Multiple sclerosis is a disease of the central nervous system thought by most to be autoimmune because it is clear that the nervous tissue is being damaged and that also the immune system is present at the actual lesion location. Efforts to find a germ that the immune system is attacking have fallen flat with conflicting and inconclusive results. We propose here that MSi [1] may be caused by chlamydia pneumoniae (CPn). In this book page I will outline the various findings in research on MS and also findings on CPn highlighting similarites.
While it is very interesting material, the reader must understand that this is a theoretical model and I am coming at it with this point of view, "If CPn causes MS what does this research mean?" I do have a bias as I begin. But I offer this to you, the reader: Everyone has a bias, I am just stating mine up front. The pharmaceutical company that is making a drug to suppress your immune system comes at the issue from a bias that MS is autoimmune, even though this is not proven but a model. So, we will start there.....
MS:Is it autoimmune?
Most of the medical community thinks MS is autoimmune because every damaged area in the MS brain has immune system cells present. Or do they? In 2004, Prineas and Barnett rocked the MS world with their paper "Relapsing and remitting multiple sclerosis: pathology of a newly forming lesion" found HERE [2]
As you can see in that paper, and I was lucky enough to read the whole citation, the notion that the immune system comes in and damages the nerves is seriously questioned. Essentially these authors found that in autopsied brain tissue, the brain had the lesions that they expected with immune system cells present, but these tissue samples ALSO had NEW lesions in which the nerve had died, but the immune system had not yet gotten there to clean the area up and remove the dead tissue. How can the immune system have caused the injury if the injury occurs before it arrived? If we understand that immunity includes cleaning up dead cells and unwanted tissue, we see there is a very good reason for the immune system to be present in the brain if a nerve has died from some other cause.
In fact this is a very logical reason for the immune system to be present because we already know that the immune system works this way naturally, this is what it is designed to do. All other theories from molecular mimicry to autoimmunity require that the body made a mistake and began attacking itself.
This work is supported by review of the issue written by Chaudhuri and referenced on pubmed HERE [3] I have been fortunate enough read this paper (the link I provide here has a "blank", you'd have to subscribe to read it) and this author is adament that MS is not autoimmune,. In an earlier paper he said;
"Multiple sclerosis (MS) is a common, disabling neurological condition whose pathogenesis is not clearly understood. Although current treatment recommendations assume an immunopathogenic disease mechanism, MS may not be an autoimmune disorder. Long-term immunological therapy for MS is in our view an untested approach, guided by uncritical acceptance of data from drug trials. We do not believe that there is convincing evidence that any of these immune-based treatments prevents long-term disease progression, or has much effect on common disabilities such as fatigue, pain, depression and cognitive impairment. The recent recommendations of the National Institute of Clinical Excellence did not address important issues regarding disease modification, management of paroxysmal symptoms and the likely therapeutic candidates for future treatment trials. We discuss treatment options for MS beyond the NICE guidelines" (Chaudhuri 2005) reference HERE [4].
A recent work by Dr Sriram of Vanderbilt University published in the Annals of Neurology and referenced HERE [5] indicates that MS is utterly different on a cellular level than EAE which is a pure autoimmune disease. There are different cytokinei [6] upregulations and a cellular immune different profile altogether, which is a critical issue because the therapies generated by looking at what impacts EAE are geared to alter these cytokines. He contends that the constant reliance on this model as a "good model" of MS and through which all treatments are brought to us limits research understandings about what MS really is. In essence we are treating EAE not MS when we bring new protocols and strategies to market via this method. It is interesting to note that EAE is curable and it has been so for decades via the same medications that do not actually help people with MS.
HERE [7]
is yet another abstract indicating that anti-inflammatory approaches may be misdirected in MS. Importantly, these authors say that even the newer immune suppressing approaches, while they do result in a large decreases in MRI activity, do not result in an improvement in disabiilty long term. Quote;
"Suppressing relapses by disease-modifying agents does not dramatically influence the progression of irreversible disability. Interferons beta reduce the relapse rate by 30% and conventional MRI activity by more than 50%. In spite of this effect on inflammation, the effect on disability is only marginal and possibly relapse-reduction-dependent. Administration of Campath-1H to patients with very active disease in terms of frequency of relapses, accumulation of disability and MRI activity, results in a profound, prolonged lymphopenia and the suppression of clinical and MRI activity, but in spite of this, clinical disability and cerebral atrophy still progress. The same experience has been reported with cladribine and autologous haematopoietic stem cell transplantation..." copied verbatim
The paper suggests that neuro regeneration and protection should be the main focus of MS strategies, not simply reducing inflammation. It also raises an important question for medicine in general in regards to currently available therapies, namely exactly what does reduction in inflammation accomplish for the MS patient and at what cost?
So here I have presented the idea that MS is not autoimmune and offered research that caused me to form that opinion. So, If MS is not autoimmune but instead a disease in which the nerves die for some reason then the immune system comes in to clean up the debris just as it is supposed to, what bacteria or virus is to blame?
The infective model of MS
The infective model of MS is the notion that MS is caused by a virus or bacteria. While numerous attempts have been made to isolate the infective organism, unfortunately no one organism has been consistently tied to MS. Several of the possibiities are human herpes 6 (roseola), epstein barr virus (mono or glandular fever), and pleomorphic bacteria like chlamydia pneumoniae, borrelia, and mycoplasma. While there are articles outlining some people finding and isolating each of these things in the MS brain, others do not find the same organism. Here in these pages we are presenting the idea of CPn as the possible infective organism but it may be that the kinds of changes we see in CPn could be common to changes seen in other bacterial infections like persistant borreliosis and potentially even viral causes. The body often uses the same strategies to do multiple things as in, for example, creating a fever in both viral and bacterial infections of many kinds. We are investigating CPn specifically here as the theoretical cause of MS because Vanderbilt University research finds CPn in higher numbers in the CFSi [8] of people with MS. Additionally, there is a lot of general research on CPn indicating it is causing a variety of chronic illnesses because it has the ability to change forms and invade the cells themselves including especially immune cells, nerve cells, vessel walls, lung tissue, and blood cells. For example, CPn is considered an emerging pathogen in atherosclerosis. See the CDC link HERE [9] It is also implicated in asthma, and some authorities such as Margaret Hammerschlag MD of the CDC are now saying that asthma, long thought to be a chronic illness of unknown pathology which has decades of research looking at genetics and other putative factors as causal, is in fact probably a chronic infection with CPn. When discussing MS specifically, it is less clear at this point although there is a lot of circumstantial evidence for CPn possibly playing a role as well as the research done at VU finding it directly.
The first people to produce work that shows CPn in the MS brain were at Vanderbilt University Sriram, Stratton and Mitchell. The first paper is here [10]. This paper is the whole citation, and it is an incredible privilege to have this paper available to us. This was reprinted on CPnhelp.org with permission. In essence, the upshot of this article is that using their techniques, the team at VU found evidence of CPn in the vast majority of MS patients. It is important to note that the team used PCRi [11] analysis, CSF immunoglobin IgG reactivity with CPn antigens and culture to evaluate the presence of CPn in these MS brains. People who produce work counter to this frequently offer a single test ie "we cultured the CSF for CPn and found none." Such "opposing" research simply does not have the authority that the original work did due to the lack of diligence. We will investigate this specific issue in depth in the next page about the debate.
Other researchers all over the world have also found CPn in MS brains. A list of some of these follows:
HERE [12] is a paper by Contini C, et al titled "Cerebrospinal fluid molecular demonstration of Chlamydia pneumoniae DNA is associated to clinical and brain magnetic resonance imaging activity in a subset of patients with relapsing-remitting multiple sclerosis". This paper found that CPn was associated with MS more often if the disease was active on MRI and if RRMSi [13]. Again this author used several detection methods. But in this paper they also found CPn in people with other neurological diseases as well, suggesting it may be able to cause several problems. This might be compared to e.coli causing a bladder infection, urethritis, or nephritis. All are urinary tract infections with slightly different locations and problems.
HERE [14] is a link to an abstract by Dong-Si T, et al titled "Increased prevalence of and gene transcription by Chlamydia pneumoniae in cerebrospinal fluid of patients with relapsing-remitting multiple sclerosis". This author again found that other neurological diseases also had increased CPn, but that in MS patinets there was increased gene trascription of CPn indicating it may be more active for them.
HERE [15] is a link to an abstract by Sotgiu s, et al titled "Chlamydia pneumoniae in the cerebrospinal fluid of patients with multiple sclerosis and neurological controls.". This author found CPn in the MS patients only, as different from others.
HERE [16] is a paper by Fainardi E, Et al titled "Intrathecal production of Chlamydia pneumoniae-specific high-affinity antibodies is significantly associated to a subset of multiple sclerosis patients with progressive forms" in which an association between CPn and MS was found. The conclusion was "These findings confirm that the presence of a humoral immune response to C. pneumoniae within the central nervous system (CNSi [17]) is not selectively restricted to MS, but is shared by several inflammatory neurological conditions. In addition, our results suggest that an intrathecali [18] production of C. pneumoniae-specific high-affinity IgG can occur in a subset of patients with MS progressive forms in which a C. pneumoniae brain chronic persistent infection may play an important pathogenetic role."
This is a sample of the work that found CPn in MS. To read more simply click one of the links and enter "multiple sclerosis chlamaydia pneumoniae" in the search box on pubmed. You'll get a whole list. Of interest note that this work is done all over the world and a considerable amount of it is done by infectious disease specialists and pathologists, not necessarily neurologists. There is other work, of course, that did not find it since this is how science works to advance understanding. For the best review of the debate on the potential for CPn to be the causitive organism in MS is found in David Wheldoni [19]'s site. There is a greater number and a more in depth evaluation of studies there. HERE [20]. The question "how do we evaluate these controversial findings?" is tackled on the Great Debate page.
Why could Cpni [21] affect MS sufferers so much?
There may be more than one explanation…
The answer could lie in a person’s genesi [22].
Amongst our genetic code we all have instructions for T-cells. These are a group of white blood cells, part of the body's immunei [23] system, that defend against infection. Whilst these T cells are necessary for us to fight infection if they run unchecked they can cause damage to the Central Nervous System (CNSi [17]) by damaging the nerve fibres. In MS patients it is possible that the cells that stop some T cells from being over efficient are not working properly.
For a more comprehensive explanation please visit
http://www.msneighborhood.com/content/in_the_news/archive_2248.aspx [24]
Or in the Blood-Brain Barrieri [25]
The brain is an especially sensitive area of the body which is protected by the Blood Brain Barrier (BBBi [26]) basically a very fine meshed sieve. Unlike the kitchen variety it is selective of what can go through. It will only allow what it needs to pass through the BBB but some infectionsi [27] get in under cover of other cells, a bit like a Trojan horse. The idea here is that Cpn has infected the brain and the BBB opens up enough to allow the body’s immune system to come and fight the infection and remove the debris. In the process the very sensitive brain could be damaged by the clean up operation.
For a more comprehensive explanation please visit
www.cpnhelp.org/?q=the_brain_and_pathogenic_ [28]
Or it could be a combination of factors, such as a BBB which does not work quite as it should and an immune systems that over-reacts. There are many other possibilities, including infection by viruses or bacteria and many others are unknown.
How Cpn could affect MS patients
Cpn is a common organism (a bacterium) which can affect many parts of the body without causing too many problems if it decides to settle in areas that are not particularly sensitive.
Many people will have sinusitis, or a dry cough, or dry skin, or what feels like an upset tummy and carry on regardless of these small discomforts.
But if the bacteria infect the brain then, over a period of years, the symptoms recognised as MS may surface. Often this first shows up as eye problems, maybe some numbness which goes away after a couple of weeks, but gradually the symptoms can become more severe and end up disabling the sufferer.
One possible reason for this is that Cpn is a slow growing organism and it could be many years before the infection is bad enough to cause the immune system to react to it so severely as to result in disablement.
For a more comprehensive explanation please visit
http://www.cpnhelp.org/?q=multiple_sclerosis_and_th [29]
www.cpnhelp.org/pdfs/Cp-MSAssoc.pdf [10]
Hello, if you have come to this page you are probably investigating this protocol and you are looking for as much information as possible. This page is not here to discourage people but to be honest in offering a more balanced picture, though I am stating up front that I am biased towards this model.
Every approach has limitations. In the field of MSi [1], even the traditional approaches have one: the autoimmune model remains unproven. Even so many pharmaceutical companies and doctors treat based on this model anyway. In a situation where something must be done for the patient or you may watch them slip away, this may be fine. But one of the biggest complaints I have against the traditional approach is the lack of honesty about this limitation and the unwillingness to discuss it with you, the person who needs treatment.
We want you to understand that the CPn/MS model has limitations as well in the interests of full disclosure and healthy scientific self-examination. These arguments may be mostly of interest to the scientifically minded and should not discourage anyone from considering this approach. But we believe you should know the scientific realities as part of your considerations. It is not a sure bet, partly because it has not been done with hundreds of MS patients so that statistics and clarity about who should be treated this way and who should not are not known. It appears clear from cases reporting here that some people experience changes dramatic enough to change EDSSi [30] scores and cause some reversal of lost function. The limitations on this page also apply generally to treatment with CAPi [31] for other diseases as well.
If you have read all the other pages in this section of the handbook on MS; Multiple Sclerosis and the CPn Model, Smoking Guns, Cellular Similarities between CPn and MS, The Great Debate and The Brain on Pathogenic treatment, you are well versed in the model we use here as a guide for treatment. It is a very good model with many reasons to think CPn is possibly the cause of MS. The question then becomes is it possible that there are any limitations to this model? Is it possible that it could be incorrect?
It is possible and this is where the limitations are.
1. It is not known if all people with MS have this kind of MS or not.
Pneumonia can be caused by a virus, a bacteria, a chemical, or even smoke inhalation. Obviously, if someone had viral pneumonia, antibiotics, which treat bacteria, would only play a supportive role in healing by preventing any bacteria from taking advantage of the already inflamed tissue and becoming a secondary issue. The actual cause of the pneumonia in that case would need to heal on its own, or possibly be treated by using antivirals.
In the same way, more than one trigger might be cause MS. If this is true, there will be some people for whom treatment works perfectly and others for whom it does not and there is no way to know ahead of time which group you would be in.
2. There is no standard lab test and no standard primer used in the MS/CPn research.
This means that many researchers use in house tests-- tests that they developed themselves. Obviously every standard test at one time was someone's in house test so this is not a criticism in and of itself, but it does mean that the research from one worker to another is not necessarily looking at the same thing. It also means that other acknowledged CPn experts in the field do not necessarily agree that "x" researcher using his in house test and who says CPn is there actually was testing for CPn.
Margaret Hammerschlag MD who is a CPn researcher says the VU work was looking at and amplifying human genetic material not CPn. VU says the supposed "clean" primers MH used to make that determination from the lab supply were themselves infected with CPn, so it was CPn they were finding not human. Other labs in other places using OTHER tests also said CPn was present in MS patients, and still others said no CPn in MS. The fact the VU team has been working on this specific issue (rather than CPn in general) for over 10 years gives them added credibility in my mind, but the fact remains that this is unresolved and there is no agreement as to how to detect cryptic CPn.
In regards to MS and the possibility that CPn is the root cause, this means that the research looking at that issue is not necessarily authoritative and the findings must be considered "preliminary". This is true for BOTH sides of the debate, those who find it AND those who do not.
This ties in to the first issue as well since it means that we can't know who to treat and who not to treat. If we had a generally accepted lab test for cryptic CPn that issue would be solved. Another route for proving that CPn causes MS is if researchers use autopsied MS brain tissue and look directly and specifically for CPn in lesions.
Until there is a test that is universally considered reliable for cryptic CPn infection, we are in a place of assessing the model for its circumstantial support. There is a large body of research on how CPn behaves in the body and about the difficulties finding it in cryptic states, which seem to fit nicely with MS. The model makes sense on many levels, but it remains unproven at this time.
3. It is possible that CPn is a bystander, a secondary infection that moves in to the MS brain potentially making the "real" cause of MS more complicated than simply a bacterial cause.
This might be compared to a person with cystic fibrosis, who has very thick secretions in the lungs due to this genetic defect, getting a bacterial pneumonia in addition to the primary disease process. The bacterial process has sinister implications for the person compromised in that way. Treating the bacteria will allow them to return to being relatively stable, but the underlying disease process is still there. It should be noted though that it is always best to treat secondary infections; one does not ignore them and they can be more problematic than the original disease process.
4. It is also possible that the real cause is a combination of infective organisms, such as viral and bacterial. If such were true, it is possible that antivirals might be needed. It is also possible that these co pathogens would not be an issue in most patients and as their immune system recovers they would be completely cleared of such secondary infections, while some other patients with more advanced secondary infections might need antivirals as well to get a complete cure. These copathogens are known to be present in CPn infection but it is not known for certain when they might need to be addressed and when they can be ignored.
5. In the lab it is possible for CPn infected mice to develop secondary autoimmune disease through epitope spreading. In other words, the body attacks the CPn but in its effort to clear the infection it also accidentally makes antibodies that are self-reactive. It is possible that CPn causes MS but that a secondary autoimmune process is also in play. If such were true, it is possible ridding the person of the infection and addressing the autoimmunity as well would best facilitate treatment. On the other hand, rheumatic fever, which is an autoimmune disease secondary to a germ (strep), is self-limiting once the germ is gone so even if CPn autoimmunity were an issue it may not be something that needs treatment.
I have been told by my neurologist that only about 10% of people with MS actually have myelini [32] active antibodies in their blood that can be treated with the new treatment in development in which they filter your blood and extract the myelin active antibodies, radiate them, and reinject them as a vaccine so your body destroys those antibodies (this treatment is called "Tovaxin"). Is it possible that 10% of people infected with CPn develop autoimmunity? Such things are unknown, but certainly could complicate the picture and the eventual "best" treatment.
The actual facts of how MS develops and what co factors are in play is unknown. The theory that CPn causes MS is plausible and very compelling, but it is possible some of these other co factors will be understood as more people are treated this way or as more research comes out.
Treating Empirically has some limitations also.
1. There is no reliable test for cryptic infection. However, empirical treatment is problematic because it may be hard to know when you have enough objective improvement to know it is working for you. In terms of MS, some of your symptoms may be caused by axonal degeneration and permanent scarring which may not go away without regeneration of some kind; it is hard to know what "I still have a weak leg" means in relation to CAPs treatment. It may be that some people with disease of shorter duration recover function with EDSS scores lowering, while others with more longstanding disability may "only" stop progressing. However it should be noted that the brain is much more plastic than used to be thought and it is likely some level of regeneration is possible if the disease process is stopped (just as people who've had strokes can recover more function with aggressive rehabilitation than anyone ever thought before recent research proved it was possible). If you do not have noticeable or dramatic exacerbations it might also be some time before you know you have stopped progressing, or if you have stopped. This can be devilishly frustrating.
2. It is possible that reactions to the antibiotics do not mean that a CPn brain infection is present. There could be other bugs, even normal intestinal bacteria, causing some systemic reaction to antibiotics. It is also possible that you are reacting to CPn in your body, but none of it has passed through the blood brain barrier and thus none is in your brain. If this were so, one could "react" to antibiotic treatment but the real MS process would go on unhindered.
3. It is also possible that the antibiotics themselves ameliorate the disease process in a way not related to their antibiotic activity. There is a fair amount of reserch on minocin, a tetracycline antibiotic closely related to doxycycline, which suggests it helps MS by altering the immune system and dampening it a little thus reducing lesion loads and exacerbations. If you are a person who believes the CPn model, you might see that relief as an antibiotic effect instead of any immune system modulation. However, one cannot determine cause by results so such positive outcomes do not prove either theory.
4. It is possible the adjuncts to treatment, the supplementsi [33], have an ameliorating effect on symptoms all by themselves. Many people who start the adjuncts first report that they already feel better before they have begun taking antibiotics. It is possible that a combination of supplements and amelioration of symptoms by the anti-inflammatory effects of antibiotics combine to create some apparent improvement independent of any antibacterial activity.
5. The protocols here are based on current research and are still evolving as new material comes out. Even if the MS/CPn model is proven it is possible the eventual protocol will include elements not now known, or that co factors will be understood and addressed in a way not now imagined.
What IS a "proven" approach?
If a person is given a pill filled with sugar, a placebo, and believes it will help, about 35% of the time it will actually help them. Their belief activates their healing in some way we do not thoroughly understand. It is more than just "thinking" they are doing better-- they really do better.
The CRAB drugs are all considered "proven" meaning that they have been given in blinded trials to larger groups of MS patients and shown to be marginally better than placebo. For more on this and why I used the word "marginal", please look at the objective Cochrane reviews of these drugs on Pubmed.
MS is a disease of unknown origin. It is often stated as being autoimmune, but that is actually an unproven theory. For autoimmiunity to be proven, it would need to be shown that a specific part of the immune system is different consistently in MS patients and that inducing this precise difference in other animals, preferably primates, results in a relapsing remitting neurodegenerative disease that eventually becomes progressive identical to MS. After decades of looking, no such trigger has been uncovered.
In light of the unknown trigger for MS what drug manufacturers can do for us now is to treat based on the generally accepted "best" theory for MS, do a trial, and see if they actually get any positive results with their drug. These trials result in "proven" therapies even though the cause of MS is still unknown: they do not prove the theory that MS is autoimmune, they only show that the approach used helps in some unknown way. These are relatively expensive trials and are undertaken for promising therapies likely to recover the cost of the trial. This is just a simple business reality, not a conspiracy.
It is extremely unlikely that CAPs will be trialed in the way described above to see if it helps patients with MS. The drugs are long off patent so they cannot generate the profits necessary to make it possible to recoup the expense.
Our best hope is for someone in academic research to look for and find CPn in MS lesions by preserving a donated MS brain properly and staining the samples near lesions correctly to see inclusions. This would result in a proven association with MS. However, even if such were discovered tomorrow it would likely be a long time before there was a universally accepted and proven antibiotic regimen for patients (although IMHOi [34] the VU protocol is the most likely due to the extensive research they have done).
As an illustrative example, it has been known for years that atherosclerotic lesions have CPn in them, yet the medical literature continues to debate whether or not it is a secondary infection or causative, whether or not intermittent mono therapy antibiotics reduce second heart attacks, whether it has triggered a secondary autoimmune attack on the blood vessels, and whether it is even possible to get rid of cryptic CPn infections. I have not yet seen anything remotely resembling a CAPs protocol being tested on atherosclerosis patients. During these years of debate on the issue, dozens of patent medicines to treat cholesterol have come out and patients needing some kind of treatment today are offered these new drugs because nothing related to CPn and atherosclerosis is proven. During these years also heart disease remains the leading cause of death. Once again we see drugs go to trials based on the most generally accepted theory, in this case that cholesterol causes atherosclerosis. This offers proprietary targets (cholesterol is a viable target for drugs) and when the created patented drug works better than placebo in reducing cholesterol, the drug is approved for use in patients. However, if CPn causes atherosclerosis, there will never be a cure by reducing cholesterol.
With a few exceptions, science moves very slowly with a lot of back and forth research before final conclusions are drawn and everyone agrees on one fact as a generally accepted principle to guide treatment. This process is greatly enhanced when a commercially viable product is the agent in question, and there is not one for CPn.
No one can or should make any promises to you about how you will do on CAPs, there are unknowns as described in this page. What I can tell you is that some people, though not all, have had verified reductions in EDSS scores using this approach and that if CPn causes MS then this is the best hope you have for a cure.
With all these limitations duly noted, there are good reasons to initiate a CAP for Cpni [21] despite these scientific uncertainties. In many cases there are really no good approved treatments for the individual person. Additionally, CAP protocols do not conflict with other approved treatments so it is certainly possible to do both. CAPs are also low risk and low cost, and if you are a person who engaged in Empirical treatment and reacted to the NACi [35], the antibiotics, or the protocol in general you know you are dealing with some kind of bacterial load, the eradication of which cannot help but improve your system.
Addendum: In a thread started to discuss this Limitations page found HERE [36] Dr aWheldon made a comment on this page that lends adds more food for thought and I have pasted it below. The link to the thread is worthwhile reading also.
Dr Wheldons's comment on this page:
I always look forward to Marie's posts; this one is an analysis of the limitations in the viewpoint that C. pneumoniae has a role in Multiple Sclerosis. It is impartial and thorough. I read it carefully and with great interest, and recommend others to read it also.
As I read it I found myself pondering the manner in which medicine is practised. It is often not very rational. I recall, as a medical student, standing in a women's ward in a big mental hospital which had been built in the 30's in beautiful countryside. It was a consultant ward round; we had almost finished. We came to one very perplexing woman who was behaving very bizarrely. Her symptoms fitted no psychiatric stereotype. The consultant clearly didn't know what to do. Two psychiatric social workers were having a private but rather loud discussion about tatting in the background. The sister was keeping her thoughts to herself. The registrar was quietly doing isometric exercises. 'Tell you what,' said the registrar, suddenly, and rather impertinently. The consultant looked at him. 'Have you a suggestion?' he asked. 'Yes,' said the registrar, smilingly. 'Let's give ECT[1] a whirl.'
I've never forgotten that phrase: 'let's give ECT a whirl.' Give it a whirl! What an odd way to recommend a much-argued treatment, and yet how refreshingly honest! There is a deadly comicality about it. The main thing about recommending something on a hunch is never to forget that it is on a hunch. When Sarah was falling through the EDSS numbers, the diagnosis made, the Internet searched, the original Vanderbilt paper discovered, the objections by Hammerschlag discovered also, I must confess that I didn't weigh all the evidence scientifically. I did a brief risk analysis (aggressive SPMSi [37]: deadly - doxycycline: one of the most harmless antibiotics available) and started. It was a hunch that maybe the Vanderbilt workers were right and that the entire neurological Home Fleet was wrong. (This was in 2003.) I remember reading an interview with Hammerschlag in which she said ". . . this study shows that it's much too soon to put MS patients on antibiotics for Chlamydia pneumoniae." And as I read these uninspired words that risk analysis went through my head. Other people's risk analyses came to mind, too: the risk that if MS has an infective input (as seems likely from the epidemiological data, even if one does not stipulate a pathogen) the administration of a T-cell immobilizing antibody may be clinically rather unwise. Hippocrates was surely right when he said: 'first, do no harm.' Many times, as a doctor, I have to make recommendations on poor or inadequate information. One has to admit to making assumptions. Often one can only say, 'If I were in your place I would take this road.'
So Marie is quite right: there is a weight of evidence on either side of the equation, and it's wise that we admit this, even if positive evidence carries more weight than negative evidence. We are still in the opening pages of the story. But I have a hunch that in 20 years' time the idea that C. pneumoniae infection is a key factor in the multifactorial illness MS will be mainstream.
[1]ECT - Electro-convulsive Therapy.
-D W
MSi [1] has been well studied for the last several decades. As a result there are volumes of knowledge about what happens inside the brain of an MS patient, though we are still very unclear on the cause. Any potential "cause" of MS has to fit with the known body of evidence for MS. Interestingly enough there are some similarities between MS on the cellular level and CPn infection and this page will explore that.
As we begin I'd like you to understand that CPn is relatively newly discovered (the 1980's) and new findings are coming out every week in this field. It is also a very different germ in that it behaves in ways that seem "wrong" based on what is "known" about germs. For example, we tend to think of resistence as occuring when a bacteria is exposed to an antibiotic then finds a way to still replicate in the presence of that antibiotic, thus remaining an active infection that we can culture. We do not recognize the kind of resistence that CPn is now proven to be capable of: exposed to an antibiotic it can become persistent, essentially going into hibernation and thus invisible and unaffected by the antibiotic, only to reactivate as soon as the threat of the antibiotic is gone. See THIS PAGE ON PERSISTENCE [38]. Though technical this paper is a wonderful review of the available research on the subject. CPn is an evolutionary coup de gras.
As backgroud for this page, bear with me as I do a quick overview of the CPn lifecycle because it is pertinent to our discussion. CPn is an obligate (it has to) intracellulari [39] ( lives inside of another cell) organsim of eukaryotic cells (cells with a nucleus). It is parasitic in nature meaning it converts the cell's energy mechanisms (mitochondria)for its own uses and leaves the host cell essentially nonfunctional for its original purpose. The elementary body (EB), a tiny hard cell with barbs on it which allow it hook on to potential host cells, is the infective form of CPn. Once contacted, EB'si [40] are carried in the blood floating around looking for a cell to hook into and parasitize. As a CPn EB sticks itself to a cell, it is included, or pulled in, to the cell in a sort of tiny bubble. There, it converts to a reticulate body (RB) which does several things. First, it grows larger by about 2 times and takes over the mitochondria. All the energy the cell can now produce is used to feed the RB which now begins metabolizing and replicating, making new EBs which will look for another new cell to infect. In order to escape detection and death, the CPn covers it's inclusion a lipid bilayer. It also turns off apoptosis in order to increase the life of the cell so its home is safe. At the same time, having an infection in the cell makes it vulnerable to death as the toxic by products of the CPn lifecycle are pushed out of the CPn inclusion and into the cytoplasm of the host cell.
Please also note that CPn was first thought to be a virus because it behaves like one: it floats around and invades your cells themselves, living off of the host cell and unable to metabolize and replicate on its own. Further research showed that it has almost all the usual cellular machinery that bacteria
have. With its own machinery, and a bacterial-size genome (not the tiny gene sequences that viruses have), it can play more tricks than viruses can play. For example, it can convert freely back and forth between these different forms, it can detect "threats" to its survival like antibiotics or gamma interferon, and then go persistent or hibernate in a non metabolic state wherein it is immune to the abxi [41]. The article on persistnce above is very good on this subject.
So let's begin noticing the cellular similarities with a well known concern in MS: The fact that nitric oxide (NO) is high. An example of MS research on this can be found HERE [42] This particular abstract was chosen for two reasons. First it shows that researchers believe that NO is part of the problem in MS, and this fact is so well established that I can't find a reference that establishes it.
So in MS the upregulation of NO is an accepted problem. Frequently we see research focused on potential strategies to reduce the NO and thus spare the nerves. But might that high NO indicate that CPn is present? In this abstract HERE [43] we have the authors showing that the body upregulates NO on purpose to defeat CPn. The organism cannot multiply in the presence of NO. This is the way the body kills unwanted villains like bacteria and viruses, with oxidative metabolites that are harmful to them, then the other immune cells like phagocytes can come in and clean up the debris. Interestingly enough, it is gamma interferon that is responsible for signalling this upregulation(and gamma interferon will come up again later). HERE [44] we have second paper in which cells that can make NO and cells that could not were compared. The NO sufficient cells were regulatory for CPn as we might expect. This is just two of the studies on this subject.
Point two from the abstract on NO in MS above was that LPSi [45] was the agent that the researchers used to damage the oligodendrocytes so that they could study the effect of NO in the MS brain. What is LPS? Lipopolysaccharide is the fragment of the outer cell of a gram negative bacteria. LPS is very toxic to cells in general, and very immunogenic causing a brisk reaction of the immune system, and here we see it is used to induce damage typical of MS damage to oligodendrocytes. LPS comes from a gram negative bacteria like CPn when it dies. This is a very important bit of circumstantial evidence for CPn causing MS. Clearly if CPn, which is a gram negative bacteria, was in the brain and died there would be oligodendrocyte damage similar to MS due to the presence of the LPS fragments released.
Lets go deeper into this subject with THIS [46] paper which discusses the microglial activation in the CNSi [17] by LPS. This paper shows that it is the microglia specifically that must respond to LPS damage of the nerves, and it also says plainly that LPS causes " injury to oligodendrocytes and myelini [32] as occurs in periventricular leukomalacia and multiple sclerosis", a direct replication of the information above. This work also says the oligodendrocyte precursor cells were damaged by the LPS. Since OPC's are another known concern in MS, LPS damage to brain tissue is a good match for MS damage. Also, note that microglial activation opens the BBBi [26] and allows peripheral immune cells like B-cells and T-cells in to the area to aid in cleanup.
HERE [47] is an abstract and link to an older paper that discusses the activation of microglia in the CNS in MS and EAE. This supports both the idea that microglial activation is normal in infection, as well as presenting the notion that microglial activation is the damaging feature of MS. These authors suggest that if we could turn off the microglial activation, the MS brain could be spared. But obviously if the brain is responding to pathogen by turning on microglia to fight the germ, ridding the brain of that pathogen "turns off" microglial activation, and it does this without leaving the brain open to opportunistic infections like PML. It leaves your brain's pathogen surveillance system intact.
Another well known fact in MS is that there is upregulation of cox 2 prostaglandins which are inflammatory.HERE [48] is one paper showing that this is true in MS. HERE [49] is another, this one also tying it in to the oligodendrocytes, which when injured send out the Cox 2 signal which results in caspase 3 activation and death. The speculated conclusion of this paper is that it is the cox 2 that causes MS oligodendrocyte damage. It supposedly does this by cox 2 upregulating by itself (autoimmune theory) and thus starting the cascade we call MS.
HERE [50] is a paper that shows that cox 2 is upregulated by the body on purpose in CPn infection. Actually, cox 2 upregulation can be inferred from the previous discussion on the LPS damage because it is stated that damaged oligodendrocytes will send out this chemical signal. Once again we see natural, expected immune reactions to infection occuring that mirror the known cellular/chemical profile in MS.
I mentioned gamma interferon above. In early studies (the 1970's) of the interferon drugs, pwMS got rapidly worse when taking gamma interferon. Yet we just showed that gamma interferon regulates CPn growth by being responsible for upregulating NO. Isn't this opposing the CPn theory? In fact in those early trials the patients given gamma interferon had myalgia, fevers, and arthralgia, and while gamma interferon itself may have caused this directly, this triad of symptoms is also common to endotoxini [51] reaction. No patient of the seven who had worsening had residual symptoms and every patient had a flare up of symptoms already known to them, suggesting pseudoflare (common in fevers, and familiar to people using the CPn protocols here as an endotoxin reaction)not a true exacerbation which would be involvement of a new area of the brain. The reference for this information is HERE [52] titled "Experimental allergic encephalomyelitis: a misleading model of multiple sclerosis." by Sriram S and Steiner I in the Annals of Neurology Dec 2005. You have to get the whole citation to read the material about the gamma interferon I mention as it is not discussed in the abstract. Might it be true these people had transient worsening due to endotoxin as the gamma interferon via nitric oxide and tryptophan depletion killed some of the CPn load? It is unusual for people to have worsening with no residual deficits. This author also mentions that gamma globulin results in an upregulation of gamma interferon without exacerbation in MS ptients. Circumstantial but possibly important information supporting the idea that gamma interferon may not be the profoundly negative influence it was thought to be.
Tryptophan is of interest in MS also and has a role in CPn regulation. In the Eur J Neurol. 2005 Aug;12(8):625-31 there was a paper titled "Interferon-beta affects the tryptophan metabolism in multiple sclerosis patients" authored by Amirkhani A, et al found HERE [53] In this work it is clear that the tryptophan pathway is altered in MS and that beta interferon plays a role in mediating this. But in CPn the body, again via the gamma interferon pathway, catabolizes tryptophan in order to deny this amino acid to the CPn which needs it to replicate. See this HERE [54] from our own archives. So tryptophan is altered in MS, but it is altered by the body in response to CPn also. Tryptophan is important because it is necessarly for making melatonin and serotonin in the brain, two important neurotransmitters associated with mood and immune function. Without adequate amounts a person is prone to depression and poor sleep, both known problems in MS.
Speaking of beta interferon, it also hampers CPn apparently. HERE [55] is a citation titled "Role of Interferon-Stimulated Gene Factor 3 and Beta Interferon in HLA Class I Enhancement in Synovial Fibroblasts upon Infection with Chlamydia trachomatis " by Jürgen Rödel, et al. Perhaps the modest improvement seen with beta interferon use in people with MS could be related to this mechanism.
Many features of MS are actually known features of EAE with the authors ASSUMING that MS has this same feature. For example, caspase 3 is a regulator of apoptosis (organized cell deathi [56]) and is seen to be upregulated in EAE. There has been speculation that caspase 3 itself may be at fault in MS, the logic being that if there was extra caspase 3 floating around it would mistakenly kill off perfectly good nerves and thus cause MS. While we do see CNS cells dying, they also would die from being infected and as discussed above, this will result in caspase 3 activation secondary to cox 2 activation caused by LPS. And all of this would cause the body to respond to the area with inflammation and immune cells to clean up the dead tissue. So it is not necessarily true that caspase 3 activation is secondary to anything other than natural response to pathogen. The Prineas and Barnett paper cited earlier also looked at caspase3 in the areas of apoptotic nerve cells. They found very little.
And here we have this PDF file which is a review of the pathology of the MS lesion found HERE [57] Note that the author of the review of the pathology of an MS lesion draws a very clear parallel between the MS brain and viral infection, saying the cellular immunopathology is the same while also noting that EAE is not the same as MS. This again supports and repeats the information offered on the page "MS and the CPn Model" which establishes that there is significant research showing MS is not autoimmune. Additionally, remember that CPn is very similar to viruses because it is an intracellular organism. Once again we have support for the notion that MS is not autoimmune and a clue that the cytokinei [6] profile we see in MS is indistinguishable from a natural reaction to a pathogen, and here on this page we are showing research that directly ties the same cytokines to CPn.
Another angle to MS which is considered an autoimmune clue which people frequently point out is that MS has been shown to have various upregulated genesi [22]. Doesn't that prove that pwMS have a problem gene that causes this abherrent reaction? Well, no it does not. The average person thinks a gene is like your eye color- it is what it is and it cannot be different. But genes turn on and off all the time and this is called upregulation and down regulation, and they do this in reaction to the environment. HERE [58] is an abstract that outlines a couple of kinds of gene upregulation in response to CPn infection. In this case the macrophages i [59](an immune system cell) have upregulated some genes and down regulated others.
In another example of genetic changes, HERE [60] is a paper that shows how CPn itself changes and upregulates a whole bunch of its genes in persistent states vs acute infection, this giving it the flexibility to do the many things it is capable of doing and making it so difficult a pathogen to eliminate.
In order to be fair it is obvious that some genes such as your HLA type impacts the way your body responds to germs. It is possible that some people with some genetic profiles respond to CPn in such a way that persistence is more likely in that individual. It would be narrow to assume that a genetic type could cause autoimmunity, but not that it could cause an atypical reaction to a bacteria.
So this page is focused on the fact that many known features of MS are also known physiological reactions to CPn infection, remembering that infections of many kinds likely have a similar if not identical profile. This is not unexpected as it has been amply pointed out by many authors that MS resembles, on a cellular level, a reaction to an infective process. The fly in the ointment has been the inability to culture anything consistently, though the known fact that CPn is possibly unculturable in the persistent state might easily account for the "we found it" and the "we tried to replicate their work and did not find it" back and forth nature of the MS/CPn research to date.
It is interesting to note that while CPn is known to live in human cells, is known to cause cellular inflammatory reactions to that cellular infection, is known to cause immune reactions and cellular death and that it is very hard (and some say impossible)to culture and complicated to kill in persistent state, we still have people who debate whether or not it is a "problem" suggesting perhaps CPn's presence is innocuous for human beings. And we also have people seeing cell death, immune response and inflammation, and who are unable culture any germs at the site continue to insist that this immune response has to be the body attacking itself for no good reason (autoimmunity)seemingly oblivious to the possibility of an intracellular infection like CPn and ignoring the limitations of current ability to find these bacteria.
At this point in time it is not proven one way or the other. We really need a test every competant researcher can do which shows the presence of CPn in MS brains to get to that level of understanding. This is all circumstantial evidence for the presence of CPn in MS brains. But also note there is nothing that is excludes the possibility of it either and the evidence indicates that if CPn WERE in a brain it would: upregulate NO, cause oligodendrocyte damage via LPS identical to MS damage, cause the cox 2 prostaglandin to be made which would signal caspase 3 and apoptosis, would damage the nerves and cause death, would cause microglial activation, would catabolize tryptophan. Since this profile of changes mirrors MS, we have a smoking gun in CPn for being involved in MS.
This is speculative and based on currently available research which may not be all inclusive, or which may not apply to you directly. It is posted here for informational and purposes. This page may be added to or revised as new material comes up......
The brain. For many the final frontier of medicine, it's fragile tissues the seat of the mind and in many ways, the very heart of personality and who we are.
What is known about this privileged area of the body is that healing is limited and things that on other parts of the body would be minor issues in the brain become devastating and life altering. A simple extavasation of blood, which in an arm is a mere bruise or hematoma, in the brain becomes a hemmorhagic stroke, the person forever altered and changed by this mere physical accident.
Why is that? Why is a minor issue on the periphery a major life changing event in the brain? Why does it not heal as does the arm? The answer lies in how the brain is set up.
The brain is a privileged area of the body. It separated from the rest of the body by the blood brain barrier which is a special different kind of endotheluim than is present in the rest of the vascular system. The BBBi [26] has very, very tight bonds between the cells and thus is very selective and allows only very specific things that the brain needs in, and keeps out other things that flow freely through the rest of the body, out. Among the things not permitted in are the immune cells of the peripheral system, like t cells, b cells, macrophages etc.
Because of this protection from the rest of the body, the brain has its own immune cells called microglia. Microglia are essentially very similar to monocytes and macrophages in other peripheral areas of the body, except that they have very specialized abilities. The microgia can send a chemical signal to the BBB to open up and allow t-cells, b-cells, monocytes and macrophages to enter if they need help cleaning up a problem inside the brain. This makes sense! How else can the "garbage" be taken out of the brain! There are well known situations that allow BBB to be opened by the microglia, for example infections, particularly any that involve the microglial cells themselves such as HIV, cytomegalovirus, the herpes viruses, and any situation in which cells inside the BBB died or were injured. It is known in vitro that CPn can invade microglia, so we might make an assumption that should that happen the BBB would be opened to clean up the area.
Microglia live in a quiet resting state termed "ramified" Ramified microglia are not activated and are easy to see in a microscope as different from the activated form which is "amoeboid", and so it is the ameboid form we see in activated microglia and it is ameboid activated microglia we see in MSi [1] lesions. It has been this fact that has led researchers to believe that the microglia are to blame for MS damage, assuming that the microglia activated mistakenly and "attacked" the nerves causing them to die. This has been presumed to be the initial event in MS and a considerable amount of research has been focused on how we can turn off the microglia in MS patients. Activated microglia express many immune factors such as interleukins and toll like receptors, many of which are also targets for therapeutic intervention by novel pharmaceuticals. However, it was the detection of ramified (not activated)microglia and no peripheral immune cells in the presence of apoptotic, dying oligodendrocytes in Prineas and Barnett's paper that indicated the nerves had died THEN the microglia and finally the peripheral immune system were recruited to the area. This stunning finding proposes a completely new idea as to why the microglia are activated and ameboid in MS: given how microglia react to cell deathi [56] it would have been their normal healthy job to open the BBB and allow t-cells b-cells and whatever else in to clean up the apoptotic mess.
Interestingly enough any activation of the immune system, either inside the brain via microglia or outside in the body by other macrophages, monocytes etc, results in profound changes in the area being repaired by the immune cells themselves. The chemical environment of the area is altered and many different genesi [22] are upregulated, cytokines respond, fluid filled with these immune factors rushes to the area and oxidative damage results secondary to all this activity. Much of this in the body outside of the CNSi [17] is no big deal, it repairs as "good as new", but this is not true of the brain. The brain, in the presence of these oxidative and otherwise toxic but necessary factors in response to pathogens, is damaged by all this immune activity. The brain literally can't tolerate normal immune responses.
Thus it is true that in the case of an infection of the brain part of the damage comes from the act of the body responding to the pathogen itself rather than any damage directly caused by that pathogen.
Why is this important to understand for us here? For several reasons which fall into the arena of my humble opinion based on my understanding of the brain. In terms of using the CAPs there is good justification for going slowly on treatment and not inspiring too large a response at one time. Your brain can only heal so much at once, and it must do that with it's limited resources. It is easy to overwhelm the brain's capacity to supply antioxidantsi [33] and nutrients needed to repair. Therefore it's probably true that a pulse of flagyl that is small as outlined in the protocols is better than large ongoing doses for long periods of time unrelieved by healing time. It may be fine for CFSi [8] patients whose infection is not in the brain to take flagyl continuously as muscle heals in ways the delicate brain can not, but the MS patient is likely to need time to repair in between.
Another reason it is important to understand is that it offers a good reason for the apparent improvements in MS patients taking immunesuppressive therapies if you accept the model of CPn as causitive for MS. CPn is a slow infection, it invades slowly and does not harm it's host very much. What's a cell here and there being used by CPn? Well if it's a brain cell you DO miss it, and more as more are invaded and lost. But if the cell with CPn in it dies, either because you were taking a flagyl pulse or because it simply died from being infected as it will in the MS patient unaware of CPn, you get acute reaction and response by the immune system as described above, resulting in even more damage to an area. Therefore, if you knock out the immune system you will seemingly get better, at least for a while, because the cytokines and other immune factors are shut off.
We can understand this if we look at it this way. If you have a cold how do you know you are invaded by a virus? Your nose is plugged up, mucous runs and you feel tired. Every one of those symptoms is caused by your immune activity NOT by the virus. If you take a steroid, thus knocking out the immune system, you will feel better immediately. But the virus then without being "checked" by immunity will get the upper hand leaving you sicker than ever in a day or so. People with HIV who have their immune systems knocked out by HIV will have this happen. They get very serious infections we do not get...and they do not have the symptoms normal people do, all because the immune system is not active. A cold virus is a quick pathogen so we can understand how it reacts to steroids and immune suppression because we see the connection clearly, in a slow virus or bacteria however the connection is not so clear.
Persistent CPn however is a slow pathogen, so the timeline for all this is years not days when we are talking about possible CPn and the brain. But the cold virus example plainly shows how a patient can seem better simply because of immune suppression. What if an MS patient is given steroids, for example during an exacerbation of MS, and MS is actually an infection, exacerbations being another time when immune activity is clearly causing symptoms? I have often heard people say that MS cannot be an infection because immunosuppression works. Really? Do steroids cure people of MS?
The long term studies on steroid use for MS are disappointing. Though people given steroids seem better than those given placebo when evaluated within a week or two of treatment, at 6 months the "gain" is gone and there is no statistical difference between treated and untreated people. Steroids do not impact the disease although in the short term they impact the symptoms.
Other immunosuppressive therapies have not had great success to date either. Most seem to help a little bit for a while, then the gains drop off with time often eventually leaving the person at a few years time functionally equal to the untreated person, in some cases in spite of the fact they remain profoundly impacted by the treatment drug. The newest drugs have no long term time frames to discuss, but read the available research carefully for yourself. If they have gains right away does it remain just as good or get even better after a couple of years? or do the gains drop off so people seem to be much better than placebo in early comparisons but in later comparisons the treated group is maybe only slightly better than the placebo group? These are important questions for the MS patient to know the answers to.
If the problem is autoimmunity then aggressively knocking out the immune system ought to result in an improvement that gets better and better as time goes on should it not? Now that the brain is relieved of this relentless attack from the immune system, should it not get better and stay better and improve even more with time? Yet time and time again the most promising therapies which prove profound decreases in lesion activity (inflammation is actually what is seen on MRI) do not result in stopped disability. In my mind, it is a concern if people have profoundly impacted immunity but after a few years are nearly in the same boat as the placebo treated persons. This suggests to me the "cause of MS" whatever it is was not stopped but that the immune system was prevented from causing secondary damage in it's efforts to heal. If there were a slow bacteria in the brain this is exactly what would be seen with immunosuppression because the bacteria would continue to slowly invade the cells but the immune system is held at bay, reducing any secondary damage from immune sustem activity yet allowing the slow infection to invade more cells to the point that impairment results anyway. This is exactly like giving steroids to a person with a cold to me, only in slow infections timelines are years long compared to the "cold" model.
Who knows what the patient thus treated will be like at later years. Will the thing that causes MS, maybe CPn, get the upper hand and will the patient go downhill faster than ever later? People with immunosuppression are at risk for cancer and infection since immunity is grossly impaired, will they succomb to such issues? And if the treated people are much better than the placebo treated group in early comparisons but in later comparisons the treated and the placebo group are only a little different did the treated patient gain anything? Since most of us will live for decades, is this temporary gain worthwhile considering the cost? These things must be evaluated carefully by the patient. Ask questions about this of your doctor and get all the answers you can. You have a right to know what is known about the treatment you are considering. You have a right to know the limitations of the treatment you are being offered including what is not known about it. In the end it is you who lives with the decision and it's results.
There may be good reasons to take abxi [41] even if CPn is NOT at fault in MS. Minocin, a tetracycline drug similar to doxycycline, has been shown to have neuroprotective and antiinflammatory aspects to it. It is being tested in conjunction with a traditional medication as an "add on" combination therapy. They will compare the combination of traditional/minocin in this test to the traditional alone, but unfortunately there is not a treatment arm with just the minocin. This is sad. Perhaps the minocin with it's antiinflammatory properties all by itself would be as effective as the combined drugs, who could know without testing this? But this obviously not in the interest of the company who is running the trial, that company being the traditional medicine. They have no interest in abxi [61] as a stand alone therapy and it would bode poorly for their drug if the minocin won out as the best therapy since it is off patent. At any rate, there is no way of knowing or guessing how much of an effect this neuroprotection and antiinflammatory action is as such quantification of this property of the minocin has not been undertaken. It might be large or insignificant, but what I can tell you is that when people like S. Sriram at Vanderbilt University Neurology Center tested people using abx and published positive results, others who did not believe this could possibly work immediately said it was these "immune modulating properties" of the drug that caused the improvement, not the antibiotic aspects of it. Interestingly enough I bet that no one ever said to you "Well, we know that abx have these protective properties how about before we give you these immunosuppressives we try that to see if it helps..."?
It makes you wonder why there is objection to anyone trying antibiotics.
Cpni [21] as the cause of MS is theoretical at this point and not proven. Most of the traditional medical communnity thinks MS is autoimmune. There is evidence that points the other way though and these pages explore these possibilities for informational puposes.
Deciding to use an experimental and unproven protocol is a decision you must make under guidance and advice of your doctor, based on your particular situation. Some people with very benign disease may want to use traditionals and wait for science to find a more certain answer. Some with more advanced disease may be at a point that for some reason they do not want or are not a candidate for the drugs available (heart disease runs in my family, I have made a personal decision not to use Novantrone, though I know some who think it was helpful for them). Some may even have tried the traditional medicines for MS and found them ineffective and they are thus without good options. These people may be interested in investigating this experimental approach. The VU released the information about the protocol they were using experimentally for just such compassionate purposes, and our pages here are for support of people doing just that. If you are in one of these situations and you decide with your doctor it makes sense for you in this site you will find others trying this approach as well as others who have had success with this approach already.
One of the biggest issues in the question of whether or not CPn is present in MSi [1] brains is the publication of work that finds no CPn in MS. It puts us in the uncomfortable position of saying that we choose to think that this researcher is correct and that one is incorrect. Since few of us are lab experts, such discernment may be based on bias and not facts. Yet there may be some very good reasons to find the work that says CPn is not in MS brains is biased itself.
To look at this chronologically we start with the Vanderbilt University (VU) work found here [10]. This paper is the whole citation. In that original work the team at VU found that pwMS (people with MS)were more likely to have CPn detected by PCRi [11] in the brain.
A top chlamydia expert, Margaret Hammerschlag MD, found the theory intriguing and conducted her own experiments in her labs. They found no CPn in any sample. The abstract may be found HERE [62]
Following that work, Dr Sriram came out and said it is very difficult to find in the brain and that it was not surprising htey did not find it. What follows is taken from HERE [63] (note: this paper was overall negative about the MS/CPn connection. It is an older paper talking about what was known at that time)
Quote from that paper:" Sriram responded by saying, "The fact that they can't find it in the brain is not surprising at all" because of difficulties his group had finding C. pneumoniae after injecting it into the brains of mice. "We know we put the bug there," he said. "But we're having difficulty finding out exactly what the conditions are to extract it from brain tissue. I don't know why."
To help settle the dispute, Sriram agreed to participate in a blinded study with three other teams. All received spinal fluid from patients with MS and controls, sent by Michael Kaufman, MD, of the MS Center of the Carolinas Medical Center in Charlotte, NC. The results, presented at the 2000 meeting of the American Neurology Association, further isolate the Vanderbilt team, who found C. pneumoniae DNA in 22 (73%) of 30 MS cases and in 5 (23%) of 22 controls. The other teams, at Johns Hopkins, the Centers for Disease Control and Prevention, and Umeå University, detected no traces of the organism.
Hammerschlag said the mass of evidence points to contamination or a lack of experience with delicate screening tests on the part of Sriram and his colleagues. "All of his work is being published in neurology journals, and they just kind of accept the methods. None of it would get published in microbiology journals," she said" end quote
This is very important. Please do note that in the teams other than VU they found no CPn. None. There have been many published papers since then by many experts all over the world finding CPn in brain samples of MS and other neurological diseases. It is peculiar that in this particular test they found absolutely none at all. But this was a long time ago as science goes and techniques have advanced since then, so the various researchers finding CPn since then may well be using much better techniques.
Let's note the VU findings in this interesting contest between labs. VU found CPn in 22 of 30 of the MS patients and in only 5 of 22 of controls. If Sriram contaminated his samples how did he manage, in a blinded sample, to contaminate primarily his MS samples? Why not contaminate most samples if his work is sloppy? Or even finding it in all of them?
It seems to me personally it would be very difficult, and statistically improbable to contaminate mainly the MS samples in a blinded study of that nature. Adding to the evidence that the VU laboratory test for CPn in CFSi [8] is finding real CPn in MS is the fact that the numbers of positive samples discovered were very similar to his previously stated numbers of positive MS samples. The VU team seems to find CPn in about 60-95% of MS CSF (multiple sclerosis cerebrospinal fluid).
Another comment in that article which points out the human side of research is in the final line of the quoted piece as it shows the opinion of one researcher stated as if it were fact. It is not exactly "scientific" but opinion, and peevish at that, to state that the neurology journals are somehow naive in what they accept and that the VU protocol "would never be published in microbiology journals". In fact, the VU lab protocol was published in a laboratory journal two years later HERE [64]
And in another paper HERE [65] we have the VU team and a team of researchers at the University of South Florida using split samples to compare results with one another. "Split samples", which were also used in the first lab contest above, means they send half any given sample to lab A and half to lab B and see if they get similar results. (Some few samples were too small to split, and VU got all of those samples resulting in the odd numbers)
In this comparison between USF and VU they both found positive samples of CPn in the MS brains using different CPn tests, confirming that it is possible to culture CPn in MS brains. The conclusion of the paper was quote "In clinically definite MS patients, the VUMC and USF detection rates were 72 and 61%, respectively, and in patients with monosymptomatic MS, the VUMC and USF detection rates were 41 and 54%, respectively. The PCR signal was positive for 7% of the OND controls at VUMC and for 16% at USF. These studies confirm our previous reports concerning the high prevalence of C. pneumoniae in the CSF of MS patients. The presence of C. pneumoniae in patients with monosymptomatic MS would also suggest that infection with the organism occurs early in the course of the disease." end quote
What we have here is a batch of evidence that indicates the VU approach is fairly effective at finding CPn in MS CSF, that at USF they also have the ability to find this, and the fact that these labs used split samples indicates that there is some concordance. In comment Sriram has been quoted as saying that the problem with the other contests where others found no CPn is that the other labs use formalin preserved brain samples, which ruins the possibility of detecting CPn. According to VU, the lab must use frozen tissue to find the CPn in these samples. USF also uses frozen samples, though they use their own unique test. This is the kind of technical detail that makes the difference, but takes time to prove the value of conclusively so everyone "knows" we must use frozen samples. Clearly in the Hammerschlag lab it is not considered important to use frozen samples.
Dr Hammerschlag is still convinced that MS has nothing to do with CPn though. As recently as 2005 she was asked to comment on some work being published by VU connecting CPn to MS and once again she talked about the 2000 lab contest in which her labs found no CPn. This comment was titled "The role of chlamydia pneumoniae in multiple sclerosis:real or fictitious? She remains adamant that the original work in which no CPn was found remains unchallenged, apparently rejecting the work of so many in the interveneing years in spite of the fact that various researchers all over the world have found at least some CPn in brain samples of many kinds. She seems very confident of her test results in which she found on CPn in MS CSF samples.
Interestingly enough though, Dr Hammerschlag herself has since authored a paper which in and of itself may offer support for the CPn theoretical model of MS causation. In this most recent work she states that we cannot culture persistent infection as it is undetectable. Now this is interesting, if a persistent infection is undetectable using currently available lab techniques, then what does it mean if you do a CPn test and it's negative? We know that CPn even in it's persistent state can cause inflammation (see smoking guns next page) so if that is true and you have an inflammatory disease of unknown etiology how can you say conclusively it is not CPn simply because you had a negative test if your own research says that persistent infections produce negative tests? It might be more accurate for her to say I do not agree with the VU methods, but I do not know if MS is related to CPn. The opinion paper indicating that we cannot culture persistent infections that she wrote is found HERE [66]
If you read it carefully, you will see she is saying that while CPn might cause chronic illness like atherosclerosis and asthma, we can't design good studies since we can't test to know if eradication of CPn occurred. She suggests that without lab work to tell you if the patient got better from eradication of the germ, you can't know why the patient got better and your study is meaningless. From a purely scientific standpoint this is correct. But we are not lab experiments as individuals, and should this be applied to patients in general, it denies that the physician is a diagnostician who has been trained to evaluate people and their physical status based on a variety of findings, not just lab work. It would be naive to imagine labwork is flawless and perfect or the the MD is helpless without it to make clinical decisions. Good grief, if this were so why see an MD at all? Why not just see the lab tech, they're the ones who do the tests!
I would again like to mention the human side of science. Science has a certain inertia. People at this level and of this stature begin to get locked in to certain points of view for a variety of reasons. Not least is that once you publish a notable finding, you may be granted funding by interested organizations to do more of the same research. This leads you to work again along the same lines and after some time goes by you have a considerable paper trail clearly placing you on one side of the scientific debate. And you really believe your point of view, witness the absolute tanacity of the autoimmune model of MS in light of the research indicating it appears that autoimmunity does not explain the facts. It is difficult for someone who has done a lot of work on an issue to go back and say, "Oh, by the way, all this work I did before was wrong the other guy was right". You could be forced into that eventually, but it will not happen without a lot of weight on the other side to pull you over. Furthermore, the sheer numbers of people on that autoimmune side of the debate means there is a real sense that "most of us are over here and of course we are right, everybody thinks so...." It might help to recognize that Freud and Jung had a lifelong debate as did Einstein and several of his compatriots. Eventually some other finding may clarify a key issue making it possible to finally see what was missed before so everything falls into place. In this debate about CPn nd MS that would be something like a conclusive photo that shows CPn in the key structures of the MS brain. For example, if someone develops a way to see CPn inclusions in oligodendrocytes and we have an unmistakeable picture of such in an MS brain, maybe in a client that also cultured negative for CPn using traditional methods, we'd have extremely persuasive material wouldn't we? We do not have anything like that now however.
At this point in time there is still considerable debate over this issue. If we had Dr Hammerschlag here she would undoubtedly discuss the technical details of this work in ways I cannot. I am not a chlamydial lab expert. But then again, Dr. Sriram is a neurologist and the director for VU's Multiple sclerosis center. He is teamed up with Dr. Stratton a microbiologist (like MH), and Dr Mitchell an MD PhD pathologist, and they have studied this material and they have made it their business to say this IS happpening in MS and have published extensively on the subject. I am not swayed to believe that Dr Hammerschlag is correct and that the VU team is off base.
So what about other researchers beyond MH and VU? Well, if you go on pubmed and put "multiple sclerosis chlamydia pneumoniae" in the search box you will get a whole list of this kind of work done all over the world by othe people. Some will support the idea, some will not. This is the way science goes, it is a back and forth process until eventually something conclusive and reproducible is put forth. As you read the research, these are the questions to keep in mind;
If a study suggests that there were no people with CPn in the brain, what tests did they use to establish that? Often we see something like the VU study which utilized several highly technical and detailed methods on CSF samples to establish that CPn was there being "countered" with a study that used a single test, sometimes even a blood test.
Or sometimes the author finds not one single case of CPn in the tissue, and you wonder, considering how often other people find it even in seemingly healthy people, how does this author find none at all?
Or sometimes we lay people cannot judge without a tip from someone inside the study, as in the case where the formalin fixed samples were used. To find that out you might need to read comments or editorials in later issues of the publishing journal.
And finally, we have the notion that persistent CPn cannot be cultured at all. If you accept this might be a possibility then testing and it's positivity becomes a somewhat moot point, the germaine issue then being who will develop a test that will find persistent CPn, and importantly, has VU done it already?
So now we come full circle to where I began this page, we are in the uncomfortable position of saying I believe this researcher and not that one, and this question becomes vitally important to us if we are in the unenviable position of suffering from MS and having no results from traditional treatment. Dare we try this treatment in spite of it's not being fully proven and in light of the fact there are some people vehemently stating it is incorrect?
I offer this and this is entirely my personal opinion: The talented and highly qualified team at VU who have published several peer reviewed papers on the subject claiming that CPn is present in at least a subset of MS patients has been focused on this specific issue now for 9 years. That's 9 years of refining their PCR techniques, 9 years of making the tests more robust and redoing tests to remove doubt, 9 years of watching the few people they've treated experimentally with antibiotics get some level of improvement (which is documented) and 9 years of focus. From this multifaceted effort they say it appears to be there in at least a subset of patients. 9 years is long enough for an MD to become a specialist in a couple of disciplines. In my book I find it impossible to imagine the VU team is not utterly expert at this by now, and more expert than any other researcher because of their focus. Add to that the fact that USF gets similar results using a different test, and that some others all over the world are also weighing in on this side of the debate and we have a good weight of evidence agreeing that CPn appears to be there in MS in at least a subset of patients.
Considering the fact that this would be treated with currently available antibiotics and it is clear that these drugs are not patent drugs and therefore not going to make anyone anywhere any money, there is no commercial interest here in manipulating the data at all, which is always a concern with commercial patent drug research. I can find no reason for the people at VU to be anything but honest in their work; it appears legitimate even if still not widely accepted yet. We will hope for some large blinded studies down the road that will make it clear to every one the exact extent of CPn incidence in MS and or some interesting other data that clarifies the issue. Another important point related to the fact CPn is treated with antibiotics is that there is no interest on the part of any drug firm to rush to VU with a large grant to further the research either. This is the reality of our commercial research system. It might be worth noting that the year before Barry Marshall proved beyond a shadow of a doubt that h.pylori caused almost all ulcers, he was still correct, even though few agreed with him. A physician I know of made the comment that "CPn could be neurology's h. pylorii [67]". The original resistence to the idea on the part of doctors who treated ulcers with surgery and bland diets and who mocked the idea of h pylorii [68] causing ulcers are not unlike the neurolosits who reject Cpni [21]/MS idea.
So that is the debate as it pertains to multiple sclerosis. I did not talk about PCR specifically or other issues about the labwork. For that please consult the other book pages.
So if we accept that labwork is not in 100% consensus about how to culture CPn in the CSF of the MS patient, nor is it even clear that persistent infection CAN be cultured, is there other circumstantial evidence that supports the theoretical model that CPn plays a role in MS? The next page is smoking guns and it talks about this issue...and I'd like to say for the person who has been into MS research for a long time, it is there that the correlations uncannily begin to fall into place, although once again we are talking about an idea, not a scientifically proven fact at this point.
Links:
[1] http://www.cpnhelp.org/taxonomy/term/6
[2] http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15048884&itool=iconabstr&query_hl=1&itool=pubmed_docsum
[3] http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15994589&itool=iconnoabstr&query_hl=3&itool=pubmed_docsum
[4] http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15820974&itool=iconabstr&query_hl=3&itool=pubmed_docsum
[5] http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=16315280&itool=iconabstr&query_hl=3&itool=pubmed_docsum
[6] http://www.cpnhelp.org/glossary/term/107
[7] http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16413961&itool=iconabstr&query_hl=12&itool=pubmed_docsum
[8] http://www.cpnhelp.org/glossary/term/163
[9] http://www.cdc.gov/ncidod/eid/vol4no4/campbell.htm
[10] http://www.cpnhelp.org/pdfs/Cp-MSAssoc.pdf
[11] http://www.cpnhelp.org/taxonomy/term/54
[12] http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15327030&itool=iconabstr&query_hl=4&itool=pubmed_docsum
[13] http://www.cpnhelp.org/glossary/term/184
[14] http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15164186&itool=iconabstr&query_hl=4&itool=pubmed_docsum
[15] http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11795458&itool=iconabstr&query_hl=4&itool=pubmed_docsum
[16] http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=14706222&itool=iconabstr&query_hl=4&itool=pubmed_docsum
[17] http://www.cpnhelp.org/glossary/term/166
[18] http://www.cpnhelp.org/glossary/term/86
[19] http://www.cpnhelp.org/taxonomy/term/36
[20] http://www.davidwheldon.co.uk/ms-treatment.html
[21] http://www.cpnhelp.org/glossary/term/167
[22] http://www.cpnhelp.org/taxonomy/term/60
[23] http://www.cpnhelp.org/taxonomy/term/64
[24] http://www.msneighborhood.com/content/in_the_news/archive_2248.aspx
[25] http://www.cpnhelp.org/glossary/term/97
[26] http://www.cpnhelp.org/glossary/term/165
[27] http://www.cpnhelp.org/taxonomy/term/58
[28] http://www.cpnhelp.org/www.cpnhelp.org/%3Fq%3Dthe_brain_and_pathogenic_
[29] http://www.cpnhelp.org/?q=multiple_sclerosis_and_th
[30] http://www.cpnhelp.org/glossary/term/171
[31] http://www.cpnhelp.org/glossary/term/168
[32] http://www.cpnhelp.org/glossary/term/100
[33] http://www.cpnhelp.org/taxonomy/term/57
[34] http://www.cpnhelp.org/glossary/term/182
[35] http://www.cpnhelp.org/chlamydia_pneumoniae/supp
[36] http://www.cpnhelp.org/maries_most_excellent_add
[37] http://www.cpnhelp.org/glossary/term/183
[38] http://www.pubmedcentral.nih.gov/pagerender.fcgi?artid=372987&pageindex=3#page
[39] http://www.cpnhelp.org/glossary/term/114
[40] http://www.cpnhelp.org/taxonomy/term/46
[41] http://www.cpnhelp.org/taxonomy/term/38
[42] http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15998743&itool=iconpmc&query_hl=1&itool=pubmed_docsum
[43] http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16333333&itool=iconabstr&query_hl=6&itool=pubmed_docsum
[44] http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12634074&itool=iconabstr&query_hl=6&itool=pubmed_docsum
[45] http://www.cpnhelp.org/taxonomy/term/30
[46] http://www.jneurosci.org/cgi/content/full/22/7/2478
[47] http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=9106073&itool=iconabstr&query_hl=13&itool=pubmed_docsum
[48] http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16512913&itool=iconabstr&query_hl=10&itool=pubmed_docsum
[49] http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16516308&itool=iconabstr&query_hl=1&itool=pubmed_docsum
[50] http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12721317&itool=iconfft&query_hl=6&itool=pubmed_docsum
[51] http://www.cpnhelp.org/glossary/term/116
[52] http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16315280&itool=iconabstr&query_hl=12&itool=pubmed_docsum
[53] http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16053472&itool=iconabstr&query_hl=16&itool=pubmed_docsum
[54] http://www.cpnhelp.org/?q=tryptophan_depletion_as_a
[55] http://iai.asm.org/cgi/content/full/70/11/6140
[56] http://www.cpnhelp.org/glossary/term/88
[57] http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=10603616
[58] http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15786718&itool=iconabstr&query_hl=4&itool=pubmed_docsum
[59] http://www.cpnhelp.org/glossary/term/187
[60] http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12620380&itool=iconabstr&query_hl=4&itool=pubmed_docsum
[61] http://www.cpnhelp.org/glossary/term/93
[62] http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11060110&itool=iconpmc&query_hl=5&itool=pubmed_docsum
[63] http://www.mult-sclerosis.org/news/Jan2001/InfectiousLinkstoMSQuestioned.html
[64] http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15482145&itool=iconabstr&query_hl=6&itool=pubmed_docsum
[65] http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12414770&itool=iconpmc&query_hl=28&itool=pubmed_docsum
[66] http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15482145&itool=iconabstr&query_hl=3&itool=pubmed_docsum
[67] http://www.cpnhelp.org/glossary/term/173
[68] http://www.cpnhelp.org/glossary/term/172