Lyme: battery won't recharge

This 32-year-old mother of two sought my attention regarding the issue of Lyme disease.  She hadn’t thought much about Lyme disease until a friend mentioned it to her.  She relates that she felt somewhat poorly since she had mono in high school.  Her energy level had always been lower than that of her peers.  She slogged through college. Classes and studying sapped all the energy she could muster. Friends went to parties but she stayed in. Exhausted. Relishing a moment to sit and recharge her batteries. Her battery, not unlike that in my iphone, would run down more easily and become harder to recharge over time.  She had aches and pains but thought it was normal. After all, she was getting older at age 21.  She managed to complete her 4-year degree and go on to have a successful career – always a struggle. She saw a succession of doctors trying to find out why she was so – so tired all the time. Her brain became foggy and it became more difficult for her to focus on much of anything for very long. Her job was in peril.  Luckily, one of her doctors suggested she had ADD and prescribed Adderall. A godsend. She was more awake during the day and was able to focus enough to get by .  Still, she felt like she was lost in a fog – something she couldn’t explain to family or friends.  Her family doctor suggested she had either fibromyalgia, chronic fatigue syndrome, stress or just depression.  He prescribed Lyrica and Cymbalta. What a disaster. She felt much worse. Further on the path of life she met her future husband, married and retired from the work force. She sought pregnancy and motherhood.  She had several miscarriages and then a pregnancy “stuck” and she carried her first born to term. Hey. She felt pretty good during the last 2 trimesters but crashed and burned after the birth of her first child.  Now she had real pain. Everything really hurt.  The pain moved from one joint to the next. She experienced joint swelling, especially in her knees and fingers.  She was referred to a rheumatologist who diagnosed “seronegative” rheumatoid arthritis and prescribed methotrexate and Enbrel. The joint pain was a little better but she otherwise felt awful.  She was more tired than ever.  She became more and more forgetful.  At 26 she felt like she had Alzheimer’s disease.  She couldn’t remember names or words. She forgot her best friend’s name. How embarrassing.  She couldn’t remember where she placed her keys or where she parked her car. She would end up someplace and have no clue how she got there. Luckily, she was able to restart the Adderall and it helped a little.  She stopped the drugs prescribed by the rheumatologist – against the advice of her primary care doctor, family and friends and started feeling a little better – in some ways. But new and different symptoms appeared. She had numbness and tingling. And weakness. Her legs weighed a ton and it was hard to walk. A neurologist said there was nothing wrong. Everyone told her they were tired of hearing her complain – so she thought (family disagreed). So, she sucked it up and suffered silently.  She got pregnant for the second time (surprised, since she rarely had sex) immaculate conception she joked – no libido and no energy -- and again, during the pregnancy felt a lot better. The forgetfulness wasn’t better but no one seemed to notice. She did. And it frightened her. After the birth of her second child all hell broke loose.  She was so tired she could barely get out of bed.  She had all sorts of pain. Joint pain, muscle pain, burning pain, electrical jolts, headaches and more.  She experienced drenching night sweats, head to toe and had to change her PJs every night.  She had become socially isolated.  Lyme was mentioned by about the only friend she had left. After doing some homework she came to see me. 

She grew up in a suburb or Maryland and her parent’s home back up to a state park. There were always deer in the yard. She loved to traipse through the woods. She remembers she once had boundless energy – until she got mono at age 15.  She remembers a few tick bites but they were removed without a second thought. She never had a rash of any kind after the bites. 

Her exam showed a chronically ill appearing young woman and signs of neuropathy. 

Labs:  Lyme Western Blot negative – but a Blot by MDL showed sub-positive reactions at multiple IgM bands, including 34 and 39. It was negative by only a few percentage points.  There was a positive anaplasmosis IgG antibody. A Babesia screen showed a positive WA1 – B. duncani antibody with a titer of 1:512 and a Giemsa stained peripheral blood slide showed evidence of atypical, small appearing inclusions in many red blood cells. 

This was 9 months ago.

She is much better now.

Discussion:  Most Lyme infections are asymptomatic.  This is also true for Babesia.  The clinical scenario of Lyme symptoms appearing after mononucleosis is something I have seen many times.  She didn’t have Lyme misdiagnosed as mono. She really had mono but the mono infection (EBV) unleashed the silent Lyme.  She has had symptomatic Lyme for more than half of her life.  Lyme frequently progresses in fits and starts showing different faces along the way – as described here. Remission of symptoms during pregnancy frequently occurs. Pregnancy by design is an immune suppressed state for protection of the fetus.  This misdiagnosis of rheumatoid arthritis is all too common. The immunosuppressive drugs may have temporarily helped some symptoms while fueling the pathogens.  It disappoints me how often neurologists dismiss findings of neuropathy as in this case.  ADD? Not really. ADD is genetic and lifelong. It would have been noticed at age 6, not adulthood.  Lyme frequently attacks neural pathways to the frontal cortex, the executive area of the brain, mimicking ADD.  Stimulants like Adderall can help mitigate symptoms – without causing harm. Fibromyalgia is another common misdiagnosis.  The drugs, (Lyrica etc.) universally make patients worse. The symptoms described above are fairly typical. There is a concern regarding the kids – who are doing well, because congenital Lyme is real.  Babesia is a big problem.  It didn’t appear clinically until after the second pregnancy.  This is not unusual.  Signs and symptoms appear when they want to. B. duncani is quite common, unlike B. microti which is quite rare. (discussed elsewhere). Anaplasmosis frequently appears as an asymptomatic testament to a bite from an infected deer tick or lone star tick. Therapy for this bug is covered with one of my first line go to drugs, doxycycline, barring no contraindications.  Doxy covers the watershed of pathogens ranging from Rickettsia to rabbit fever (tularemia). Admittedly, doxy is not the first line therapy for tularemia, which I never see, but provides some coverage.  Doxy either weakly or strongly hits most, if not all of the common coinfections. 

Treatment:  No two patients are exactly alike. A lot is determined by the intensity of Herxheimer reactions. Fortunately, her reactions were intense but relatively short lived and tolerable.  Babesia seems harder to treat these days and perhaps more resistant. We were able to heel the symptoms with a combination of atovaquone, artemisinin-based therapy and a couple of others (discussed elsewhere). Lyme, I believe, is best managed with a cocktail of several drugs. If the response to oral antibiotics is inadequate intravenous antibiotics may be called for. Here, there were clear reasons for IV therapy -- brain involvement, the severity of the disease and its long-standing nature. The mainstay of IV therapy is still Rocephin until something better comes along.  Daptomycin, also discussed elsewhere, is not a realistic option so others synergistic agents are used along with a cephalosporin. Zithromax for example, can be given IV and dovetails for the treatment of Babesia. After some mixing and matching of multiple antibiotics and antimalarials my patient is feeling much better. Not cured, but up and about with a smile and a reasonable quality of life. She no longer feels guilty about dumping the kids in day care and onto their overworked father. Lyme cases are not all this easy and not all this hard. IV therapy requires multiple agents and must be continued for an extended period of time. Patients are transitioned to oral therapy when IV antibiotics are withdrawn (not yet for this patient).  Clinical decisions are based on clinical parameters which are mostly subjective. How do you feel?  There are no other good clinical metrics. 

The statements are based on my opinions and clinical experience.  This “case” is not based on one patient, (although a reader or two may be sure it is about her) but rather an amalgam of several patients and accurate as such.

Disclaimers and caveats:  Colleagues on the IDSA side of the fence feel that neuro-Lyme cannot be established with a spinal tap. I disagree. Technical stuff. An examination of CSF (cerebral spinal fluid) is relatively insensitive. The most common positive findings are nonspecific – elevated protein and slight elevation of white blood cells.  Tests which may be positive, including testing for Western Blot antibodies are nonstandard.  The gold standard PCR is an elusive standard.  This is a very insensitive parameter. All PCRs are not the same. Bacteria, prokaryotic organisms, lack a nucleus. Most of the reading DNA is a straight nuclear-like fragment. Standard testing may get negative results because the primer regions are not as conserved as thought.  IgeneX gets more positives because a second set of primers aligns with a plasmid-based fragment of DNA. 

Anyway – Lyme is a tissue bug and not always found in body fluids.  Other tests, including an MRI and/or a nuclear medicine brain scan may show abnormalities. I think the diagnosis of neuro-Lyme is largely a clinical one. That’s my opinion (shared by may others). 

IDSA colleagues do not agree with the long-term use of antibiotics and believe this belief is shored up by scientific evidence.  A perusal of my last several blog posts provides arguments to the contrary. 

One must call into question the use of arcane and intellectual arguments for the instruction of clinical decisions.  Clinical decisions are just that: clinical.

I am not making recommendations for the treatment of any one particular patient. I am loosely describing principals of therapy which may be considered, based on an ILADS vs IDSA perspective of the disease. One must always be aware of the risks of antibiotic therapy which include C. diff colitis, which can be serious and rarely fatal.  Antibiotics are not to be used without a great deal of thought. Risks and benefits must be balanced.  Antibiotics should only be prescribed by a knowledgeable physician, familiar with the pharmacology of the agents and side effects.  IV therapy by indwelling catheters, e.g. PICC, has risk, including blot clots and rarely sepsis. Professional nursing agencies and staff must be engaged.  Probiotics are important and must always be used. 

There term ILADS vs IDSA is used to provide general context.  The disagreement is about the role of chronic infection and whether or not long term, intensive therapy is appropriate.  One needs not be a member of or subscriber to either of the organizations on this basis.

My iPhone 7 actually works just fine. (Boy, I really am getting paranoid).

Available by appointment, new patients welcomed.

How doctors think: Lumping vs splitting

Lumping and splitting. On the one hand one, overarching diagnosis explains the whole case and on the other hand the case if finely dissected to include many components. Doctors can err in either direction. In medical school and later in residency -- many eons ago, I learned mostly the splitting approach.  For example, a patient recently presented to my office for a second opinion.   This 36-year-old female complained of an illness which started 2 years ago. First, she noticed fatigue and low-grade fevers. She developed drenching night sweats. Then she experienced diffuse, migratory joint pain and some swelling in both hands. She experienced severe pain on the bottom of her feet making it difficult to get out of bed in the morning and bear weight. She began to experience crushing fatigue-- even showering was a chore and trouble sleeping. She began to experience frequent, pounding headaches which could last for a day or 2 every other week. She experienced brain fog, memory loss, occasional confusion and trouble thinking clearly at times.  She experienced some eye pain and redness along with severe light sensitivity.  She experienced numbness and tingling and a loss of balance. She experienced depression, anxiety and bouts of rage. She had complained to her primary care doctor over several visits. He seemed to blow her off.  The she saw a nurse practitioner who ordered a Lyme test, a Western Blot sent to LabCorp.  The test was read as positive, IgM bands 23 and 41 present.  She was referred to an infectious disease specialist who took a history and looked at the labs. He proceeded to draw confusing graphs-- scribbled on exam table paper, and explained to her why she did not and could not have Lyme and the test was a false positive.  This patient lives in a Lyme endemic area and spends a lot of time outdoors. Many of her neighbors have suffered with the illness.  She has no recollection of a tick bite or a rash. She did some research and thought the ID doctor might be wrong. 

The splitting approach parses out symptoms/problems   A problem list could look like this:  Fatigue. Change in mental status. Eye pain.  Joint pain.  Headaches.  Positive Lyme IgM.  And so on. 

Ddx– differential diagnoses are then constructed for each problem.  For example – this is the non-Lyme doctor’s thinking. 

Fatigue -- Rule out:  sleep disorder, sleep apnea, infection, autoimmune disease, chronic fatigue syndrome, fibromyalgia and others. 

Mental status change or altered mental status:  R/O (rule out) meningitis, encephalitis, brain tumor, intracranial bleed – like subdural hematoma, metabolic/toxin issue – like liver failure and others. 

Joint pain:  R/O rheumatoid arthritis, other collagen vascular illness, crystal arthropathy—like gout, infection, Lyme disease and others. 

Headaches: R/O migraine, migraine variant, tension headache, brain tumor, sinusitis, TMJ etc. 

Peripheral neuropathy:  R/O diabetes/pre-diabetes, thyroid disease, b12 deficiency, multiple myeloma and other cancer – Lyme somewhere down the list.

Positive Lyme test: False positive according to specialist. R/O a true positive. 

Others problems may be deconstructed in a similar fashion.  

The lumping approaches seeks an overarching hypothesis that connects all the dots. An LLMD might diagnose Lyme with a high level of certainty.  A mainstream doctor might think fibromyalgia.

Lumping is a good start but this shortcut may lead to misdiagnosis. For example, complaints include headache (new onset severe headache) and altered mental status. We must consider the possibility of glioblastoma/brain tumor and other serious intracranial pathology. The MRI cannot be skipped.  A non-contrast study is without risk. In addition, the MRI may reveal findings characteristic of Lyme disease. 

I think it is very likely this patient has Lyme and coinfections (Babesia and Bartonella).  Some splitting is necessary. Lyme therapy can be started. At the same time various key studies are ordered. For example:  Sleep study PSM, to exclude sleep apnea and other sleep disorders; blood glucose (maybe A1c), B12 and folate, thyroid screen, celiac screen, immunofixation RE multiple myeloma and MUGUS, selected other tests to excludes other causes of neuropathy. An EMG/NCV might be ordered to exclude CIDP. (Not a definitive test).  Autoimmune disorder may be considered. Testing for rheumatoid arthritis, lupus and select others may offer alternative diagnosis explaining joint pain, eye symptoms and others.  Too much splitting can be problematic and leave the primary problem(s) unattended to.  I saw a patient today who was informed by a previous doctor that Lyme couldn’t be treated with sleep apnea unresolved. Not so. Other patients may have inappropriate delays of therapy because of genetic issues, for example MHTFR epitopes. 60% of the general population has mutations and variants of the gene. 

Splitting leads to a wide rage of considerations interfacing with internal medicine and multiple subspecialties.  Clumping focuses on patterns and connectivity.  The logic is:  It is much more likely that a previously healthy young woman has one diagnosis rather than many – logic dictates the overarching diagnosis.  (Occam’s Razor). A good rule, but not entirely dependable.  Dr. Afrin wrote the book “Never Bet Against Occam.” Using the same principal, his overarching diagnosis would be mast cell activation disorder. The two diagnoses may co-exist in this patient. 

A disease oriented view of medicine – something presented at typical medical conferences, lends itself to a top down approach – lumping.  This approach may lead to rigid, dogmatic views such as those held by the IDSA.  A "Grand Rounds" model, found at some institutions, shows a bottom up approach.  However, where institutions (virtually everywhere) have banned Lyme as a consideration, the presentations, thought to be thorough and complete, are sorely lacking. 

Evidenced Based Medicine, another look.

I want to re-visit the concept of Evidence based medicine. Its got its own acronym, EBM and is the basis for scientific, Western Medicine. Everyone agrees it’s the best system. Well … not everyone.  There is also something called science based medicine.  As I recently read, EBM is a subset of science based medicine. EBM is a paradigm in and of itself.  Paradigms are inherently flawed constructs and ultimately fold or mold as science marches on. A work product of EBM is the manufacture of guidelines. 

The Institute of Medicine has proposed metrics for assessing guidelines. Some of these include the following:

1)     All potential biases and financial conflicts of interest must be listed.

2)     Different medical specialties should contribute to the guidelines so that a “blind-spot” of a particular sub-specialty go unaddressed.

3)     There should be a period of public comment before guidelines are advanced.

4)     Political biases should be taken into account

5)     Patient preferences should be considered

6)     Input from other ancillary medical fields and alternative fields be considered

7)     There needs to be in place a mechanism for ongoing correction - adjustment as information changes.

8)     It should be recognized that the “evidence” in support of many guidelines is weak.

9)     Guidelines are to help doctors do a better job and not to be the basis of insurance company denials and/or Medical Board investigations. Guidelines are voluntary, not the law.

10)  Guidelines should not be used for “cook book” medicine. Patients are all different. Different genetics, comorbidities etc. 

11)  The expanding role of personal medicine must be recognized.

Evidence is graded. Some of this evidence is very weak and/or subjective but it still valued in the EBM paradigm.

The IOM points out that in 2017, according to the IDSA, only 14% of its guidelines for 400 diseases is based on strong evidence. 

My source is UpToDate, the most widely used web based text/resource used by physicians around the globe. 

There are very thoughtful academics who have a clear appreciation of the pitfalls of EBM and guidelines. 

Evidence based medicine holds up the blinded randomized control study as a gold standard. The studies are frequently subjected to statistic machinations, especially the metanalysis. Medical studies may be flawed, fatally so at times and in many ways. Some problems include: investigator bias, patient selection bias, study cohort poorly chosen, poor choices of study treatment/intervention, poor endpoints chosen, poor understanding of the disease, over generalization of results, improper use of statistics, a blatant disregard for other points of view and a supercilious view of other investigators. For example, the last, highly touted placebo-controlled NIH-sponsored study was published in 2007 (Fallon).  IDSA “experts” disregarded the views of the lead author, positing their own biased views.  Other EBM sources are reviews of literature, expert opinion, case studies and uncontrolled studies. Somehow, guidelines, not part and parcel of the EBM level of evidence have become accepted as “evidence.” Evidence is a collection of facts, reports and opinions. This is not the same as proof.  What is given no role in the hierarchy is SCIENCE. Plausibility. Basic science reveals details on a molecular or test tube basis.  This sort of evidence can be very instructive.  For example, to date, multiple studies have demonstrated that Lyme has never been eradicated in any of the 3 animal models and that Lyme is nearly impossible to eradicate in a test tube.  Nevertheless, based on “evidence,” experts insist Lyme is easily eradicated with 3 weeks of doxycycline in virtually all humans. The experts are subject to Paradigm Bias -- leading to certain false and inevitable conclusions.  When higher level Science is considered in the calculation, the conclusions are clearly absurd. 

When weak evidence, including poorly done studies and expert opinion becomes the “truth” then the EBM model may be twisted, leading to pseudoscience – or anti-science.  

Chronic Lyme disease advocates have been repeatedly called Anti-science.

A wise man once told me:  watch what they accuse you of – that’s what they are up to.    

I have railed against EBM in part because it has been weaponized against me.  Evidence based medicine is a tool. It is a work in progress.  Science leads us to truths – but only partial truths - because there is always more to learn.  Evidence based medicine surely fails when it does not distinguish between fact and theory, hypothesis and truth.  Scientists pursue knowledge using time-honored methods. The methods are always imperfect and may get incorrect results. Science searches for fundamental truths about the world we live in. Science is motivated by curiosity. A desire to know. Science asks questions and seeks answers. With every answer many more questions inevitably arise. Only an arrogant fool thinks he has all the answers.  

A word about empiricism. There is much for Western Doctors to learn from ancient traditions of healing from places like China, India, the Americas and remote tropical jungles. I don’t know how acupuncture works, but it works on dogs and as far as I can tell, dogs aren’t subject to placebo effects. Science doesn’t insist the therapies are ineffective. Rational scientist can apply inductive reasoning and deductive reasoning and have open minds. It is the job of science to figure out why the therapies work. It is impossible to judge plausibility when the mechanism is unknown. Physicians and scientists should have a healthy dose of skepticism but also an open mind.  Closed minds are impossible to pry open.  As Einstein tells us. Imagination is much more important than knowledge.  Knowledge is limited and imagination is not. 

I like EMB (with science based medicine) – when it is understood within context and properly applied; when science, plausibility and common sense are valued; when bloated egos are removed from the equation; when its flaws and limitations are taken into account; when guidelines are properly applied and most of all, when its methods are applied with intelligence and thoughtfulness.

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