PANS, Lyme and delayed treatment

A lovely 17-year-old young woman presented to my practice about a year ago.  The patient’s mother has a history of Lyme disease and belies that she transmitted Lyme to her daughter in utero. Maybe. The patient suffered with a number of severe infections early in life: pneumonia, age 2 months, periorbital cellulitis age 4 months, chronic tonsillitis age 2 and chronic mycoplasma infection.  Something different also happened at age 6. She experienced an abrupt onset of tics and Tourette’s syndrome. Her pediatrician diagnosed PANDAS and prescribed a course of amoxicillin which seemed to be only somewhat helpful. After 10 days the pediatrician refused to prescribe additional antibiotics because tests for Strep were all negative: rapid strep test, throat culture, ASO titer and aniti-DNAse B.   See a psychiatrist, not PANDAS. Her enlightened pediatrician was aware of PANDAS, pediatric autoimmune neurological disorder associated with streptococcus (grp A, B-hemolytic). The hallmark of the disorder is that it comes on suddenly and is associated with strep. It is an autoimmune condition. Although even this is hotly debated, at least some pediatricians believed PANDAS required long-term antibiotics. The patient's mother always suspected Lyme. PANS (pediatric autoimmune neurological syndrome -- without the strep) was an emerging concept. L:yme and other infections could be alternate culprits. At age 12 the patient experienced transient swelling of a knee and soon thereafter developed severe neuropsychological symptoms which became progressively disabling. My patient developed a strange ailment: confessional OCD, characterized by telling her mother repetitively the same horrible thoughts: “Would I be punished (go to jail) if I drown the cat?” you get the idea. 

The patient subsequently developed frontal lobe symptoms (like pseudo-bulbar dementia). For example, she would burst in laughter or tears, uncontrollably, for no good reason. Despite all, my patient managed to do well in school until 7^th grade. Then her grades took a nose dive from As to Ds.

Mom had daughter tested for Lyme:  10/10 IgG bands on the CDC surveillance test. Her pediatrician made little of this. Mom took her daughter to a variety of Lyme doctors who prescribed a parade of antibiotics and even Mepron for possible babesiosis. None of this was helpful.

Shortly before she saw me a neuro-pediatrician told her about a test from Moeculera Lab which measures anti-neuronal antibodies and is a marker for PANS. Mom had the costly test run and the results were resoundingly positive. More than one Lyme doctor refused to look into IVIG. Getting IVIG for PANS is difficult.  Most insurance companies refuse to cover it because the FDA says they can.  Luckily we also found a defect in humoral immunity via pneumonia vaccine challenge and the insurer now agreed to cover the cost of IVIG (not for PANS).

My patient was prescribed a combination of continuous antibiotics and IVIG.

One year later. She is essentially back to normal. No OCD or inappropriate behavior. Getting straight As in school. Well-adjusted and doing great.

Important note. The patient had a tick bite on her ear age 2.  Lyme can be transmitted by a deer tick in a child in a thin skin region, such as the ear (case report at ILADS conference several years ago) in as little as 4 hours.  Early life severe infections may be explained by an immune defect, shown to be present, not Lyme), My patient had normal growth and development and had no learning disorders.

In my, albeit somewhat limited experience, children who acquire Lyme in utero have autism spectrum disorder (Asburger’s) and/or a learning, developmental disorder.  

The Hallmark of PANS is that it hits suddenly: one day your child is normal and the next neuropsychiatric symptoms occur.

My important take away message is that even though many years passed between the onset of OCD etc... and IVIG therapy, the IVIG therapy may still be very effective. 

I currently have a 31-year-old male patient which a very similar tale, disabled and dysfunctional. Because of money problems the Molecular test is still pending.  He has been treated by numerous Lyme doctors over a period of 15 years. Antibiotics alone have never helped. The diagnosis had never been considered – until now.  

Cyst busters? We had it wrong all along.

Research from Dr. Zhang’s lab at JH shatters many iconic beliefs about Lyme therapies.

We know that Lyme disease, or rather the causative organism, Borrelia burdorferi, is very difficult eradicate. In vitro (in a test tube) it took a combination of 3 antibiotics to accomplish the task. Doxycycline was a requirement. The other drugs are either unavailable or prohibitively expensive, (cefoperazone and daptomycin).

Persistent viability of the spirochete relates to its ability to form round body forms and other pleomorphic variants and to from aggregates of spirochetes protected by a muccopolysaccharide covering. Rather that the terms: L forms, cyst forms and biofilm colonies, Dr. Zhang simplifies: there are two groups,rapidly dividing forms (spirochetes) and stationary forms (persisters).

Cocktails of drugs are needed to eradicate the organism. At this point we know little about the synergy of various combinations.

First off, this is not new, but Lyme does not form L-forms. L forms are bacterial lacking a cell wall, like mycoplasma.  Alternatively, some gram negative bacteria, treated with antibiotics shed their cells walls transforming into L forms. L forms cannot survive outside the milieu of the intracellular cytoplasm of the host cells. Lyme spirochetes are encased in a dual membrane, not a cell wall.  Although the bacteria may have an intracellular location they are primarily extracellular. Cell wall drugs work because the Lyme spirochetes have something like an internal skeleton comprised of cell wall material, peptidoglycans. Lyme does not form true cysts. The terms round body form and pleomorphic variants is more accurate.

I don’t like the term cyst busters (always reminds me of ghost busters). It may be easier to consider Lyme as a dichotomy of spirochetes and persisters.

I am sorry that I have bored you so far. The rest may be of greater interest.

Doxycycline remains the first line when it comes to treating spirochete forms. Doxy has no impact on stationary forms. You already knew this.

New facts:

Flagyl is not a “cyst buster.” It does not kill stationary forms any better than doxycycline. ( you probably did not know this) This also true for amoxicillin. Ceftin does have the ability to kill both active and stationary forms of Lyme. Rifampin does not kill Lyme by itself but confers persister killing effects to doxycycline and amoxicillin.

I was sure that Tindamax must kill stationary forms. It works so well in the clinical setting. So I asked Dr. Zhang and he responded. Unpublished data show that Tindamax is ineffective against stationary form of Lyme, perhaps slightly better than Flagyl. How could I be so wrong?

Then there is a long list of drugs that kill Lyme better than currently used drugs, at least in a test tube. Two drugs stand out: Diflucan and Artemisinin.

Why do Flagyl and Tindamax work so well? These drugs have excellent penetration into tissues and into the brain. Perhaps this property and synergy explain clinical effectiveness.  Tindamax (one of my favorites) is known to concentrate in bodily fluids and tissues extremely well.

Doctors have added Flagyl and Tindamax to Omnicef and Ceftin – for decades, because they are “cyst busters.”  These doctors had wrong the whole time. It was always the other way around.

Ceftin remains a highly touted Lyme drug. It is said to be the only second generation cephalosporin that penetrates the blood brain barrier. Omnicef is a third generation cephalosporin, like Rocephin. All third generation drugs can pass through the BBB. Early studies cited in the literature proved that Ceftin was effective in treating early Lyme patients with EM rash. It was not studied for late state Lyme disease, unlike doxycycline. 

All cephalosporins do a poor job of getting into the brain. They only penetrate the brain when there is active inflammation in the meninges (lining around the brain). Oral drugs like Ceftin and Omnicef have poor uptake into the brain in patients with chronic Lyme encephalopathy. Tindamax and Flagyl may not kill persisters better than the others  but they penetrate hard to reach places including the brain.

Amoxicillin, which like Ceftin/Omnicef does not kill persisters but amoxicillin has slightly better penetration into the brain/central nervous system. I have found it more effective in most patients.

Then we are left with the question: how do we kill Lyme persisters in the brain?

IV Rocephin, with adequate brain penetration does have anti-persister properties. Perhaps IV Ceftin (cefuroxime) Zinacef, works better – worth a try.

Obvioiusly we can’t order IV antibiotics for everybody.

Rifampin crosses the BBB well and should boost the anti-persister effectiveness of drugs such as doxycycline. I have found this clinically to be the case.

Test tube results to not always translate into clinical results. Sulfa drugs kill persister and penetrate well into the brain; clinical efficacy in my practice has been lacking.

What about Diflucan? penetrates well into the brain and kills persisters.  Role in Lyme to be determined.

Artemisinin? This drug has a short half-life. This is why a derivative combined with a longer acting agent (Coartem) has greater efficacy for malaria/babesiosis.  Artemisinin has fair brain penetration. It has activity against Lyme persisters. Clinical use for Lyme unknown.

We had a lot of stuff wrong but new doors have been opened as the search for the best way to treat Lyme goes on.

Lyme with IgM Western Blot bands only: can it be chronic Lyme? (revisited)

Warning: Even though I tried to simplify this piece I find it is quite complex. Read it slowly.


I have written hundreds of entries in this blog over many years. Consistently, the most popular entry (2010) is: "I have Lyme IgM antibodies only, could I have chronic Lyme?" I am sure readers are consistently hearing from a wide pool of the doctors the answer to this question is no. These doctors are wrong and I will try to explain why in a way I hope my readers will understand.  IgM antibodies are the first antibodies made by "virgin" B cells when a new problem (new germ for example) requires the production of antibodies. This is referred to as a humoral response and is the primary responsibility of the "acquired immune system," contrasted with the innate immune system. Antibody production is a specific learned function of the immune system. IgG antibodies follow IgM antibodies as activated B cells morph into plasma (antibody factories) and the immune response matures. It is reasoned that with persisting infection IgG antibodies will invariably be ramped up as IgM antibodies fade. It is further reasoned that persistent of IgM antibodies in the absence of IgG antibodies is physiologically impossible and therefore such a finding must be a false positive. This line of reasoning is cogent and sensible but is false. My contention is backed up by current science. In a recent, peer reviewed study, A cohort of Lyme patients followed longitudinally was found to manifest only weak IgM responses and no IgG responses. Class switching with transition of B cells to plasma cells failed to occur. This same group of patients was found to have more chronic symptoms.


Link:  Whttp://dx.doi.org/10.1371%2Fjournal.pone.0093243 


Antibodies also called immunoglobulins or Igs. Igs consists of proteins - light chains and heavy chains which form a Y shaped structure. There are various classes of Igs with somewhat different functions: IgA, IgM, IgG, IgD and IgE. IgG has 4 subclasses. There are fixed and variable regions of antibodies. Here I discuss only IgM and IgG. Immunoglobulins are diverse and our immune system can manufacture one hundred million variants - give or take. Variable Ig regions become custom made "keys" which fit into the locks (antigenic determinants) found on Lyme bacteria. These keys (made from light chains) do not change as the antibody class shifts. Constant, variable, heavy chains are swapped out as IgMs transition to IgGs. The portion of the antibody which binds to antigens does not change.  Antigenic determinants are targets on the bacteria which promote the formation of antibodies. These targets, may for example, be outer surface proteins or fragments of flagella - bacterial tails. Bound up antigens and antibodies appear as bands on Western Blot strips at specific sites based on molecular weight of the antigen fragments.


IgM and IgG have different functions - otherwise our bodies wouldn't bother making both types. IgMs are the largest of the antibodies and tend to be produced as pentamers (instead of monomers) the product of 5 IgMs complexed together. IgM antibodies are good at agglutinating masses of germs and activating a cascade of proteins called complement which directly destroys the invading bacteria. Right away there is a problem. Lyme are well known to inactivate complement activity from the get-go. IgM antibodies are active in the blood but are too large to diffuse into the spaces between cells.


IgG antibodies, which are smaller and able to diffuse into the spaces between cells - where Lyme lives - are frequently never produced.


Here is another puzzle piece. Some bands are known to be specific, others less so. Two specific bands (based on antigenic determinants) only appear late during the course of infection. The 31 and 34 bands (outer surface proteins A and B) only appear with infection of greater than 6 month duration.  Yet, in many cases we only find IgM antibodies directed against these two determinants. This is further proof of the concept that chronic, persisting infection may (in the case of Lyme) only elicit IgM antibodies without the appearance of the more active IgG varieties.


Parasites and pathogens evolve mechanisms to evade host defenses and to persist. Here we see that Lyme may allow only the production of weak IgM antibodies, cripple the ability of these antibodies to offer their best fight and completely block the manufacture of Ig G antibodies which would present a more serious threat.


Lyme spirochetes are extremely "smart." From Zhang we learn that antibiotics cannot kill Lyme in a test tube. Peristers are protected in round forms and within biolfim colonies. Here I discuss a mechanism which enhances survivability of the spirochetes in vitro, living systems. Well known research has shown that Lyme are not eradicated in mice, dogs or primates and that the spirochetes persist in humans after treatment.


In summary, not only is it possible for only IgM antibodies to be seen in chronic Lyme but it seems likely that this is the predominant scenario.


Researches like Fallon had an impossible task of finding subjects for clinical trials. The mythical patients with 5/10 CDC IgG antibodies comprised less than 5% of his overall patient population of patients known to suffer with chronic, tertiary neuro-Lyme involving the brain.


Dear reader, if this was all too much to follow the take home message is that most patients with chronic Lyme disease have only IgM bands.














case of Lyme this "normal" immune process appears to more often be the exception rather than the rule.

Lyme antibiotics revisited

There are a surprising number of drugs, many of which are not antibiotics, which have anti-lyme/anti-persister effects. An additional 113 agents are presented by Zhang in the latest article published in “antibiotics” September, 2015. Some of these drugs are in common use, amongst Lyme patients – but to treat something else. The list includes antibiotics, antivirals, antifungals, anthelminthics and antiparasitics. Other, unexpected agents are in the list include an arcane antidepressant. Of course daptomycin heads the list. Drugs already in common use include: artemisinin (very effective), Diflucan-fluconazole (very effective) and rifamycin related agents. The latter two from this list are referred to as active hits. Other less active hits include some quinolones (not in clinical use) and a limited list of cell wall agents, available, but also not generally used. Rifampin (rifamycin) is of greater interest to me. My grasp of this drug has evolved. ALS (Advanced Laboratory Services) adds rifampin to culture medium to cultivate Borrelia. This might lead one to conclude that rifampin does not kill Lyme. Studies show that Rifampin kills persister forms of Lyme, not spirochetes: makes sense. Lyme is rarely found in blood. The few free swimmers are referred to as planktonic. These are motile spirochete forms. Spirochete forms are not killed by Rifampin and therefore can be cultured in a medium containing rifampin.  The antipersister properties of rifampin are well known for the treatment of tuberculosis which requires the use of 4 antibiotics over a period of many months.

A new study published in “Nature” Lehar et al, discuses a novel approach for the treatment of Staph aureus. The study states that Staph bacteria hide inside cells, a protected milieu. (Mouse model). Staph aureus survive within phagocytic macrophages (the cells which “eat” and eliminate offending pathogens). The S. aureus were found to spread via a Trojan horse mechanism, a mechanism also employed by Lyme. The most potent anti-Staph aureus, MRSA antibiotics, vancomycin and daptomycin were unable to eradicate intracellular MRSA staph. In the mouse, intracellular infection allowed widespread invasion into many organs, including the brain. Not good.

These researchers took a fresh approach to killing S. aureus. The idea was to clone antibodies against S. aueus, find the best antibody and link it to an antibiotic creating a new molecule, an “antibody-antibiotic conjugate.

The antibiotic chosen for the project was neither vancomycin nor daptomycin. The drug was from the rifamycin class of antibiotics. Compared with vancomycin and daptomycin the minimal inhibitory concentration of the rifampin-like drug, intracellular and extracellular, was infinitely (slight exaggeration) better than the other two drugs. The second best drug studied was a forth agent, linezolid by the way. The rifamycin class of antibiotics were praised for: high potency, unaltered bactericidal activity in low phagosomal pH and an ability to withstand intracellular insults.

This new “AAC” compound was more effective than all other agents and able to clear the S. aureus in the mouse, including organisms hiding inside the intracellular niche. This new class of drug will not be available for human use, if it pans out, for a good 10 years or more.

I will not say exactly how I treat patients (which varies quite a bit), but...

The news about rifampin and related drugs is good. Perhaps with antibodies already present in our system we can hope for a similar result. The new compound is made of a rifampin-liked drug linked to a specific antibody.  

I have long thought that rifampin was essential for treating Bartonella. Maybe this is wrong. Maybe the extra Herx that occurs with the addition of Rifampin because is due to killing a variety of pathogens living within cells, perhaps including Lyme and Staph for all we know.

The paradigm of treating Lyme is expanding and becoming more complex. An understanding of the pharmacology of individual drugs, synergistic properties, tissue penetration and many other factors must be understood by an experienced clinician in the formulation of effective drug cocktails. Individual responses to drugs are quite variable. There is not a one size fits all approach that is consistently effective.

Lyme, gluten, mast cell activation, neuroinflammation: novel paradigm, novel approach with rapid therapeutic response

The vast majority of my patients eventually improve. Many struggle for months or years but eventually emerge from the darkness of chronic Lyme. Occasionally everything comes together and patients improve rapidly. This happened with the following patient.

A 38 year old female presented with a chronic, multisystem disorder of over 7 years. Symptoms included severe fatigue and post exertional fatigue and malaise. Sleep was never restorative. She developed orthostatic intolerance and was diagnosed with a POTS variant. Symptoms included: brain fog, memory loss, ringing in the ears, shortness of breath, air hunger, heaviness in her legs, diffuse aches and pains, headaches, loss of balance, episodes of confusion and mood changes. She presented with a near zero quality of life. Over the course of time she had a spinal tap for a severe headache. Weakness progressed and she was no longer able to open jars. She walked leaning to the right and had poor balance. She had severe episodes of confusion, for example, forgetting that her cousin had children. She experienced depression and irritability. She was diagnosed with asthma but inhalers did not help. She suffers with chronic sinus congestion. She is very sensitive to loud noises. She experiences night sweats, air hunger and weepiness. She has sensitivities to environmental factors and most medicines. Florinef, prescribed for POTS caused suicidal ideation. She had similar reactions with several antidepressants. Her overarching complaint  is cognitive dysfunction. At times she  has felt that she is developing Alzheimer’s disease. She has also suffered with chronic anxiety.

Lab results: Celiac panel Deamidated Gliadin Abs IgA 12 (nl 0-19), Lyme WB bands minimally reactive, non-diagnostic (2 laboratories), blood smear equivocal results.

Here was my thinking: Clinically she has adrenal fatigue: cortisol might help, effects on depression could be one way or the other. Her case suggests there is a mast cell issue, treatment might help. She looks neurotoxic, possibly due to infection, Lyme, Babesia etc. Patients in this boat frequently have paradoxical responses to serotonin antidepressants – avoid them.  She has gluten sensitivity. the anti-gliadin antibody is unusually high (below celiac disease range) and likely indicates a significant gluten issue.

I began to treat her: gluten free and low histamine diet. Low dose Cortef. Therapy to reduce neuroinflammation: decrease glutamate toxicity in the brain (caused by neurotoxin QUIN) and decrease glial cell activation, a major factor in brain inflammation. I chose the off label use of the Alzheimer’s drug Namenda which specifically addresses the glutamate issue. Then I chose doxycycline, an antibiotic known to decrease neuroinflammation acting as a potent glial cell inhibitor. I prescribed Pepcid, antihistamines and Xanax to reduce mast cell effects. I told her to combine Xanax with an antihistamine for Herxheimer effects. Xanax also has anti-anxiety and antidepressant properties. The cortisol was prescribed for adrenal dysfunction and POTS to some extent but also reduces mast cell hyper-reactivity. The doxy was prescribed at a low dose.

One month after I began treatment she returned feeling great. More than 50% better – after 8 years of misery.

I think she likely has Lyme disease. She has a history of exposure with high risk activities in endemic areas. Babesia seems very likely as well.

Treatment of ancillary issues, especially with an eye for brain inflammation and careful use of antibiotics was key and led to a great initial response. As always. We still have a long journey ahead.