one can determine infection is present without detecting the causative organism itself.

In the mid-1800s, doctors and others believed that patients' exposure to bad air in hospitals are what lead to infection in wounds. Washrooms for doctors' hands and patients' wounds were not available. Washing hands before seeing a patient was not considered necessary to avoid infection - the idea never entered one's mind.

One doctor, Dr. Joseph Lister, learned about Louis Pasteur's research that rotting and fermentation could occur under anaerobic conditions if microbes were present. By learning more about Pasteur's hypothesis as to what could prevent rotting and how this might apply to infections, Lister decided to conduct his own experiments. Even though he could not see the microbes themselves he could see the results of his research: antiseptics prevented infections in wounds fron taking hold.  

Lister went on to encourage doctors he supervised to wash their hands before surgery and use antiseptics - even though at the time doctors thought it was unnecessary and a joke at first. Nonetheless,  as time went on, others began to adopt his practices and went on to prevent many cases of infection and sepsis.

For centuries, scientists hypothesized that extrasolar planets existed. But it is difficult to directly detect them. Most extrasolar planets are detected through indirect detection methods such as measuring radial velocity or the Doppler method, by observing the drop in brightness emitted by a distant star due to a planet's transit in front of its disk, and by using several other methods. In astronomy, one can observe a number of planetary bodies' presence through the use of inference. By looking at different stars, we can infer something about the planets orbiting them - even if we can't see the planets with our own naked eye - or in some cases, even with a telescope.

These are just two examples where inference leads to association and discovery.

But here we are, in 2012, and it seems that the power of inference is somehow broken in doctors and neighbors who leap to the conclusion about patients who have symptoms they do not understand or which they have trouble offering an official diagnosis.

Like the doctors who believed patients were getting infections from bad air in the hospital without any particular data to support their conclusion - some doctors today are making snap judgments that patients' symptoms are due to their own neurotic imaginings.

The truth is, it might not be that easily determined why it is some patients are having the symptoms they do.

Instead of saying these three words, "I don't know," when there is no quick answer as to why a patient has particular symptoms, some doctors readily fall back on a psychological cause. Often without any particular training in psychology. Often without any psychological and neurological testing of the patient in front of them. Often without any rule-outs to determine if some underlying medical condition could be contributing to their patient's symptoms.

And sometimes, even with training, there is a risk their diagnosis is wrong. Because if one doctor looks through the same lens of his own area of specialization every day, sometimes it's difficult to consider presentations from a different angle.

While the debate about the cause continues, the recent outbreak of a strange rash of illnesses in upstate LeRoy, New York, could be one example of making a snap judgment based on a psychological condition.

A group of young women (and as it turned out later, one young man who didn't know them) in high school began exhibiting strange behavior last year. They have had unusual tics and verbal outbursts similar to those found in Tourette's syndrome.

They were taken to various medical professionals to be interviewed and examined, and the initial diagnosis which was offered was "conversion disorder". Conversion disorder used to be previously known as "hysteria", and before Freud used the term, hysteria was associated with people who were malingerers, had weak nerves, or had some meaningless disturbances. No reason for these behaviors was ever given back then beyond having poor character or a weak constitution.

Today, conversion disorder is not the same thing. It's not thought to be due to malingering or feigning illness - it is a genuine psychiatric disorder which is not related to any underlying neurological or infectious cause and is rooted in extreme stress and anxiety. One could argue it is a physiological and biochemical response to stress.

But given its psychological origins, some parents disagreed with this diagnosis outright - and feeling that their own kids could not have this disorder, they sought second opinions. With further investigation into biological causes for their symptoms, one doctor diagnosed a young woman in neighboring Corinth, New York, with Lyme disease and is apparently evaluating some of the students from LeRoy.

Today, months after the original outbreak, debate over what exactly is the cause of all these students' unusual symptoms has continued. One physician who treated some of the girls classified the disorder as PANDAS, related to streptococcal virus. Some of the girls got better under treatment for PANDAS. Some have not. Some doctors do not even think all the students suffer from the same condition as their individual presentations are somewhat different.

Where can anyone rest with this, with the knowledge that people that exhibit unusual behavior may not have it "all in their heads" and are not "making it up"?  And that similar symptoms might stem from different causes?

One must appreciate that sometimes it takes time to sleuth out the proper diagnosis. But one must also begin to appreciate that it is way past time to stop discriminating against people and labeling their motives and essential character as human beings if they engage in unusual behavior - whether it began with a traumatic experience or a tick bite.

Even if it turns out some of these young women have a disorder which was triggered by extreme stress, that does not mean they are faking it. It would be a genuine medical problem that requires treatment, just as PANDAS and Lyme disease need treatment.

From the infectious disease angle, this is not the only item to hit the news in recent months which brought up discussion about the possible relationship between bacteria and behavior.

Researcher Jaroslav Flegr has been investigating the relationship between infection with toxoplasmosis in people and their behavior, and already found some significant relationships. The psychological symptoms caused by toxoplasmosis are usually more subtle, so far, than what has been observed in these young women with tics and vocalizations - but they are further evidence that it is not always going to be clear if we alone are driving our behavior - or if a visiting microbe onboard is.

Other mental illnesses have been investigated for an infectious cause, such as schizophrenia - and various viruses and microbes have been implicated in or associated with its development.

Regardless of whether one diagnoses a patient with a psychological disorder or a physical condition, all of this should make us stop for a moment and think about how we as a society think about mental and physical illness in this country:  The gap between what is a biologically-based illness and what is a psychologically-based illness is closing and becoming blurred. With this change, greater acceptance and understanding of those with symptoms which affect them cognitively, neurologically, and psychologically is bound to occur.

It's been a long slow climb to work to remove the stigma that comes with mental illness in the United States. And it continues in part because of a tendency to believe that everyone has control over their own behavior. Tied very intimately to that idea is a belief that everyone has control over their bodies as well. Which is nice and a comforting thought to have, and most people who are completely healthy live with the privilege of this experience without ever experiencing anything else.

But once you have become incredibly ill, it becomes clear just how much is not under one's control. If you get into a car accident and have a spinal injury that is obvious to everyone, no one can ever tell you how long it will take to completely heal from your injury. Often it isn't clear if you'll completely heal at all.

The same applies to people who have been affected mentally - and not by choice, any more than the person who injures their spine in an accident. People who were healthy and "had it all together" can fall victim to an infection, genetic and environmental factors, temporary or permanent side effects of prescription medication, a car accident, or other traumas which leave them both physically and mentally affected.

The results are not something that is "all in their head" - if that phrase is meant to apply to an idea of them imagining it. On the contrary, having an infection or trauma which affects your brain is literally "all in your head" - and is in no way, shape, or form, imagining it. It is a harsh reality one must live with every day. It will mean not having control over your behavior and reactions to certain stimuli such as noise, light, the sense of touch, music, scents, the taste of certain foods, and then some.

To the outside observer, these reactions may seem strange. And even by the person having them, they are, and they are often aware their own reactions are atypical. But to the person who is living with them, it is what they have to live with and work around.

Antibiotics or other medications may bring their reactions under control and help. It may make life more predictable for those affected and those close to them who witness their behavior. And if anything, people who observe the change which occurs under such treatment over time should grasp that their symptoms have been due to their being ill and not because they were trying to get attention.

In regards to the practice of telling patients that a condition is imaginary, I have hoped that by 2012 we would have gotten much further by now and stopped this practice.  That we wouldn't be seeing young women in the prime of their lives with careers and hopes for the future lose all that and be told that their symptoms are only about trying to get attention by being sick.

It reminds me of stories of doctors who accused women back in the late 1800's of suffering from "hysteria" when they may have had multiple sclerosis. It reminds me of stories of doctors who accused patients in the 1980's through the present that it was "all in their heads" when they have CFS/ME. It reminds me of stories of doctors who today are saying those with chronic Lyme disease are "faking it" and aren't really sick - or perhaps they are depressed.

No doubt, depression can be a serious and debilitating condition in its own right which requires medical treatment and cannot be solved just by pulling oneself up by one's own bootstraps. We've moved beyond some of the stigma attached to depression and understand today that it is not a sign of poor character or laziness. But let's be sure to not confuse one disease or condition with another just because some of their symptoms overlap.

All this said, it is clear to me after having done extensive research on Lyme disease that everyone who has persisting symptoms related to Lyme disease after a tick bite and its initial treatment is not well. It's not "all in our heads"- even if for some of us the damage may be literally in our heads.

Lyme disease affects each of us somewhat differently - some of us have more neurological, cognitive, and/or psychological manifestations of disease than others. Given the pathogenesis of this disease, these differences should be no surprise: without early treatment during the acute stage, Borrelia bacteria disseminates throughout the body and can affect different organs and tissues - and at times, affects the nervous system, too.

Even if one does not believe in a model of chronic infection after initial antibiotic use, there is no reason to doubt that someone affected by this disease would have some damage done by its presence. This damage can lead to all kinds of problems of varying frequency and duration - damage which doctors should be well aware of and be attentive to just as they would for other medical conditions.

The effects of Lyme disease on people - particularly disseminated and late stage Lyme disease - are real and variable. Even if it becomes a post-infectious autoimmune condition, the damage done is real. The resulting symptoms need to be dealt with effectively. Medical societies and professionals need to step up to the plate and recognize them rather than write them off as imagined.

Related items of interest:

Dr. Phil Show In Three Parts - See the entire segment on Chronic Lyme disease.
Emory University Center for Ethics on an explanation that psychiatric illness is not imagined but a real condition - plus a mention that there is growing evidence of a biological basis for psychiatric disorders.
Economist on the pros and cons of toxoplasmosis.

* Stephanie, when interviewed on the show, stated she has had symptoms on and off for five years. According to her Twitter account and other online resources, she had a turn for the worse beginning in October 2011 and has been consistently ill since November 2011. So she hasn't yet been seriously symptomatic for the same period of time I was - let's hope she isn't.

Image Credit: 
Sick Girl, 1910 (Poland) - From under US-PD license.

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Thursday, April 12, 2012

0 Commentary: Antibiotics Are Only One Tool - I Want Others.

A few weeks ago, I commented on a Wall Street Journal blog post about chronic Lyme disease. Since then, I have been reflecting on this response to my comments there:
"Camp Other – The cure for chronic Lyme is known. If you want a sustainable, long term cure, you can gamble on long term antibiotics, or can you take an alternative approach, which consists of doing between 20 and 50 different things, including Low Dose Naltrexone. Yes, they get you to a cure, at which point a good alkaline diet, oxygenation, vitamin D, etc etc etc should maintain health.
 Easier said than done though. Even when you cure your Lyme, you need to maintain the healthy diet, and some of the supplements that got you there. You also want to do genetic testing for things like methylation, as part of treament and post-cure maintenance. I’m certainly not banking on the Viral Genetics research. It could be many years before that turns into a drug we could take. I already know people who are fully cured and back to their old lives, so it is curable with current knowledge."
And I also sadly know people who are not fully cured with current knowledge.

Reflecting on this, it's not an easy statement for me to make - but I don't think the cure for chronic Lyme disease is entirely known.

If it were known, then all the patients I know would have had the treatment they needed and would be better now. But some of them are not. And I don't think it's some personal failing that they aren't or that they haven't done the right things - it's that their individual condition is different and may require different treatment - including treatments which haven't even been developed yet.

I can see that long term antibiotics, some alternative medicine, or some combination of the two have helped a number of people improve their condition and alleviate symptoms. Many have gotten their old life back. But it's never been guaranteed that any of these treatments will work for everyone.

 Even the Lyme disease patient support groups have often repeated the statement, "Every patient is different," and Polly Murray herself stated in her book, The Widening Circle:
"I am struck by how Lyme disease never seems to act exactly the way it is supposed to, how each individual seems to respond differently to the spirochete."
I'm a fairly pragmatic person, so my basic position on using antibiotics to treat persisting symptoms related to Lyme disease has been that if they might offer relief and improve your quality of life, if nothing else has helped, and a doctor has agreed to this treatment - then try them. Use them, while being aware that there are risks in taking them longer term - and note that perhaps there are even unforeseen consequences of which scientists are not yet aware.

But while I've been an advocate for the use of longer than standard courses of antibiotics in the subset of patients with Lyme disease who have persisting symptoms and I feel they saved my life, I have never wanted that to be the end of the story. Because it seems to me that even if they do help, if they don't cure everyone then more research is needed for effective treatment which helps all patients.

If there is evidence that comes out of Embers' Rhesus Macaque study - along with others - that Borrelia burgdorferi s.l. does have a persister cell phenotype as part of its pathogenesis, then more antibiotics may only be a maintenance treatment at best. What would really be needed is a treatment which reactivates the dormant persisters and kills them - something which antibiotics alone cannot do.

Persister cells are tolerant to antibiotics. So in theory, it may be that antibiotics of some kind plus a metabolite would be needed to eradicate any remaining spirochetes.

In the long run, I'd like to see more effective, less expensive treatments of shorter duration for my condition.

I'd like to avoid taking antibiotics out of concern for my poor digestive system and my palate, which is disgusted with bitter tasting substances rolled into barely swallowable pills in general.

I'd like to avoid the strange side effects which I have experienced which, thankfully, in most cases abated after the first week or two of treatment - yet they inexplicably seemed to be those which are less common to experience and more difficult to cope with.

Antibiotics are great tool and have helped a great number of people - and they have helped me, too. But I think it's time to look past long term antibiotics alone and push for research on other avenues of treatment.

Researching them doesn't mean abandoning antibiotic use entirely - they are scientifically proven effective against Lyme disease and its coinfections. Researching other avenues means investigating what else can be done to help patients improve their quality of life and to find something that could cure them in less time. It means exploring more options, not fewer. It means more patient freedom, not less.

 If at one point I seemed to strongly advocate Viral Genetics' VGV-L candidate for the treatment of chronic Lyme disease, it isn't because I am certain it will work. I don't know for sure that it will. I am hoping, though, that it will help at least some portion of those of us suffering and will not have serious side effects.

And I'm hoping it marks the beginning of more research into different ways to treat patients who are suffering with persistent symptoms. The antibiotics will still be there if you need them - and after how much of them I've already consumed, I'd rather not need them. I'd like to try something else if I can. A round of Buhner's herbs, perhaps - or perhaps something entirely new.

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