burr2005.pdf

ADVANCED TOPICS IN

LYME DISEASE

DIAGNOSTIC HINTS AND TREATMENT GUIDELINES FOR LYME AND OTHER TICK BORNE

ILLNESSES

JOSEPH J. BURRASCANO JR., M.D.

Fifteenth Edition

2005

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Welcome to the fifteenth edition of the “Guidelines”. Since the last edition, enough new information has

become available to justify this revision. New insights regarding co-infections, test refinements, and new

treatment regimens are included.

I once again extend my best wishes to the many patients and caregivers who deal with Lyme, and a

sincere thank you to my colleagues whose endless contributions have helped me shape my approach to

tick borne illnesses. I hope that my new edition proves to be useful. Happy reading!

BACKGROUND INFORMATION

In general, you can think of Lyme as having three categories: acute, early disseminated, and chronic. The

sooner treatment is begun after the start of the infection, the higher the success rate. However, since it is

easiest to cure early disease, this category of Lyme must be taken seriously. Undertreated infections will

inevitably resurface, usually as chronic Lyme, with its tremendous problems of morbidity and difficulty with

diagnosis and treatment. So, while the bulk of this document focuses of the more problematic chronic

patient, strong emphasis is also placed on earlier stages of this illness.

A very important issue is the definition of “Chronic Lyme Disease”. Based on my clinical data and the

latest published information, I offer the following definition. To be said to have chronic Lyme, these three

criteria must be present:

1. Illness present for at least one year

2. Have persistent major neurologic involvement (such as encephalitis/encephalopathy, meningitis, etc.)

or active arthritic manifestations (active synovitis).

3. Still have active infection with B. burgdorferi (Bb), regardless of prior antibiotic therapy (if any).

Chronic Lyme is an altogether different illness than earlier types, mainly because of the inhibitory effect on

the immune system (Bb has been demonstrated in vitro to both inhibit and kill B- and T-cells, and will

decrease the count of the CD-57 subset of the natural killer cells). As a result, not only is the infection with

Bb perpetuated, but the entire issue of co-infections arises. Ticks may contain and transmit to the host a

multitude of potential pathogens. The clinical presentation of Lyme therefore reflects which pathogens are

present and in what proportion. Apparently, in early infections, before extensive damage to the immune

system has occurred, if the germ load of the co-infectors is low, and the Lyme is treated, many of the

other tick-transmitted microbes can be contained and eliminated by the immune system. However, in the

chronic patient, invariably the illness reflects a mixed infection, the individual components of which are

now active enough that they too must be treated. In addition, many latent infections which may have pre-

dated the tick bite, for example herpes viruses, can reactivate, thus adding to the illness.

An unfortunate corollary is that serologic tests can become less sensitive as the infections progress,

obviously because of the decreased immune response upon which these tests are based. Not surprisingly

the seronegative patient will convert to seropositive 36% of the time after antibiotic treatment is begun and

a recovery is underway.

The severity of the clinical illness is directly proportional to the spirochete load, the duration of infection,

and the presence of co-infections. These factors also are proportional to the intensity and duration of

treatment needed for recovery. More severe illness also results from other causes of weakened defenses,

such as from severe stress, immunosuppressant medications, and severe intercurrent illnesses. This is

why steroids and other immunosuppressive medications are contraindicated in Lyme.

Many collateral conditions result in those who have been chronically ill so it is not surprising that damage

to virtually all bodily systems can result. Therefore to fully recover not only do all of the active infections

have to be treated, but all of these other issues must be addressed in a thorough and systematic manner.

No single treatment or medication will result in full recovery of the more ill patient. Only by addressing all

of these issues and engineering treatments and solutions for all of them will we be able to restore full

health to our patients.

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It is clear that in the great majority of patients, chronic Lyme is a disease affecting predominantly the

nervous system. Thus, careful evaluation often includes neuropsychiatric testing, SPECT and MRI brain

scans, CSF analysis when appropriate, regular input from Lyme-aware neurologists and psychiatrists, pain

clinics, and occasionally specialists in psychopharmacology.

As an extension of the effect of chronic Lyme Disease on the central nervous system, there often is a

deleterious effect on the hypothalamic-pituitary axis. Varying degrees of pituitary insufficiency are being

seen in these patients, the correction of which has resulted in restoration of energy, stamina and libido,

and resolution of persistent hypotension. Unfortunately, not all specialists recognize pituitary insufficiency,

partly because of the difficulty in making the laboratory diagnosis. However, the potential benefits of

diagnosing and treating this justify the effort needed for full evaluation. Interestingly, in a significant

number of these patients, successful treatment of the infections can result in a reversal of the hormonal

dysfunction, and hormone replacement therapies can be tapered off!

The concept of a "therapeutic alliance" between the caregiver and patient must again be emphasized.

This means that the patient has to work with and become part of the medical team, and must take

responsibility for complying with the recommendations given, maintaining the best possible health status,

reporting promptly any problems or new symptoms, and especially in realizing that despite all our best

efforts, success in diagnosis and treatment is never assured. The medical team must make great efforts

to listen carefully to the patient and not be too quick to dismiss seemingly bizarre or illogical complaints.

CO-INFECTION

A huge body of research and clinical experience has demonstrated the nearly universal phenomenon in

Lyme patients of co-infection with multiple tick-borne pathogens. Significant numbers of Lyme patients

have been shown to also carry Babesia species, Ehrlichias, Anaplasmas, Mycoplasmas, Bartonellas and

viruses. Rarely, yeast forms have been seen in peripheral blood. Studies have shown that co-infection

results in a more severe clinical presentation, with more organ damage, and the pathogens become more

difficult to eradicate. It is known that Babesia infections, like Lyme Borreliosis, are immunosuppressive.

There are changes in the clinical presentation compared to when each infection is present individually,

with different symptoms, and atypical signs. There may be decreased reliability of standard diagnostic

tests, and most importantly, there is recognition that chronic, persistent forms of each of these infections

do indeed exist. As time goes by, I am convinced that even more pathogens will be found.

Therefore, real, clinical Lyme as we have come to know it, especially the later and more severe

presentations, probably represents a mixed infection. I will leave to the reader the implications of how this

may explain the discrepancy between laboratory study of pure Borrelia infections, and what front line

physicians have been seeing for years in real patients.

Because of this, I have a loose definition of “Lyme Disease”: I see it as more than an infection with

Borrelia burgdorferi, I see it as the illness that results from the bite of an infected tick, thus incorporating all

the pathogens and corollary conditions. I again emphasize this because all of these infections and

conditions must be addressed and treated if a full recovery is to occur.

The evaluation of a Lyme patient must begin with testing for all currently known tick borne pathogens.

Serological studies for Borrelia, Babesia, Bartonella and Ehrlichia should be combined where appropriate

with direct antigen assays. Antigen detection tests (antigen capture and PCR) are especially helpful in

evaluating the seronegative patient and those still ill or relapsing after therapy. Unfortunately, over a

dozen protozoans other than Babesia microti can be found in ticks, yet commercial tests for only B. microti

and WA-1 are available at this time, so as in Borrelia, clinical assessment is the primary diagnostic tool.

In Ehrlichiosis, test for both the monocytic and granulocytic forms. Many presently uncharacterized

Ehrlichia-like organisms can be found in ticks and may not be picked up by currently available assays, so

in this illness too, serologies are only an adjunct in making the diagnosis.

COLLATERAL CONDITIONS

Experience has shown that collateral conditions exist in those who have been ill a long time. The

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evaluation should include testing both for differential diagnosis and for uncovering other subtle

abnormalities that may coexist.

Test B12 levels , and be prepared to aggressively treat with parenteral formulations. If neurologic

involvement is severe, then consideration should be given to treatment with methylcobalamin (as outlined

below in the section on nutritional support).

Magnesium deficiency is very often present and quite severe. Hyperreflexia, muscle twitches, myocardial

irritability, poor stamina and recurrent tight muscle spasms are clues to this deficiency. Magnesium is

predominantly an intracellular ion, so blood level testing is of little value. Oral preparations are acceptable

for maintenance, but most need additional, parenteral dosing: 1 gram IV or IM at least once a week until

neuromuscular irritability has cleared.

Pituitary and other endocrine abnormalities are far more common than generally realized. Evaluate fully,

including growth hormone levels. When testing the thyroid, measure free T3 and free T4 levels and TSH.

Nuclear scanning and testing for autoantibodies may be necessary. Quite often, a full battery of

provocative tests is in order to fully define the problem.

Activation of the inflammatory cascade has been implicated in blockade of cellular hormone receptors.

One example of this is insulin resistance, which may partly account for the dyslipidemia and weight gain

that is noted in 80% of chronic Lyme patients. Clinical hypothyroidism can result from receptor blockade

and thus hypothyroidism can exist despite normal serum hormone levels. In addition to measuring free T3

and T4 levels, check basal A.M. body temperatures. If hypothyroidism is found, you may need to treat

with both T3 and T4 preparations until blood levels of both are normalized.

Neurally mediated hypotension (NMH) is not uncommon, and is diagnosed by tilt table testing.

Symptoms can include palpitations lightheadedness and shakiness especially after exertion and

prolonged standing, heat intolerance, dizziness, and fainting (or near fainting). NMH can result from

autonomic neuropathy and endocrine dyscrasias. If NMH is present, treatment can dramatically lessen

fatigue, palpitations and wooziness, and increase stamina. This test should be done by a cardiologist and

include Isuprel challenge. This will demonstrate not only if NMH is present, but also the relative

contributions of hypovolemia and sympathetic dysfunction. Immediate supportive therapy is based on

blood volume expansion (increased sodium and fluid intake and possibly Florinef plus potassium). If not

sufficient, beta blockade may be added based on response to the Isuprel challenge. The long term

solution involves restoring proper hormone levels and treating the Lyme to address this and the autonomic

dysfunction.

SPECT scanning of the brain- Unlike MRI and CT scans, which show structure, SPECT scans show

function. So SPECT scans give us information unattainable through X-rays, CT scans, MRI’s, or even

spinal taps. In majority of chronic Lyme Borreliosis patients, these scans are abnormal. Although not

diagnostic of Lyme specifically, if the scan is abnormal, the scan can not only quantify the abnormalities,

but the pattern can help to differentiate medical from psychiatric causes of these changes. Furthermore,

repeat scans after a course of treatment can be used to assess treatment efficacy. Note that improvement

in scans lag behind clinical improvement by many months.

If done by knowledgeable radiologists using high-resolution equipment, scanning will show characteristic

abnormalities in Lyme encephalopathy- global hypoperfusion (may be homogenous or heterogeneous).

What these scans demonstrate is neuronal dysfunction and/or varying degrees of cerebral vasculitis. To

assess the relative contributions of these two processes, the SPECT scan is done before and after

acetazolamide. If the post acetazolamide scan shows significant reversibility of the abnormalities, then

vasoconstriction is present, and can be treated with vasodilators, which may clear some cognitive

symptoms. Therapy can include acetazolamide, serotonin agonists and even Ginkgo biloba. Therapeutic

trials of these may be needed.

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Under certain circumstances, two SPECT scans are done. The second must be done on a different day,

after IV administration of Diamox (acetazolamide). This medication, also used for glaucoma, can actually

augment blood flow in the brain. This technique can help to differentiate whether an abnormal scan is the

result of poor blood flow, or poor neuron health.

You should not be given Diamox if you have:

- severe kidney/liver disease

- electrolyte abnormalities

- pregnancy

- sulfa allergy

- recent stroke

- high dose aspirin treatment

The most frequent side effects after Diamox administration are numbness of the face or arms, ears

ringing, nausea, and drowsiness. If present, these symptoms can last several hours or even extend into

the next day. The patient should not go to the test alone due to these possible side effects.

Two different researchers have provided evidence that B. burgdorferi, like many other pathogenic

bacteria, can produce neurotoxins . Clinical trials aimed at removing these toxins have proven helpful in a

small subset of pateints. I will discuss this in more detail in a later section.

LYME BORRELIOSIS

DIAGNOSTIC HINTS

Lyme is diagnosed clinically, as no currently available test, no matter the source or type, is definitive in

ruling in or ruling out infection with these pathogens, or whether these infections are responsible for the

patient's symptoms. The entire clinical picture must be taken into account, including a search for

concurrent conditions and alternate diagnoses, and other reasons for some of the presenting complaints.

Often, much of the diagnostic process in late, disseminated Lyme involves ruling out other illnesses and

defining the extent of damage that might require separate evaluation and treatment.

Consideration should be given to tick exposure, rashes (even atypical ones), evolution of typical

symptoms in a previously asymptomatic individual, and results of tests for tick-borne pathogens. Another

very important factor is response to treatment- presence or absence of Jarisch Herxheimer-like reactions,

the classic four-week cycle of waxing and waning of symptoms, and improvement with therapy.

ERYTHEMA MIGRANS

Erythema migrans (EM) is diagnostic of Bb infection, but is present in fewer than half . Even if present, it

may go unnoticed by the patient. It is an erythematous, centrifugally expanding lesion that is raised and

warm. Sometimes there is mild stinging or pruritus. The EM rash will begin four days to several weeks

after the bite, and may be associated with constitutional symptoms. Multiple lesions are present less than

10% of the time, but do represent disseminated disease. Some lesions have an atypical appearance and

skin biopsy specimens may be helpful. When an ulcerated or vesicular center is seen, this may represent

a mixed infection, involving other organisms besides B. burgdorferi.

After a tick bite, serologic tests (ELISA. IFA, western blots, etc.) are not expected to become positive until

several weeks have passed. Therefore, if EM is present, treatment must begin immediately, and one

should not wait for results of Borrelia tests. You should not miss the chance to treat early disease, for this

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