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Thursday, July 30, 2015
Occams Razor: Lyme and Mast Cells
A 38 year old female who lives in the Pittsburg area had a purplish rash appear on her calf in the summer of 2013. The rash expanded. The calf became red, swollen, warm to the touch and very painful. She sought care at the local emergency room. She recalled a tick bite on her leg a month before, sometime in May, but thought nothing of it at the time. (She dearly wishes she knew then what she knows now). The doctors at the hospital thought she had either cellulitis, an infection of the fatty tissues under the skin, typically caused by strep or staph bacteria or a blood clot (DVT). She was given a single dose of an IV antibiotic. The ultrasound scan showed a blood clot: the infection hypothesis was disregarded. She was sent home from the hospital 2 days later with a prescription for a blood thinner. While in the hospital she felt generally lousy and had a low grade fever; these symptoms were dismissed.
She was discharged home and she promptly developed a collection of alarming symptoms. She had a stiff neck, chills, fevers - now to over 102 and a dry cough. She had a spinal tap and blood studies. The findings were elevated liver function tests and a low platelet count. She was given steroids and sent home with "asceptic meningitis." The term is a misnomer. Asceptic means devoid of germs. Asceptic meningitis is synonymous with viral meningitis. The spinal fluid was not entirely normal: a few white blood cells were seen and the protein was a little high, nonspecific findings. No evidence of bacterial meningitis.
Sent home after another 2 day admission she developed profound and generalized weakness. She soon found herself in a wheelchair. She developed strange cognitive deficits finding it hard to communicate. And she developed labored breathing: she was gasping for air for no good reason. A recent chest Xray was normal. She started to have random wandering or migratory joint pains: a hip one day, a knee the next and then a wrist and fingers and so on.
She went to her family doctor who ordered a Lyme test. The results were CDC positive: positive EIA first stage followed by positive Western Blot, IgM only. Her family doctor consulted a well respected fount of the best, current medical information: "Up To Date," and dutifully prescribed a 3 week course of doxycycline.
Instead of getting better she got worse. Now she complained of head and facial swelling, headaches, severe sensitivity to light and sound, disabling - bone weary exhaustion 24/7, numbness and tingling, loss of balance, neck pain, abdominal pain, nausea, forgetfulness, trouble speaking, flulike symptoms and severe drenching night sweats. This on top of worsening, diffuse pain involving large, medium and small joints - variable and asymmetric.
Her family doctor referred her to specialists: Neurology, Rheumatology, Hematology (all the -ologists): nothing found. Then she was referred to psychiatry. The psychiatrist said it was not in his field: she was medically ill --- with something.
She made the rounds: Mayo, Johns Hopkins, a few others and then me.
She transferred from a wheelchair to a chair on the other side of my desk. As she recalled her story she appeared severely short of breath, gasping between phrases. (I wanted to give her IV Mepron - no - not literally).
Needless to say, I proceeded with my workup. Her neurological examination was abnormal. Her limbs were weak, especially on the right. Her reflexes were abnormal and she exhibited a Hoffman's sign. She was unable to sense cold on her feet or feel a tuning fork vibrating against bones in her feet. She had a loss of position sense. She could not tell whether a wiggled big toe was pointing up or down. Her gait was abnormal and she failed a Romberg test (put your feet together and close your eyes) tumbling to the right.
Laboratory testing was negative for coinfection by serology (antibodies) but a stained drop of blood on a slide revealed parasites within red blood cells.
We know the patient was misdiagnosed by doctors, initially fixated on cellulitis vs blood clot. In fact the apparent cellulitis was the product of a very aggressive EM rash presentation. The blood clot was a secondary effect of pressure on blood vessels within the calf. Spinal fluid is frequently glossed over when typical bacterial meningitis (like pneumoccocal) is not present. The "viral" meningitis was in fact Lyme meningitis which might have been evident if different tests were done. The Lyme section in Up-To-Date is written by orthodox IDSA, 2006 panel members. The specialists seem to never diagnose Lyme correctly because they are working within a different box with a different set of rules. The neurologist never seem to understand: Lyme attack many facets of the nervous system causing bizarre - disconnected presentations. Doctors are frequently hammers in search of nails. For rheumatologists the nail is fibromyalgia. Sadly, everything about this case is "typical," something I see over and over again. This patient was needlessly punished, robbed of quality life -- because of a childish squabble led by a troupe of academic physicians who are now being challenged on their home turf by a new kind of Lyme clinic at Johns Hopkins.
After aggressive therapy for Lyme and coinfections for nearly a year and a half she felt much better, stopped treatment and was "lost to followup."
This April this year she called me. Another tick bite. Attached for only a few hours at best.
I called in a 3 week course of doxycycline.
Unfortunately, the bottom fell out and she became severe ill once more.
In addition to the usual therapy, 2 months ago I tried something else and she is feeling so much better, quality of life restored.
I have become a bit of a hammer looking for nails -- mast cells. It is the only way I can get a handle on this disorder. More often than not these cells are major players.
And now I take a major detour.
In front of me is a consultation note from a hematology professor from the University of Minnesota, Dr. Lawrence Afrin. A brilliant man. In all fairness, the note discusses a patients who really did not get better with a year of intravenous Rocephin. This patient's story is somewhat different. She has suffered with years of POTS, arthritis, thyroid disease, small fiber neuropathy, cognitive dysfunction, brain MRI showing white matter disease, unexplained abdominal pain, vomiting, discolored feet, sleep apnea - obstructive and central, blood clots, pelvic pain syncope and other unexplained symptoms.
The doctor describes her highly positive review of systems: she endorses a wide range of intermittent, chronic/recurrent, waxing and waning issues, mostly subjection (occasionally objective) which include fevers, flushing, feeling cold, fatigue (often to the point of exhaustion), malaise, headaches, diffusely migratory aching/pain, diffuse migratory pruritus (itching), unprovoked soaking night sweats, unprovoked fluctuations in appetite, eye irritation, episodic loss of focus, nasal congestion, swooshing in head...the list goes on.
Laboratory testing showed elevated 24 hour urine 11-beta-prostaglandin-F2-alpha level. He states that this is not a definitive test; he wants to make the diagnosis of mast cell activation syndrome stating "there is no other human disease he is aware of" that can cause all of these issues. He pedantically discusses an array of diagnostic tests and genetic variables that makes my head spin.
This single progress note could be made into a chapter in a text book, (one that would be both difficult to read and be understood by the non-specialist practitioner).
The author evokes Occams Razor (the idea that the simplest explanation is usually the correct one): he strongly doubts that she ever had Lyme disease. He states that IgeneX is an outlier lab, the only lab to find "evidence" of Lyme when other laboratories cannot. Not true. A recent peer reviewed study from Columbia University completely vindicates the unfairly maligned lab. killing the messenger is always easier -- when you don't want to hear the message.
Learning about mast cells and their role in inflammation has been eye opening for me and helping many patients. Mast cell disorders, as discussed in current medical literature, are seen as an increasingly heterogeneous assortment of disorders. Mast cells are heterogeneous themselves. Lyme and other infections trigger mast cell activation and this is supported by peer reviewed studies.
Lyme in many ways is a disease mediated by the immune system. These odd spirochetes with lippoproteins jetting out from a double membrane cause disproportionate immune responses: cytokine storms and ill-defined autoimmunity are frequently pointed to. In my, perhaps, overly simplistic "simple country doctor" brain I imagine a scenario where all roads lead to Rome. Immune repsonses - cytokines, helper cells, killer cells, antibodies, complement (effector mechanisms - the business end of immune responses) all converge on mast cells. These cells and their attendant mediators play a large and under appreciated role in what we experience as inflammation.
Perhaps tendencies for excessive mast cell activation are largely genetic. The doctor rightfully discusses influences from genetics and epigenetics yet to be understood. All human disease is the product of genetic tendencies combined with environmental stimuli (frequently infection). Inflammation is always a double edged sword. Without inflammatory responses we could not survive the hostile world of microbes and mutated cells that would do us in. On the other hand, all chronic diseases, like heart disease and diabetes are now seen as disorders of inappropriate chronic inflammation.
A new tool. A new synthesis. My message for the much-smarter-than-me professor is: there is at least one more disease (other than straight mast cell disease) that can explain your patients seemingly crazy symptoms. Occams Razor is only a suggestion. Look deeper.