LymeNet Law Pages
Case History Document
Joseph Natole, Jr. M.D., Petitioner v Michigan Board of Medicine, Respondent
Title: AMICUS BRIEF OF LYME ALLIANCE OF SOUTH CENTRAL MICHIGAN
|Entered By: Ira M Maurer/LymeNet||Date Created: 10/22/97|
|Document Type: Other|
STATE OF MICHIGAN
IN THE CIRCUIT COURT FOR THE COUNTY OF SAGINAW
In the Matter of )
JOSEPH NATOLE, JR., M.D. ) Case No. 96-15560-AA
Hon. Robert Kaczmarek
MICHIGAN BOARD OF MEDICINE, )
AMICUS BRIEF OF
LYME ALLIANCE OF SOUTH CENTRAL MICHIGAN
The Lyme Alliance of South Central Michigan (The Alliance), by counsel, for its Amicus Brief; states as follows:
The Lyme Alliance is a non-profit organization serving Southern Michigan with its mission to provide education and support to Lyme disease patients and the public at large. Many of the Alliance's constituents suffer from symptoms of chronic Lyme disease, a devastating and sometimes fatal illness which is at present controversial and incompletely understood. It is not the interest of the Alliance to second-guess Dr. Natole or the Board of Medicine as to the proper diagnosis or treatment of any of the thirty-odd patients at issue in the underlying proceeding, and the Court should be clear that the Alliance does not presume to do so.
However, what does concern the Alliance is the potential of this Court's ruling to limit or perhaps eliminate effective treatment for chronic Lyme disease patients. Simply put, if this Court should determine that Dr. Natole committed malpractice per se by prescribing extended antibiotics for patients believed to have chronic Lyme disease, as a matter of certainty physicians in Michigan (and elsewhere) will be reluctant to provide this type of therapy to Lyme disease patients in the future. As will appear below, the phenomenon of seronegative disease and persistent infection is real, and this Court's ruling has the potential to have a chilling effect on the treatment of this subset of Lyme disease patients.
Much is known about Lyme disease, which often responds quite well to antibiotics if treated early. However, important questions remain unanswered. The primary controversy at issue in this case involves the problem of persistent disease, namely whether chronic sufferers really have Lyme disease or have a "post-Lyme syndrome", or whether ongoing symptoms are linked to ongoing Lyme disease infection. This primary issue involves two secondary factors: first is the accurate diagnosis of Lyme disease in the setting of chronic disease and, second, for patients suffering from persistent infection, providing optimal therapy. Only by first addressing these factors can the ultimate issue of "standard of care versus malpractice" be intelligently assessed.
The Alliance will attempt to address these issues through peer-reviewed medical literature, a source of information both reliable and conservative, as well as other reference material. It is the hope of the Alliance that the Court will find this information of benefit to its overview of the issues presented in Dr. Natole's case.
1. Defining Standard of Care Versus Malpractice Generally
The Court of Appeals of Michigan has addressed the issue of "standard of care" at least once. In Shumake v. Travelers Insurance Company, 147 Mich App. 600, 383 N.W. 2d 259 (1985), the Court relied on a number of decisions from sister jurisdictions in determining whether a treatment is appropriate or "medically necessary." It is apparent from these decisions that some flexibility is contemplated. See, Abernathy v. Prudential Ins. Co. of America, 274 S.C. 368, 264 S.E. 2d 836 (1980) (equating "necessary treatment" with appropriate treatment); Victum V. Martin, 367 Mass. 440, 326 N.E. 2d 12 (1975) (necessary means "wise in light of the facts known at the time rendered"); McLaughlin v. Connecticut General Life Ins.. Co., 565 F. Supp. 434 N.D. Cal. 1983) ("necessary care" implies that care is in some degree beneficial to the patient); and Group Hospitalization. Inc. v. Levin, 305 A. 2d 248 CD.C. App 1973) ("necessary" means reasonably calculated to shorten and relieve pain and effectuate the most rapid recovery possible).
Courts have also addressed the related issue of "accepted medical practice." In Bucci v. Blue Cross-Blue Shield of Connecticut, 764 F. Supp. 728 (D.Conn. 1991), the Court was called upon to determine whether a certain cancer therapy was excluded under an insurance policy as "not being recognized as accepted medical practice." Id at 729. There, the Court weighed the insurer's judgment on "accepted medical practice" under a highly deferential arbitrary and capricious standard, echoing Shumake in its observation that the issue may be inherently ambiguous in the context of modern medicine:
The policy sets no standard by which that acceptance is to be measured. Should it then be reasonable, substantial, responsible, or other such imprecise standard? If the standard used is to be regarded as anything other than arbitrary or capricious, a procedure may be found not to constitute accepted medical practice only when there is no reasonably substantial, qualified, responsible, relevant segment of the medical community which accepts the procedure as properly within the range of appropriate medical treatment; under the circumstances of the case, as judged by the standards of the medical community. Much as in a malpractice setting, if the contemporary standards of the medical community would deem the treatment applied or used in the circumstances of the particular case, as consistent with the exercise of medical judgment, in the view of a reasonable number of practitioners qualified to treat the malady in question, then the treatment must be found to be accepted medical practice. If such were the case, then a finding that the treatment was not so accepted could only be arbitrary and capricious.
Id. at 732 (emphasis added).
The foregoing authorities are consistent with the common sense view taken in Shumake, which recognized that a "standard of care" might well encompass a range of competing treatments, each of which was an accepted medical practice even if only "a strong and viable minority" of practitioners employed a treatment, notwithstanding that the "weight of authority" might hold a contrary view. Shumake, 383 N.W.2d at 262.
Again, the court should be clear that optimal duration of treatment in the chronic setting remains to be defined. A recent editorial summarized the problem:
...[D]espite some strongly stated opinions and theoretical cost-benefit analyses... there has been no controlled study to evaluate the proper type and duration of antibiotic therapy in persistent Lyme disease. The presumption that 1 month of treatment should cure Lyme disease now appears to be incorrect, as many practitioners are finding that a longer duration of therapy is needed to achieve significant improvement or cure. With its slow in vitro replication time and its likely persistence as an intracellular infection, both longer duration of therapy and the use of intracellular-penetrating antibiotics, such as the tetracyclines and macrolides, would be predicted to be the optimal approaches to successful treatment. Properly designed clinical trials are needed to address these issues.
Donta, S.T., Lyme Disease: A Clinical Challenge, Journal of Spirochetal and Tick-Borne Diseases, Vol 2., No.3 (1995), Exhibit 1.
(Back to The Alliance Welcome Page)
2. The Controversy Over Persistent Infection Remains Unsettled.
In June of 1995, the National Institutes of Health (NIH) began soliciting requests for proposals to open a clinical trial evaluating the effectiveness of current regimens in the treatment of chronic Lyme disease:
Recently, the term Post-Lyme Disease Syndrome (PLDS) has been used to describe a condition of chronic or intermittent symptoms which is related to [Lyme Disease]. The cause of PLDS is not known, but at least two possibilities have been suggested. The first is that it is the manifestation of a chronic active infection of Borrelia burgdofferi that has escaped control or eradication with the use of conventional antibiotic regimens.
A second possibility is that PLDS may be due to permanent damage caused by the original infectious process . . . The purpose of this solicitation is to develop the research infrastructure needed to address two essential issues: the evaluation of therapeutic approaches to treat patients with chronic Lyme disease and the pathological basis/bases of this condition.
See, NIH Guide, Vol.24, No.22, June 16,1995, Exhibit 2.
It is readily apparent from the NIH's request for proposal that the cause of chronic Lyme disease remains unknown, with at least two competing theories for the reality of persistent symptoms. One of these theories is that espoused by Dr. Natole; ongoing symptoms are indicative of ongoing and active infection. This theory has neither been proven nor disproved by clinical trials. These unanswered questions are precisely why the NIH seeks to open clinical trials on the subject.
Looking again to Shumake, the unsettled state of knowledge in this area is highly relevant (and perhaps dispositive) of the question as to whether Dr. Natole was within the standard of care in his treatment of chronic Lyme patients. Shumake involved Laetrile for the treatment of cancer; the Court of Appeals noted that Laetrile is a useless and perhaps dangerous therapy.
Nonetheless, the Court ruled that Laetrile was "necessary" for the treatment of the patient's cancer in that case:
[S]ince medicine is an evolving science in which treatments are at one time regarded as valid and later discredited, we hold that a decision as to necessity shall be reviewed in light of knowledge which existed at the time the decision was rendered.
Shumake, 383 N.W.2d at 264.
[T]here was no definitive determination in the scientific community or the courts with respect to Laetrile's effectiveness through 1980 [the time the patient was treated]. Effectiveness had not yet been proven nor disproved. Indeed, these decisions indicate that the debate on Laetrile was still raging in 1980 and that notable institutions were still investigating its use ... Due to the diversity of opinion and Laetrile's questionable status at that time, we believe that a physician could properly exercise discretion so as to determine that Laetrile was necessary and required for the treatment of cancer during that period.
Id. at 265.
Shumake was recently applied to another case involving the appropriate treatment for chronic Lyme, Urffer v. Michigan Educational Special Services Association. et al, No.94-069462-ck, in the Circuit Court for the County of Jackson. In Urffer, the patients health plan had taken the position that extended treatment was not "medically necessary" - i.e., that it was malpractice to provide long-term antibiotic treatment for chronic Lyme disease, questioning both the diagnosis and treatment approach. See Urffer Transcript on Motion for Summary Disposition, pp.9-13. Exhibit 3. There, the defendants emphasized that the standard of care for the treatment of Lyme disease remains unsettled - as did the Court. In ruling for the plaintiff, Judge Perlos emphasized that . . . "it doesn't appear as though the treatment for Lyme disease is really settled in the United States" and that physicians could legitimately differ as to the interpretation of the data at this point. Id. at 14-15. Thus, under Michigan law applying Shumake, there is precedent holding that physicians do not fall below or outside the standard of care by providing extended antibiotic treatment for chronic Lyme disease.
Two things are certain at this point. First, as reflected by the NIH proposal, there is currently a debate in the medical community as to whether chronic Lyme disease represents a "post-Lyme disease syndrome" following eradication of the Lyme disease bacterium, or whether it signals ongoing infection. Secondly, no one in the medical community is currently able to definitively answer this question until well-designed clinical trials are completed. Until this question is conclusively settled, under Michigan law physicians cannot be faulted for treating patients upon the assumption that ongoing symptoms are caused by ongoing infection.
3. Treatment of Lyme Disease Generally
Lyme disease is a recently described bacterial infection caused by Borrelia burgdorferi, which, like the causative organisms of syphilis and relapsing fever, is a spirochete. Lyme disease is believed to be most commonly transmitted through tick bites.
Depending on the time of treatment, the bacteria are capable of spreading throughout the body and causing multi-system disorders affecting such organs as the skin, joints, the nervous system and the heart. Like its cousin that causes syphilis, the Lyme disease organism manifests itself through a host of symptoms which can mimic other disorders such as multiple sclerosis, chronic fatigue syndrome, and arthritis.
The disease has been described in three stages:
·Stage 1: Early manifestations frequently characterized by a rash and flu-like symptoms; ·Stage 2: Cardiac and early neurological manifestations characterized by atrioventricular conduction disorders and neurological problems such as short term memory loss, attention deficits, major depression, anxiety and panic attacks and extreme fatigue; and ·Stage 3: Chronic disabling arthritis and serious neurological manifestations such as seizures, obsessive/compulsive disorder, language processing difficulties, Alzheimer-type symptoms, nerve tissue damage to eyes and other organs including the brain, bladder problems, frontal lobe destruction; all of which may render patients non-functional.
There is little controversy that the earlier one treats Lyme disease, the greater the chance for a complete cure. Standard treatment for early Lyme disease (Stage 1) typically consists of common oral antibiotics (e.g. doxycycline or amoxicillin) administered for two to four weeks. Treatment for cardiac and early neurological problems characterizing Stage 2 Lyme disease infection may require intravenous antibiotics (e.g., ceftriaxone) for two to four weeks, or oral antibiotics for at least four months or until resolution of symptoms, whichever is longer. These regimens are sometimes, though by no means always, sufficient to treat Lyme disease which has not yet become entrenched in a chronic phase.
It is the treatment of Stage 3 Lyme disease which presents most of the controversy, as chronic disease often demands an open-ended approach using relatively high doses of antibiotics for an extended time. A standard medical text notes the following:
A general consensus is arising among clinicians most familiar with this disorder that late disease is the most difficult to treat and refractoriness to various treatment modalities is often seen. Intravenous ceifriaxone 2 grams per day for 14 days has recently been favored in publications for this stage. Unfortunately, the long-term efficiency in practice falls below what has been published. It is conceivable that late disease represents the greatest adaption of the microbe to its host environment. In turn, its reproduction rate may be far slower than its in vitro rate, leading to a greater need for prolonged therapy as well as optimal antibiotic tissue penetration. Treatment of the kind outlined for Stage lB parenchymal disease [i.e., longer oral therapy] is at times more efficient than a short course of intravenous ceftriaxone. Unfortunately, symptomatic flares as a result of treatment are often seen. This likely represents tissue deposition of immune complexes formed as a result of antibiotic-induced release of antigen from its parenchymous sites.* Interruption of treatment typically aborts the flares. A treatment approach that allows for ongoing clearance of immune complexes via scheduled interruption of treatment seems to be the most efficient oral therapy...Treatment should be continued beyond clearance of symptoms, or at least four months, whichever is longer.
*This refers to the phenomenon of the Jarisch-Herxheimer reactions, wherein the patient infected with a spirochetal disease actually appears to worsen on therapy as a reaction to toxins being released by dying bacteria.
Conn's Current Therapy, Lyme Disease, p. 104(1 991). Exhibit 4. Conn's Current Therapv is a standard reference text. That physicians are in the real world actually treating chronic Lyme disease with extended courses of antibiotics is corroborated somewhat by an informal poll of physicians attending conferences on Lyme disease in 1990. This survey suggested that "50% of the responders considered using antibiotics for a time greater than one year in a symptomatic seropositive Lyme disease patient. Almost that same number would extend therapy to 1 1/2 years if needed". See katzel, et at, "Is there a Consensus in Treatment of Lyme Borreliosis?", Lyme Disease 1991: Patient/physician Perspectives from the U.S. and Canada, pp.36-43(1991), Exhibit 5. Nevertheless, the medical literature continues to emphasize a lack of certainty: "Because there are only a few available studies comparing different treatment regimens in nervous-system Lyme borreliosis, recommendations of a specific treatment guideline is impossible at this time. Occasional treatment failures occur with current regimes and practice varies widely." Halperin, et at, Practice Parameters for the Diagnosis of Patients with Nervous System Lyme Borreliosis (Lyme Disease), Neurology 1996; 46:619-627, Exhibit 6.
Given an overview of the literature, the trend which is emerging recognizes the reality of persistent infection and is moving in the direction of longer and more aggressive courses of therapy. Initially, researchers were skeptical that antibiotics were helpful at all in the treatment of Lyme disease. See Steere, Erythema Chronicum Migrans & Lyme Arthritis: The Enlarging Clinical Spectrum, Ann. Int. Med. 1977; 86: 685-698. More recently, one of these researchers, Dr. Alan Steere, came around to the notion that antibiotics are effective and, while acknowledging that persistent infection may be the cause of chronic Lyme disease, notes that There is no convincing evidence that courses of antibiotics for many months are of benefit for the treatment of Lyme disease". See Steere Letter to Editor, Science, Vol.271, March 1996, Exhibit 7. Given that the context of the letter arises out of an article reporting the NIH plan to sponsor clinical trials, in essence Dr. Steere is simply stating that no clinical trials have been done. As will be demonstrated herein, there is abundant evidence from the medical literature reporting treatment failures requiring re-treatment with prolonged therapy.
4.The Phenomenon of Seronegativity
As stated earlier, the phenomenon of seronegative Lyme disease is very real. Because serologic tests are the most widely used, the realization that patients may test negative, but still be infected, must be acknowledged. As the following quote reveals, prudent practitioners, especially those treating patients in endemic areas, should not rely on negative serologic tests to conclude that a patient is not infected with Borrelia burgdorferi.
There are two areas of major clinical significance in which current knowledge about Lyme disease remains incomplete: diagnosis and the optimal treatment for patients with persistent symptoms. Because currently available serologic tests are not always reliable, Lyme disease remains a clinical diagnosis that is based on a constellation of typical patterns. Diagnostic difficulty arises when patients present with symptoms that are nonspecific or atypical for Lyme disease. If these patients test positive for Borrelia burgdorfed, they may be told that they have falsely positive test results. If they test negative, they may be told that they clearly do not have Lyme disease. Although the latter conclusions may be accurate in many cases, the absence of reliable laboratory tests makes such conclusions impossible to draw definitively. Although the prevalence of patients with seronegative Lyme disease is not known, such patients clearly do exist. Faced with diagnostic uncertainty, some clinicians may choose not to treat in order to avoid the risks of antibiotic therapy. Other clinicians who work in endemic areas may recommend an empirical trial of antibiotics because of what they judge to be a greater risk that a potentially multi-systemic chronic infection may progress if untreated.
Fallon, et al.1 Lyme Disease: A Neuropsychiatric Illness, Am. J. Psychiatry, November 1994, 151:11 at 1579, Exhibit 8.
The existence of seronegative Lyme disease has been well-documented. In fact, at least one study, conducted by J. L. Bakken, has shown that over one-half of the forty-five laboratories studied reported falsely negative values in a known positive serum sample from a patient with Lyme disease. See Cintron, et at, Spirochetal diseases of the nervous system, Current Opinion in Neurology, 1994,7:217-222 at 220, Exhibit 9. Another study revealed that despite a negative serology for Lyme disease, there was laboratory evidence of active infection in the patient's cerebro-spinal fluid even after prolonged antibiotic treatment. See Lawrence, et al., Seronegative Chronic Relapsing Neuroborreliosis, Eur. Neurol., 1995,35:113-117, Exhibit 10. Yet another study revealed a patient who was seronegative for five years, during which she sustained "severe and irreversible neurologic injury." See Liegner, Lyme Disease: The Sensible Pursuit of Answers, Journal of Clinical Microbiology, Aug.1993, Vol.31, No. 8:1981-63 at 1961, Exhibit 11. Dr. Steere's article on Lyme disease reports still another study in which seventeen patients who demonstrated clinical symptoms of Lyme disease were seronegative. These patients' mononuclear cells later showed the presence of Borrelia burgdorferi. See Steere, Lyme Disease, New England Journal of Medicine, Aug.1989, Vol.321, No.9: 586-596 at 592, Exhibit 12.
Conversely, other studies have demonstrated the existence of false-positive serologic results. One such study found four patients who tested positive after serologic tests, then determined later that these patients did not suffer from Lyme disease. See Kaell, et al., Occurrence of Antibodies to Borrelia Burgdorferi in Patients with Non-spirochetal Subacute Bacterial Endocarditis, Annals of Internal Medicine, Dec.1993, Vol.119, No.111:1079-1083, Exhibit 13.
Data on the prevalence of seronegative Lyme disease patients has been hindered by the lack of knowledge surrounding seronegativity. Seronegativity, however, must be acknowledged as a very real occurrence with regard to Lyme disease, as the following passage by Dr. Kenneth Liegner indicates:
Many clinicians and scientists admit that seronegative Lyme disease exists but maintain that it is a rare phenomenon. Indeed, for study purposes, many academic centers have specifically excluded patients presenting with symptoms possibly compatible with Lyme disease who are seronegative. This may be a serious conceptual and methodological error. Present understanding of the human immune response to Borrelia burgdorfed infection is rudimentary. . . In patients for which a state of antigen excess exists, free antibodies may escape detection and may be revealed only after use of methods to dissociate such immune complexes. Thus, the very patients who are unable to generate detectable levels of free antibodies, who are least apt to contain the infection, and who may present with the more serious illness among those with Lyme disease are least likely to be offered treatment ... seronegativity is a real phenomenon in Lyme disease, occurring in both early and late stages.
Acceptance of the possibility of seronegative Lyme disease makes empirical treatment for patients in whom Lyme disease is clinically suspected imperative, even if serologic tests are negative.
See Liegner, supra at 1961-62 (emphasis added), Exhibit 11.
Due to the inherent problems associated with other testing methods, diagnosis of Lyme disease is most commonly performed using serological tests. See Halperin, et at, supra at 619, Exhibit 6; Cintron, et al., Spirochetal Diseases of the Nervous System, Current Opinion in Neurology, 1994, 7:217-222 at 220, Exhibit 9. Even so, limitations in current diagnostic technology result in problems because the serological tests are indirect; they detect only possible exposure to Borrelia burgdorferi, not active infection as a result of exposure to the organism. See Halperin, supra, Exhibit 6; Cintron, et al., supra, Exhibit 9. Stated differently, currently available serological tests, such as ELISA, rely on the immune response following exposure to Borrelia burgdorferi, but they can be unreliable, with both false positive and false negative results. See Fallon, et al., supra at 1573, Exhibit 8. The unreliability of results of serological tests is compounded by the fact that the interpretation of serologic tests for anti-Borrelia burgdorferi antibodies is difficult. See Halperin, et al., supra at 621, Exhibit 6.
The literature also suggests that, due to the unreliability of the available tests, the diagnosis of Lyme disease must be made on a clinical basis. See Letters to Editor, JAMA, 1993, 270:2682, Exhibit 14; see also Liegner, Borrelia burgdorferi - Seek and Ye Shall Find, Expanding the Envelope, Journal of Spirochetal and Tick-Borne Diseases, 1994, Vol. 1, No.4, at 80, Exhibit 15.
Seronegative results may be present for a myriad of reasons. If a patient is tested too early after an initial infection, the patient may not have acquired an antibody response. Some cases have shown that antibiotic treatment at an early stage in the infection may actually short circuit the humoral immune response. Further, free antibodies may not be detected due to the Borrelia antibodies being bound within circulating immune complexes. Finally, variations in antigenic standardization of Lyme disease assays among laboratories may result in both false positive and false negative results. Fallon, et al., supra at 1574, Exhibit 6. Another problem with serological tests lies in the fact that the organism is tissue-tropic, meaning that the absence of detection in body fluids does not preclude the presence of the organism in interstitial, intracellular, and parenchymal sites. See Liegner, supra at 79, Exhibit 15.
Some of the other tests used to detect infection are the Western Blot, culturing of the spirochete, and polymerase chain reaction (PCR). The principal role of the Western Blot test is to differentiate false from true-positive serological tests. The Western Blot test is not effective in aiding physicians who diagnose clinical symptoms in patients who are seronegative, as it does not detect the presence of Bonrelia burgdoferi in seronegative cases. Id.
Proving infection by direct culture is not usually feasible, as the Borrelia burgdorferi organism is very difficult to culture from clinical material. According to the literature, the culture method is not widely applicable because the necessary specialized media are not generally available and successful culturing requires considerable technical skill. See Halperin, et al., supra at 621, Exhibit 6. PCR testing is also unreliable, as false-positives due to contamination make this technique problematic, while false negatives also occur. Another problem with PCR is that it cannot determine whether the DNA is from live bacteria, as opposed to residual proteins from dead organisms. Id. at 622, Exhibit 6.
In short, existing tests, while helpful, are not completely reliable and both sides agree that ultimately Lyme disease remains a clinical diagnosis. It cannot, therefore, be said that a physician who treats a seronegative patient for Lyme disease based upon clinical symptoms, has fallen below the applicable standard of care. To the contrary, until reliable testing is available, the prudent practitioner will continue to interpret existing tests as non-definitive and to be considered only as one factor of the entire clinical impression.
5.The Phenomenon of Persistent Disease.
Inextricably intertwined with the question of the proper treatment and duration of treatment of Lyme disease is the problem of persistent disease. One school of thought, championed by Dr. Steere, holds that only a small percentage of patients who are incompletely treated initially continue to have active disease, and that the vast majority of chronic sufferers previously administered two to four week courses of antibiotics are suffering from a post-Lyme disease syndrome, or were misdiagnosed and suffered from something else, such as arthritis or fibramyalgia. See Steere, et al, Over-diagnosis of Lyme Disease, JAMA, 1993,269:1812, Exhibit 16.
It is apparent from the response of the medical community to Steere's article in the JAMA that his views are not universally held. See Letters to Editor, supra, Exhibit 14. Steere was criticized for ignoring NIH guidelines for the clinical diagnosis of Lyme disease and for placing unwarranted reliance on admittedly unreliable testing. Moreover, some physicians noted that the assumption that recurrence of symptoms should actually be attributed to chronic fatigue or fibromyalgia was essentially a leap of faith in the absence of a test demonstrating cure, and in the absence of any tests demonstrating the existence of these two syndromes. Id.
The most damaging data refuting the Steere school of thought involves the many documenting active and persistent infection following "curative" doses of antibiotics. One study evaluating treatment of patients with neurological problems observed that:
Six months after treatment [with 2 grams of intravenous cefiriaxone for 14 days], more than one-third of the patients either had relapsed or were no better. In addition, more than half had previously received antibiotic therapy thought to be appropriate for their stage of disease and still had progression of the illness. The likely reason for relapse is failure to eradicate the spirochete completely with a two week course of intravenous cefiriaxone therapy.
Logician, et al., Chronic Neurological Manifestations of Lyme Disease, New England Journal of Medicine 199O; 323:1438-44, at 1443, Exhibit 17. Over half of the patients in this study group had already been treated with antibiotics prior to receiving intravenous ceftriaxone, suggesting that more aggressive courses of therapy are necessary to eradicate the organism. Dr. Steere was one of the authors of that study.
In an earlier case report authored in part by Dr. Steere, physicians reported an instance where a woman with Lyme disease failed to respond to a two-month course of antibiotics considered to be adequate, ultimately dying of the disease. Spirochetes were recovered from the plaintiff's lymph nodes despite high doses of antibiotics, the physicians admitting frankly that there was no clear explanation for the treatment failure. See Kirsch, et al., Fatal Adult Respiratory Distress Syndrome in a Patient With Lyme Disease, JAMA 1988; 259:2737-2739, Exhibit 18.
In another case, a woman with Lyme disease was treated with a six-month course of antibiotics. Despite being seronegative following treatment, the patient again became symptomatic. The patient developed the rash characteristic of Lyme disease; a skin biopsy showed active Lyme disease, confirmed by polymerase chain reaction tests specific to Borrelia burgdoferi DNA. Symptoms resolved after ten months of therapy, leading the physicians to conclude that there is a "need to treat some patients who have Lyme disease for longer than currently recommended regimens, which we believe are inadequate for such patients." See Liegner, et al., Recurrent Erythema Migrans Despite Extended Antibiotic Treatment With Minocycline in a Patient With Persisting Borrelia Burgdorferi Infection, Journal of the American Academy of Dermatology, 1993; 28:312-14, Exhibit 19.
Similarly, a Swedish group was able to cultivate Lyme disease spirochetes from the skin lesions of patients who had high levels of antibodies to Lyme disease, some of whom had the disease for over ten years. This led the researchers to conclude that the spirochetes could survive in the human body for a considerable time, despite immune defenses. See Asbrink, et al., Successful Cultivation of Spirochetes From Skin Lesions of Patients With Erythema Chronicum Migrans, Acta. Path. Microbiol. Immunol. Scand., Sect. 8, 93:161-163,1985, Exhibit 20.
An Italian group documented a case in which a Lyme disease patient was treated with intravenous penicillin for three weeks, which proved ineffective; spirochetes were subsequently identified in a biopsy of the patient's spleen. These physicians remarked that: "The discovery of borrelia-like spirochetes in the spleen of this patient two years after the onset of clinical manifestations supports the view that the infection in [Lyme disease] may undergo a chronic course. If treatment of [Lyme disease] is inadequate, the spleen could represent a sanctuary of the spirochetes and show evidence of chronic reaction" See Cimmino, et al., "Spirochetes in the Spleen of a Patient With Chronic Lvme Disease". Am. J. Clin. Pathol., 1989; 91:95-97, Exhibit 21.
Later, Cimmino reported the cases of two patients with chronic Lyme arthritis who had failed to be cured with short courses of antibiotics. One patient required six months of penicillin before being cured, leading these physicians to conclude that long courses of antibiotics were necessary to sustain the therapeutic levels of drugs needed to inhibit replication and to kill the organism when it left the spleen, synovial membranes or intracellular sites serving as sanctuaries. See Cimmino, et al., Long Term Treatment of Chronic Lyme Arthritis With Benzathine Penicillin, Ann. Rheum. Dis. 1992; 51:1C07-1OCS, Exhibit 22.
In another case, a woman was treated with a combination of antibiotics believed to be effective; the patient progressed and worsened despite high doses of antibiotics. Following surgery, electron microscopy of a ligament specimen revealed spirochetes deeply entrenched in this tissue, suggesting that the ligaments provided a privileged site in which the spirochetes were protected from otherwise lethal concentrations of antibiotic drugs. Subsequently, live spirochetes were cultured from these tissue samples, confirming that the bacteria had managed to evade the drugs. See Haupi, et al., Persistence of Borrelia Burgdorferi In Ligamentous Tissue From a Patient With Chronic Lyme Borreliosis, Arthritis and Rheumatism, Vol.36, No.11, November, 1993, pp.1621-1626. Exhibit 23.
Another report documents persistent spirochetal infection in the synovial tissues of a Lyme disease patient with arthritis. Despite multiple courses of antibiotics, tissue examination of a biopsy specimen revealed intact Lyme disease bacteria, consistent with persistent infection. See Battafarano, et al., Chronic Septic Arthritis Caused by Borrelia burgdorferi, Clinical Orthopaedics and Related Research, No.297, pp.238-241(1993), Exhibit 24.
In another case, a man from Missouri was treated with high doses of penicillin for six months; he relapsed and spirochetes were subsequently cultured from his blood. The patient was placed back on antibiotics and responded to therapy. See Masters, et al., Spirochetemia After Continuous High-Dose Oral Amoxicillin Therapy, Infectious Disease in Clinical Practice, Vol.3, No.3, pp.207-2C8, Exhibit 25.
Other doctors reported six instances in which spirochetes were isolated from cerebrospinal fluid and skin biopsies; these patients had previously been treated with doses of penicillin and tetracycline otherwise believed to be curative. See Preac-Mursik, et al., Survival of Borrelia Burgdorferi in Antibiotically Treated Patients With Lyme Borreliosis, Infection, 17 (1989) No.6, Exhibit 26.
In a study done to test the hypothesis that Lyme disease spirochetes persist in causing Lyme arthritis, the synovial fluid of six of seven patients tested positive by polymerase chain reaction. The researchers concluded that their data "show the intra-articular persistence of Borrelia burgdorferi nucleic acids in Lyme arthritis and suggest that persistent organisms and their components are important in maintaining ongoing immune and inflammatory processes even among some antibiotic-treated patients." See Bradley, et al., The Persistence of Spirochetal Nucleic Acids in Active Lyme Arthritis, Ann. Int. Med. 1994; 120:457-489, Exhibit 27.
Preac-Mursic described a patient with blurred vision who had been treated with two separate month-long cycles of tetracycline believed to be curative for Lyme disease. After several years of chronic symptoms, her physicians were able to culture Lyme disease spirochetes from an iris biopsy. In discussing this and several similar cases, the authors emphasized that the cause of persistent disease is poorly understood at this time:
How often Borrelia burgdorferi may persist in the [cerebrospinal fluid], skin, or other tissues after therapy or its effect in producing atypical manifestations of the disease is not known. The reason for the persistence of Borrelia burgdorferi in patients after the treatment with antibiotics is not completely understood. A number of factors may play a role, e.g. virulence of Borrelia burgdoferi, tissue penetration with antibiotics, insufficient antibiotic therapy (either duration or dose), intracellular location of borrelise, possibility of Borrelia burgdorferi survival in tissue and certain types of cells, and not least the immunity of patients. The capacity of Borrelia burgdorferi to hide in various human tissue (heart muscle, spleen, brain) and an insufficient antibiotic tissue level are critical for the therapy.
See Preac-Mursic et al., First Isolation of Borrelia Burgdorferi From an Iris Biopsy, J. Clin. Neuro-onthalmol., Vol.13, No.3,1993, Exhibit 28.
MacDonald, et al., investigated the implications of the slow growth cycle of Lyme disease bacteria in a study of sixty-three patients; sixteen biopsies yielded spirochetes after incubation periods of up to ten months, suggesting that the organism may be very slow to replicate in some situations. The clinical significance of this was explained as follows:
Aggressive antibiotic therapy of Lyme borreliosis may fail to eradicate the clinical symptoms of the infection. Some cases that appear to be treatment failure may actually be due to reinfection. However, at least two well-documented cases of Lyme borreliosis have been described which demonstrate that the infection may relapse in spite of parenteral antibiotic therapy administered over a time of course which would be expected to kill all spirochetes with a cell division cycle of between 6 to 12 h[ours]. Antibiotics are only able to kill actively dividing borrelia. If a borrelial cell does not divide at least once during the period of antibiotic therapy, it may persist in the host and produce relapse or recrudescence of disease. Therefore, some cases of Lyme borreliosis may require prolonged periods ofantibiotic therapy to influence those cell lines of Borrelia burgdorferi with a very slow cycle of cell division.
See MacDonald, et al., Clinical Implications of Delayed Growth of the Lyme Borreliosis Spirochete, Acta Tropica, 48 (1991)89-94, Exhibit 29. Thus, the clinical observation that prolonged therapy is often needed to eradicate the organism is supported by laboratory observations, and is not merely anecdotal.
Other studies have documented the ability of the spirochetes to shield themselves from antibiotics by hiding within skin fibroblasts, suggesting that Lyme disease may be sequestered in a protective niche within the host. Long-term survival is made possible since antibiotics are much less concentrated within the cells than in plasma fluids. This suggests the need for antibiotics such as the macrolides, which are superior to penicillin and tetracycline in penetrating cell walls.
See Klempner. et al., Invasion of Human Skin Fibroblasts By the Lyme Disease Spirochete, JID 1993:167 (May), Exhibit 30; Georgilis. et al., Fibroblasts Protect the Lyme Disease Spirochete, Borrelia Burgdorferi. From Ceftriaxone in Vitro, JID 1992:166 (August), Exhibit 31. In fact, studies have corroborated this hypothesis by demonstrating that antibiotics with good intercellular penetration (doxycycline and erythromycin) were more effective than penicillin when the spirochete was cultured in the presence of human cells thought to be responsible for the protective effect. See Brouqui, et al., Eucaryotic Cells Protect Borrelia Burgdorferi From the Action of Penicillin and Ceifriaxone but Not From the Action of Doxycycline and Erythromycin, Antimicrobial Acents and Chemotherapy, June 1996, p.1552-1554, Exhibit A.
A study recently published in Infection reports the striking finding that the spirochete may actually change form in response to antibiotics such as penicillin. In samples of spirochetes persisting after exposure to penicillin, 60-80% had an atypical form many lacked cell walls, had their rates of replication slowed, or assumed an encysted form. Since penicillin and similar antibiotics are only active against microbes with cell walls in the stage of active multiplication, this ability to alter form may be an important reason underlying the organism's ability to resist antibiotics and persist in a chronic form. See Preac-Mursic, et al., Formation and Cultivation of Borrelia Burgdorferi Spheroplast-L Form Variants, Infection 24(1996) Vol.3, Exhibit B.
In discussing the studies documenting persistent infection, one Lyme disease expert summarized the clinical conclusions a practitioner might draw from such data:
These observations lead one to the conclusions that certain subsets of patients with Lyme disease may require prolonged antibiotic treatment and that presently available chemotherapeutic modalities may be suppressing but not eradicating the infection. Thus, individuals who have demonstrated relapses following aggressive treatment may require an open-ended antibiotic approach provided they are deriving clinical benefit and are not experiencing any adverse effects and that they wish to be treated.
See Liegner, Lyme Disease: The Sensible Pursuit of Answers, Journal of Clinical Microbiology, Aug.1993, pp.1961 - 1963, Exhibit 11. Liegner's approach, as well as that of Paul Lavole, Exhibit 4, logical and based upon reliable data, is essentially that which is faulted by the Board of Medicine - "allowing an open-ended antibiotic approach" to patients deriving clinical benefit who wish to be treated in that fashion.
It is important to note that Dr. Joseph Burrascano, Jr., M.D., whom Dr. Natole has generally subscribed to in developing his treatment regime, has continuously published treatment options and guidelines for Lyme disease from early (stage 1) through chronic (stage 3) Lyme disease since 1989. Dr. Burrascano indicated the difficulties of treating late stage Lyme disease while utilizing a wide range of oral and intravenous antibiotics. "Currently, no definitive tests are available for assessing the complete absence of spirochetes in patients. Only through a careful evaluation of individual clinical data can the optimum duration of treatment be established. Our observations indicate that if antibiotic therapy is terminated before the major active symptoms have cleared, a relapse is likely." See Internal Medicine For the Specialist - Rheumatology/Infectious Diseases, IM I Vol 10 No.12, December, 1989, pages 102-107, Exhibit C. et al., Dr. Burrascano currently states "The diagnosis of Lyme disease is made on clinical grounds, as no currently available test, no matter the source or type, is definitive in confirming whether an infection with Borrelia burgdorferi is present, or if so, whether the infection is responsible for the patient's symptoms." See 1997 Conn's Current Therapy, published by W.B. Saunders Company, edited by Robert E. Rakel, M.D., Professor and Chairman, Department of Family Medicine, Associate Dean for Academic and Clinical Affairs, Baylor College of Medicine, Houston, Texas. Latest Approved Methods Of Treatment For The Practicing Physician. Lyme Disease - method of Joseph J. Burrascano, Jr. M.D. East Hamptom, New York, page vii and pages 140-143, Exhibit D, et al..
Based upon the foregoing, Dr. Natole and physicians like him are hardly out of the mainstream. There is overwhelming evidence to support the hypothesis that some patients are not cured with short courses of therapy; that persistent disease can be demonstrated both clinically and in the laboratory, and that such patients in many cases respond to aggressive retreatment. One could convincingly argue that a doctor who failed to treat a patient presenting with symptoms of chronic Lyme disease might fall below the standard of care given what we now know about persistent infection and treatment failure. Until clinical trials are completed, this issue remains open for argument; in the interim, the standard of care must continue to make room for both approaches.
Based upon the foregoing, The Alliance respectfully submits that a number of points relevant to Dr. Natole's case are supported by the medical literature on Lyme disease. First, serological tests for Lyme disease remain somewhat unreliable and cannot be blindly relied upon to confirm or rule out Lyme disease; Lyme disease remains a clinical diagnosis. Second, the phenomenon of persistent infection is real and, therefore, extended courses of antibiotics are necessary to eradicate residual disease. Thirdly, the school of thought recognizing the problem of persistent disease and the need for extended antibiotic therapy is based on sound scientific theory and laboratory and clinical data. This group of physicians is not a fringe element of quacks, but rather the group that has been paying attention to the growing body of literature on this illness. Fourth, until well-designed clinical trials are able to answer a number of important questions, a legitimate debate will continue to rage.
From a scientific standpoint, there is no basis for the Board of Medicine to arbitrarily impose a standard of care which allows only short courses of therapy, and only then based upon positive serological tests. The assertion that there is no such thing as persistent disease is simply not supported by the data in peer reviewed scientific literature or other reference material. To disregard this data and impose an arbitrary standard of care is not good medicine and does a great injustice to patients who need treatment for chronic Lyme disease.
LYME ALLIANCE OF
SOUTH CENTRAL MICHIGAN
Douglas M. Coleman
HUDGINS CARTER & COLEMAN
515 King Street, Suite 340
Alexandria, VA 22314
Martin G. Lozier
Charles H. Ayrnond, P.C.
100 5. Jackson Street, Suite 206
Jackson, MI 49201
The Lyme Disease Network of NJ, Inc.
43 Winton Road
East Brunswick, NJ 08816