Friday, February 9, 2018

POTS: nuts and bolts


Postural orthostatic hypotension syndrome is one of the most common medical issues encountered in my medical practice. I would like to review the basics to help cut through some of confusion that surrounds the syndrome.  I sometimes refer to POTS as a “disorder” rather than disease; I make this distinction because POTS is triggered by something and I want to find out what it is.  Patients are told that POTS is a chronic “disease” which may or may not get better over a period of years. Those who suffer know that POTS can be devastating and disabling.  POTS results from an imbalance of the nervous system.  The autonomic nervous system which I think of as “automatic nervous system” unexpectedly breaks down.  The autonomic nervous system regulates numerous functions we take for granted on any given day. When the system stops working properly the consequences can be horrible. A lot of POTS patients go from one doctor to the next never receiving the correct diagnosis. The chief complaint may not give the diagnosis away.  POTS is a mainstream disease but one of which doctors are ill informed. Most physicians fail to recognize the common symptoms of POTS.  Many mistakenly think it is a rare condition when it is in fact quite common. 
Patients are misdiagnosed because the symptoms sound like so many other things; the symptoms are considered “vague” or “no disease causes all of those symptoms”.  POTS patients may experience fatigue, exhaustion, inability to get out of bed, inability to tend to usual activities of daily living, brain fog, weakness, pain, trouble standing, trouble exercising, problems with sweating, bowel/bladder dysfunction, racing heart, palpitations, headaches and many others. Symptoms range from very mild to very severe.   Symptoms mimic those of other multisystem disorders, including Lyme, MCAS, fibromyalgia and CFS. Sometimes these syndromes coexist. POTS should be easy to diagnose: unlike other multisystem disorders, POTS has a clear calling card. If a patient tells a doctor:  when I stand up my heart rate goes crazy high and I feel dizzy, like I might pass out, and it only gets when I lie down, the doctor should have an Ah Ha moment. But not necessarily. At this late date, many primary care physicians, cardiologists and other specialist are unfamiliar with the syndrome. Doctors are more familiar with Potts – TB of the spine, something they will never see in clinical practice. 
Vital signs change when the patient changes position (orthostatic). Doctors may be focused on blood pressure, wrong metric. With POTS the blood pressure doesn’t change; it is the pulse or heart rate that changes. 
The diagnosis may be made in the office. The heart rate is measured supine, sitting and standing at intervals over several, up to 10 minutes. 
When a normal person goes from lying to standing the heart rate may go up 15 beats per minute or so but it rapidly returns to baseline and is within normal limits (60 – 100).
With POTS the heart rate climbs 30 points or more and stays there. The elevated heart rate, tachycardia may increase over time rather than normalizing. Other conditions that cause a rapid pulse, like atrial fibrillation need to be ruled out with an EGK.  The POTS patient may feel weak and have trouble standing beyond 2-10 minutes. If this occurs the patient must immediately sit down/lie down. For adults the positive POTS diagnosis cut off is defined as difference of 30 beats per minute or more or a sustained heart rate of greater than 120.  With kids there is more variability. Standards exist because – we need standards. A lot of POTS patients don’t meet the criteria.  A negative test does not exclude the diagnosis. Sometimes, where there is doubt, other tests, like a formal tilt table test may be ordered. Alternatively, the patient and/or family can track vital signs at home.  
So, what gives?
When we go from lying down to standing there is a rapid shift of fluids in our bodies. About 1/3 of circulating blood/fluids follows gravity and pools downward. This is a dramatic change in our physiology. Normally our bodies respond quickly: blood vessels, mostly the medium sized arterioles constrict and narrow - like pinching a garden hose and pressure is restored and blood flows to essential organs, especially the brain.  Without the blood, oxygen and glucose required by the brain we lose consciousness or experience syncope.  The appropriate physiological response described in controlled by the autonomic nervous system. 
The autonomic nerve fibers “fire”, cause the blood vessels to constrict – or to dilate, as appropriate. When the autonomic system fails to send the proper message the arterioles do not constrict and narrow, the blood vessels remain in the wide-open position; adequate perfusion (blood flow) to the brain and other organs does not occur.  The body tries to compensate by speeding the heart rate in an effort to increase blood flow to the target organs. The heart rate goes up but the organs are still without adequate blood flow (hypoperfused).  Given Einstein’s definition of insanity: doing the same thing over and over and expecting a different result, our bodies are insane. The pointless increase in heart rate occurs each time. 
The autonomic system is comprised of two parts. The sympathetic and the parasympathetic nervous systems. Dysfunction of the system is called dysautonomia with POTS the most obvious manifestation.  The nervous system is dived into 2 parts: the central nervous system (brain and spinal cord) and the peripheral nervous system (nerves that branch off from the spinal cord). The autonomic nervous system is part of the peripheral nervous system. The autonomic nervous system is partially controlled by the brain (central nervous system).   
Nerve transmission, communication of one nerve cell with another, involves chemicals (molecules) called neurotransmitters. For the sympathetic nervous system, the chemical is adrenalin (norepinephrine). The sympathetic nervous system is famously associated with the “fight or flight” response -- increased heart rate and blood pressure, pupillary dilatation, increased sweating, hyper-alertness and others.  The parasympathetic nervous system uses the neurotransmitter acetylcholine and is associated with a relaxed state – eating and digesting a meal, resting, bowel, bladder and sexual functions and others. Both systems must function for homeostasis, balance throughout the body to occur at any point in time. 
How do we treat POTS?
Patients may improve tremendously with treatment, but there is no specific treatment or cure.  Goals of therapy are:  correct abnormal physiology, treat symptoms and improve function and quality of life. (Treat underlying cause(s) if possible). 
The first step in therapy usually is to increase the volume of fluids in the body, specifically circulating volume of fluids. The principal is straightforward. More fluid equates with more pressure. The higher pressure drives more blood to brain and vital organs despite abnormal neuro-vascular dysfunction (autonomic dysfunction).
Patients are encouraged to increase fluid and sodium intake. Sports drinks and salt tablets may help. The drug fludrocortisone, Florinef may be prescribed.  The drug acts like the kidney hormone aldosterone causing our kidneys retain more salt and water. When available, IV normal saline solution dripped in overnight can be very useful.   

When fludrocortisone fails, another drugs that causes water retention may be helpful.  Desmopressin or DDAP.  It is an analogue of anti-diuretic hormone, secreted by the pituitary gland.  A diuretic causes urination and water loss.  Anti-diuretic hormone does the opposite: it causes the retention of water. The drug is used for other diseases and may be re-purposed for POTS. 
Lower body strengthening, with exercises like bicycling or rowing may help.  Increased muscle tone helps push fluid in the lower parts of the bodies upwards towards the heart. 
The arterioles responsible for vascular pressure can be directed stimulated to contract and narrow with the drug midodrine. Midodrine is perhaps the most commonly use pharmacotherapy for POTS.  Improved perfusion to the brain and other organs may occur with postural change despite dysautonomia (dysfunction of autonomic nervous system).   The drug can elevate blood pressure and needs monitoring. 
Beta blockers which lower heart rate are sometimes prescribed. These drugs can make things worse. Tachycardia is a compensatory response. I typically consider adding a beta blocker only when other pharmacotherapies are in place. 
Mestinon, pyridostigmine, prevents the degradation of the neurotransmitter acetylcholine and may help parasympathetic dysfunction. The drug may be more helpful in certain specific clinical scenarios. 
Clonidine, a blood pressure drug has central effects on the brains output of adrenalin and may be helpful in some cases. 
Antidepressant drugs, which variably effect the neurotransmitters serotonin, norepinephrine, dopamine may be beneficial.  
Stimulant drugs like Adderall with dopaminergic effects in the brain may help some patients. 
Many other agents may help in some cases. 
Who gets POTS?
POTS can occur with either sex and at any age, but more often than not, its victims are teenage girls and/or young women in their 20s. Older adults with chronic illness -- diabetes, Parkinson’s disease and others may get POTS-dysautonomia. The widely held theory is that most cases of POTS are triggered by a viral infection.  Most cases are said to be “idiopathic” – cause unknown, also translated: the patient is pathological and the doctor is an idiot. POTS can accompany other syndromes or constellation of syndromes, for example MCAS and EDS or hypermobile joint syndrome. 
In my practice, many POTS patients also suffer with Lyme disease and tickborne disease, the presumptive trigger for the illness. 
POTS is a multisystem disease with widely variable clinical manifestations. Misdiagnoses are common. Incorrect diagnoses may include: exercise intolerance syndrome, fibromyalgia, chronic fatigue syndrome, depression, psychosomatic disorders and others.  Diagnosis is generally not difficult. Or the diagnosis is impossible if the evaluating clinician has not heard of the disease.  Specialized tests including tilt table and QSART are rarely needed.  
Non-specific management of symptoms is important.  This includes: sleep, pain, brain fog, depression, lack of conditioning and others.
A good support network is key. 
The long-term prognosis is good.  Treating the underlying disease is essential.

Monday, February 5, 2018

MCAS, mast cell activtion syndrome, nuts and bolts


Mast cell activation syndrome – MCAS – a stand-alone theory of everything.  The disorder is not accepted by mainstream medicine.  Hematologist deal with a set of serious disorders which may involve tumors but that’s is not what we are going to discuss--not to say mast cell activation syndrome is not a serious disorder. It can be deadly serious.  MCAS is a novel way of looking at disease and is used to explain many diseases, symptoms and syndromes. 
What is a mast cell? Mast cells are important actors within the immune system. Stained, under the microscope, they are plump purple cells. They are like other cells found in the blood (eosinophils, basophils) But these cells are located in tissues, various organs, outside the blood stream and around blood vessels. Mast cells have a role in allergies and killing certain parasitic worms. Not the topic of the day. We are interested in inappropriate action of the cells.  
The granules inside the cells contain various substances which cause inflammation. These granules contain things like:  enzymes, histamine, leukotrienes and prostaglandins. 
Activation:  These caustic immune cells release many inflammatory substances causing severe swelling, immune responses and local tissue injury.  Instead of killing parasitic worms or attacking an allergen mast cells are attacking us and damaging our tissues. Mast cells are omnipresent and symptoms vary depending on which tissues are attacked.   For example, if mast cells activate in the intestinal tract symptoms may include bloating, diarrhea, GERD and other dysfunction. Mast cell activation in muscles and joints causes joint pain and swelling. Mast cells activating in the brain may cause brain fog, headaches and neuropsychiatric symptoms.  Diffuse mast cell activation can cause a “multisystem” presentation: fatigue, brain fog, joint pain, muscle pain, bowel and bladder dysfunction, neurological dysfunction, change in mood, confusion and many others. 
Patients may experience one mysterious problem after the next.  Symptoms may come and go over many years. Doctors scratch their heads or diagnose a psychosomatic disorder. Doctors will not think: MCAS.  MCAS is a new paradigm on the edge of medical practice and medical science. Doctors don’t know about it – except for the few. 
MCAS can explain a lot. 
Mast cells don’t typically act on their own. They are triggered by something. Triggers vary widely from one person to the next. 
Certain clinical scenarios make us think MCAS. Patients with hypermobility joint syndrome and POTS invariably also have MCAS. Lyme spirochetes may be a trigger as well as other infections. 
We look for clues: Recurring hives, unexplained itching, dermatographia and facial flushing. Patients may report sensitivity to scents and smells and to variation in temperature – hot or cold. A patient I saw today is sensitive to certain fabrics.  Chemicals may be a trigger. Foods and medicines are common triggers. It may be the inert ingredients in pills that triggers the response and some patients have all their meds compounded.  All of the above may be absent. 
Herxheimer reactions may have a MCAS component and may respond to appropriate therapy. 
Are there lab tests? Iffy. Labs tend to positive only in severe forms of the disease, not the syndromes we are discussing.  Occasionally serum tryptase or histamine may be elevated.  24-hour urine tests are sometimes abnormal. The diagnosis is usually clinical. 
MCAS is treatable -- frequently with remarkable results and commonly used meds are extremely safe. 
Diet may help.  Certain foods are known to be high in histamine or trigger histamine release. Reducing intake of certain foods can help.  Well-known examples include tomatoes, strawberries, avocado, nuts and deli meats. You may only have to cut down on certain foods, not eliminate them completely. Food reactions vary a lot amongst individuals. 
MCAS is not an allergic reaction. For example, an allergy to peanuts is something different, mediated by different pathways in the immune system. Still – there is some overlap. 
Meds. In most cases patients respond to simple, safe meds. But may have to take a lot of them.  The treatment has 2 parts:  Blocking the effects of inflammatory substances released from mast cells and stabilizing mast cells so they don’t activate in the first place.  There are 2 kinds of histamine receptors called H1 and H2.  H1 blockers are the familiar antihistamines. MCAS requires higher doses, and multiple antihistamines. The H2 blocker are thought of as ulcer/heartburn drugs, they block the production of stomach acid. The H2 receptors have other functions and blocking the receptors helps. Blocking leukotrienes (Singulair) is helpful.  Prostaglandin blockers, anti-inflammatories like aspirin may help. Stabilization is more problematic.  Cromolyn would be great but has poor bioavailabity but may still be effective. Ketotifen is mast cell stabilizer with antihistaminic properties.  It is available through compounding pharmacies. Effective mast cell stabilizers may include benzodiazepines and cannabinoids. More difficult cases may be treated with the asthma/hives injectable Xolair and an array of immunosuppressive drugs.

Friday, January 26, 2018

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.


Thursday, January 11, 2018

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. 

Friday, January 5, 2018

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.




Wednesday, December 27, 2017

All I got was a 41 band. All I got were IgM bands -- could it be chronic Lyme? The Western Blot revisited.

Many patients and others continue to inquire:

All I got was a 41 band - do I have Lyme?    Lyme test is IgM positive, could it be chronic Lyme?

Its complicated.

If the text is too hard to follow or boring, there are pictures below. 

It helps if you know a little about laboratory medicine.

The Western Blot and ELISA tests, the tests most often used, are indirect tests. Rather than looking for direct evidence of infection, e.g. finding specific DNA, These tests look for foot prints: Antibodies or specific immunoglobulins.  These tiny proteins are made by the immune system in response to recognized pathogenic (disease-causing) germs -- bacteria, fungi, protozoans and viruses primarily.
There are a lot of reasons why Lyme antibody tests are not that great:  People are genetically programmed to respond differently; Lyme strains vary, species vary; the commonly used test is based on a single Lyme strain and other species may not react to the test -- and some variations in immune response may be random.  Perhaps most important: the test is incorrectly calibrated, based on false assertions. 
Before we get to the Western Blot, let's first discuss the ELISA. Enzyme Linked Immunosorbent assay.  This is the test most commonly used, at least for screening. 
All diagnostic serological (from blood-serum) lab tests need controls, positive and negative.  
A positive control is a known "serum" full of Lyme antibodies, against which a patient's serum is compared. A negative control is a known serum, ostensibly with no Lyme antibodies. (The availability of true negative controls has been a debatable point).

In order to proceed, we need Lyme antigen -- proteins and polysaccharides, which stimulate antibody formation.  The raw material comes from a culture of a subspecies subset of Lyme bacteria. This is the stuff we make Lyme antibodies against if we are infected. 
Roughly, a bunch of Lyme bacteria are put in a "blender," or sonicated. 
ELISA.   Sticky Lyme antigen is adhered to the surface of small wells . Serum is added. Lyme antibodies present in the patient test serum should tightly bind to the Lyme antigens on the bottom of the well. There is some nonspecific binding by "promiscuous" antibodies that apparently will stick to anything. The test well are washed thoroughly to remove debris and nonspecific antibodies. After the first stage we have -- Lyme bacteria antigens "glued" to the bottom of a well (test tube equivalent) with Lyme antibodies tightly adhering to antigenic parts of the Lyme bacteria.  Antigenic parts are those that stimulate the immune system and thereby stimulate the production of antibodies. 
ELISA stands for Enzyme linked Immuno-sorbent assay. Antibodies are shaped like a Y.  There are 3 points of contact, with the potential to bind to a receptor  A second, known antibody which reacts to other antibodies -- this antibody grabs on to other antibodies, latches on to one of the remaining 3 legs of the Y shaped antigen bound antibody.  A protein called an enzyme is attached to a leg of the second antibody.  The enzyme turns color when a reagent is added to the tubes/wells. The intensity of color increases if more antibodies are bound to the antigen. Patient serum with a high concentration of Lyme antibodies induces an intense color change. If no Lyme antibodies are present no color change or only a slight color change occurs. A mild amount of color is thought to be normal and due to nonspecific, promiscuous antibodies bound to the Lyme antigens.  Basically:  More color, more antibodies; less color, fewer antibodies. The results are recorded as an index.

This test has the advantage of including all Lyme antibodies that might be present in the patient's serum. The test incorporates polysaccharide (sugar) based antigens and the Western Blot considers only protein antigens.

The test and the results it produces are controversial because of two differing beliefs about the inherent nature of the disease. One group thinks the test is inaccurate because it causes too many false positives.  The other group feels the test fails because of false negatives.

The test needs a cut off point -- how much color change is needed for a positive. The cut off for a positive test is based on a control.

The positive control is based on an ideal serum with a robust immune response, typically found in acute phase of the disease.  Excluded are: patients who have been sick for a long time, patients who have a weak immune response, patients with a different strain of Lyme and many others. 
To make matters worse, the test is entirely predicated on a single strain of Borrelia burgdorferi, the B31 strain. The test will like fail when a patient is infected with other strains and/or species of Lyme.

Doctors talk about whether or not a test is sensitive or it is specific.

A test is sensitive if it excludes false negatives. A test is specific when all the positive are "true positives." There is always a balance. When you increase sensitivity you decrease specificity. When you increase specificity you decrease sensitivity.  
The ELISA I state of the art technology and widely used. Why does Lyme testing require 2 steps, an ELISA followed by a Western Blot?  In the past the same procedure was needed for HIV. Now, with a new and improved ELISA, an HIV Western blot is no longer required. The complexity of testing underlies the overarching war about the disease in general.

The Western Blot is considered both a sensitive and specific test. It is superior to the ELISA. A mix of Lyme antigens is placed into a gel.  When an electric current is applied, proteins from the Lyme parts separate out based on the weight of individual proteins. Antigenic proteins are spread out in a linear fashion across the gel.  The separated proteins are transferred to a strip of nitrocellulose -- something like a strip of paper. The test proteins typically was molecular weights of 18 kilo Daltons to 93 kilo Daltons. 
The antigen/protein laden strips are incubated with serum. Antibodies present in the serum will bind to the individual proteins on the strips. A reagent is added and bars or bands appear across the strip.
Band position and name corresponds to the molecular weight of the particular Lyme antigen.
Some bands are very specific. The likelihood of non specific antibody binding to the teased out protein approximates is low.  The CDC formula is based on a total number of bands appearing from a set and does not consider the importance of particular bands. The CDC standard is derived from a 1994 convention at which time a standard for surveillance was established.

The Western Blot suffers with many of the shortcomings of the ELISA.  The accuracy of the test depends on the validity of the controls.

A picture is worth a thousand words. Let me a review a few images, typical of what I work with on a daily basis.




These results are from MDL.  A specialty laboratory in NJ.  This is an IgG strip. It incorporates a test for antibodies against 12 bands or 12 antigen proteins of the corresponding weight. Ten bands are based on the 1994 standard and 2 additional bands, 31 and 34 are tested separately. That is why these numbered bands are out of place on the strip.  IgM strips are prepared separately by using separate reagents.  The bottom strip is the positive control - high levels of specific antibody directed against the blot proteins. The top line is the patient result. No negative control is provided. 

CAVEAT;   INTERPRETATIONS DISCUSSED ARE THE OPINION OF THE AUTHOR AND MAY BE CONTROVERSIAL AND OPPOSED BY MOST AUTHORITIES. 

This test is CDC negative.
Patient antibodies react to nearly every band. This strip appears blatantly positive.  However, according to the manufacturer, the intensity of the response is too weak to call positive. A band is considered positive if the intensity is at least 60%  of the control. For example, the 93 band has an intensity of 45% of the control. Based on this standard, only the 41 band is counted positive. This interpretation is wrong, I think, because the lower limit of a positive results is incorrect -- based on incorrect assumptions regarding the control.  I call this test positive.   Any band 30% of the control or more -- and more so bands of 40% or more, likely represents Lyme antibody binding and not nonspecific throw away binding. 







This is a negative IgM strip.  Only the 41 band appears. The diagnosis of Lyme should not be based solely on the appearance of the 41 band which itself is considered less specific than several others. 






This is another example of a CDC negative which I consider positive.  The 4 reported bands are all specific. The 39 band -- just 4 percentage points shy of the lab internal cutoff, is perhaps the most specific band, and to the best of my knowledge cross reactivity does not exist. The test is positive by other non-CDC internal laboratory criteria. 












This is a typical LabCorp or Quest report.  As you see, bands are not represented numerically. Bands are reported present or absent.  The results are not determined by a computer which measures pixels, as in the case of MDL, but rather by a technician  eyeballing the strips.  These bands are highly specific, especially the 39 band. I consider this strip likely positive but I would repeat the test from a reference lab before passing judgement. 
























The Blot is highly positive although it is CDC negative.  The CDC requires 5 specific bands not present on this strip.  Several very specific bands are clearly present. 







This report is from IgeneX.  Results are presented is a different format.

IgM: is it chronic Lyme?

I don't care if the bands are IgM or IgG. Lyme IgM bands may persist for years after acute infection.  IgG bands may never appear. 

The 41 band as the sole finding does not lead credence to the diagnosis of Lyme.  It also does not exclude the diagnosis. 


Lyme antibodies do not fit into the traditional mold.  For example, IgM antibodies to the 31 and 34 bands may be present, even though these antigenic proteins do not appear until at least 6 months following initial infection.   The 31 band is associated with outer surface protein A. This protein is expressed with attachment to the tick gut and down-regulates - disappears after infection. It only shows up in the host many months after acute infection.  If you believe that Lyme IgM antibodies disappear within weeks after acute infection, as proposed by the CDC, this paradox is impossible to explain. The cop out that it must be a false positive doesn't fly.

There is a story of repeated by physicians which confuses patients as well as their doctors. This is how the immune system works: IgM and IgG responses are predictable. IgM antibodies appear early, immediately after infection. The better, protective IgG antibodies quickly emerge as  IgM antibodies decline. When the patient recovers from the illness, higher levels of IgG antibodies are present and no IgM is detectable. Therefore in late Lyme, only IgG antibodies are present.

For one thing, "late Lyme" and "chronic Lyme" may not be the same.

Forget this scenario.  Lyme is different.

How do I interpret results?  First, it is important to recognize limitations of these tests. The tests are not automated and require many steps performed by humans, therefore, the chance of error is high. Generally, the results from the 3 labs above are trustworthy. I do not follow any particular guideline approach. Standards which require 2 of the following or 5 etc. lock you in. I would rather interpret results case by case. In my opinion, reading a Western Blot is something like reading an X-ray. A lot of factors are considered --  on the other hand, sometimes Interpreting Blots is like reading tea leaves.  Lab tests are adjunctive and cannot be relied upon as the sole means of diagnosing this complex, enigmatic disorder called Lyme disease. 

Even more important: the CDC standard is for surveillance -- purposes of monitoring the advance of the infection. This should not be relied upon as a diagnostic standard.