Search This Blog

Wednesday, November 22, 2017

Introducing Lyme counselor/therapist, common neuropsychological manifestations of Lyme

Introducing, Brittany Goff, MSW, LYME COUNSELING in my office, appointments available, Call: 240-702-0138.  Brittany is a former Lyme patient, fully in remission. We did Monster’s Inside Me several years ago together. She knows what its like to have Lyme and coinfections. 
We are working together on patients with Lyme brain syndromes.  Patients may have a variety of manifestations. These include:  inflammatory encephalopathy, autoimmune syndromes, neurotransmitter imbalances, specific neurological syndromes (stroke-like, MS-like) and of course neuropsychiatric manifestations.
Chronic disseminated Lyme: a neuropsychiatric illness,
Things we commonly encounter AND TREAT: 
Anxiety, Panic, ADD-like symptoms, mood swings, depression, OCD. Others.
Can be caused by any and all tickborne syndromes,
Sudden or acute onset of OCD symptoms, anxiety or TICS, following infection, classically with Strep, but also with Lyme, Bartonella and others,
You may have PANDAS or PANS, primarily in children, but also in adults,
Confusion, disorientation, brain fog, can’t find words, feels like Alzheimer’s,
Caused by Lyme encephalopathy, general Lyme associated brain dysfunction,
Severe anxiety,
May be due to imbalance of neurotransmitter, GABA,
Newly acquired ADD, attention deficit syndrome,
May be due to imbalance of neurotransmitter dopamine, frontal lobe dysfunction, executive dysfunction,
Head pressure, symptoms too weird to put into words, depersonalization, sense of unreality,
May go along with primary autoimmune encephalitis,
Depression, sudden unexplained bouts of crying,
Frequently seen with cerebral babesiosis,
Severe irritability, anxiety, anger, rage, “Lyme rage”
Frequently caused by cerebral bartonellosis (Bartonella infection),
Behavioral and psychological symptoms associated with stroke-like or MS-like, physical symptoms,
Commonly seen with all the above,
Social isolation and alienation, loss of family and friends, no energy to go out with friends or family, unable to plan ahead,
Lyme disease and all its trappings,
Sometimes commonly used drugs, like antidepressants, make things worse because Lyme brains are wired differently. We may have some insights. 

Thursday, November 16, 2017

Lyme treatment notes, November 2017

Treating Lyme disease. Treating Lyme is empirical.  There are published studies showing the efficacy of amoxicillin, doxycycline, Ceftin and a few others. There are no published studies which compare the efficacy of various antibiotic combinations that have been used in clinical practice. 
Test tube data confirms the notion, that in-vitro, drug combinations are needed to effectively treat the disease. Zhang has showed in various studies, that specific 3 drug combinations are the most effective – in a test tube setting.  
There are clinical scenarios which offer support for the notion that Lyme patients may do best with cocktail treatments, for example, tuberculosis is routinely with a cocktail of 4 drugs.  TB and Lyme share common features. Both are diseases associated with pleomorphic, polymorphic, persister forms of the organism. 
Zhang compared the efficacy of various antibiotics against cultures of Lyme spirochetes and more recently specifically to Lyme round body variants. Lyme round body forms were “induced” when Lyme cultures were exposed to amoxicillin. Interestingly, Zhang was able to culture the round forms and achieve pure cultures of the round form of Lyme. Although metabolically sluggish, compared to spirochete forms, the variants replicated in-vitro, without converting to spirochete form. The results of the two studies were somewhat different. In the first study, Lyme cultures were treated with antibiotics. Persister forms were induced which included small numbers of round body forms and biofilm like colonies.  In the second study the efficacy of antibiotics against pure round body forms was evaluated.
Changing one variable – a significant one – changed the efficacy of some of the same drugs. Test tube studies do not directly translate into studies in animals (otherwise we could skip this laborious step). There are many known and unknown variables in play when the same drugs are used in a mouse or a human instead of in a test tube. What happens in a mouse may be different from what happens in a dog, primate or human.  In vitro provides clues for in vitro research and cannot be directly translated into what might work best for humans. 
A scientist who performs such studies and reports results, Cannot, should not and will not make recommendations about how to treat patients based on in-vitro, test tube findings.  A PhD scientist cannot make any recommendations regarding patient therapy. Even if the scientist also has an MD, as in the case of Dr. Zhang.  Patients frequently tell me: this is what Dr. S or Dr. Z recommends, etc. Not correct. 
Practicing doctors can file the information in the back of their brains and consider it, tangentially, when they make relevant treatment decisions.  

Lyme treatment notes, November 2017,
Doxycycline remains a key part of most protocols.  As mono-therapy it has limitations. It cannot kill persister form and round body forms. Something is generally added.  Empirically it has been found that 3 drug combinations work best, also supported by in vitro evidence.  When doxycycline is poorly tolerated because of GI intolerance, a compounded liposomal form obviates the problem. Minocycline is an alternative, which I have found is less effective.  
Liposomal forms of a variety of antibiotics are now available and in use. 
Rifampin has been used successfully when combined with doxycycline. Rifampin was previously shown to confer an antipersister properties to doxycycline (in vitro). Rifampin is very active against Bartonella. Severe Bartonella Herxheimer reactions may occur, possibly an unwanted effect. A positive benefit of rifampin is that it may dovetail with treatment targeting Bartonella species. Sometimes, when Rifampin is poorly tolerated, its weaker cousin, Mycobutin can be tried, less effective in my experience. 
Clinically, Tindamax has performed well when combined with doxycycline. An in-vitro study by Dr. Sapi showed Tindamax is highly active against round forms and biofilm forms of Lyme.  This was not supported by Zhang’s first studies. However, Tindamax demonstrated activity against round forms in the more recent study by Zhang.  Other, similar, antiparasitic drugs used have included Flagyl and Alinia.  Albendazole works differently, is very expensive, and primarily used for worms or adjunctive to Babesia therapy. Tindamax has great bioavailability and concentrates well in all tissues, very effective. 
Artemisinin, commonly used as an adjunct in the treatment of babesiosis, found to have great activity against round body forms of Lyme. An earlier study showed it had mild anti-Lyme effects. Artemisinin is used worldwide for Malaria and has other purported medical benefits.  This drug, available over the counter is prescribed in a variety of ways. Combination of therapies of doxycycline and artemisinin also dovetail with anti-Babesia therapy, if indicated.  Artemisinin not to be confused with artemisia. One derived from the other. 
Cefuroxime, Ceftin may also be synergistic with doxycycline. Other cephalosporins may be more effective in a test tube, but this is the clinically available agent. For example, a combination of doxycycline, Ceftin and artemisinin may be helpful, with or without the addition of Tindamax or Rifampin. 

Cipro is active against round forms of Lyme. Cipro performed better than other drugs in the class. There has been a lot of concern about quinolone associated tendon rupture. This is a real concern.  Some drugs of the class are preferred. Cipro is somewhat safer than its primary competitor, Levaquin.  Cipro is also active against Bartonella. The drug is available in a lower dose which can be titrated. Not a go-to at this time.

Bactrim.  Sulfa drugs are alluded to (Zhang), like sulfacetamide, only available in eye drops. Bactrim is what we have (see Dapsone). It is a multipurpose drug.  It may be active against Lyme persisters and round forms (2 Zhang studies). It is active against Bartonella and it has some anti-Babesia activity when combined with drugs like Mepron. It is a hit or miss drug in my experience when it comes specifically to Lyme. 
Biaxin   A macrolide antibiotics. Has moderate anti-Lyme effects, and in my experience, it is quite synergistic when combined with other antibiotics, including doxycycline and amoxicillin or Ceftin. Despite theory, it is active in the brain and therefore must adequately cross the blood brain barrier. Zithromax, the other option in this family is used primarily for Babesiosis. Biaxin and Zithromax cross over with Bartonella therapies. 
Penicillin:  Amoxicillin can be an effective piece of a variety of regimens. Intramuscular Bicillin, long acting penicillin is effective and must be dosed at least weekly. It is painful and expensive.  It should not be used as monotherapy. 
Dapsone.  There is a lot of buzz about this as an antipersister drug. Didn’t show up in Zhang’s screening in-vitro.  The drug has several uses which include leprosy. It is used for a variety of inflammatory skin conditions, including dermatitis herpetiformis, the rash seen in celiac disease, hidradenitis and acne (topically). It is a sulfa drug. Based on its mechanism of action it should be effective against round forms, perhaps better than Bactrim – to be determined. It may be somewhat more toxic however. 
VSL#3 DS.  The microbiome, which we wreak havoc upon, is a key part of our immune system.  The double strength packet is a pharmaceutical dose, over 900 billion units of bacteria, lactobacillus and Bifidobacterium species primarily. 
IV antibiotics are frequently called for.  Rocephin is the mainstay.   It may have antipersister effects. It is frequently used synergistically with other antibiotics.  IV Flagyl replaces oral Tindamax.  IV Zithromax has been effective when used together with Rocephin and Flagyl.  IV doxycycline can be very effective at times. Vancomycin is a big gun but was shown to be active against persisters.  Nothing beats daptomycin but it costs $400.00 per dose.  Many other IV antibiotics have been used.
Others: The Urinary system drug fosfomycin is a broad-spectrum drug and is reported be highly active against round body forms of Lyme. It is available in both oral and IV forms. May be explored in the future. 
This is by no means an exhaustive list of drugs used in the treatment of Lyme disease.

We have a decent armamentarium.
Many of my colleagues (Lyme doctors, aka LLMDs) have different strategies.  Some doctors are tentative and use creative schedules, like drug A Monday, Wednesday and Friday, drug B Tuesday and Thursday and drug C weekends only.  Sometimes very low doses are used, perhaps in an effort to avoid Herxheimer reactions.  Some physicians use high doses of antibiotics, welcoming Herxheimer responses. Some only recommend pulse schedules. For example, meds taken 2 weeks on, then one week off.  There are an infinite number of possible pulse schedules.  
I typically use continuous therapy. I find pulsing to be a useful strategy when weaning patients from antibiotics down the road.  My philosophy about Herxheimer reactions is somewhere in the middle.  Mild to moderate reactions are acceptable. Severe reactions are potentially harmful - to be avoided.
There is no right way to prescribe antibiotics for chronic Lyme disease based on the current state of the art. (There may be wrong ways).  No one has the magic formula. What works for one may not work for another. Every patient is unique. I work with each patient searching for the solution that works best for him/her. 
Some physicians prefer standardization and same-ism for purposes of learning and research. Essentially each patient gets approximately the same therapy.  Again, there is no one right way.  It is a matter of personal preference.  Patients should know the physician’s philosophy.
These notes refer to Lyme only. It therefore does not describe typical complete therapy for a typical patient. 
Treatment frequently entails therapy for Lyme and coinfections at the same time making things more complicated. 
The listed drugs are those commonly used in clinical practice. Comments regarding test-tube research may be interesting, but are in way directly determinative of therapeutic choices. 
There is no new magic bullet, but we learn something new every day.


The reader may notice that 2 recent posts are contradictory.  September vs November, 2017.  Comments in September are based on information published by a group in California, at Stanford. The latter comments are based on work from Baltimore, MD, Johns Hopkins.
Both groups screened drug libraries looking for "hits" highly active against Lyme. They got dramatically different results. What's going on!  The California group based their research on 2 strains of Borrelia burgdorferi frequently found in the West Coast and the Hopkins group used the standard B31 strain commonly found --  where? This may account for some of the differences. 

Tuesday, November 14, 2017

Diagnosis of chronic Lyme disease

Lyme. How do you diagnose it?  Here I am talking about the chronic form of the disease, not the acute form. You made have heard, Lyme is a clinical diagnosis?  What does that mean? Roughly, it translates: Your doctor may diagnose Lyme despite negative objective data, such as laboratory tests. How do we get there?  For one thing, your doctor needs to have a high index of suspicion, something  qualitative, although based on something quantitative.  I going to make a controversial statement. Lyme can only be accurately diagnosed by a physician who is appropriately qualified. A doctor needs to know: how common the disease, geographically, around his/her medical practice, where the patient lives and the patient's travel history. The physician knows to assess the patient's risk with regard to lifestyle.  The physician processes a good understanding of the wide range of symptoms and syndromes associated with Lyme and related infections, which may include very strange symptoms – or common symptoms. The term index of suspicion refers to a prioritization of possibilities. Doctors who are qualified to make the diagnosis are doctors who are properly informed;  it has nothing to do specialty, subspecialty, diplomas on the wall or letters at the end of a name. For example, infectious disease experts and rheumatologists do not automatically qualify as doctors who can at this time, accurately diagnose Lyme disease.  When a doctor evaluates any patient, consciously or unconsciously, he/she constructs a list of possible diagnoses, referred to as differential diagnoses or diagnosis. Lets briefly discuss an example. A patient complains of sudden knee pain. Here is how 2 doctors might consider possible causes, in order of likelihood.  

Doctor A (low index of suspicion for Lyme):  Trauma. Other structural disruption of joint. Aches and pains of life. General inflammation, bursitis. Osteoarthritis. Autoimmune - RA, lupus. Reactive arthritis, Reiter's syndrome. Crystal arthritis, gout, pseudogout. Infectious arthritis, GC, Chlamydia, Staph, other. Lyme disease, other inflammatory diseases like Crohn's disease and others. 

Doctor B (high suspicion): Trauma, Lyme disease and then all the others (different order). 

Caveat: Dr. B has no business diagnosing Lyme or anything else, if he/she is not intimately familiar with the above causes of joint pain. You can't rule out something else if you're not aware that that something is exists. The entities listed about are covered in depth in medical school and CME courses, and many are seen in clinical practice.  The requirement that the doctor be informed about non Lyme issues, better than average, is something that cuts both ways.
The CDC estimates there are 300,000 new cases of Lyme each year, this is called the incidence of disease. The 30,000 yearly number is based on reporting criteria, to be used for epidemiological trends, not a pronouncement of the actual number of cases. The number of people with Lyme disease  in the population as a whole, with any stage of the illness, is called the prevalence of the disease. This number may encompass asymptomatic cases, since they may become ill at some time in the future. If you don’t believe in chronic Lyme, you would argue against these inclusion criteria. We may infer that an astronomical number of Americans may have some form of Lyme disease. We don’t really know the true number, but it is very large. Some new cases occur in patients already suffering with the disease. This adds to the incidence number but doesn’t change prevalence. Eighty percent of acute cases get better with standard therapy etc. These cases are excluded from prevalence and so on. 
Most patients with Lyme, were at some point told their problem is:  psychosomatic, fibromyalgia, stress, depression etc. Alternatively, they are misdiagnosed with rheumatoid arthritis, multiple sclerosis etc. Why? In 2018, most doctors have a low index of suspicion for Lyme. Depression is very high on their radar. Why? Something is seriously wrong with organized medicine which has buried the biggest epidemic of our time. Makes you angry. Doctors in general are programmed to think of Lyme as only acute Lyme. The false narrative is repeated: Tick bite, bull’s eye rash or Bell’s Palsy, swollen knee, carditis, meningitis and that about it. Lyme is acute not chronic. Lyme is geographically limited. Blood tests are reliable, especially in chronic cases. Same for the past 20 plus years. 

A doctor should recall something he heard in medical school (at least I remember it):  When a patient has an unusual presentation, it is more likely caused by a common disease than an uncommon one.  Assuming a high index of suspicion, this notion was tailored made for Lyme. Patients may present with a single issue, like tendinitis or night sweats or the acute knee pain, discussed above. More often, patients present with a collection of complaints reflecting involvement of multiple organ systems. I start with the patient history in this discussion of diagnosing Lyme disease and this is a clear reason why. Making the correct diagnosis of an illness relies on the following with relative import of contribution, 85% history, 10% physical and 5% lab. This was also tailor made for Lyme. Diagnosis is based eighty-five percent on a patient’s history.  Stop obsessing about CDC positive, IGM vs IgG etc.  I think a major obstacle here is that patients have been told by a zillion doctor that they don’t have Lyme. Patients want the feel of a piece of paper that says, Lyme positive, so they can be at last vindicated. Sorry to burst your bubble. When you take your lab results back to your Ivy League experts, they say, the testing laboratory is garbage, they don’t believe it, it’s a false positive or something along those lines. 
Patients with chronic Lyme have a lot of symptoms and frequently strange symptoms. (You don’t have to have all of these, or any of these to have Lyme).  Patients are tired and nearly all complain of poor or interrupted sleep. Many have fevers, night sweats etc. Their endurance is shot. When they try to exercise it’s a disaster and it takes days to recover. They may have a variety of skin problems. Vision is weird, they can’t focus, and the eye doctor says everything is perfect. They have ringing in the ears. They have swelling of lymph nodes. They having breathing difficulties, especially the classic “air hunger,” can’t take a deep breath or find enough air in the room. They have heart palpitations and skipped beats. They have chest pain. Their bowels and bladder don’t work right. They have headaches, front or back, with neck pain. They have pain of variable intensity, mild to incapacitating. The pain is migratory (travels). One days it’s the knees and elbows and next day it’s the hands, wrists and fingers, etc. Usually joints don’t swell, sometimes they do. Muscles hurt. Tendons hurt. Patients experience shin pain and foot pain. Patients usually have neurological symptoms: dizziness, off balance, numbness and tingling, burning sensations, electrical sensations, weakness, clumsiness, dropping things, etc. Most have psychological and psychiatric symptoms. and/or changes in cognition.  Brain fog. Can’t remember names of things. Memory loss. Confusion. Getting lost. Putting things in the wrong places. Can’t pay attention or focus. Feel like they are getting Alzheimer’s etc. Worried they can no longer do their job.  Craziness. Depression. Mood swings. Crying for no particular reason. Irritable, angry, rageful.  Bipolar symptoms, ADD symptoms, even hallucinations and, Other.
Clarification: the term Lyme,  as I use it, generically includes common coinfections. 
Geography: Lyme is more common in Maine than Arizona.  This doesn't exclude Lyme from consideration in Arizona.  Informed doctors have a good sense for the incidence and the presence of the disease in different locales. CDC reports must be viewed in context.  For example, when the CDC says no cases of Lyme were reported in Georgia, these facts are in play: The disease is miserably underreported in some states, counties and cities.  This may be largely due to physician misinformation and ignorance. Many doctors are fair with the diagnosis of acute Lyme disease. Predictably,  large numbers of cases should be expected up and down the Eastern Seaboard. These states have certain factors in common: bird migration, fauna and flora, mouse and deer populations and tick population. High risk, outdoor activity is more common in the South. Few cases of Lyme would be expected in arid, dry dessert regions of the country on the same basis. 
The idea that Lyme is only found in the Mid-Atlantic and the Northeast is part of an antiquated, false narrative. 
Some people fill out check lists on line which are scored. Standard instruments may have value as a screening tool.  I like to get the history directly from the patient. The “flavor” of the patient’s experiences, contextually, is very helpful. Some patients check off every symptom, but when questioned may say, I had a little of this or that 5 years ago, etc. Diagnosis must be confirmed by the physician. 
There are of course patients with other presentations, like a new headache that won’t go away and many, many others. Those cases may be more difficult. A patient I saw today presented only with insomnia and new severe, persistent, daily headaches. In these cases testing may be more important.
The physical exam frequently gives clues, discussed elsewhere. If laboratory results are only 5% inputted data needed for diagnosis of Lyme disease, then it is much more important to adjust attitudes (physicians and community) rather than develop new testing technology. New technology may be important in the future for many applications. 
If this is correct, it is a bad idea to spend a ton on lab studies, some of which are still in beta testing. A Lyme Western Blot from a specialty lab like MDL or IgeneX and a coinfection panel which can be obtained from standard mill labs, LabCorp and Quest. There are many variants. I like to add C6 peptide. Bartonella henselae antibodies, not PCR. Babesia microti antibodies. Babesia duncani WA1 antibodies (Quest). Ehrlichia and Anaplasma antibodies. Rickettsia, RMSF or Rocky Mountain Spotted Fever antibodies and that’s about it. If I want to look more carefully for Babesia I do a Giemsa in my office or consider a FISH IgeneX.  That’s it. When in doubt, I might order the occasional Ispot test. Nanotechnology may be on the horizon. Generally it is not helpful to order serial Western Blots, except for “seroconversion” test. Repeating the same test over and over again, expecting a different result is the definition of insanity. There are many opinions about laboratory testing which are equally valid. This is my opinion only.
Key points: clinical diagnosis – detailed history is key.  High index of suspicion. Doctor must be knowledgeable about the disease. Patients must also be knowledgeable about the disease need to be their own advocates.    
Problem with better test:  No matter how great the test is, the nonbelievers, who currently control the world of medicine, will find ways to discount the tests and otherwise disparage the results and the doctors who order the tests.  
Remember: If a patient has a rare presentation, it is more likely due to a common illness than a rare illness. And, Lyme is a common illness. 

Does it sound like I am saying only doctors known as LLMDS can diagnose Lyme. In fact, this is what I am saying. Even if another doctor gets the diagnosis right, they will not understand the disease and therefore not prescribe the correct medicine(s).
Perhaps you are thinking: That's all well and good but, after considering all the factors, my doctor is not sure if I have Lyme. 
In this case, the doctor must go back to square one and construct an exhaustive list of possibilities, including such things as cancer. The doctor must carefully go the list, one by one, and eliminate all the possibilities.  At the end of the day, with all other causes of symptoms or illness eliminated, Lyme is all that's left. It's the Sherlock Holmes rule of medicine: Once you have eliminated the impossible, then whatever remains must be the answer. 
The doctor may be worried that there is something he/she forgot to check.  This is fine.  Doctors would do a better job all around if they thought of their diagnoses as hypotheses, a theory that might explain things. For example if it fibromyalgia was a hypothesis, rather than a diagnosis, the treating physician might be less upset when a competing hypothesis, e.g. Lyme, is inserted.  With this in mind, Lyme can be a tentative or working diagnosis, a hypothesis. If things don't go as expected it may be useful to go back to square one. 

Thursday, November 9, 2017

Doctors. Part 2

Here is another view with a crazy dichotomy.

Doctors may be divided into two groups. Let me call the first group the Harvard Group.  These docs are up to date with the latest research and recommendations. They have baskets in which to place everything. These physicians function within comfortable boundaries. They are OK with the notion that 40% of patient symptoms remain unexplained. They believe medical practice must be based on evidence and science, with strict adherence to the creed and this makes them the best doctors possible, in keeping with the current state of the art.  These docs are smart and have encyclopedic knowledge, without question. They are as sharp as the scalpels they expertly wield.
The doctors share core beliefs.  Leaders of the group are held in very high esteem and are granted unbridled authority to orchestrate policies and beliefs. Members of the group go to many of the same meetings. Group members, or congregants  if you like,  do the bidding of the leaders and their controlling agencies. Group members believe they alone have a path to truth. It is my thesis that wittingly or otherwise, said doctors are members of a religious order.  
The second group of doctors, let’s call them "Hippie" doctors, know the science and guidelines alluded to, although the Harvards are sure the hippie docs are unaware, because they are certain the hips would follow the guidelines if they knew about them. They are wrong.  The hippie docs have different guiding principals. Hip docs values empiricism, the notion that clinical experience is meaningful and invaluable, and an indispensable source of information.  This idea makes the Harvards shudder.  Heresy. The hippie docs are not limited to published guidelines. They are not guided by the religion of absolutism, but instead they are guided by a patient-centric view of medicine.  The Harvards see the hippies as ill-informed and reckless, placing their patients at risk, venturing outside “The Standard of Care.”. The hippie docs have a different view.  They feel the standards are a carefully manufactured product of a system which cranks out policies, volumes of truth as it were, to be followed meticulously -- the basis of the religion of Medicine, which is to be follow with unflinching fealty. The believers believe. Everything you need to know is right there. Hippie docs disagree. The recommendations have worth, but are only a starting point. The hippie world is relative, not absolute and imbued with change, learning and curiosity and guided by the bond between patient and heeler. Don’t they know? Those precious guidelines change all the time. 
Hippie docs ask the impudent question:  If Harvard, Mayo, Hopkins and others have thoroughly evaluated patients, and their high priests and temples of Medical orthodoxy have found no answers and offer nothing for patients whose suffering is great, even to the point of suicidal thoughts and actions, why are they so troubled and angered when a hippie doc tries something different. Repugnant? Heresy?  It’s your faith, not mine.
Is medicine a science? Certainly, the practice of medicine is not science. Science describes methods and processes which lead to the discovery of new truths about the universe around us. 
The revered medical study is the basis for the religion of modern medicine.  Typically, a cohort of patients is identified, thought to have the same disease. A hypothesis or theory is to be tested. Is treatment A is superior to treatment B?   The cohort of patients randomly receive either A or  B and perhaps C, a placebo – if it is safe and meets ethical requirements.  The investigators, the doctor-scientists, are blinded, not knowing who is getting A and who is getting B. At a preplanned time, treatment is stopped and the patients are assessed for predetermined outcomes,  by a metric which will decide which of the treatments was the most helpful.  The results are given to statisticians who help interpret the findings.  Results may be reviewed by “peers,” experts in the given field, and written up and published in an appropriate journal.  
Sound great. What’s wrong with this?
Details. Is the cohort really homogenous or composed of numerous subtypes? For example, with most diseases, the genetics have not been worked out. Perhaps the cohort is not homogenous. Maybe it is comprised many subtypes predicated on genetic variable that have not yet been discovered. Perhaps the results measure an average which may not apply to an individual member of a subgroup.   Were the right outcomes measures and how were they measured? To what extent can the results be generalized, extrapolated to provide a greater, more clinically useful purpose?  This thing is a lot harder that is sounds. 
Here is a big problem:  repeat studies consistently come up with different results?  Different investigators looking at the same thing get different results.  To get around this, doctors like to combine multiple studies, which don’t agree, and average them out.   Seriously. Let’s assume only one study is accurate. The best study with the most accurate results might be cancelled out when averaged with a lot of other studies that missed the boat.   More studies are done, looking for clarification. New medical headlines daily proclaim results from the latest study, informing us what is really true. Extra, extra, read all about it.   The revered evidence based guidelines change all the time, and sometimes change they back again as the famous pendulum swings to and fro. We have investigator biases.  Who funded the study? Who do they work for? A pharmaceutical company?? This stuff is really hard to get right. 
Classically science is done like this. A scientist develops a hypothesis. He/she constructs an experiment which sets out to prove whether the hypothesis is correct.  For the results to be considered valid, the exact same result must be found repeatedly, over time, in different places and under the aegis of different investigators who follow the same procedures and processes which are clearly described. 
Medical studies are nothing like this.  Investigators rarely agree.  OK. So, medicine is a “soft science.” 
Let’s look at the world of Lyme. How do we find cohorts?  There is vast disagreement regarding: clinical features and symptoms of the disease, manifestations of the disease and the meaning of laboratory tests. That’s a problem.  What has been studied is a small subset of patients defined by investigators determined to show that chronic Lyme does not exist. That’s a problem.  The cohort is always the same: documented history of acute Lyme disease history ofearly treatment, subsequent chronic symptoms and tests positive with a particular, unusual finding on a test. It is one cohort which is hugely atypical of the group. That’s a problem. Most Lyme patients in my orbit aren’t diagnosed early and don’t have typical manifestations defined by former Lyme investigators. What about treatment A?  It is always the same: IV Rocephin. Is that the only intervention that should be studied?  What are the metrics and endpoints?  On the face of it, the challenges might seem unfathomable. 
For the sake of argument, let's say one of the Lyme studies was spot on. The question then is, what was proved?  Most studies reveal a fragment of a fragment of a piece of a very large puzzle. The disease and its permutations and then the construction of appropriate clinical studies to fill in many blanks is so complicated it makes your head spin to contemplate.  Studies provides a single point of data, a dot you could write on a blank piece of paper.
Did I mention the investigators were biased?  Despite these objections, some of the investigators draw vast conclusions with vast generalizations and extrapolations from something very small.  I would say they paint a masterpiece, like Renoir’s Boating Party, hanging in the Phillips collection in D.C., using only a single period at the end of a sentence. Very skilled. 
What are we to think of the guidelines? Another masterpiece. Perhaps the portrait of a young woman, wistfully looking out a window, in chiaroscuro, by no less than the master Vermeer, hanging in the National Gallery. A must see.
A thing of great beauty. And to think, made entirely out of whole cloth.   
The gospel of Saint IDSA. 

There is clearly a war about Lyme disease. Should we debate guidelines? Absolutely not. We are so far from that making any sense. How do you make guidelines about a disease over which there is tremendous disagreement - a disease of which we still no very little and are missing huge pieces of a larger puzzle?  When sets of evidence based guidelines diverge 180 degrees guidelines are a game: each side picks the evidence it likes and the interpretations it likes to support a thesis. This is not a debate club. We are talking about patient lives. 
How do we (hippie docs) care for our patients? 
We have spent an awful lot of time and an awful lot of energy looking for ways to help our patients, and we keep learning and getting better at what we do. I value the traditions of medicine: patient histories, physical exams, organization of problems, logical thinking, the Socratic method of learning.  This is the heart and soul of the medicine I like to remember.  Maybe someday the two groups of doctors currently fighting to the death will learn to treat each other with mutual respect. That unfortunately is a tall order and may be decades off. 

This piece is a little satiric, but its all true. 

Tuesday, November 7, 2017

A theory about doctors

When Christopher Columbus landed in the Bahamas and Hispaniola in 1492 he was absolutely convinced he had reached India or thereabouts, the Indies he called it.(Became West Indies) He didn’t know about the Pacific Ocean and apparently was bad a math, having determined that he had travelled the correct number of miles to reach the Indies. Others, better at math knew he was wrong.  He landed in the Bahamas and was convinced he was in the old world.  He completed a total of 4 voyages to the Americas, still trying to convince King Ferdinand that he would bring back the riches of Asia. He was convinced the world had a circumference of 17,000 miles instead of the correct 25,000 miles. He believed what he wanted to believe, irrespective of clear facts. Human nature has not changed. When investigators have strongly held pre-existing beliefs they take the evidence and fold it into their model. This remains a great human failing.   Einstein understood that facts and knowledge were limiting, as he often said, it is imagination that opens up vast possibilities. 
In 2007, Fallon shows in a highly esteemed, NIH sponsored, peer reviewed study, that patients with post treatment Lyme with neuroborreliosis achieved improvements in cognition with a course of intravenous Rocephin and that the gains disappeared after less than 6 months when treatment was withdrawn.  The IDSA somehow concludes that these findings refute the presence of Lyme persistence after treatment.  These folks are smarter than that.  If they are right, and antibiotics make people smarter (not by killing germs) then I certainly want to get my hands on some! 
Chronic Lyme is it real. Do organisms persist after treatment?  This question is settled. Borrelia burgdorferi bacteria persist in mice, dogs, primates, test tubes and people. No one has demonstrated eradication of organisms in any of the animal studies. And it was really very hard to kill all the bacteria in a test tube, requiring 3 very potent drugs. I agree that the vast majority of bugs are gone after a reasonable course of antibiotics.  I don’t know why some patients need to be on IV antibiotics for many months to achieve improvements.  The collective, empiric experience, of many doctors and many patients is that these very aggressive therapies are at times what it takes. Elite colleagues are quick to deny a patient therapy because it shouldn’t work according to their particular theory. We became doctors to help patients, not to push dogma. Investigators, trying to prove a square is a wheel, over and over again, waste a lot of energy and resources, when they could be searching for real answers. 
We live in a time where a functional MRI – I learn today, can be used to show whether a young person has suicidal thoughts with accuracy. We have unbelievable medical and scientific technology, yet we are antediluvian when it comes to Lyme disease. Those who pull the levers of power are incredibly stubborn, like Columbus, who was sure he had circumnavigated the globe when he bumped into the Americas. 
Is there something inherently wrong with doctors, as a whole – ID doctors in particular?
I have heard the same story a million times. Patients tell me, “I told my doctor I was feeling better when I was on the antibiotics but symptoms came back when the antibiotic was stopped.” My doctor said, “I’m not going to give you any more antibiotics.” No reason given.  You would think the patient is asking for heroin. Why don’t doctors listen to their patients, why don’t doctors trust their patients, why don’t doctors believe in their patients and why don’t they respect their patients? 

There are several reasons. Here is an off the wall theory:  Doctors are imbued with prejudice against their patients stemming from the way doctors are trained. 
When I was an intern, we all read the book “The House of God.” A satiric look at a medical internship.  Much of what one might read in that book is closer to the truth than one would ever want to believe.

These are ancient memories and I hope they are outdated. 
Medical students frequently have first patient contact experiences with the sickest of the sick, including many suffering souls in the final days and hours of their lives.  Mentors and attending instructors objectify patients, a defense mechanism. The attending physician might recommend: take a look my liver in 202, the yellow man with esophageal varices, interesting case; or my lung cancer in 204 with Pancoast tumor syndrome, a must see.  You really don’t want to every be an “interesting case.” Impersonal, groups of young doctors, wearing white coats of varying lengths, round on hospital patients, poking and prodding. These teams of doctors in training provide hospital care for groups of patients called their “service” New admissions frequently are via the emergency room and are referred to as “hits.” Patients suffering with dementia and other debilitating chronic illnesses earn the awful name: GOMER (get out of my emergency room).  An obtunded patient’s mouth is open and the residents/interns call it an “O sign.” If the tongue is also protruding to the side it’s called a “Q sign.” The upper level residents think this is all very cute and very funny. I heard skid row alcoholics in DTs called SHPOS -- Sub-human-piece-of-s.  The new world of medical learning exists in its own space, with its own rules and cultural norms.  These awful things and many others were routine in my experience and were normalized. The mentality was frequently modeled by mentors of the new batch of doctors.   
An exhausted intern, having worked straight since 7am the day before, finally lays down on his bunk and puts his feet up, shoes on, and hears words through the public-address system he dreads: “Code Blue ER.” If the patient survives he will admit the patient to the ICU/CCU.  That beyond exhausted medical resident secretly hopes this one doesn’t make it, so he can get that one hour of sleep.

These were formative experiences. 
I am absolutely sure many colleagues will deny ever experiencing anything remotely like what I describe above. Perhaps their experiences were different.  Perhaps they have selective memories. 
If so, the question remains: why are these intelligent, highly trained physicians, disrespectful, arrogant and condescending to their patient who is simply asking the question? “Why can’t I have more antibiotics?”
As I stated. I have not done any research.
It’s just a theory.

Monday, November 6, 2017

Elevated rheumatoid factor -- and anti-CCP antibodies present. Lyme or rheumatoid arthritis.

A 54-year-old male presented to me within the last few weeks, having self-diagnosed himself with Lyme disease.  He asked for a Lyme test because of some unexplained tendinitis and a few unexplained aches and pains, which he appeared not be terribly concerned about.  His past history was remarkable for a skin disorder diagnosed as intractable eczema, although treated with UV therapy, typical of psoriasis. He states there had been no allergy workup, that he knew about. He went to his family doctor and asked for a Lyme test. He told his GP that previously, doxycycline made his eczema flare, so amoxicillin was prescribed. When he was getting worse, now with significant joint pain, after 1-2 weeks, he sought my attention. 

This amiable gentleman has a very positive demeanor and a healthy dose of denial – maybe a little to “healthy.”  
His IgE level of over 4000 was “off the chart.”  I have another patient with primary hyper-IgE syndrome which is an immune deficiency in and of itself. In this case, the elevation is due to severe allergies (demonstrated with food, RAST testing). This was not his chief complaint, but I have to see where all symptoms and problems lead and connect the dots. Oddly, his repeat Lyme test was negative, but his Babesia test was positive. (He has a history of night sweat dating back years which he had discounted).  To add another layer of confusion, his rheumatoid and anti-CCP antibody tiers were sky high.
There was no history of significant joint swelling or joint deformities. His joint pain was asymmetrical and involved primarily large, rather than small joints. 
I will segue from here to a discussion of elevated rheumatoid factor level.  A lot of patients see a rheumatologist long before seeing me, in this case his only doctors were his GP and his dermatologist. I was the first to order the tests. 
RA or rheumatoid arthritis, is an autoimmune disorder, primarily involving joints, but which may involve other organ systems at times (extra-articular manifestations). It is also traditionally classified as a collagen vascular disorder. 
Typically, the disease affects young women, not middle age men. Typically, involvement begins with small joints, hands and fingers (middle knuckles), is symmetric and is associated with swelling, frequently progressing to deformity. 
There are atypical cases. A middle age man presenting with a unilateral (single) knee swelling and pain, may indeed have rheumatoid arthritis: this would be a rarity. 
Rheumatoid arthritis has no connection to Lyme disease or any other tickborne disease. Or does it?  This patient has severe allergic disease and may also have a form of autoimmune disease. Is there any connection?  I don’t think there is. 
A positive rheumatoid factor is frequently elevated in my Lyme patients and usually resolves with treatment.
I have tended to be dismissive of an elevated RA when the anti-CCP antibody is negative – the confirmatory test.
All permutations are possible.  It is possible to have RA with both tests negative (RA factor and CCP antibodies) or with one negative and one positive. Similarly, it is possible to NOT have RA with both tests positive. An absolute diagnosis cannot be made simply based on finding one or both of these antibodies. This concept applies to ANA and others markers of rheumatologic disease.  Both rheumatoid arthritis and Lyme are diagnosed clinically, not reliably by a blood test.  I have heard it said that there is no real rheumatoid arthritis and no real lupus, it is all really Lyme. This is incorrect. These diseases existed long before Lyme came onto the scene. 

Lyme does not cause RA, at least not directly. I have several patients with classic RA triggered by Lyme disease. These patients were genetically predisposed to the illness. If not Lyme, something else may have triggered the disease at some point, including emotional stress. 
In the most common scenario, Lyme triggers false positive tests for rheumatoid arthritis, usually rheumatoid factor, but occasionally anti-CCP antibodies; and, these antibodies disappear when Lyme is successfully treated. The term false positive may be confusing. These antibodies are in fact present (real) but they are NOT elevated because of RA but because of Lyme inflammation of joints. Successful treatment of Lyme refers to a therapy with antimicrobial agents which eliminates all joint pain and swelling.  Getting there may be difficult. Over time, with treatment, RA factor and CCP antibodies slowly come down and then disappear. 
Plaquenil has may have some mild “anti-Lyme” properties.  Some patients benefit from its anti-inflammatory, immune modulating effects. (Also used in RA and lupus). 
The theory that Lyme persists in intracellular structures and that alkalization of the intracellular milieu (with Plaquenil) facilitates the antibacterial properties of drugs like Biaxin is NOT correct. 
We know Lyme persistence has to do with pleomorphism (round bodied forms) and biofilm formations. We also know that Lyme bacteria are predominantly extracellular and rarely intracellular. Known facts contradict the theory. 
The skin disease is this patient is allergic and/or mast cell mediated, not autoimmune and unrelated to Lyme disease. 
It is important not to confuse different, abnormal (pathological) immune responses: mast cell disease, allergic disease, autoimmune disease, Herxheimer reactions (excessive immune responsiveness) and immunodeficiency. These are all very different entities.

PS:  High IgE not caused by Babesia, only caused by parasitic worms.  (worms, wheezes and whacky diseases). 

Friday, November 3, 2017

A fit middle age woman couldn't walk without severe shortness of breath: problem solved.

She couldn’t walk up the hill anymore. She was an avid walker and had been in excellent shape.  I had been treating her for Lyme disease for about a year. She was doing better, except breathing wasn’t right and ability to walk past the mailbox. 

Of course, we jump on the diagnosis of Babesia. Babesia causes air hunger.  Babesia is associated with the famous triad:  night sweats/fevers – air hunger – episodic tearfulness.

This 50-year-old female, whose job, working in a nursery, made her a prime candidate to get Lyme.  This was her second experience with the monster – dismissed by mainstream medicine. She had suffered with Lyme in the past, never Babesia. Lyme of 9 years ago was better, she thought.  Now she experienced recurrent fatigue, achiness, brain fog and some joint pain and swelling.  She had a happy life and had never encountered depression. She was a little down because of the disease, but not particularly depressed.  She did have hot flashes and night sweats but her family doctor and GYN said it was part of menopause. She had some swelling in her fingers and her family doctor diagnosed rheumatoid arthritis. She knew it was Lyme instead. And she was right.

The Lyme test performed by her Family doctor was IgM positive and she was told she likely had another bout of acute Lyme disease. Her doctor prescribed 3 weeks of doxycycline and told her that was all that was required even though she felt poorly for the preceding 6 months – or more. Obviously not true, it has taken a year to get her nearly back to normal.

I repeated her Lyme test. It was IgM positive, IgG negative. An IgM 34 band also reacted strongly.

Multiple drug allergies made treatment problematic.  She developed an allergy to doxycycline and was allergic to Biaxin and possibly Bactrim.

Most of her symptoms improved with Ceftin, Tindamax and others.

Babesia I treated with Cleocin, which she tolerated, and the usual drugs. Mepron usually works. I start with 2 tsp twice daily because I have found that one tsp doesn’t work anymore.  This didn’t help. I tried Malarone, high dose artemisinin, cryptolepis and the new darling Daraprim. Nothing worked.  Maybe she didn’t have Babesia.

If the treatment doesn’t work, reconsider the diagnosis. With Lyme and coinfections, the diagnoses is a hypothesis (true with or without positive lab tests). The hypothesis is only shown correct when a desired response occurs. My thinking was, she had Lyme and she had trouble breathing, therefore she likely had Babesia. Maybe I was wrong. So, I looked elsewhere.

I sent her to a lung specialist. Pulmonary function tests showed possible small airway disease. Probably insignificant. We tried inhalers to no avail. A chest X-ray showed some old scarring in the base of a lung. A CT was done and now small kidney stones and something in the liver was found. A CT of abdomen is pending.   

I still didn’t know why she was short of breath.

Babesia tends to cause air hunger, qualitatively different from typical breathlessness. Many patients are able to exercise but experience odd, episodic bouts of a sensation of not getting full breath – finding oxygen in the room. Scary. I have seen a few patients present with cough. She didn't fit the typical mold. The shortness of breath was severe, yet unexplained and frightening. She never had problems at rest or what sounded like air hunger.  I thought about Babesia symptoms again:  achiness, muscle pain, headache – usually frontal, depression with or without bouts of crying, fevers, flulike episodes and night sweats and day sweats. The sweats are frequently drenching. Patients sweat profusely after hot showers. Others.

She primarily had trouble walking up hills - or more than down the driveway to the mailbox. Not typical air hunger. She only had trouble with exertion. She had some sweats but was also in the midst of menopause.

Otherwise, she was doing fairly well.

How about the lab?  Negative. Antibodies for B. microti and B. duncani can be obtained through Quest and others. LabCorp stopped offering B. duncani again. I think the test via Quest is as good as others. Please note:  Quest acquired Focus lab, a pioneer in B. duncani testing with published studies. I did my in-house Giemsa stain: nada. I didn’t send her blood for PCR or FISH test available through IgeneX, although this would have been a reasonable consideration.  I have found the DNA and RNA tests have a low yield. Generally, If I can’t find parasites on a freshly stained blood film these tests will be negative as well.

Standard  tests for a host of unknown Babesia species is unavailable. I believe there a lot of unknowns out there.

Mystery species of Babesia? As an aside, a mysterious Babesia has been found to cause severe sickness in African Lions courtesy of local ticks.

OK. The story ends well.  I used to use a lot of Coartem but have shied away recently, convincing myself that high-dose artemisinin is equally effective -  and I thought somewhat safer. 

I have found frequent dosing, such as 3 days on, 4 days off with careful monitoring of liver functions may be required. A single dose, approved by the FDA for Malaria, will not work. 

I added Coartem to other anti-Babesia therapies AND, admittedly to my surprise, she came in beaming the other day – one month after starting Coartem. 

She was walking up hills, 2 miles and breathing well.  And the “menopause sweats” were nearly gone as well.  A happy camper. A happy doctor. 
We know nothing of drug resistance patterns of various species of Babesia. For that reason the most effective therapy varies considerable from one patient to the next. Trial and error. Creativity and combinations are frequently needed. 

Please note:  There is no particular duration of therapy for Babesia therapy. The notion (myth) that 4 months works because that is the life span of red blood cells is completely incorrect.  With the right - effective therapy, positive results may be seen quickly, within days at times, please continue an effective therapy for several months after symptoms abate to avoid recurrence with a resistant organism.
A commonly applied theory is flawed: "just assume patients have all the coinfections and treat everyone for everything" is problematic.  For example, therapy with Zithromax or Clindamycine with Mepron and artemisinin, a common approach and would never have worked. for this patient Further assumptions about the direction of therapy would be wrong as well.  You have to tease out the threads with each patient. 

Thursday, November 2, 2017

The difficult patient

The difficult patient. This is the patient I keep seeing lately. This a definite cohort with many similar features.  The telltale signs of coinfection, Babesia and Bartonella are there. It should be simple, but it’s not.  Every effort to treat is met with intolerable reactions. Nothing is tolerated.  
Patient I saw today. She is a woman in her 20s who has likely had congenital Lyme. She had developmental delays and sensory integration problems which were treated successfully with therapy in childhood. She had cognitive processing issues and was otherwise GT. This has persisted. 
I have been treating her for 18 months. Before me she saw every Lyme doctor in the community. She likes me because I treat more things and have helped her the most.  She was bed-ridden and housebound for years. She is out of bed, out of the house and able to take some classes at community college. 
Fatigue and collapse. This has improved. She suffers with longstanding POTS secondary to autonomic dysfunction which was not well managed.  I find this to be “low hanging fruit” and straightforward to manage. Florinef, Midodrine, antidepressant, stimulants and others as needed.  Still discussion of stimulants below. 
I diagnosed MCAS (mast cell activation syndrome). This was something new. Treatment has made a big difference. Again, this can be relatively easy to treat (in most cases). I have discussed treatment elsewhere. Diet is important. 
We are addressing other peripheral issues: mold exposure, methylation defect etc. Not as helpful as advertised by some. 
The real core issue, I think, is autoimmune encephalitis. The horrific reactions these patients have when therapies for Babesia and Bartonella are introduced are not Herxheimer reaction. It is a huge mistake to keep pushing a particular therapy with the belief there will be a rainbow on the other side of the mountain. It is not going to happen. 
Treating these infections intensely stirs up the underlying autoimmune pathology. 
For this patient and others in a same or similar boat, pushing any Babesia therapy has led to depression and even suicidal ideation. Pushing Bartonella therapy is equally disastrous. 
Objective tests may provide clues:  GAD-65 aby may be elevated; Cunningham panel show neuro-autoantibodies, especially against dopamine receptors and SPECT scans are abnormal with diffuse hypoperfusion of cortical and deeper areas of the brain. 
I don’t recommend spending a lot of money on these tests if not covered by insurance. 
The collective experience of most patients:  alternative therapies including chelation for ostensible heavy metal toxicity have not helped. 
Experience with hyperbaric oxygen has been disappointing. Somewhat helpful, not amazingly so. 
Steroids may work but this is a slippery slope.  Moderate doses of Cortef, as in this case, help with: inflammation, POTS and possible adrenal dysfunction without causing excessive immunosuppression. 
This patient has daily low-grade fevers – about 100.5, night sweats, air hunger, depression, mood swings, irritability and purple stretch marks. Of course, she also has malaise, poor sleep, joint pain and a host of other symptoms. 
Despite all this, she is functioning better than she has in years. 
This 21-year-old takes a very long list of meds.  
IVIG helps in some cases. She will never get approved. Some patients have  experienced vast improvement with IVIG.  Not always a panacea, IVIG can be incredibly effective when available. It has to be dosed appropriately. 
IVIG is dose 1.5 – 2 gm/kg.  It may take 6-9 months before improvements are seen. 
Generally, I think treating Babesia before Bartonella is best. But this is not always the case.  Running through an army of Babesia meds: artemisinin, Mepron, Daraprim and others, we found she tolerates Cryptolepis best. We are trying this slowly. Daraprim recently caused a severe dip in her depression. I am promoting Babesia therapy because I think it is behind the fevers. 
Bartonella could also be causing the fevers. A word about Rifampin, Mycobutin: Reactions to these meds can be beyond horrible. High fevers are common along with severe psychiatric symptoms. Stop immediately. I don’t think it’s an allergic reaction. It happens too often to be a drug reaction. And I don’t think it’s a Herxheimer reaction. I think the drugs elicit a severe autoimmune response.  Sometimes, the potent anti-bartonella drug, gentamycin, will be well tolerated. I don't know why. 
This brings us around to IV antibiotic therapy. Sometimes IV meds are better tolerated. 
Sometimes, IV Rocephin, hitting Borrelia hard, seems to quiet the entire process down and allow other therapies to proceed. Rocephin has immunomodulatory effects n the brain, apart from it germ killing property. I don’t think we know the whole story but we know the drug reduces the toxic effect of the neurotransmitter, glutamate which is promoted by an accumulation of brain toxins which are very slow to exit through the blood brain barrier. 
Another important therapy is addressing neurotransmitter imbalances. 
Many patients have GABA deficits. They may or may not have GAD-65 antibodies. These patients may benefit from benzodiazepines and gabapentin. Worries about addiction may be unwarranted. In addition, these drugs are excellent mast cell stabilizers, if this is part of the equation. 
Patients have antibodies which attack dopamine receptors and become relatively dopamine deficient.  The use of dopamine agonists such as Ritalin, Adderall can be very helpful. Many, or most patients have executive function issues ameliorated by these drugs. Crashes described by many can be managed when the meds are dosed properly. 
Patients have been to specialist al around the east coast, some are Lyme/bartonella friendly.  There is a definite bottleneck without a clear path. We are all missing something. Be careful before considering immunosuppressive therapy. IV Rituximab has been very helpful, in at least one patient, who receives other therapies described above. 
For now, we chip away, celebrate our successes and stay the course.