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.

Tuesday, March 10, 2015

What is Bartonella?

What is Bartonella? When one forays into the world of chronic Lyme disease the word Bartonella immediately comes up. What is it? I have written about it from time to time and treated it for a long time. What do we know?  Medical textbooks and published papers are at odds with “Lyme” literature. Bartonella is classified as a new and emerging infectious disease. Clinical infection is largely seen as opportunistic. This means that Bartonella under normal circumstances is unlikely to cause clinical disease: it has low pathogenicity. Commercial laboratories only offer serological tests for two species, B. henselae and B. quintana.  Newer information informs us that numerous other species, including: B. koehlerae, B. vinsonii and B. berkhoffi have been found in the blood of Lyme patients. Doctors have known about the prevalence of Bartonella species in some populations for some time. A study published in 1996 looked at the incidence of three species of Bartonella found in inner-city IV drug users in Baltimore: 33% showed antibodies for Bartonella elizabethae, 11% B. henselae and 10% B. quintanta. This population was not tested for scores of other Bartonella species; infection may be universal in this population. Unlike Lyme, it is well known that Bartonella is transmitted by other biting insects, fleas, flies and mosquitoes, not just ticks. IDSA types still like to argue about whether or not Bartonella is a tickborne illness. Some people like to argue about everything. It is fact, not conjecture, that Bartonella may be transmitted by tick bite. Severe forms of the disease are well described by mainstream medicine: cat scratch fever, trench fever, angiomatosis, endocarditis and others. The more nuanced forms of disease, including those seen in Lyme sufferers, are invisible to mainstream medicine. Mainstream doctors need to look a little closer.  In 2007 a paper in “Infection,” described vasculitis and polyneuropathy caused by B. henselae. A well-known paper published in a CDC journal in 2012 made connections between Bartonella and Lyme. The paper connected non-specific symptoms: fatigue, neurologic and neurocognitive abnormalities and joint and muscle pain previously described in occupationally at-risk patient populations.  The Bartonella I think of has greater specificity. A characteristic rash, shown below, parallel red lines or discolored stretch marks, is not described in mainstream medical literature. Red bumps or papules may be seen in life-threatening disease (angiomatosis) according to the usual sources, not the rash pictured below. The Bartonella which causes tendinitis, typically plantar fasciitis (pain on the bottom of the feet) and shin splints is not described in mainstream medical literature. 

 Bartonella, as I know it, is frequently associated with specific neuropsychiatric symptoms, which may include:  irritability, anxiety, rage and many others. This too is not described in mainstream literature. Bartonella as a potential cause of other medical syndromes, for example, interstitial cystitis is also not described in mainstream in medical literature. Then there is the issue of treatment. Bartonella is supposed to respond to tetracycalines and Biaxin according to standard sources. In my world Bartonella responds best to Rifampin and the other drugs do not work.

Although many think of Bartonella as primarily a red blood cell bacteria, it actually primarily resides primarily within endothelial cells, the cells that line the inside of blood vessels. The bacteria is transmitted by an influx of red blood cells which play a role in its life-cycle.  Because of its intracellular locus Bartonella can be as intractable as the other Lyme-associated microbes. 

Here is a snapshot from one of my patients last week. 

This 30 year old male had been in clinical remission from Lyme disease for over a year, after 2 years of extensive treatment. A perfect storm of emotionally stressful events occurred in his life and symptoms returned. He complained of severe fatigue, cognitive difficulties, muscle and joint pains and severe depression. He suffered with anxiety, most Lyme patients do, but he denied irritability, anger, rage and foot pain. And, he had never had a rash like this before. He does have a history of a prior Bull’s eye rash.

Bartonella causes inflammation of blood vessels, a form of vasculitis which likely causes this characteristic rash, undiscovered by mainstream medicine. Vasculitis in the brain is well known to cause neuropsychiatric symptoms, for example, lupus vasculitis. The mechanism of synergy, by which Lyme and Bartonella seem to cause specific psychiatric symptoms is unknown. 

In this patient, Bartonella was always there, even though clinical Lyme was conquered.  Unfortunately, emotional stress weakened the immune system and the tiger got of the cage. 

Specific treatment may not always be needed; therapy decisions are based on the clinical scenario of the patient undergoing treatment.

Here are some general pointers regarding treatment. I have found that rifampin works the best. It must always be given with another antibiotic (to prevent rapidly occurring resistance). Commonly prescribed co-therapies include Zithromax, doxycycline and Bactrim. Bactrim has mild anti-Bartonella effects and is a good add on to rifampin.  Quinolones, including the widely touted Levaquin may be used. I do not like to use this class of drugs because of side effects, which include: spontaneous tendon rupture and high rate of causing C. diff colitis. When I do use a quinolone I usually reach for Cipro because it is a little less toxic and can be started at lower doses and gradually ramped up. When these measure failure, gentamycin or tobramycin are usually very effective. These drugs can only been given IV or IM, have toxicity and requiring close monitoring. 

Atypical syndromes, like interstitial cystitis, may respond best to combinations of Zithromax, rifampin and doxycycline or minocycline. 

The question, “what is Bartonella?” has certainly not fully been answered. But, clinical approaches to what I like to call “Bartonella syndrome,” have evolved and generally perform well in the clinical setting. 

Much of this piece is based on the clinical experience of many doctors and patients, not what is considered medical "evidence." A patient I spoke with last week thought this kind of information constituted evidence as defined by evidence based medicine. "Evidence based medicine," which underpins mainstream medical practices relies on published studies but primarily on the opinion of experts who have interpreted the published studies, especially the ones they like.