The Brain and Pathogenic Treatment

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 [1] 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 [2] 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 [3] 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 [4] 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 [5] 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 [6] 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 [7] 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 [8] 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 [9] 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 [10] 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.