Tuesday, April 21, 2009

Neuroprotection: Let the doctor speak!

Last night I heard a doctor try to tell Diane Rehm about neuroprotection. She cut him off. I think we should have heard him out.

Again we hear that there is no "evidence" to support chronic Lyme. There is no evidence to support the use of prolonged antibiotic therapy in patients with persistent Lyme related symptoms. Such are the proclamations made by "experts" who have evaluated the results of 3 NIH sponsored studies. These clinical studies sponsored by the NIH have been woefully misinterpreted. At any rate, none of these studies claim that the Lyme organisms have been eradicated or provide any scientific evidence to support this contention.

Then, when naysayers admit that such therapies seem to help patients, they claim it is due to other, non-specific effects of antibiotics.(Let the doctor speak) After all there are no germs to be killed. Based on what science have such experts concluded that there are no germs to be killed? Sounds like a bait and switch tactic to me.

How can the deniers have it both ways? Do the drugs help or don't they?

Beta-Lactam antibiotics may indeed offer neuroprotection. Included here are drugs in the penicillin family and the cephalosporin family. Animal studies have shown that Rocephin has neuroprotective properties in animal models. These drugs upregulate a molecule called GLT1 which in turn inhibits gluatamate. Glutamate is the principal "excitatory" neurotransmitter in the nervous system. Inflammation of the nervous system, both acute and chronic is associated with "glutamine toxicity." It is thought that drugs such as Rocephin may provide clinical benefits for a wide array of neurological disorders. For example,Rocephin has been shown to improve the clinical course of ALS in the mouse model.

Minocyline is reported to have neuroprotective effects due to inhibition of 5-lipoxygenases, a pro-inflammatory enzyme associated with the aging brain.

Antibiotics are reported to have anti-inflammatory properties independent of their germ killing effects. Some medical literature suggests that tetracycalines are inti-inflammatory because they inhibit nitric oxide. Cipro decreases inflammatory cytokines including: TNF-alpha, IL-6 and others. Erythromycins are said to inhibit cytokine production. And so on.

Naysayers, who deny chronic Lyme say patients improve because of these non-specific effects. Does this argument hold any water? NO!

Let us consider the use of Rocephin in a "neuroborreliosis" patient. This individual has an encephalopathy characterized by significant mental status changes. The brain MRI may be normal or abnormal. The SPECT/PET scan may be normal or abnormal. Something has caused a severe acquired brain disorder. If it is not Lyme disease they what else is it pray tell? After treatment with Rocephin the patients improves, perhaps to the point of baseline health. Here is a fantastic medical success story. Why would any physician be unhappy with the result for this patient regardless of one's beliefs?

My suspicion is that the neuroprotective effects may be playing a significant role. The primary effect of the drug however is to combat spirochetes in the brain.

The same arguments can be made down the line. If antibiotics have additional effects which benefit our patients great, what a plus!

None of this information "proves" that chronic Lyme is not real. The points are interesting but are not scientific evidence that chronic Lyme is not real. In fact they are irrelevant distractions from the debate at hand.

We know that chronic, persistent Lyme disease is real. Lyme hides in niches which cannot be accessed by the immune system. Bb binds to proteins in the intracellular matrix such as decorin. Bb can acquire antigen markers from host endothelial cells to camouflage itself. Bb can enter fibroblasts, an intracellular protected niche. Bb can enter immune privileged areas such as the brain where the immune responses are limited. It can morph into intracellular forms which cannot be accessed by the acquired immune responses. In this arena only primitive, innate immune responses are active; it has been established that such responses are unable to sterilize the cells of such organisms. Lyme spirochetes can morph into a cystic form not destroyed by immune responses. Bb can rearrange the structure of surface antigens by recombination with plasmids. All of these assertions are very well documented in peer reviewed literature and texts.

Animal models and human models have both demonstrated the persistence of the organism after large courses of antibiotic therapy in various tissues. This too is well documented in peer reviewed literature.

Patients with chronic Lyme have been shown to have consistent, reproducible clinical syndromes associated with characteristic physical and laboratory findings.

I treat these patient in my office every day, and for the most part they all get better.

Some of sickest patients I have encountered in my now lengthy medical career seem to be caught between the cracks of a dysfunctional medical system, the byproduct of misguided politics, and a stubborn refusal to really consider all the evidence.

Please let the doctor speak.

13 comments:

Moosie said...

Hi doc, I particularly enjoyed this post. I read all your posts, and just want to thank you again for sharing all this. You frame the issues very well.

Paraisos said...

And while caught in the cracks of the dysfunctional system, dying in pain and confusion, with no one knowing what to do or how to take care of him - her.
Let the one Doctor that knows talk, and please stop the talking of those who don't care and just fight to win an argument of negligence to the patients!
Thank you Doctor for being there; hope we can be there too, functioning normally as others!

Joanne said...

Hi Thank you for posting this and your many other posts. I and many others find them very interesting and rewarding knowing that you and a handfull of other courageous doctors are working towards clarifying the situation over this truely awfull illness and it's politics.

I am one of the lucky patients whose GP suspected Lyme and followed ILADS, eventually I saw LLMD in UK and am now nearly 100% recovered whilst on antibiotics. I can again walk upstairs something I could not do for 3 1/2 years. I can again enjoy gardening. I was lucky a chance course of Amoxicillin improved my arthritis muscle weakness and caused GP to suspect Lyme.

Thank you for all you do to fight our cause and seek to educate those who are prepared to open their eyes and ears.
Best wishes

lymie said...

Isn't it amazing that the doctor you are referring to on the program (Baker), who thinks improvement is strictly due to antibiotic effects aside from germ killing--amazing that this person formerly worked at the NIH, in charge of lyme disease programs! Apparently he learned nothing from the experience. And did nothing to help the patients they were studying.

Is this what we are getting from taxpayer funding of NIH? Ignorance and obstruction? When I say ignorance, it is the most charitable explanation. Not one I really believe. Because they do know better and are deliberately doing things that hurt patients and public health. How have we gotten to the point that medical ethics are on a par with those in the financial world?

Not saying all medical people are like this, clearly there are exceptions, including the one who writes this blog.

But when the general public asks why the NIH and IDSA would do such a thing, it is hard to know what to say. Who would have thought it could ever happen? It is almost unimaginable that these people who are in positions of trust would carry on a campaign that damages public health and sick people. And yet they are doing it.

Moosie said...

@lymie:
"But when the general public asks why the NIH and IDSA would do such a thing, it is hard to know what to say."

I struggle with this. As I try to explain the problem of lyme standard of care to folks who aren't personally involved, I begin to sound paranoid and delusional. I try to stay focused on the facts, but when the inevitable question arises "why do they act this way?", I just don't know how to respond. I end up saying it's probably largely personal and institutional arrogance, hubris and pride. But even to me this sounds like an insufficient reason for many intelligent people to refuse to look at facts objectively.

Personally, through all this, I'm fortunate that I had a firm lyme diagnosis originally, was perfectly fine physically and mentally, got bit, and it all went to hell. Then I got on abx and short-term I herx like crazy, and long-term I'm improving. Of course it's lyme. Nothing else makes a lick of sense.

girl mark said...
This comment has been removed by the author.
girl mark said...

Bravo, Doctor- this is a particularly concise post.

I've been wondering about the glutamate theory around Rocephin.

(if I understand correctly, Brian Fallon's NIH study speculated that the short-term cognitive improvements and subsequent cognitive symptoms relapse that occured during their patients' relatively short Rocephin courses may have been related to this effect. The rest of us speculate that since LLMD's sometimes give a much longer course of rocephin with good, lasting results and a return to baseline health and cognition is seen, the short course in that NIH study may not have been long enough for them to eradicate spirochetes to completely rid the patients of their most persistent symptoms. It would be interesting to see a follow-up on those particular patients)

It seems like the glutamate theory may be useful, even if it's just a secondary effect of Rocephin, which not everyone can be on.

Has anyone ever prescribed other glutamate-inhibiting drugs for neuroborreliosis? I believe some of these are being developed for Alzheimers' patients, how far along is that particular research?

I recently re-started Welchol after a 5-week-long relapse, and saw a huge improvement in my ability to think straight, have energy, and some other symptom reduction. If Welchol works on us by lowering C-reactive Protein, perhaps there's an equivalent 'supportive therapy' drug that may help patients whose symptoms are glutamate related?

All in addition to anti-spirochetal therapy of course.

Lyme report: Montgomery County, MD said...

Namenda works on gluatamte and helps cognitive dysfunction.

Lamictal may have some modest effects here.

Welchol may remove neurotoxins but it also lowers CRP which I have mentioned in the past.

m said...

there's a test for CRP- so the CRP/Welchol or Questran connection seems like an "easy" theory to test (in the ideal world anyway). Has anyone done this test for heart disease reasons, and later gone on cholestyramine or Welchol or Questran for Lyme or high cholesterol and seen improvements on the test (I don't know if CRP is something one regularly monitors in a heart disease patient but that seemed like the reason the test is given). Seems like something one of you doctors who might be reading this blog might have in your medical records.

Is there a test for whether glutamate or glutamate sensitivity is causing Alzheimers' symptoms, or is Nemanda just given under the clinical assumption that glutamate might be the issue for a given patient?

girl mark said...

oops, posted while signed in under wrong account. That last question was a follow-up to my CRP one.

Leslie said...

Curious to your opinion on AAPS letter to ISDA:

http://www.lymedisease.org/news/lymepolicywonk/115.html

Thanks for sharing your stories and experience!

gale said...

Personally I believe that Lyme (as a Borrelia-infection) has been and is still overrated.When trying to explain why people are so sick.As you have been the first to point out there are so many unresolved mysteries concerning the unidentified organisms that Dr K has seen in the wet-mounts.
In this connection,do you know of any tick borne pathogene that seems to invade PMNs?
Gale

Anthony Murawski said...

I've discovered what appears to be a promising option for symptom reduction and neuroprotection in Lyme disease: low-dose ketamine.

In 2006, I learned of a very successful, small-scale clinical trial of low-dose ketamine for treatment-resistant depression. The results were preliminary and short-lived, but promising. I had forgotten about this study until a few weeks ago, so I started researching whether ketamine has anti-inflammatory properties. I’ve reviewed about 300 journal articles so far. Here’s what I’ve found:

Ketamine is a potent anti-inflammatory. Even in low doses, it suppresses TNF-alpha and IL-6. Because of this, ketamine is used for neuroprotective purposes after brain trauma and stroke. Ketamine targets the glutamergic system. It easily crosses the blood-brain barrier, and has been shown with SPECT analysis in human studies to increase cerebral perfusion.

Small-scale clinical trials and case studies have shown low-dose ketamine to be effective in reducing symptoms of refractory depression, refractory fibroymyalgia, and refractory chronic regional pain syndrome. The most severe cases of refractory CRPS may require an anesthetic dose. All three of these conditions are sometimes manifestations of Lyme disease. For what it's worth, case studies have also shown good results with other conditions that are sometimes manifestations of Lyme disease, e.g. explosive disorder, MS, stroke, and restless legs. A significant percentage of refractory FM and CRPS patients are getting months of symptom relief after low-dose infusions repeated over several successive days. The few case studies on repeat dosing for refractory depression patients suggest that this method also produces longer-lasting results -- up to 28 days of relief after infusion on five successive days, with very fast results. I’ll follow up in the next few days with efficacy data.

Many studies have demonstrated that ketamine is not neurotoxic, and does not suppress natural killer T-cells or polymorphonuclear leukocytes unless it is given in massive doses, or at the anesthetic dose for very long periods of time. Animal data suggests that prolonged exposure at anesthetic doses might be neurotoxic to human brain cells during the brain-growth spurt, when these cells are particularly vulnerable (during the third trimester through three years of age).

Ketamine by IV infusion is the most effective delivery method. The dose for refractory depression is usually 0.5 mg/kg over 40 minutes. This is much lower than the anesthetic dose, which is usually started at about 2 mg/kg infused over 60 seconds to induce the first ten minutes of general anesthesia. At the subanesthetic dose, there is no respiratory depression, so I don’t see any need for an anesthesiologist. The dissociative side-effects are minimal and transient. Fluctuations in blood pressure are common. It seems wise to do at least the first few infusions under medical supervision. No serious adverse events have been reported in at least 500 people who have received low-dose infusions.