Blood brain barrier

A lot of patients are concerned about the blood brain barrier (BBB). They want to know which antibiotics pass through it and/or if only intravenous antibiotics are able to traverse it.

Well then, what is the BBB? It is a diffusion barrier created by special features of small blood vessels leading to the brain. The lining of these vessels, the endothelium, contains unique cellular elements. Tight junctions in the endothelium (inside walls of blood vessels) are made up of a number of factors including "astrocyte end-feet." Astrocytes are supporting cells found in the brain. Most importantly, the BBB keeps out most blood borne substances including antibodies. Antibiotics that cross the BBB tend to have certain physical characteristics including: small molecular size, being lipophilic, binding to fatty molecules on cell membranes, low plasma protein binding and other specialized characteristics.

One of the best drugs is the original, used to syphilis, penicillin. Penicillin derivatives like amoxicillin are also effective. Cephalosporins do not do as good a job; there is some penetration. Then for brain penetration amoxicillin is a better choice than the popular Ceftin and Omnicef. Quinolones do an excellent job crossing the BBB (Levaquin, Cipro and others). Tetracylines are at the top of the list, especially doxycycline. Macrolides, (Biaxin, Zithromax) do a poor job because of their size. Flagyl and Tindamax,which are small and lipophilic, do a great job of passing through the BBB.  Rifamycins (Rifampin) are large and penetrates poorly into the brain. Sulfonomides and Trimethoprim, the ingredients in Bactrim, fulfil the right criteria and pass well through the BBB. This is by no means a comprehensive list of all antibiotics which has been used for Lyme disease.

I haven't talked about Rocephin, our favorite intravenous Lyme drug. It is a cephalosporin. Above I state above this class of drugs generally has poor penetration into the brain. Apparently some cephalosporins penetrate better than others. Literature about Rocephin is mixed;  but contrary to many claims, it does pass the blood brain barrier. Let me mention that Rocephin is used a lot for meningitis. In typical meningitis with active inflammation, there is a breakdown of the BBB and most antibiotics penetrate. With typical chronic Lyme, neuroborreliosis patients, there is no active inflammation. High doses of the drug, with high serum levels obviates the BBB problem. Rocephin is generally tolerated at high doses. Rocephin has other favorable properties: the long half life with once daily dosing,  makes it easy to use this effective intravenous therapy at home. Even though some oral medications have better penetration through the BBB:  the IV route makes Rocephin work better.

Quinolones are the only class of antibiotics I am familiar with when given orally achieve serum concentrations which approach those of IV infusion.

The susceptibility of the organisms to the drug being used is the most important factor.

In reading about the BBB it is fascinating to learn that many other brain diseases may be due to defects in the integrity of the BBB. For example autoimmune brain diseases like MS only occur when antibodies pass through the brain's shield. The same may be true for Alzheimer's disease and other neuro-degenerative diseases which could be characterized primarily, as disorders of the blood brain barrier.

One last point: in general, large bacteria cannot pass through the BBB;  but thin, slippery Borrelia spirochetes, including of course, Borrelia burdorferi, drill through the gauntlet with ease. The brain is a safe haven for Lyme but very few other bacteria are able to get in. But it seems that intraerythrocytic germs like Bartonella and Babesia might hitch-hike in on the backs of red blood cells.

Babesia, chronic daily headache, Lyme tests and Virginia politics

Two years symptom free and now she is beginning to relapse. She did her best to ignore her symptoms willing them to go away -- to no avail. Four years ago after two years of disability, having seen 20 doctors, she came to me for the treatment of Lyme disease. Numerous doctors thought she had Lyme disease but they all ruled it out when the test was negative. There was certainly exposure: she lives in a suburb of Northern Virginia and routinely sees scores of deer running through the back yard, even lying on the flower beds. But she never tested positive. Early 13 band tests showed no reactivity. A better Western Blot showed indeterminate reactivity at the IgM 39,41 positions and now, a 52 band blot from Stony Brook (done prior to the relapse) showed 5 first timer IgG bands. She had 4/5 of the CDC surveillance criteria bands plus -- the 37 band, the highly specific band which can only be gotten from SB. She also had a few less specific IgM bands.

It started with headache, new onset chronic daily headache, other neurological symptoms, twitching and tingling, some joint pain and some brain fog. She really didn't tell me about the night sweats until the second visit. Interestingly, if the Lyme tests were wanting, this was not the case for Babesia. She tested positive for both B. duncani and B. microti. She responded well to Zithromax and Mepron then; I'll see if it still works. We are seeing a lot of resistance to Mepron and having to use other therapies these days.

The fatigue has returned. Her muscles have started twitching again and she can't feel hot or cold on her hands. And --- no headaches or air hunger, but night sweats have started up again.

Her examination confirms signs of peripheral neuropathy.

Since she has lived a cloistered life I don't think she was reinfected. So why did she have both Babesias?. Same tick, different tick? An academic question. We now know -  if we didn't know it then, duncani is much more prevalent than microti here in Midatlantic ground zero-ville.
We have talked about a lot of co-infection with multiple strains of Lyme but not much about multiple species of Babesia. It is still troubling: we don't have a narrative to explain chronic, persistent Babesia.

I have made a conscious decision to keep this blog apolitical --  but...

The bill on Governor McDonnell's desk is important. Friends from Natcaplyme.org are asking you to go to their website and vote. I think the best feature of the bill is that it may open the door for patients to look further. And -- just maybe -- it will educate a few doctors as well.

Babesia relapses just like Lyme. Where-ever the one goeth the other doth surely follow. New onset of chronic daily headaches, not on the radar of neurologists and mainstream medicine, should always raise the question of Babesia. This symptoms can be as disabling as any other Lyme symptoms; and in this case, a young woman lost two years of life because of it. People are coinfected with multiple Babesia species. Maybe, as with Lyme strains, the different Babesia are associated with different syndromes. We know that repeating the wrong Lyme test, the 13 bander designed for surveillance by the CDC is very unlikely to be helpful;  patients and doctors targeted by the new bill in VA need to hear this. And again we see, chronic Lyme can be associated with either IgG or IgM bands or both and the CDC cutoff is arbitrary. The bill is a great start.

Go to church

This 37 year old office manager says she hasn't felt well for half her life; and she's pretty angry about it; and for good reason.

She believes she has been sick 1/2 her life. She had mono when she was 15 and says she never completely recovered. She continued to have chronic fatigue, punctuated by bouts of  fever, malaise and flulike symptoms. Her doctors said she was healthy. She knew little to nothing about Lyme disease during those years.  In March 2009 she went to her family doctor with a small tick imbedded in her back and asked him to remove it. He immediately told her that this small dark tick was not a Lyme tick. She was taken aback; the thought of Lyme disease had not occurred to her. She got sicker than usual: more fatigue and dizziness. One month later she returned to the same doctor. Three weeks after the last visit she found a tick attached to her thigh and now she had a rash. The doctor opined that the rash was too soon for Lyme disease. He prescribed one week of doxycycline to cover his bases.  He ordered a Lyme test which was negative, confirming his original impression.

Then she became much sicker:  fevers and malaise, joint pains and swelling, increased fatigue and cognitive problems. Her doctor told her that nothing was wrong, it was a spiritual issue, and that she should go to church.

Over time she had the kind of fatigue that makes it hard to lift your head from a pillow. She developed psychological symptoms: irritability, mood swings with emotional lability, an inability to focus or get much done. With increasing memory loss she had confusion and disorientation. Anxiety, and then panic attacks became prominent. Other physical symptoms intensified:  night sweats and fevers, headaches, tingling sensation, a feeling of bugs crawling under her skin, weakness making it hard to walk at times, generalized pain with more joint pains with swelling, chills, insomnia, weight loss, cold intolerance, blurred vision and other strange changes in vision, ringing in the ears, painful and swollen glands, air hunger and more.  She seemed to have everything on the expansive list of  possible Lyme symptoms.

Her family doctor reaffirmed his prior diagnosis: there was nothing wrong. He repeated blood work including a Lyme test - everything was normal.

She came to the diagnosis of Lyme on her own, as so often happens; then she came in to see me.

After 18 months of intensive treatment for Lyme disease and coinfections, she has improved tremendously. Her life is back.

Fantastic news. A pending bill in Virginia will require all doctors to inform patients about the pitfalls of the test whenever they order a Lyme. Hopefully this will inform doctors as much as it does patients.

Virulent Lyme strains and another look at biofilms

I have recently seen two young men, in previous robust health, who have been stricken with subacute progressive Lyme disease with both neurological and` musculoskeletal manifestation. These patients had been athletes in tip-top shape. Now suddenly plagued by weakness, fatigue and cognitive issues are fully disabled. The question then comes up: why did these two become so sick. This continues to be a vexing issue.

A study published in the New England Journal of Medicine this past fall finally put to bed the debate. Not. There is no chronic Lyme according to Dr. Steere. Study subjects had discrete bouts of stage 1 LD with rash and had recovered between each discrete episode. Multiple strains of Lyme were found with separate infections. It was then suggested that chronic Lyme is a product of new infection, not relapse from the original  infection.

I think most doctors are in agreement that Lyme disease can be cured when caught in the early stages with an EM rash. What this study does show is that there are a multitude of Lyme strains present in the same geographical local - the same cohort of ticks.

These various strains have difference virulence factors and predilections to cause on sort of disease over another. I suspect these two men became so ill because they were unlucky enough to be a victim of the wrong tick, one harboring a very nasty variation of Borrelia burdorferi.

In one case, the young man had already received standard care with 28 day of intravenous Rocephin. The ID specialist said there was nothing else to be done and that he might be disabled for the rest of his life. This will not happen Mr. IDSA.

There arises confusion about what is chronic Lyme disease. The IDSA  defines it to be symptoms which recur after a properly treated bout of acute Lyme. But is not what we are talking about. We are talking about disseminated bacterial organisms which persist despite antibiotic therapy and continue to make the patient ill. These patients are hard to treat, but treatment can make them better.

The topic of biofilms came up in my office today, as it frequently does. There seems to be a lot of misunderstanding here. It turns out that bacteria are social creatures. They frequently form aggregates sealed off in a weird mix of muccopolysacchrides and pieces of DNA. The bacteria in these walled off areas seem to have an uncanny intelligence, communicating with one another by quorum sensing.  Organisms in biofilms may be a 1000 times (or more) resistant to antibiotics compared with singular organisms. The biofilms disperse organisms from time to time which then set up new colonies.

Lyme is not unique. About 80% of human infections are associated with biofilms. Biofilms are omnipresent. They are the slime adherent to the inside of your pipes and hoses. They are the plaque on your teeth. Chronic sinusitis may never clear until the biofilms are surgically removed.

Biofilms have efflux pumps which pump out antibiotics. They clearly contribute to the chronicity of the disease, to what extent is not clear.

Patients have frequently asked me if they have cystic forms of the spirochetes? Everyone does, it goes with the territory. Likewise, everyone has biofilms.

There seems to be a mistaken notion that biofilms can be degraded with proteolytic enzymes like nattokinase. Since biofilms are not protein based this does not make sense.

I have thought there is no specific way of  treating biofilms. I have felt that antibiotics like Tindamax which have better biofilm penetration, finding the right antibiotics, ones that work synergistically and using IV antibiotics to better saturate tissues were the way to go.

It does seem that dispersement of biofilms is a desired goal since bacteria are much easier to kill in free planktonic state. There are a couple of enzymes which facilitate this process but they are not available for clinical use. It has also been found that nitric acid, an important molecule, may facilitates the dispersal of biofilms. Apparently the best promoter of nitric acid is the amino acid arginine which can be taken as a supplement.

Brittany's Babesia

My patient, Brittany's story was recently featured in the Animal Planet's "Monsters Inside Me." The producer told me he would shoot me a copy of the episode before it aired so I could correct mistakes. This did not happen. Brittany did not test positive for B. microti as stated; she tested positive for B. duncani, also known as WA1. This is the west coast species and not supposed to be here. One of my patient documents his experience with two Johns Hopkins infectious disease doctors on youtube,  regarding his B. duncani infection. In his case, B. duncani was proved not only by an antibody test but also positive by gold standard RNA and DNA tests, FISH and PCR. The ID doctors did not know what he was talking about and one offered to call a psychiatrist.

Here is an interesting tidbit fro a study published by the American Society of Microbiology, Clinical Vaccine and Immunology, November 2010.

They looked at "clinical specimens," sera sent for diagnostic purposes and random sera of donated blood, from different geographic regions of the United States, including my state of Maryland in the years, 2008, 2009.

It turns out that B. duncani was widely distributed across the US. Seropositivity for B. duncani was 27% of clinical specimens and 2% of blood donor specimens. B. microti was found only in 0.4% of donor specimens. If my math is any good B. duncani was 500% more prevalent than B. microti nation-wide.

The potential ramification of these findings can be considered. Two percent of blood donors tested positive for exposure to B. duncani. Since blood donors are generally healthy people and other species of Babesia were not tested for  -  the percent of Americans exposed to Babesia could be a number much greater than 2%.  The CDC recognizes that three other species of Babesia: CA1, MO1 and divergens can cause human disease in this country. And many LLMDS believe that numerous unknown Babesias may cause human disease. There are over 100 known species of Babesia associated with animal disease.

If 2% of Americans test positive for Babesia, then about 6 million Americans test positive. This number could be very conservative since is looks at healthy adults and does not include other species. Three additional species are recognized by the CDC : MO1, CA1 and B divergens to cause human disease in the US. And many LLMDS think scores of other Babesia species may be involved in human disease. Not unreasonable: over 100 species are known to cause animal disease.

If only a small fraction of Lyme patients test positive for Babesia, my experience, then one could guess that the number of Lyme infected individuals is 6 million times a larger number.

But I guess you already knew this.

Another look at gluten

I have long thought that gluten free diets are way over-prescribed for Lyme patients. Celiac disease, the most extreme form of gluten intolerance is relatively rare. Wheat, the primary source of gluten, was the first  grain cultivated by our ancestors dating back more than 10,000 years. We have be eating a lot of guten for thousands of years, I have been interested in the "island where people forget to die," a small Greek island with  more men per-capita living over the age of 100 than any place else on earth  -  and coarse bread is a staple in their diet. But perhaps my logic is a bit flawed. Gluten intolerance is part of the spectrum of autoimmune diseases. The incidence of  autoimmune diseases is climbing, including celiac disease. It seems mainstream science is catching up to what many "holistic" practitioners already knew. Gluten sensitivity is a real disorder, apart from celiac disease, per researches from the University of Maryland.  There is no reliable diagnostic test for the disorder. Saliva samples and stool samples for anti-gliadin antibodies may be helpful but  may also over-call the diagnosis. There may be other clues: the presence of markers for autoimmunity such as a slightly elevated ANA, B12 or folic acid deficiencies may suggest a  maladsorption issue. I think all minimal or borderline abnormalities on a standard celiac disease panel should be considered. Classic celiac disease with significant gastrointestinal symptoms or the characteristic, dermatitis herpetiformis rash may be completely absent. Patients may experience fatigue, chronic fatigue syndrome, generalized pain, fibromyalgia, brain fog or peripheral neuropathy. As mentioned in my last post, gluten sensitivity should always be considered in chronic fatigue syndrome, known to be associated with immuno-dysregulation. A celiac test, for what its worth, is always included in my initial workup of new patients.

A young woman recently came to see me with complaints compatible with chronic Lyme. On closer questioning she admitted that a gluten free diets had resolved nearly all of her symptoms. As I tried to figure out what to do her sagacious father suggested she stay on a gluten free diet to find out what symptoms, if any, remained. Great idea.

That having been said, I still think that most Lyme patients do not need a gluten free diet. It is required for a relatively small percent of patients and it is an onerous undertaking.

There are genetic factors which predispose patients to have the illness, HLA types, DQ2 and DQ8 may be checked. Ultimately, in many cases,  the only way to know if the diet will help is to try it for 8-12 weeks.

There remains the question of whether Lyme causes gluten problems. The answer is, I don't know, maybe. There is evidence that infections may precipitate the appearance of celiac disease, the frequency or which increases with age.

Chronic fatigue syndrome, Lyme, Babesia, and Adrenal fatigue

I have been treating this patient for a few months. This 42 year old female came to see me for a Lyme evaluation.  Lyme didn't seem likely, but since her husband suffers with chronic Lyme disease she decided to check out this possibility. Her chief complaint was fatigue. She carried the diagnosis of chronic fatigue syndrome.

She feels she has been tired her entire life, at least since age 19. At age 20 she was diagnosed with depression. Various antidepressants were prescribed with minimal benefit. A sleep study(polysomnogram)  was negative. The MSLT, multiple sleep latency test was slight abnormal but did not meet the criteria for narcolepsy. She has been  treated with 600 mg of Nuvigil( a very high dose), without any benefit - this is unusual. Her symptoms had become significantly worse over the last year. She had episodes of profound fatigue and perhaps weakness of her legs. At  times it was  difficult for her to get out of bed in the morning. Other symptoms included: mild brain fog, rare knee pain and some numbness and tingling. She had a history of night sweats which stopped one year ago. She had persistent loose stools, short of diarrhea. She has been seeing a psychiatrist for years. Recently anxiety has become worse along with  panic attacks. She complained of the inability to accomplish tasks, difficulty handling stress, and indecisiveness.

Lab tests showed serological positivity to Babesia microti and Lyme. In addition, there was evidence of adrenal dysfunction. The ACTH level was very high, 98, while the cortisol level was 14, within the normal range.

In addition to chronic Lyme disease I felt she suffered with adrenal fatigue. The diagnosis is associated with dysfunction of the hypothalamic's-pituitary-adrenal axis. The ACTH level should not have been elevated in the face of a normal cortisol level.

Her treatment then included: typical antibiotics  -  plus Cortef. After only 6 weeks she claimed that "this  was the best she had felt in years!"  She states she now feels normal. Gone were fatigue and cognitive symptoms.She was incredulous, as were her psychiatrist and sleep specialist. Side effects of therapy included, nausea and constipation -  surprisingly, rather than diarrhea.

In patients who have been chronically ill for years or even decades, adrenal fatigue must be considered along with other potential causes. Patients with chronic fatigue syndrome should always have sleep studies including the MSLT  and be evaluated for gluten sensitivity, thyroid disease, and a variety of other disorders.