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.

Tuesday, July 14, 2015

Lyme and multifocal motor neuropathy and hammers

Warning: this case is complicated and the medical stuff is hard to follow if you do not have a science  or medical background. 

I recently met a 50 year-old female who came into my office in a wheelchair seeking help for Lyme disease. She had been under the care of another “Lyme” doctor for 3 years. She suffered with a neurological disease causing progressive weakness. The illness started more than 15 years ago but has rapidly progressed over the last three years. Until 3 years ago she had been a patient at Johns Hopkins. At this point she states that she had a bad experience there, mostly within the department of neurology. Doctors had bandied her about and been unable to diagnose her. She feels that no one ever listed to her. According to various consulting physicians things did not fit together in her case. One physician told her he had finally figured out what was wrong with her: she had chronic fatigue syndrome and fibromyalgia! One of her S, reluctantly, prescribed IVIG which she stopped 3 years ago because it wasn’t helping. 

For the past three years she had been under the care of a “Lyme doctor” who had treated her with a steady diet of supplements and antibiotics while her condition continued to worsen. 

It is at this point she came to see me. Searching through the morass of medical records from “the Johns” I found a copy of an EMG/NCV performed several years ago. It showed a demyelinating peripheral neuropathy. She additionally informed me that she had a small fiber biopsy which was abnormal as well. Some of the puzzle pieces which did not fit together were: a diagnosis of neutrally mediated hypotension per tilt table test without POTS and other evidence of autoimmune disease. Of particular interest was the presence of elevated anti-GAD antibodies. She recalled that several years ago she was prescribed Klonopin which initially helped some of her symptoms but the effects were not durable. At Hopkins a Lyme test (ELISA only) was negative and this possibility was dismissed.
When she saw the Lyme doctor he ordered a test for Lyme from IgeneX which showed a weak positive response with two positive, specific IgG bands present. This was the sole basis for the Lyme diagnosis. When she took antibiotics she frequently experienced chills, sweats and low grade fevers followed by worsening of weakness which did not recover with continued therapy or with cessation of therapy. 

My examination showed an ill appearing female seated in a wheelchair. She had a resting heart rate of 100 and a blood pressure of 150/80. (These vital signs were “normal” for her). The examination was remarkable for some muscle wasting in her upper extremities. Moderate weakness of both upper and lower extremities was present. An absence of deep tendon reflexes globally was present. The sensory exam was completely normal. The remainder of the neurological exam and the general physical exam was within normal limits.

Lab findings: Lyme Western Blots were sent to two reference laboratories, MDL and Stony Brook. The MDL strip showed a positive IgG 41 band only. The Stony Brook test showed a few non-specific IgG and IgM bands.  The remainder of the test series was positive for an elevated anti-GAD antibody and otherwise unremarkable.

So what’s going on?

Discussion of case: This patient has a CIDP-like illness affecting only motor neurons. The diagnosis may be something called multifocal motor neuropathy. Features that favor the diagnosis are: demyelinating neuropathy, progressive nature of illness and the absence of deep tendon reflexes. Lyme is not the primary issue here. Lyme is known to cause primarily axonal neuropathy although I have seen both types of neuropathy in patients with Lyme disease. Which is which?  Slowing with nerve conduction testing (the shock test) shows axonal dysfunction and reduced amplitude of wave on EMG (needle test) shows demyelinating neuropathy. CIDP is thought of as a chronic form of Guillain-Barre syndrome and MMN (multifocal motor neuropathy) is related to CIDP which stands for: chronic inflammatory demyelinating polyneuropathy. Neutrally mediated hypotension is a disorder of the central nervous system and should not be seen in any of these diseases which only involved the peripheral nervous system. At any rate, the peripheral neuropathy component is due to an autoimmune disease and IVIG is the appropriate therapy.  Lyme on another infection may have incited the disease in someone with a genetic predisposition as is likely in this case. It certainly sounds like this is the case as she experiences classic Herxheimer reactions when she takes antibiotics. A worsening of symptoms in this scenario sometimes called a neurological Herxheimer reaction.  The inflammation which ensues when the offending germs are killed causes a worsening of disease which does not improve even with cessation of therapy. In other words, the cure may be worse than the illness.  The elevated anti-GAD antibodies is something of a red herring; it is evidence of a second, unrelated, autoimmune disorder and something which may respond to a different kind of therapy. Centrally mediated hypertension is another red herring as noted above, but this finding makes sense within the context of multisystem disease, especially Lyme disease.

Patient Lyme disease have weird symptoms and syndromes which cannot easily be connected in a linear fashion.  Symptoms and syndromes which forgot to read the textbook followed by academic specialist.

The presence of anti-GAD antibodies is something seen in disorder called stiff man syndrome.  These antibodies block the GABAergic system and drugs like Klonopin are the appropriate therapy.
One Lesson is: Do not be a hammer and see everything as a nail.  Another is: if a treatment is making the patient worse, step back and take another look. If you are a Lyme doctor you have to be an expert in everything. Other medical specialists will not help since they do not believe in Lyme disease. Other physicians will give up when everything does not fit together and seem to inevitably reach into their bag of tricks and pull out the “go see a shrink” card. I have seen the same scenario unfurl repeatedly in multiple patients whereas many neurologist are unfamiliar with the disorders. There are some knowledgeable specialist who can be helpful out there – somewhere.

My recommendations: Do not take antibiotics at this time. Restart IVIG and do not stop, consider the treatment as indefinite (then consider antibiotic therapy) and start hyperbaric oxygen therapy and get a home unit: this will be a very long term form of therapy. Other supplemental therapies may be helpful but this is my core recommendation. I recommend the patient start low doses of drugs like Klonopin and /or Neurontin which may also help with neuropathy symptoms.

The idea that killing germs will fix everything is not only wrong but may be detrimental as well.

Keep in mind that hyperbaric oxygen heals nerves and also kills germs. Herxheimer responses are likely to occur.
A repeat EMG/NCV is needed to determine disease progression and other studies. 

I think this patient will get better but it is going to take some time.

Tuesday, July 7, 2015

Medical Board v Jaller: We won!

Many patients have expressed concern: will I still be around to care for them?  The answer is a resounding yes.

The settlement reached between myself and the Maryland Board of Medicine is an astounding victory.

I was granted full license to continue practicing in exactly the same way I have for years without any restrictions.

A war over ideology was replaced by a reprimand of an administrative nature: the best possible outcome given the posture of members of the Board.

I have my attorney Bill Askinazi and the Maryland assistant Attorney General, Victoria Peppers to thank for this great outcome.

The case landed on Ms. Pepper’s lap. My lawyer did a very good job educating the assistant AG regarding the Lyme story. Becoming knowledgeable about the controversies and the two standards of care, Ms Peppers concluded, and I paraphrase: The state of Maryland has long accepted the right of doctors to diagnosis and treat patients by means not accepted by the majority of the medical community. These statements follow the precedent set by the 2010 Medical Board letter which stated that the Board would not prosecute doctors who treat Lyme disease with long-term antibiotics.  

Twenty-five pages of charges – all based on IDSA peer review were largely discarded in the findings of fact.

I accepted a reprimand from the Board, agreeing to:

Document differential diagnosis:

Document referrals to specialist.

Better explain rationale for treatment and medications.

Do a better job monitoring patients on IV antibiotics for side effects.

These are things I already do for the most part. Much of the criticism was based on charting from as far back as 2009.  

All charges related to:  The diagnosis of Lyme and  coinfections and the general ILADS' approach to therapy (save doing a better job explaining the basis of therapy) were dismissed.

I am on probation for a year but only for the above admin items. Lyme controversies will not be at issue during the period of probation: supported by the record of the hearing.