B12

How important is vitamin B12?

For years doctors gave patients injections of that red liquid in their hips for low energy.
Patients left the office feeling energized with an increased sense of well being.

The practice has been eschewed by conscientious doctors in more recent decades: no scientific rationale - just a placebo effect. The elixir is red - red placebos work best. In evidence based medicine, B12 deficiency may be due to maladsorption or an autoimmune disorder. Blood levels are only low when less than 211. Other countries, including Japan have set the bar for normalcy higher - 500 or more. This is quite a difference.

B12 does many things in the body -- in conjunction with folic acid. It helps regulate the production of red blood cells and DNA synthesis. It facilitates the synthesis of myelin, the protective covering around nerves, and it likely has many other functions which are enumerated in a variety of published sources.

Lower B12 levels, less than 500 have been associated with a variety of neuro-psychiatric disorders, inclusive of cognitive dysfunction. B12 supplementation has helped with neuropathies of various sorts despite normal blood levels according to American standards. Neurologists who discount Lyme as a possible cause of peripheral neuropathy readily recommend generous supplementation with B vitamins.

Commercially, B12 is available as cyanocobalamin, an inactive form. It must be converted into one of two active forms, including methylcobalamine. Many clinicians feel that that the expensive methylcobalamine is the only clinically effective form of the vitamin. Based on my survey of the literature the jury is out on this one.

Patients with neuropathy, cognitive issues and perhaps many other issues may benefit from supplementation. Most of my patients have B12 levels which average around 350. This water soluble vitamin has no toxicity. B12 must be given with folic acid. If oral supplementation is ineffective the old "placebo" (B12 shots) can't hurt.

Gluten

A very sick Lyme, a middle age male with: Babesia/ neuroborreliosis/abnormal SPECT scan is now feeling normal off antibiotics after 2 years of treatment. He also has "gluten sensitvity." Two children and a sister have celiac disease. He has tested negative for celiac. His TtG Iga is negative (supposedly an accurate screening test). Two gastric biopsies, the "gold standard" for celiac were negative. Nonetheless, tiny amounts of gluten cause symptoms: pains, fatigue, rash, neuropathy, and gastrointestinal symptoms, including GERD. Gluten free diets are difficult. Food advertised as gluten free may contain trace amounts of gluten and rapidly set off symptoms. Conclusion: gluten sensitivity exists along a continuum. Standard tests only reveal gross disease with macroscopic loss of intestinal villae. Other patients may have ultra-microscpic changes, not observed with standard tests. In predisposed individuals, gluten causes extreme immune reactivity. These symptoms must be teased out from those of Lyme

Co-morbidity

I had a recent conversation with a patient. I told her we need to sort out other co-morbidities. Co-infections? No. This was a new term for this very Lyme literate patient. I was not saying the patient did not have Lyme disease. Not at all. Patients with Lyme disease frequently have a variety of other medical problems which contribute to their illness to varying extents. And, in some cases, it is not Lyme which is making the patient ill, regardless of what the Western Blot says: if the signs and symptoms do not fit -- Lyme may not be the primary issue. Or, perhaps Lyme's contribution to the illness is minor. For example:

Fatigue--profound fatigue, is almost invariably a prominent symptom. What else causes this? Other causes include hypothyroidism, B12 deficiency, anemia, depression and insomnia. After these are excluded, my patients are sent for sleep studies. Sleep disorders are a major cause of fatigue. Lyme patients have higher rates of sleep disorders compared to the general population. Patients may have obstructive sleep apnea (OSA) or central sleep apnea, a brain disease. Sleep apnea is associated with numerous other medical disorders: cardiovascular disease, diabetes and others. Sleep apnea is also associated with neuro-cognitive dysfunction -- sound familiar? And sleep apnea is associated with alterations of immune function. Specifically, high levels of inflammatory cytokines, TNF alpha, interleukins have been measured in these patients. Sleep apnea is a significant co-morbidity which interfers with the healing process.

Oher sleep orders are common as well. Restless leg syndrome is a common cause of poor quality, non-restorative sleep. This condition may be respond to supplementation with high doses of iron, sometimes intravenously, based on ferritin levels (it is not clear why these patients have profound depletion of iron). This movement disorder shares common features with Parkinson's disease, a movement disorder mediated by dopamine deficiency in the basal ganglia, a deep area of the brain. Both disorders are treated with dopamine agonists such as Mirapex. This should not be confused with cortical brain dysfunction--loss of executive dysfunction--related to insufficient dopamine activity in the cerebral cortex. This is treated with dopamine agonists such as stimulants which work in these areas of the brain.

A second sleep test, an MSLT can evaluate for narcolepsy and other disorders. Narcolepsy has been considered a disorder of arousal but is now understood to be a disorder of sleep. This may be effectively treated with Xyrem, a drug which is safe but suffers a bad reputation.

Sleep disorders: a common co-morbidity, cause fatigue and cognitive impairments, as well as mood changes and irritability. Not to say I don't start Lyme therapy early in the process - I must also fix the "non-Lyme" to see what remains.

This is but one example of numerous potential co-morbidities.

Patients may have: rare genetic disorders, rare metabolic disorders - or acquired mutisytem-disorders. One of my patient suffers with stiff man syndrome. This is a rare autoimmune disease caused by destruction of a GABA precursor. Another suffers with a toxic yeast syndrome which mimics chronic Lyme. Neuro-cognitive changes and new onset headaches may be caused a brain tumors or other cancers. It is know that Lyme may be associated with brain tumors.

Medical texts are ripe with esoteric diseases: mystery diagnoses. These are the patients that seek our help. It is not always Lyme.

Text book

A new patient walked in: a youthful 29 year old female. She wasn't feeling as good as she looked. She suffered with diffuse, migratory muscle and joint pain. She had tingling in her hands, shortness of breath, night sweats, headaches and pain on the soles of her feet. Her brain was foggy: poor concentration, focus and slow processing. She asked me if I thought she might have Lyme disease. I replied: "My G-d, you are right out of the textbook." Then I realized: " Well no, there actually is no text book." One has to be written.

She had a tick bite, a small "seed" tick, 2 years ago. It was accompanied by a red rash, maybe 5cm in size based on her description. "It wasn't a bulls eye."

She saw her family doctor. He told her she was just getting old (29?), that's why she had the symptoms. I asked how old the doctor was. Ancient. She talked her doctor into ordering a Lyme test. The Western Blot showed 28 and 41 bands only. Not Lyme disease.

Her family doctor referred her to: a rheumatologist, a neurologist and an infectious disease specialist. She figured it must be one disease -- she only needed one doctor. Smart girl. An Internet search led her to Lyme disease and then to me.

Doxy failure

14 months ago, a 47 year old male first consulted with me. His illness started after a physical injury sustained working in his garden. He first developed low back pain -- diagnosed as a strain. He went on to develop knee pain, fevers to 102, a red streaky rash on his abdomen, sweating and color changes in his fingers. He went to the ER: he had been ill for 3 weeks. A two tier, CDC surveillance test was positive for Lyme. He was treated with 3 weeks of Doxycyline and felt better. His past medical history is positive for Chrohn's disease.

Three month later he developed recurrent, progressive symptoms -- muscle pain -- increasing joint pain -- profound fatigue, and, drenching night sweats. New neurological symptoms appeared: numbness and tingling, memory loss and cognitive dysfunction.

He presented to me for further care. A 13 band WB showed 3/3 IgM bands. Non diagnostic Bb IgG WB bands were present. He was seronegative for Babesia microti/duncani. He was treated for chronic Lyme disease and Babesiosis, diagnosed clinically.

After many months of antibiotic therapy his disease is in remission, still on antibiotics.

Additional data: C6 peptide ELISA had been 6.41 initially and is n0w 2.3. C4a levels have been elevated. CD 57 levels have been normal. A wet mount showed no bacteria.

His previously active inflammatory bowel disease is now quiescent. A recent colonoscopy was normal.

Three weeks of Doxy for acute Lyme failed. This may be more frequent that commonly held. It has been suggested by some that this is due to co-infections. I am not sure. The average person, with an intact immune system, should be able to throw off both Babesia and Bartonella.

Perhaps in some cases, Lyme is able to sequester itself quickly. Other explanations may be offered. Perhaps in some, already-infected asymptomatic patients, clinical Lyme is triggered by a new infection. The other possibility is a bit more frightening. Perhaps strains of Lyme are now resistance to Doxy. This could explain some Doxy failures with response to other treatments, such as Amox/Biaxin. This patient did respond to Doxy at first. But, partial resistance is know to occur with other bacteria. This is all thinking out loud conjecture.

Lyme disease is associated with a multitude of autoimmune diseases. Crohn's and ulcerative colitis are both autoimmune diseases. Coincidence?

Lyme Rage

A 36 year old female was treated for severe Lyme disease and neuroborreliosis. A course of IV antibiotics was successful 2 years ago. I explained to her the need for maintenance therapy. She took oral antibiotics for a few months, but tiring of the medicines, she sought alternatives, such as A Rife machine. She had been treated for Lyme, Babesia and Bartonella. Her case had been well documented: abnormal MRI, abnormal SPECT scan and multiple positive Western Blot Lyme bands. The aches and pains returned, slowly. The mental confusion returned, slowly. She returned for further treatment 6 months ago. This happy-go-lucky soul had turned into someone else. She was was filled with unbridled rage. She told me she literally felt like killing someone. She was just waiting for that someone to cross her path so she could act out her rage. She meant business.

Several months into therapy she returned to her normal self. The anger disappeared gradually, and then it was gone--after treatment with a second course of IV therapy. Now, several months off IVs, she is largely symptom free, the disease controlled with oral antibiotics. The smile has returned to her face. She is once again a kind and gentle soul.

Evidence based medicine: a critical appraisal

So called "evidence based medicine" has done more to harm medicine than anything else I can recall during my 30 year tenure in medicine. Doctors have become technicians, rather than practitioners following in the traditions of healers who have come before.

When I was in college, science as we know it, existed within a framework-a caste system-a pecking order. Mathematics was considered the purest science: provable with irrefutable equations. Physics took second place. It described fundamental properties of the world/universe around us, supported by mathematical equations. Chemistry followed next and then biology. The order of descent was based on how hard, irrefutable and provable the conclusions were. All science is validated by the scientific method: a theory or hypothesis is proved by well designed experiments which can be replicated in a variety of places, times and circumstances.

When I entered medicine in the 1980s, medicine was more than a job or ordinary profession. It was a commitment, a lofty avocation, a calling of sorts. (at least according to my father)--I agree. Medicine was a healing art, in the tradition of the many who had preceded us, predicated on science. It was not a science.

Sometime around 1995 the term "evidence based medicine" insinuated itself, increasingly into the verbiage of the profession. I suspect it was in large part driven by managed care companies, looking to control costs, and then, high powered medical institutions jumped onto the band-wagon, in the belief that medicine was really science, not art: throwing out the baby with the bathwater.

Properly designed controlled medical studies were carefully analyzed by statisticians. Sometimes multiple studies were combined and analyzed-- meta-analysis. Problem. Only a few potential questions were addressed. Most studies were funded, at least partly, by big Pharma, with pre-existing agendas, undoubtedly tied to feathering the pockets of CEOs and stock holders (follow the money). Medical research, by its very nature, is simplistic. In truth, it is impossible to do proper science when it comes to studying something as complicated as people. Newer studies replace and refute older ones on a regular basis. It is impossible to control the variables, many of which are unknown, poorly understood or yet to be discovered. If it takes a room of statisticians, as is frequently the case, to prove a point, it should give one pause.

The single biggest problem: data obtained from a single study is extrapolated widely, to support wide ranging conclusions, based on faulty logic superimposed on bad science.

To makes things worse, evidence, as it were, is now broken down into levels/categories-- again, a pecking order. Most in the profession have accepted this new and improved medicine without giving its precepts a second thought.

First we have placebo controlled, double blinded, randomized studies, the results of which are statistically validated and replicated in subsequent studies.
Then we have non blinded controlled studies, non-controlled studies, head to head studies, published studies, clinical reports published in journals and lastly recommendations of a body of experts--my perennial favorite.

How can opinion be science?

So, let us get back to Lyme, the subject of this blog. The Klemper, Krupp and Fallon studies, are in my mind, weak science at best. They also all have somewhat different study designs and conclusions. The limitations of these studies has been discussed in detail elsewhere. The "experts" put these findings together and give us a final product: evidence based guidelines.

The better science is what physicians seem to dismiss and ignore: test tube science and other forms of "basic" science. Borrelia has been shown to convert from spirochete to cyst forms in the laboratory and back the other way. Spirochetes have been shown to exist as L-forms. Research in immunology support beliefs that infected hosts cannot be sterilized of Lyme. Human and animal models have proved that Lyme persists in the face of massive doses of antibiotics. This sort of science can control the variables. It can be replicated in multiple settings over time. The same cannot be said for clinical studies, the type of science clinical doctors rely upon, which are pooled into meta-analyses, looking for statistically significant conclusions. I could go on, write a book about this subject, with foot notes and citations. Not here.

This post is a about "evidence based medicine." In my opinion, this is a sham, a fraud. Perhaps it works for HMO physicians who are required to see patients in 6 minutes: cookbook medicine. It is not a useful tool for thoughtful, curious physicians, intent on practicing their art to the best of their ability. Patients are all different as are all physicians. Diseases are nuanced and complex.
The practice of medicine is a mosaic of science, judgment, clinical experience and yes-intuition, a clinical nose, the product of years of practice.

So yes, this dumbed down version of medicine has now framed the basis for the national debate about lower cost, higher quality medicine. According to national political "experts", electronic medical records and evidenced based medicine (the mantra), will solve systemic problems with our health care system.

Who decides which evidence we use? Ivory tower physicians. Iconic figures. The Gary Wormsers of the world. Doctors for the most part, are reassured by practice guidelines: complex decisions have already been decided for them. A few other physicians, the outliers, and their demanding-annoying patients, just won't go away. It is no wonder that many readers shudder when the hear the words: evidence based medicine.

Every pre-med student is ultimately asked the question: why do you want to become a doctor. Inevitably, they all give the same, banal answer: I want to help people.

For those of us who want to be included amongst healers who use science, the state of the art as it exists at any particular point in time, as a basis, but only a starting point for the practice of their art: the art of healing; this answer turns out, in the final analysis, to not be so banal after all.

Evidence based medicine? Thumbs down.

H. pylori

My patient, age 32: "This is the best I have felt in five years. I feel like a whole organism. Rashes on my body, face-circles under my eyes, they have all cleared. My abdominal pain is all gone. My acid reflux is gone. Total body stiffness and pain are gone--after 5 years. Fatigue is gone: I am so energetic. My body has changed. My middle section has reduced in size. The bloating and swelling is gone. My appetite is better: I am know longer hungry all the time. My taste buds work better. My neighbors have so much energy, now I am like them. Thank you."

"Did you have any side effects from the medicine?"

"For the first two weeks I had nightmares--mild headaches, then everything went away."

One month prior to this visit, a test for H. pylori was positive: the IgM ELISA. Most labs only perform the IgG ELISA. I request the IgA, IgM and IgG antibodies for H. pylori (Helicobacter pylori). Any one could be positive. IgA goes along with mucosal disease and IgM indicates active disease.

This patient has a number of chronic medical problems. The test was ordered because of persistent heartburn (GERD). Her treatment: Nexium 40mg 2x daily, Biaxin 500mg 2x daily and Amoxil one gram 2x daily, for 30 days. She has been off therapy for a week and is continuing to improve. I told her if symptoms return maybe we should retreat.

I leave this vignette for you to interpret.

Three patients today: wet mounts, osteomyelitis and ulcerative colitis

This 35 year old female went to the local ER in October 2008. She had a rash, fever to 101 f, and chills. She was sent home without treatment. I saw her in the office a few days later. She had a very large and very red inflammed EM rash on her right chest wall. I decided to be aggressive. I double covered with Amoxil one gram twice daily and Doxy 100mg twice daily for 30 days.
I saw her 4 weeks later; everything had resolved. In June 2009 she complained of new onset fatigue--severe, disabling for several months, brain fog and word retrieval difficulties. Lab testing was then performed. A CD57 count was 28. A standard Lyme Western Blot showed 41 bands. The Babesia WA 1 aby reacted 1:256, the lowest positive titer. A Clongen WB showed multiple bands, including IgM 23 and 41. A wet mount was performed. This showed numerous small round bacteria--presumptive of a Bartonella species and "numerous large elongated extracellular motile organisms(look like a protozoan or tiny round worm)." Contemporaneously, she developed pelvic pain. She was treated with: Amoxicillin, Zithromax, Rifampin and Tindamax. This was followed by a course of Levaquin. She improved nearly 100% within 7 months-- except for pelvic pain. At her request, a repeat wet mount was performed. This time scarce, elongated, curved, extracellular organisms were seen. The Bartonella like organisms were gone. Quite a change! I empirically prescribed a course of Levaquin and Tindamax. Her gyn and GI have been unable to diagnose the source of the pelvic pain.

A second patient, a 40 something neuroscientist, has been treated for Lyme with cognitive dysfunction for 6 months. Physical symptoms have improved, but cognitive difficulties remain.
She is unable to focus, concentrate or process. Her short memory is very poor. I asked her to have a brain MRI and a SPECT scan done, but she told me she "forgot." I bring this patient up because of her past medical history. Nine years ago she developed a bone infection- osteomyelitis, in an ankle following surgical repair of a fracture. She was treated with two courses of IV antibiotics, 9 weeks each. In addition, she was treated with extensive courses of oral antibiotics. All told, she took antibiotics for 4 consecutive YEARS. She finally improved after hardware was removed from her ankle. A consultant from the infectious disease department at Johns Hopkins University, where she was treated stated that she might require life-time antibiotic therapy.

A third patient, a 50 year old woman, with a history of ulcerative colitis developed acute Lyme disease in 2007. All 13 Western Blot Bands were present. She also has had a persistent, marked elevated ANA level. She saw me after failing standard treatment (3 weeks of doxycyline). She continued to have joint pain and fatigue. She improved over a couple of months and therapy was discontinued. She had recurrent symptoms over the next year: mostly joint pain. Further courses of antibiotics (short term) were prescribed with improvements. When I saw her in late 2008 she was well. Soon thereafter she experienced a recurrence of ulcerative colitis-- after a 10 year remission. This episode was controlled with steroids and maintenance Cloazol . At the end of 2009 she suffered a severe, uncontrolled relapse of her colitis. She was treated with: Remicaide, high doses of Colazol, 6-MP and steroids. The Remicaide, given at Johns Hopkins, was not effective. The Hopkins' GI recommeded a total colectomy (resection of colon) for non-responsive disease. Not done. Her local GI got the disease under control with high dose, tapered steroids. She remembered something I once told her. She recently sent colon biopsy fragment to Clongen. The PCR test of the biopsy specimen was POSITIVE FOR LYME. Be careful what you wish for! Flagyl has given her diarrhea in the past. I cautiously prescribed a course of Cipro--today. I spoke with Dr. Kilani. "We don't know what these results mean. The presence of DNA in the biopsy material does not tell us if viable organisms are present." The suffers with autoimmune disease. Did Lyme trigger her colitis or did the immunologial effects of treating Lyme trigger the disease. She will see her GI next week. I am sure he will have fun trying to make sense of the results.

I am really not trying to pick on Hopkins. It remains one of the best tertiary medical centers in the country--in most matters.

The eye of the beholder: a specialist

Published studies do show that chronic Lyme improves with long term antibiotic therapy.

Donta, 1997, Boston University published a study of 277 patients with chronic Lyme disease.
He reported that patients frequently did not improve for several weeks. After 2 months 33% of patients had improved, after 5 months, 61% had improved. He claimed 20% of patients were cured, 10% did not improve, and 70% showed some improvement. The duration of the study was for 1 to 11 months. He concluded: CONTROLLED STUDIES NEED TO BE CONDUCTED TO VALIDATE THESE OBSERVATIONS.

In 2003, Donta published a study on the use of Biaxin, Biaxin with Plaquenil and Plaquenil alone.
The effective therapy was Biaxin and Plaquenil. Conclusion: THESE RESULTS SUPPORT THE HYPOTHESISIS THAT lYME BORRELIA RESIDE IN AN ACID ENDOSOME.....

Cameron, 2008, published a double-blind placebo controlled clinical trial.

He replaced the term chronic Lyme disease with Lyme disease with persistent symptoms (LDPS). He found a 46% improvement of subjective quality of life in treated patients and vs 18% in non treated patients. He concluded: WORTHY OF FURTHER STUDY.

Clarrisou et al, 2009, Med Mal Infect, published: Efficacy of long-term antibiotics in patients with a chronic Tick Associated Poly-organic Syndrome (TAPOS
Investigators keep inventing new terminology for the same disease. Why?
A cohort of 100 patients was followed. The study showed favorable results in subjective symptoms. The authors point out flaws and limitations of their study but recommend: RANDOMIZED, DOUBLE BLIND STUDY.

The number of patients studied in all of these studies was significantly higher than the number of patients studied in the 3 NIH sponsored studies. This has mostly to do with study design and patient selection limitations.

Hopkins-Harvard-Yale-IDSA-CDC: Where are you?

Those folks are sticking with the "Best science."

Problem: best science supports these conclusions (fatigue, qualitly of life) if you take another look at the Krupp and Fallon outcomes. A patient suffering with Lyme and chronic fatigue recently told me: " Hell, I would gladly go on 3 months of IV Rocephin if it only helped with fatigue."

I asked an esteemed professor(infectious disease) from Hopkins about his success with severe neruo-syphilis He told me with pride that he has treated it, (it is rare these days)--the penultimate expert. I asked him about patients with severe brain damage. "When the squash is gone there is no squash." Good answer. Even patients with persistent vegetative states have been shown to frequently have significant neurological and cognitive activity.

Patients with neuroborreliosis have recovered. SPECT scans, PET scans have improved. Patients with neuro-syphilis-dementia (general paresis) have been treated with only penicllin. These patients pathologically have blebs and cysts in their brains, similar to those seen in patients with neuroborrelosis. As stated, there are not many of these patients around anymore. There have been no studies since TUSKEGEE. How would neuro-syphilis patients do if they were treated with other therapies, including IV Flagyl? Not studied

How about this:

Why don't we let psychologists and psychiatrists evaluate cognitive functioning, radiologists evaluate objective, radigrophic signs of improvement and neurologist evaluate for evidence of neurological improvements. How about listening to our patients as well? I know--a novel concept.

Why does a professor of of infectious disease medicine, with little or no knowledge of these other fields, tell us about squash, a "fancy" designation for brain?-- what are his qualifications to tell us that chronic Lyme disease--including neuroborreliosis does not exist?

I went to medical school, internship and residency.
We made round, sometimes with esteemed attendings: we were intimidated: they knew everything, we were abysmally ignorant. We were ready to be chastised; we were swine waiting for pearls to be cast to our feet. I remember, Super-star attendings--Power, honor, prestige: with it comes a sense of infallibility--after all, you are the last word, the highest authority. You have to be self assured. Perfectly understandable. That is why I became a generalist, not a specialist. It is understandable. Nonetheless: sometimes you are wrong, dead wrong.

Fallon and fatigue

An NIH study published in Neurology, 2008, lead investigator Brian Fallon has been misinterpreted by many in the Lyme community. The study was carefully performed using the highest level of scientific procedures. Patient selection was meticulous. The study was a randomized, placebo controlled study for Lyme encephalopathy (neuroborreliosis) and the results were published in a prestigious, peer reviewed journal. Dr. Fallon reported that the studied patient population suffered with... "moderate cognitive impairment, physical dysfunction comparable to patients with congestive heart failure, and fatigue comparable to patients with multiple sclerosis." The treatment arm of the study evaluated patients with established Lyme disease, seropositive by the CDC requirement of 5/10 positive IgG bands, who had previously been treated with 3 weeks of IV Rocephin. Patients were treated with 10 additional weeks of Rocephin. The study found significant short term improvements in cognitive dysfunction, but not memory in the treated group. A sustained improvement in fatigue was shown.

The investigators reported a 19% rate of complications. This does not comport with my clinical experience.

Dr Fallon recommended against the use of 10 weeks of Rocephin followed by 14 weeks of no therapy. He does report antibiotic associated improvement with regard to disabling symptoms such as pain and fatigue, particularly in patients who suffered the most at the outset of the trial. This was not a primary end point of the study, but the results were significant. Fallon also noted that the Krupp study showed significant improvement in fatigue.

"Conclusions regarding the benefit of repeated IV antibiotic therapy for this set of symptoms must await further investigation."

The IDSA still concludes that this study conclusively demonstrates that chronic Lyme disease does not exist. This is not true. Further study is needed. With regard to cognitive improvements several other conclusions might be suggested: the patients needed longer courses of antibiotic or perhaps gains could be sustained when IV therapy was followed up with oral therapy.

Of course, this study does not address the subject of co-infections. It does not address the need to treat L-forms and especially cyst forms which have been shown to be prominent in the brain.

Yesterday I had the opportunity to discus these issues with a Hopkins professor of infectious disease. He claimed that ALL the good science proves that chronic Lyme does not exist. He was steadfast in his opinion. When queried, he admitted he knows nothing about the Columbia/Fallon study. He asked if it was"good" science. He was oblivious to the fact that the Fallon study was third NIH-sponsored study cited by his colleagues to support the absolute belief that chronic Lyme does not exist. Apparently only the Klempner and Krupp studies are worthy of consideration. But what about that pesky Krupp study?

I have a simple question: how does Rocephin improve fatigue, demonstrated in clinical trials, the best science? If the patients do not have persistent infection with Borrelia burdorferi, what is the mechanism by which antibiotics help fatigue?

Sleep helps fatigue. Caffeine and stimulants help fatigue. Antibiotics?

Maybe when I needed to pull those all nighter to cram for chemistry finals in college I should have been popping penicillin instead of gulping down pots of coffee.

A proposal for a clinical study

Medical science--clinical studies, must be taken with a grain of salt. It is nearly impossible to do science when the thing being studied is as complex and multi-faceted as a human. Such studies attempt to prove that treatment A is better than a placebo (a pretty low standard) or that treatment A is superior to treatment B. The group under study is supposed to be homogeneous--a cohort with the same disease process. I would suggest it is nearly impossible to find a cohort of patients with exactly the same disease. Ultimately, many confounding variables make this sort of science difficult to do and to validate.

All the randomized-placebo-double blind-peer reviewed studies for chronic or post Lyme disease look at lot alike. All patients had prior, treated Lyme disease. All had had received "standard" therapy. And, all had persistent symptoms in the face of prior therapy. "Long term therapy" was defined as limited courses of Rocephin with or without courses of doxycyline. Generally, patient selection required CDC-IgG positivity, 5/10 bands. Of interest, Klempner also studied "sero-negative" patients. This is anomalous since the IDSA has generally claimed that seronegative patients do not suffer with Lyme disease.

Insanity has been defined as: doing the same thing over and over again-- expecting a different result.

I would suggest that another kind of study be designed and carried out. Patients with the same general set of symptoms, for example: migratory joint pains, fatigue and cognitive impairment plus positive Lyme Western Blocks by IgM or IgG standards should be studied. Patients from this cohort should be randomized into two arms: a head-to-head study. Group A would receive IDSA recommended therapy and group B would receive LLMD style therapy. Objective measurements of progress would be agreed upon. These might include: symptom lists, psychometric testing, physical exams and perhaps lab parameters such as a highly sensitive C-reactive protein. Patients would be periodically assessed over a prolonged period of time. For example, patients could be assessed every 3 months for a period of one to two years.

LLMDS in the study could agree upon some general standards, for example, Babesia could be treated with Mepron and Zithromax for 8 weeks. If there were no clinical response, a second course might be Larium plus Artemesin. In general, the physicians would be given flexibility to treat patients differently, based on clinical experience.

This is the sort of study which might provide convincing evidence that treatment for chronic Lyme disease is effective. The disease is different in every patient. It is nuanced. It is complex. Standard study designs which look at only one variable, will never prove the benefits of long term treatment for Lyme disease.

I hear a lot of talk about the need for Lyme studies.

I think, first potential investigators need to develop a study design. The teams needs then to find a partner with credibility and prestige, such as NIH. The cost could be low, particularly if this sort of head to head study could be "piggy-backed" onto another planned or ongoing study. Results, hopefully favorable ones, could be published in a major, peer reviewed journal.

Lyme 2010: A brief update

Diagnosis remains clinical. Laboratory data should not be over-emphasized. Lyme Western Blots from Igenex, MDL and Clongen are helpful. I prefer Clongen. They provide quality pictures of blot strips which quantitatively compare patient reactivity to controls. C4a is a good marker of infection, better than CD57. Other clues include: reversed vitamin D levels, elevated CRP, low/normal B12 and folic acid levels, and low white blood cell counts. Blood wet mounts reliably show motile round bacteria---presumptive Bartonella species. A large percent of patient have the BBB triad: Borrelia, Bartonella, Babesia.

Primary oral therapy with Doxycycline and Tindamax is excellent. Killing cysts early seems to improve outcomes. Tindamax is clearly better than Flagyl and Albendazole. Biaxin is a second choice in patient's who cannot tolerate Doxy. When Biaxin is used patients seem to do better when a beta lactam is added:Amoxicillin/Ceftin/Omnicel. The benefits of Plaquenil are not clear. Rather than having an anti-cyst effect, it promotes cyst formation. Many antibiotics used for Lyme also have mild effects against Bartonella as well. In patients with neurocognitive deficits, Lyme and Bart are generally both a factor. Bartonella/brain Herxes can be extremely severe. Anti-Bart therapy is such patients needs to be gradually ramped up. Drugs with low anti-Bart activity include: Doxy and Biaxin even though these drugs are thought to be only Lyme drugs. Minocycline is a little more active against Bart. Zithromax orally is a poor Lyme drug and has mild anti-Bart effects. Rifampin is somewhat more active against Bart. Bactrim is quite effective and quinolones are very active: Cipro followed by Levaquin and then Factive. Cipro and especially Factive are also good Lyme drugs. Factive is a fabulous Lyme drug.

Many strains of Babesia appear to be very resistant. I suspect like malaria, these bugs have a propensity for developing resistance. When Mepron, Malarone and Artemesin are relatively ineffective, Larium may be surprisingly effective. I generally like to treat Lyme first. The exception is patients with dramatic Babesia symptoms: drenching sweats. As a rule, patients respond quickly once the sweating stops.

I agree with the Martz approach to IV antibiotics: layering. I start with Rocephin, add Zithromax and then Flagyl. Works very well. Other IV antibiotics may be helpful but responses are more variable. Tigacyl has been disappointing in my practice.

Patient should be treated with IV antibiotics for at least 12 weeks, longer if possible. Gains from IV therapy require ongoing therapy with potent oral antibiotics or the gains will vanish. Factive and Tindamax are superb. Factive is costly. Doxy is a good alternative. A subset of patients only do well when beta lactams are continued. Biaxin and Amoxicillin remains an excellent choice of therapy.

Supplements? vitamin D3, 2000-4000IU seems helpful. Probiotics are critical. A good mix of acidophilus type, 30 billion twice daily and Sacchromyces works well. Supplementation with yogurt is better yet. A balanced diet is helpful: fruits, berries, nuts, fish and a wide variety of vegetables of different colors--broccoli to red peppers. Sugar is always bad. I am not yet sold on other supplements. Transfer factor which is basically colostrum may be helpful. If B12 and folic acid are low-- supplement. These patients are probably nutritionally depleted and should also be given B complex and multivitamins.

The body cannot be sterilized of Lyme bacteria. Intracellular bacteria will always persist.
Unfortunately, many patients require maintenance therapy. I have seen many patients who have been "cured" by other physicians, but complain of incomplete recovery or relapse.

Not all Lyme infected patients required treatment. I only test patients who are symptomatic.
No--it is not sexually transmitted or transmitted by mosquitoes or flies. It may be transmitted via placenta to newborns. This can be very problematic. I treat pregnant Lyme patients with low dose Amoxicillin.

There is no one right way to treat Lyme disease. At times you have to be creative--and, never give up. Individual responses to therapy are impossible to predict.

Patients with autoimmune neuropathy may get much worse with therapy. This is one of the most challenging group of patients. IViG should be considered if possible. Sometimes steroids are needed, despite all the caveats. Antibiotic therapy must be titrated very gingerly.

Welchol works very well in some patients--especially with neurocognitive issues. Long term therapy may be required. It also lowers CRP and inflammation.

Straight IV fluids, normal saline solution may be given to patients on IV antibiotics to flush out toxins? or circulating immune complexes. It may reduce Herxes and make patients feel better.

Politics: no change except Connecticut. Patients must understand that doctors who treat Lyme disease face ridicule from their colleagues and possible censure from medical boards.

The IgM question: Is it chronic Lyme disease?

Many patients have been told by their physicians they do not have chronic Lyme disease because Western blot antibodies are in the IgM class, not the IgG class. The doctors themselves may be confused -- or adamant. The adamant ones very likely don't believe chronic Lyme exists. If you, on the other hand, believe chronic Lyme is real, you may want to discount opinions proffered by those who do not share those beliefs.

Lyme acts differently immunologically than many other germs. Patients with only IgM antibodies may have Lyme and or/ chronic Lyme.  In the typical scenario of  antibody response to infection the immune system makes IgM antibodies in early infection and then makes IgG antibodies in late infection. As the amount of IgG increases IgM decreases and then goes away.  This is not always the case. Lyme is a clear exception to this rule.

Peer reviewed medical studies have contributed to the confusion. Selection bias inherent to published studies is one problem.  The only patients selected for NIH sponsored clinical trials have had IgG, not IgM antibodies. One investigator, Brian Fallon, who treats a lot of Lyme patients, found it challenging to find patients with the 5/10 IgG band requirement; less than 5% of his patients fulfilled the study entry requirement. All studies require certain criteria for inclusion in the study. These criteria were used for standardization and in no way suggest or prove that a particular IgG response is needed for the diagnosis.

A large chunk of chronic Lyme patients have only IgM responses. Some have mixed IgM and IgG responses. In some cases IgG responses are favored and in others IgM.

Those from the no-such-thing as chronic Lyme camp stake out the position that persistent IgM responses without later production IgG antibodies represent false positive responses.  Patients with only IgM responses are told that they in fact never had Lyme, or they may be told they have Lyme but it must have a new case.  Science tells us something else. Some patients make only IgM antibodies. And it is known that IgM and/or IgG antibodies may persist for years after acute infection.(Steere). The CDC has not been helpful.  The CDC two tier test, ELISA followed by Western Blot standard was developed for surveillance, not clinical diagnosis. The claim that the test lacks accuracy in early Lyme but is virtually 100% accurate in late stage Lyme is crazy and has no basis in science -- or published evidence. This unfounded statement unfortunately lends credence to the Lyme deniers who push the falsehood that IgM bands equal false positive.

IgeneX has published its finding that 2 specific IgM or IgG are diagnostic of the disease, stage of the illness not withstanding.  Aucott has found that 20% of patients with treated acute Lyme are unable to produce IgG antibodies, likely a genetic variable. Steere published data showing persistence of IgM antibodies in late Lyme in the 1990s. This knowledge is not new.  Existing literature supports the idea that certain Western Blot antibodies are highly specific for Lyme. If specific antibodies are present it is unlikely they are the product of a false positive test, irrespective of antibody class.  When only IgM antibodies appear there is a alternate hypothesis. The persistence of IgM antibodies may suggest the immune system is "chronically" seeing Borrelia as an acute--new infection. This interpretation is applied by doctors in other situations. For example EBV. IgM EBV antibodies are frequently interpreted as evidence of reactivation of the infection.

Antibodies are the result of "humoral" immunity or acquired immunity. The immune system "reads" the pathogenic germ and turns the information over to the body's antibody factory. IgM and IgG antibodies are produced by the same cells: B lymphocytes. These lymphocytes may become plasma cells. The change from IgM to IgG is due to a genetically directed molecular switching mechanism. This class switching--IgM to IgG-- may not occur or occur poorly. We don't know why but these facts have been established by evidence based science.

In my experience, Lyme patients, on average, produce slightly more IgM than IgG antibodies. This may be hard to see since most IgM assays present limited data (few bands). Certain antibodies, for example: 18, 23, 31, 34, 39 41 and 93 are HIGHLY specific for exposure to Lyme bacteria and this is well described in many places.

Doctors known as LLMDs have know for decades that the IgM vs IgG class distinction does not apply to Lyme.

Addendum:  Antibodies are Y shaped molecules/proteins made up of heavy chain and light chains.  Some portions are variable and some portions are invariable.  Binding to antigen occurs when a variable portion at the end of one leg of the Y has a structure reconfigured (controlled by gene modification).  This is the part which is analogous to taking a key to hardware store to have it copied. A generic antibody is like the blank key. The key (specific antibody) is formed through a complex process. The same cells, B lymphocytes/plasma cells that make IgM antibodies also make IgG antibodies. When the class of antibody is changed it is referred to as isotopic switching.  Here is the critical piece of information: the key - the variable portion of the antibody is unchanged when IgM is changed to IgG. Rather an invariant heavy chain is swapped out. Meaning: the specificity of IgM antibodies is identical to the specificity of IgG antibodies. Remember, the immune system is controlled by mediators, cytokines. The switch from one class to the next is controlled by cytokines. IgM antibodies induce cytokines which differ from those of IgG antibodies. This is why IgM and IgG antibodies have different biological properties. The cytokines communicate with different parts of the most complex system (immune system) in the body outside of the brain and the wide array of moving parts are given different tasks. IgM signals are different from IgG signals. It should all work together for the most effective killing of unwanted pathogens. The operative word is should. 

Germs evolve. Germs are smart. If a pathogen can modify the signals and confuse the cells, if gives the highly motivated germ a leg up, a survival advantage, and we know that Lyme infection can modify cytokine responses. Maybe that is why isotopic switching, IgM to IgG fails for many patients. 

Take home point:  the part of the antibody that specifically binds to the antigen is 100% unchanged when IgM antibodies are replaced by IgG counterparts. 

If you suspect you suffer with manifestations of Lyme disease only an experienced knowledgeable doctor can make the diagnosis.

Please see other BLOG posts for more information regarding this issue.

Post-Lyme syndrome

A 68 year old female consulted with me one year ago. She had been ill for over 4 years. At the outset she had flu like symptoms and a rash on her neck. A 2 tier Lyme WB was positive by CDC criteria. She was treated with antibiotics 4 four months by her primary care physician. The physician pronounced her cured and refused to extend the course of therapy. Her symptoms returned with a vengeance. She developed more pains, joint swelling, numbness and tingling, fatigue, and cognitive dysfunction. She had progressive memory loss. She could not focus, concentrate, process or retrieve words and thoughts. She had episodes of confusion and disorientation. She saw numerous doctors, all of whom were dismissive, if not rude. She was told her symptoms were normal for a woman her age. Then after doing her own research on the Internet she ordered an IgeneX test.

The Lyme IgM Western showed bands: 18 28, 30, 39, 41 and 58. A C6 peptide antibody was 0.86. Her CD57 was 18.

When I first saw her the physical exam showed difficulty with word search and moderate short term memory deficits. Positive findings included: bilateral weakness in the upper extremities, absent deep tendon reflexes in the knees and ankles, decreased pin-prick sensations in 4 extremities and decreased vibratory sense in the feet and lower extremities.

The brain MRI showed scattered white matter lesions-non-specific. The brain SPECT showed decreased activity in the the left anterior temporal region.

After one year of treatment she is about 90% better. Her cognitive functions are nearly normal. Her treatment included: Omnicef, Biaxin, Plaquenil, Tindamax, Zithromax, Mepron, Malarone, Artemesin, Bactrim, Amoxicillin, and Doxycyline.

Comments:
This patient's story is illustrative of care given to similar patients by many LLMDs.
There is good evidence: patient's history, physical exam, laboratory test result and brain imaging all support the diagnosis of CNS Lyme/Lyme encephalopathy/neuroborreliosis etc --even to well informed IDSA physicians. The science suggests that all such patients should be considered for intravenous antibiotics, no matter which side of the fence you are on. In this case, the patient improved with only oral (extended-plus-co-infection) anti-microbials.

The IDSA view is that chronic Lyme disease does not exist. The IDSA has no argument with the existence of a post-Lyme syndrome. The authors of NIH sponsored studies have expressed empathy for such patients. Their suffering is real. The investigators and CDC claim current evidence does not support the use of long term antibiotics for such patients. It recognizes the genuine suffering of such patients and that this suffering is causally related to previous, (treated) Lyme disease. Fair enough. (I disagree).

But something strange has happened. Patients who seek the attention of ID doctors and rhematologist, even those with "CDC positive" results are treated as pariahs. Despite hard evidence, the patients are herded out of these physicians offices as quickly as possible. They are still told: you are depressed, you just need to exercise and loose weight, you have fibromyalgia, you are just imagining your symptoms, you spend too much time on the Internet, there is nothing wrong with you, I don't care what the tests say--you don't have Lyme and so on.

I went to medical school--admittedly some time ago. I thought doctors are supposed to be empathetic and kind to patients. Instead, many doctors are belittling, dismissive and bellicose.
They don't have to agree with the ILADS/LLMD approach, but for heaven's sake, they have a diagnosis to rest their hats on: post-Lyme syndrome-"a poorly characterized autoimmune syndrome."

They should at least read their own literature. These physicians should be supportive, offer a diagnosis, explain the diagnosis, its pathogenesis prognosis and therapy.(If they believe the party line?). These understanding physicians should prescribe therapies to alleviate or ameliorate the suffering of their patients. Instead, they appear to be taking out their disdain for LLMDS on their patients. Ironically, this may be a good thing because the patients keep looking until they find us. (I don't want to give "the other side" any good ideas).

Lyme does not cause Alzheimer's disease

All disease results from the interplay of genes and environment. DNA, whose mysteries are slowly being unravelled, is the blue-print of everything we are and everything we will be. Four base pairs- codons- genes- make proteins which control everything else. Infections: viruses, parasites, bacteria--in some cases Borrelia burdorferi, become environmental factors which interact within a genetically encoded milieu. The relative importance of heredity and environment vary greatly depending on the disease. For example, if you are born with the cystic fibrosis gene your fate is predetermined before you are born. On the other hand, as with many other diseases--cancers, diabetes, coronary heart disease, multiple sclerosis and others, this interplay of genes and environment is no so easy to predict.

Alzheimer's disease, multiple sclerosis, lupus, arthritis and many other diseases are not caused by Lyme disease, or at least directly, as many patients mistakenly believe. Lyme may be an environmental factor associated with many diseases.

Susceptibility to Lyme is genetically coded and so is the virulence of a particle strain of the Lyme bacteria. In general, patients with chronic Lyme disease have central nervous system (brain) involvement, more often than not. Their clinical features are all quite different.

Borrelia burdorferi, unlike most other bacteria, is able to readily cross the blood brain barrier-- taking up residence within the brain. Inside the brain the spirochetes are seen as: atypical cystic forms, granular forms, blebs, rolled forms, colonies, rings, stretched strands, spherules and others.

Associated neuro-inflamation is complex and has been well described. Inflammation occurs as Bb encounters local immune cells such as macrophages and dendritic cells. Cytokines and chemokines induce inflammatory responses. Other immune cells, killer T-cells and B cells are activated. Bb can invade local glial cells and astrocytes. OspA is upregulated which induces apoptosis (cell death). Neurotoxins are produced. Nitric oxide and quinolinic acid have neuro-toxic effects. Autoimmune reactions also occur. There are different models of autoimmunity. Perhaps both molecular mimicry and Innocent bystander mechanisms occur. Lyme spirochetes have been observed in patients with concomitant Alzheimer's disease. Lyme does not cause Alzheimer's disease.

Alzheimer's disease has been studied for many decades. Various genetic mechanisms have been clearly established. Pathologically, Alzheimer's is characterized by an accumulation of amyloid protein in the brain neurofibrillary "plaques and tangles" and tau proteins. In animal models it has been shown that Alzheimer's does not occur when the protein which regulates the degradation of amyloid precursor is up-regulated.

Alzheimer's disease is considered the most common type of dementia. Dementia is characterized by chronic, progressive, global loss of cognitive functions. Numerous forms of dementia have been described. BSE (mad cow disease) is called prion disease. It is associated with mutated proteins in the brain. Lewey body dementia is associated with Parkinson's disease.

Rare genetic disorders, such as forms of porphyria can be associated with dementia (The madness of King George). Dementia may be the result of min-strokes and many other syndromes to numerous to list here. These syndromes may appear similar in the peri-morbid state, but they have clear differences in the earlier stages of the disease.

Of course, dementia can be associated with infection. For example, HIV and chronic CNS fungal infection are established causes of dementia. The dementia which most closely resembles Lyme dementia--neuroborreliosis associated dementia, is the dementia of neuro-syphilis. Syphilitic dementia is called "general paresis" and is known to be the cause of death of many historical characters.

Thankfully, most patients with neuroborreliosis do not develop dementia. They may suffer with severe cognitive deficits but these deficits are not global in nature. Patients usually maintain the ability to perform most activities of daily living. Certain cognitive processes in most Lyme patients remain relatively unaffected. SPECT/PET scans show patchy dysfunction. In Alzheimer's disease, the scans are global--not spotty.

Make no mistake. Neuroborreliosis is a devastating disease. Its treatment remains challenging. Still, many patients experience remarkable recoveries/remissions.

Amongst many in the Lyme community there is a reductionist tendency to oversimplify and claim that everything is caused by Lyme disease. This is neither true nor helpful.

Both sides must learn to speak a common language to find areas of disagreement and agreement.

Everyone has Lyme disease

The last post was not a real patient. It was a composite of several patient. I pushed the envelope a bit--providing the appearance of mixed symptoms. Here is the problem.

Remember, when the original ELISA(EIA) test for Lyme was developed, many "normal" controls tested positive. Lyme couldn't be that prevalent--at least that is what the early investigators thought. This is why the bar was set high, hence, the confirmatory Western Blot.

It unknown how many people in an endemic area are infected with Lyme. Is it 10%? Is it 90%. We have no idea. For the sake of argument, let us say the number is 50%. We then have no clue what percent are "symptomatic". Furthermore, we do not have a clear definition of what "normal" is. There are natural physiological changes which occur with aging. I am 54 years old. If I play tennis, my brain may tell my body to do the same things it did when I was 20---not going to happen.

Asking patients to answer specific questions in inherently problematic. When a patient comes in with a long list of clear symptoms it is one thing. When positives are elicited only when a patient is queried, it may mean something entirely different. If a patient thinks long enough about any question, a positive response may be forthcoming. A lot has to do with the individual's personality.

As physicians know, testing becomes meaningful when the "pretest" clinical sense, points in that direction. Testing for Lyme is unreliable. A basic rule of thumb for me is: treat the patient, not the lab. Most patients don't want to shell out the money for a speciality Lyme WB. "Just send the test to Labcorp." And, if an Igenex is done-- the results borderline positive, what does this mean? Only a physician's clinical judgment can decide if a patient's symptoms are likely the consequences of chronic Lyme disease.

Most major scientific breakthroughs have been made by young people, under age 30. Mathematical abilities decline with age, although verbal abilities do not, and in fact may improve.
So what is there to do when a patient appears "normal" by the physician's best judgement? Again, there is no definition of normal. When queried, most over 50 year olds have some aches and pains with exercises, but recover quickly. Perhaps there are some mild cognitive changes(?normal). Nonetheless, the "patient" feels normal. He has no fatigue or functional incapacity. Testing is not done simply because other family members have chronic Lyme disease.

If I treat what am I treating? What is the goal? What is the endpoint?

This is why I recommended watchful waiting. Otherwise, if one looks hard enough--turns over every rock: everyone has Lyme disease. Patients who suffer with Lyme disease see this case through a different lens--the lens of their illness. It is just not that simple.

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