Tuesday, March 31, 2015

Potential for new Lyme therapy: bursting the bubble.

A say the problem with Lyme is “6 old men”. I say this somewhat metaphorically. But a small group of older academic physicians developed a paradigm years ago and has continued to successfully convince the faithful. 

A current patient has been admitted to multiple hospitals. This suffering teenage female suffers with severe neurological signs and symptoms. I had the opportunity to speak with one of her hospital doctors, trained in both infectious diseases and immunology. He asked me why I thought the IDSA guidelines were wrong. He let me speak and he was a good listener as I waxed eloquently (or so I thought). At the end of my well-crafted diatribe he was entirely unconvinced. My patient, a young woman, suffering in the most horrific way has been bandied about from one hospital to the next. It seems each institution is more eager to get rid of her than the last. At the last hospital her mother was told, there are some patients that never get diagnosed. Lyme had well been treated with more than a month of Rocephin. It was something other than Lyme. Why do I think the IDSA is wrong?  The patient’s mother was challenged with same question and she gave her best lay explanation. When Mom read “Cure Unkown” she had an “Ah ha” moment and realized the disease is political and has now learned to save her breath. The IDSA is wrong because of history, politics and a paradigm war. Perhaps there has been a debate about the "science" as is oft said. I think the answer to this question can only really be explained contextually.

It is so brutally unfair that anguished parents fighting for their critically ill daughter are asked to take part in this fight.

This article published in the NYTs is very instructive in this regard. 

Stalking Dr. Steere Over Lyme Disease, By DAVID GRANN Published:   June 17, 2001

Although this piece was written 14 years ago, nothing, or very little has changed. Dr. Steere, a once virtuoso violinist whose career was cut short by a finger injury turned his focus to medicine. By serendipity Lyme fell into his lap and he has been a Moses of the field for the last 40 years. Comtempory medicine has no experience with a multisystem disease such as Lyme disease. The specialization of American medicine makes it more difficult for physicians to see recurring patterns of the disease. Patients instead are diagnosed with psychosomatic disease, fibromyalgia or chronic fatigue syndrome. It is fascinating that Dr. Steere says that chronic Lyme has become a garbage can diagnosis and that fibromyalgia is frequently the real answer.   Dr Steere tells the reporter: “there is no controversy amongst scientist.” The 6 old men and their cohorts live in a bubble, have lunch with each other and validate their beliefs: Lyme is easily treated with short courses of antibiotics. Their influence continues to have far reaching consequences leading to devastation for so many Lyme patients.

Personal attacks, such as in the case of Dr. Steere, have an effect opposite of that desired. The besieged only become defensive, clinging more tenaciously than before to their flawed system of belief.

Science is the best weapon we have. It is finally catching up.

Fourteen years later after this interview, when nothing seems to have changed, a study published a few days ago in PLOS one by Auwaerter, (Feng, Zhang) a stalwart “Steerite” leading the charge in the Lyme war against the Burrasconites, firmly contradicts the basis of the Steere hypothesis. 

In this study the Hopkins’ group admits the cause of ‘Post-Lyme” is uncertain. The idea that Lyme bacteria persist after 2-4 weeks of amoxicillin is “controversial” according to the authors of the study, who then proceed to provide clear, concise and convincing evidence that Borrelia burgdorferi, the Lyme agent,cannot in any world, possibly be killed by this recommended therapy.
The evidence is clear, there is no single drug is capable of eliminating Lyme persisters in mice, dogs, primates and humans -- or in a test tube.  There is no known combination of two drugs that can eliminate Lyme persisters.The authors have discovered a single combination of three drugs: daptomycin + cefoperazone + doxycycline  processing the unique ability to eliminate Lyme persisters in a test tube. This is a huge step forward. 

We may not be able to readily adopt this study for clinical purposes. Daptomycin is an extremely expensive drug and is currently reserved for the sickest hospitalized patients. Infectious disease physician's "stewardship" over antibiotics will likely be a roadblock against the use of this potent drug, and, third party payers, hiding behind the banner of FDA approval will likely not pay for it.  Cefoperazone I have tried to prescribe; pharmacists have told me it is not available.

Only a veritable nuclear bomb of antibiotics could kill all the Lyme in a test tube. Still, Dr. Auewater (at his other job), along with the coterie of Steerites  will continue to tell us the pea shooter therapy is all our patients should ever need. 

The young woman described above, in a wheelchair, delirious half the time, in incredible pain, diaphoretic, with apnea and with constant “pseudoseizures and lapses of consciousness whose blood tests show serological evidence of Lyme, Babesia and Anaplasmosis cannot be helped by science, only by the art of medicine based on years of learning and experience. The Steere camp has no answers but is quick to judge.

The nuclear option, if available, would have to used for care. For example, the patient above has severe Herxheimer reactions with low dose minocycline. Medicine will remain an art as well as a science for the foreseeable future.

New research at the test tube level with drugs such as Claritin and the "nuclear option" may prove to be helpful. Test tube science does not always translate into clinical cures but may certainly provide key, new evidence.

The study gives us another rock to throw at the edifice of the Steere - IDSA - CDC dogma.  It remains a David vs Goliath battle. For now, Lyme remains a political disease. We know the science, which are adversaries claim to hide behind, will prevail in the end.


Wednesday, March 25, 2015

Mast cells and Lyme

Lyme can be thought of as a disease of inflammation. It has been established that small numbers of spirochetes can cause inflammation and symptoms referable to the infected organ. Usually when we talk about immune reactions to infection we are talking about innate immune responses and acquired immune responses. The innate immune system, innately recognizes foreign, unwanted antigens and attacks them with ready-made defenses which include killer T cells and complement fixation. The acquired immune responses process involves an elegant system which “reads” the antigens (histocompatibility molecules/ antigen presenting cells) leading to the production of specific antibodies which mark the antigen, with laser like precision, for destruction. This process involves chemical mediators: chemokines and cytokines, helper T cells, killer T cells, B cells, macrophages and a host of other blood cells which partake in this incredibly complex process. But alas, I have been missing something all along. Mast cells?

We know that the related eosinophils, basophils along with mast cells cause allergic symptoms and participate in the killing worms and parasites. But they do much more. 

I recently met with a patient in my office. When I met this young woman several years ago she looked terrified. She had made the rounds, been to countless doctors who had been unable to help her. She was doubtful that I would be able to offer any help. She suffered with a complex multisystem disorder, as do many of my patients. She presented with evidence of Lyme and coinfections and was treated accordingly. She suffered with severe weakness and dizziness. Additional testing revealed she suffered with POTS syndrome, postural orthostatic tachycardia syndrome. This disorder has been discussed elsewhere. This condition presents as an “autonomic neuropathy.” The cardiac manifestation are well known. This disorder can have protean other effects which include dysfunction of the gastrointestinal system. In her case she was intolerant of nearly all foods. She developed poor motility affecting her entire digestive tract. She experienced terrible pain and bloating with each meal.  She struggle to maintain her weight and a marginally acceptable nutritional status. The most aggressive Lyme and POTS therapy failed to quell the severely dysfunctional gastrointestinal system. This went on for years.  Each day brought indescribable misery. I was at a loss for what to do. But something remarkable happened the other day. With a broad smile she said she was tolerating and enjoying many foods, all because she had started a new medicine, ketotifen. This had been added for a suspected mast cell disorder.

Mast cell activation disorder relates to a different kind of inflammation, one that can cause chronic, multisystem disease which remits and relapses displaying unpredictable and diverse symptoms. This disorder is discussed in detail by Dr. Afrin, a hematologist in 2013. His treatise was describing something that sounded like Lyme disease. This disorder presents as a “mystery diagnosis” which takes 10 years or more on average to diagnose. Patients are typically diagnosed with a psychiatric disorder rather than a physical one. These patients, like Lyme patients report bizarre symptoms and unusual constellations of symptoms. The author describes repetitious patterns which he learned to recognize over time.

When we look at a CBC, the most commonly ordered routine test, we find that white blood cells are broken down into various types. We usually pay no attention no basophils which may be seen in 0-2% of circulating blood cells. Eosinophils, which we associate with allergies and parasitic diseases may draw our attention.

Basophil and eosinophils are part of a category of blood cells are granulocytes. When these cells rupture histamine, heparin and many other immune-active, vasoactive and inflammatory substances are released into the blood stream. Mast cells are essentially stationary, tissue basophils found in all the tissues of our bodies to varying degrees. These cells may rupture inappropriately, in a wide range of tissues causing the diverse symptoms alluded to.  These cells play an important role in our immune system when things are functioning properly.  These cells participate in the killing of an array of pathogens, not just worms, as we may have thought. A published study suggests that Borrelia burgdorferi is a good activator of mast cells.  It is probably unrelated, but tick bites have a unique property of attracting large numbers of mast cells.

Histamine is the substance of greatest clinical importance. 

Ketotifen, the above mentioned drug, is both an antihistamine and a mast cell stabilizer. Mast cell stabilizers are sometimes used for the treatment of typical allergies. These agents stop mast cells from rupturing and releasing their toxic granules. Ketotifen, alluded to above, is not available in the U.S. but can be obtained via compounding pharmacies. Treatment of “mast cell activation disorder” can be challenging. What works for one patient may not work for another.  Drugs which may be effective include antihistamines. There are two types of histamine receptors, H1 and H2. H1 is associated with typical seasonal allergies and H2 receptors stimulate the production as gastric acid. Common H1 blockers include Benadryl, Claritin, Allegra and Zyrtec. Common H2 blockers include Zantac and Pepcid. One drug from each category is used in combination. Benzodiazepine sedatives like Xanax and Ativan are also used for mast cell stabilization. NSAIDS may be helpful. Cromolyn is the best known mast stabilizer and it is available in a number of forms including oral Gastrocrom. Ketotifen is a valuable agent. Numerous other treatments exist.  Patients are not cured but their symptoms are managed.  As with Lyme, laboratory tests for the disorder have limited value.  Positive results are more likely to be found during a flare-up. The most common test ordered is a measurement of serum tryptase and histamine levels.

In summary, mast cell activation disorder, MCAD and Lyme can appear identical and Lyme may be a cause of MCAD.  Diagnosing and treating this disorder can be invaluable.

Friday, March 20, 2015

Is it Lyme or MS? (revisited)

A 45 year old male recently presented to my practice. He suffered with a progressive, debilitating, multisystem disease over a period of 5 years. An MRI of the brain was performed and the results were unnerving. The scan showed numerous white matter lesions, greater than 20. The diagnosis of MS was suggested by the radiologist.

Mainstream authorities all agree: There is no diagnostic test for MS. The diagnosis can only be made when other causes of the symptoms and findings have been ruled out. It is a diagnosis of exclusion. MRI protocols, proteins in the spinal fluid, abnormal evoked potentials, alone or in combination cannot conclusively make the diagnosis the MS. 

This patient lives in a Lyme endemic area and has had numerous tick bites over a period of many years. He suffers with fatigue, weakness, trouble walking, poor endurance, headaches, cognitive symptoms and memory loss, depression, tinnitus, night sweats, flulike symptoms, migratory joint pain, mood swings and episodes of rage.

The left lower extremity was particularly weak showing a “foot drop,” apparent with gait testing. The patient was instructed to walk on his heels but the left foot is unable to elevate and the foot flops to the floor. An EMG showed the cause to be inflammation of the peroneal nerve, a peripheral nerve. This is not a feature of MS which involves only the central nervous system. Lyme, however, effects all aspects of the nervous system.

White matter lesions in the brain reflect damage of heavily myelinated nerve fibers in the deep portions of the brain. Myelin is a white, fatty, insulating substance which covers these neurons. Some nerve cells are not covered by myelin, for example, those covering the top of the brain. These nerve cells have a gray appearance hence the cortex (outer surface) of the brain, is composed of gray matter.
White matter lesions can have many causes. They can be normal; you are allowed one per decade of life. The lesions may be seen with atherosclerosis, diabetes causing small blood vessel disease, hypertension, migraines, infections, vasculitis and Lyme disease and there are many other potential causes listed in texts and various sources.

Multiple sclerosis is characterized as a demyelinating disease. It results from an autoimmune process which attacks this coating of the deep nerve cells. MS is divided into 4 types. In 85% of cases it is relapsing and remitting. Patients have discrete neurological events (central nervous system only) which generally get better over time. MS is not diagnosed based on a single event. Subsequent events occur over time involving different parts of the central nervous system.

Typical “events” may include: optic neuritis with loss of vision; weakness, generally localized; numbness and shooting pains originating from the central nervous system, vertigo and loss of bowel and/or bladder function.  In most cases patients get better. Interim periods of time, devoid of symptoms, are followed recurring events causing different symptoms. Over time, the symptoms may not remit and become permanent.

These events are dramatic and distinct. MS is a disease of fits and starts.

The Multiple Sclerosis Society states common symptoms of MS include: fatigue, trouble walking, numbness and tingling, weakness, changes in vision, changes in bowel and bladder function, changes in cognition, depression and pain. The National Multiple Sclerosis Society states that one half of MS patients end up with a chronic pain syndrome. By my way of thinking, the recognition of such symptoms after the fact speaks to a more insidious, gradual inflammatory brain disorder and a multisystem disorder more characteristic of late Lyme disease. Why has the disease morphed?

MS is not defined by MRI findings. In the case of the above mentioned patient, there is a history of tick bite, positive Lyme test and evidence of a progressive, multisystem disease. These white matter lesions, numerous as they are, are most likely the results of Lyme, neuroborreliosis.

The cause(s) of MS are thought to be both genetic and environmental (including infection).

MS has an interesting epidemiology. Cases are rare around the equator. The incidence increases proportionally to the distance one is away from the equator. For example, it is more prevalent in the Northern U.S. and Candida and Northern Europe and Scandinavia. The rule does not hold true for the Asian continent where the incidence remains relatively low throughout the continent. Sporadic epidemics of MS have been described, suggesting an unknown, probably viral, infectious cause. Chamydia pneumonia has been shown to be the culprit in some cases. Coincidently, there is a lot of overlap between the geographic distribution of MS and Lyme. 

The MS Society has a clear opinion about Lyme: it is not associated with MS. It is easy for the Society to make this claim: they follow the IDSA approach. Lyme responds to 3 weeks of antibiotics. White matter lesions in a previously treated Lyme patient are therefore the result of MS, not Lyme. 

How Lyme causes these lesions is not entirely clear. It has been proposed that the highly immuno-inflammatory proteins expressed on the surface of Lyme spirochetes may evoke an autoimmune reaction, one that has not yet been categorized. This raises the question: are some forms of neuro-Lyme a type of MS or a close relative? Can Lyme cause MS?

This is a murky arena. A subset of patients may respond best to MS therapy combined with Lyme therapy. Perhaps some patients do have both Lyme and MS.

There exist 10 FDA approved drugs for the long term management of MS. Some suppress the immune system, like drugs used by rheumatologist for rheumatoid arthritis. Others modulate immune responses and others have anti-viral properties. Neurologist typically treat acute flares of disease with high doses of intravenous steroids. Many of my patients got worse when given steroids. When patients have Lyme (and are also treated by neurologists for MS) I like to steer them to immune modulating and antiviral therapy (interferon).

Clearly, MS is a real disease, apart from Lyme. Not all MS is caused by Lyme. However, there seems to be a large universe of patients suffering with Lyme disease who have been incorrectly diagnosed with MS.

P.S. After only a month of oral doxycycline the patient has experienced dramatic improvements in many symptoms.