LymeNet Newsletter Volume 4 Issue 10

Volume: 4
Issue: 10
Date: 19-Jul-96

Table of Contents:

I. LDF: Notes from the IXth Annual LDF Scientific Conference (Part 3 of 3) II. About The LymeNet Newsletter

Newsletter:

*********************************************************************** * The National Lyme Disease Network * * LymeNet Newsletter * ***********************************************************************

IDX# Volume 4 - Number 10 - 7/19/96 IDX# INDEX IDX# IDX# I. LDF: Notes from the IXth Annual LDF Scientific Conference IDX# (Part 3 of 3) IDX# II. About The LymeNet Newsletter IDX#

I. LDF: Notes from the IXth Annual LDF Scientific Conference (Part 3 of 3) ----------------------------------------------------------------------- Sender: Lloyd E. Miller, DVM <[email protected]>

Notes from the Ninth Annual Scientific Conference Lyme Disease Foundation -- April 19-20, 1996 -- Westin Copley Plaza Hotel, Boston, Massachusetts, USA Prepared by Lloyd E. Miller, DVM ----------------------------------------------------------------------- Every effort has been made to report the speaker's statements and to report suggested drug doses accurately. However, typos do occur and as information gets passed around or edited mistakes can occur. The reader is cautioned to not take any medication before checking the accuracy of name and dose recommendations with the speaker.

Selected abstract statements have been included in the notes.

The notes themselves are from statements made by the speakers.

My editorial comments will be found in brackets like this [COMMENT].

Full abstracts are available electronically from the Lyme/Other Zoonoses section in the Public Health Forum on Compuserve.

*** Lyme Disease and the Clinical Spectrum of Antibiotic-Responsive Chronic Meningoencephalomyelitides - Kenneth B. Liegner, M.D.

FROM DR. LIEGNERS NOTES: * Background: During the past 10 years numerous individuals with Lyme disease having neurologic illness have been evaluated in depth. Four representative cases which have been worked up in detail illustrate the clinical spectrum, diagnostic conundrum, and therapeutic principles applicable in neurologic Lyme disease.

FALSE TEACHINGS IN LYME DISEASE:

1) Patients with late Lyme disease are almost invariably seropositive.

2) 28 days of intravenous antibiotic therapy is virtually always curative; continued symptoms following such treatment means that the diagnosis was wrong.

3) Neurologic Lyme disease is established by selective intrathecal antibody synthesis; in its absence one can feel confident there is no central nervous system infection by Bb.

4) It is easy to distinguish neurologic Lyme disease from multiple sclerosis.

CONCLUSIONS:

1) Borrelia burgdorferi produces chronic infection of the central nervous system.

2) Current therapeutic approaches, including intensive application of the most potent antibiotics known to man may be unable to cure the infection in some patients.

3) Seronegative Lyme disease may not be rare and seronegativity may predispose patients to the development of more serious neurologic sequelae of Lyme disease.

4) Adequate evaluation of patients to determine whether or not Lyme disease is present requires application of not only standard serologic methods, but also "cutting edge" direct antigen detection methods. One cannot depend on a single laboratory in serologic testing for Lyme disease.

5) Lyme immunoblots should be performed when Lyme disease is clinically suspected regardless of whether or not Lyme ELISAs are positive because Western blots can be positive or suspicious when ELISAs are negative. Perversely, a negative Western blot does not negate a positive ELISA since diagnostic Western blots can be very slow to evolve. ELISA and Western blot results can fluctuate over time and in response to application of treatment. It may take more than a decade for conclusive serologic proof of Lyme disease to develop in patients having clear clinical histories indicative of Lyme disease. Expansion of bands on Western blots over time is indirect evidence of chronic persisting infection.

6) In addition to allowing for observation for evidence of clinical improvement under empiric therapy (e.g. therapeuticus ex euvantibus), intensive treatment of patients who may possibly have neurologic Lyme disease may allow uncovering of serologic and/or direct antigen evidence of Lyme disease when "cutting-edge" methods are used serially.

7) Lyme disease may produce a neurologic illness virtually clinically indistinguishable from multiple sclerosis; CSF parameters thought to be pathognomonic for M.S. have been shown, at least in one case, to resolve and virtually normalize with intensive intravenous antibiotic therapy, and to reoccur with cessation of such therapy, along with relapse. Lyme disease may be one definable and treatable cause of multiple sclerosis, at least for some patients.

8) Systematic controlled prospective studies of "standard" versus intravenous antibiotic therapy should be considered for patients with multiple sclerosis.

9) Patients diagnosed with multiple sclerosis deserve to be fully re-evaluated using modern methods of study in serum and CSF to determine whether they might have neurologic Lyme disease. When clinically indicated, empiric trials of treatment along with intensive scientific study of clinical response, CSF parameters, standard and research assays for Lyme disease, and neuroimaging should be considered in individual cases of neurologic illness which may be either CNS Lyme disease or multiple sclerosis.

10) Lyme disease should be considered in the differential diagnosis of a wide range of neurologic syndromes. Other neurologic illnesses besides M.S. might similarly be studied using modern methods to determine if there may be an underlying borrelial etiology. Acknowledgment of the possibility of chronic persistent CNS infection by Bb opens the door to fruitful consideration of pathogenetic mechanisms and therapeutic interventions a variety of neurologic illnesses.

11) For some patients, prolonged antibiotic therapy, including intravenous therapy, is absolutely essential to permit neurologic recovery from chronic CNS Lyme disease, and to avert progressive neurologic deterioration.

12) Improved therapeutic approaches are desperately needed for Lyme disease in general and particularly for chronic neurologic Lyme disease. Treatment aimed at "sterilizing" the body of borrelia needs to be designed and trialed.

13) As long as there continues to be chronic persistent denial of the problem of chronic persistent infection in Lyme disease, necessary resources will not be allocated to permit improved solutions.

[ COMMENT: Dr. Liegner presented four very difficult cases of Lyme disease that demonstrated the difficulties of diagnosing and treating Lyme disease. The diversity of the disease regarding symptom presentation and the diversity of response to various therapies is also quite dramatic. The diagnosis of Lyme disease still must be made on clinical grounds with a high degree of suspicion by the doctor and confirmation of the diagnosis can take a very long time requiring investigational methods not currently available to the general medical profession. There can be no doubt that chronic persistent Lyme disease is due to chronic persistent infection based on the evidence presented with each of these cases. The cases demonstrated quite succinctly the truth of all the above statements. ]

*** Neurologic Complications of Late and Chronic Lyme Disease - Patricia K. Coyle, M.D.

FROM THE ABSTRACT: * Both the central and peripheral nervous systems are major target organs in this infection [B. burgdorferi]. * Late Lyme disease can be operationally defined as the symptomatic abnormalities associated with untreated B. burgdorferi infection or greater than three months duration. * Chronic Lyme disease can be operationally defined as the symptomatic abnormalities which are temporally related to B. burgdorferi infection, and which continue as persistent problems for months to years following antibiotic treatment. * Three characteristic syndromes have been reported in late Lyme disease. These are mild encephalopathy, characterized by problems in attention, memory, word retrieval, and processing; a chronic polyradiculoneuropathy; and encephalomyelitis with parenchymal involvement * Chronic Lyme disease is characterized by major cognitive, pain, and fatigue complaints.

FROM THE NOTES: * Major symptoms of chronic Lyme disease: cognitive, fatigue / malaise, generalized pain and headache. * Minor symptoms of chronic Lyme disease: dizziness, paresthesias, mood changes, and sleep disturbance. * Antibody findings in late and chronic Lyme disease: 1. IgM response (free and complexed) which is unusual finding because IgM is not generally found late in the course of an infectious disease. No current explanation. 2. IgG2 subclass of immunoglobins predominate - usually it is IgG1. 3. Antibodies to both OspA and B can be found. OspA reemerges in late disease. 4. Loss of antibodies resulting in seronegative status. 5. Autoantibodies - maybe anticardiolepin can be found. * Preliminary studies correlate cognitive defects with immune and CNS findings. * Quantitatively brain SPECT cerebral blood flow hypoperfusion deficit can be demonstrated. * Possible pathologic mechanisms of chronic Lyme disease : 1. Persistent CNS infection. 2. Persistent immune / inflammatory process.
3. A combination of 1 and 2. * Chronic Lyme disease clinically: Seropositive documented prior Lyme disease with appropriate antibiotic treatment with continued fatigue lasting > 6 months with no other documentable reason. * Clinical studies - illness duration 4 years - major problems: fatigue (81%), arthralgia (68%), myalgias (57%), headache (55%), and memory problems (53%). 81% of patients were still seropositive; 75% met CDC definition; 60% from hyperendemic areas.

[ COMMENT: This was an excellent presentation. Unfortunately not enough time was allotted. Therefore the notes only report a fraction of the information. I hope that Dr. Coyle will continue to publish the results of her very important studies. Of significance is that Dr. Coyle and others are beginning to change their opinions about chronic Lyme disease. Now recognizing that not only is there such an entity as chronic Lyme disease but also that its main involvement is the nervous system and that it indeed probably involves chronic persistent infection in at least some cases. To quote Dr. Coyle "true chronic Lyme disease is a neurologic disorder." ]

*** Lyme Disease vs. Depression vs. Somatization: Cognitive Tests & Functional Imaging - Brian A. Fallon, M.D.

FROM THE ABSTRACT: * Not infrequently physicians are faced with the task of differentiating persistent Lyme disease (LD) from Somatization and Depression. * The use of neuropsychological tests to differentiate Lyme-related vs. depression-related cognitive problems will be discussed. * The application of SPECT imaging to neuropsychiatry and to Lyme disease in particular will be addressed, emphasizing patterns typical of depression vs. Lyme encephalopathy.

FROM THE NOTES: * In a study of hypochondria involving 10 patients 5 did not have the condition. Of these 5 two had Lyme. * Lyme symptoms described: major depression; compulsive disorders; panic attacks; depersonalization ("spaced out"); anorexia nervosa (rare); disorientation (lose the way - lasts 3-5 minutes); violent outbursts; irritability; personality change; dementia; paranoia (fairly common); thought disorders; delusions; auditory / olfactory hallucinations. * Major depression 3 times more common in Lyme disease versus lupus or rheumatoid arthritis. * Clues to differentiate psychologic disorder from Lyme: 1. Atypical features of psychologic disorder in LD. 2. Atypical response to psycotropic medications in LD. 3. Failure to respond to previously effective psycotropic medications. 4. Prior history of psychologic disorder? 5. Family history of psychologic disorder? 6. History of exposure to Lyme disease? 7. Markers of Lyme disease - EM? * Common symptoms of late neuroborreliosis: *Intense* fatigue;
headache; light / sound sensitivity; cognitive tracking difficulties; dyslexia; disorientation; ; tingling / burning / numbness; shooting pains; insomnia / sleep disturbances; memory deficits (esp. retrieval and verbal fluency). * Fatigue has positive correlation in memory performance - depression does not. * SPECT scan of brain provides information about blood flow and metabolism: Increased blood flow = increased metabolism. 1. Scan results different in depression, Alzheimer's, Huntington's, stimulant intoxication, and obsessive-compulsive disorder. 2. Lyme scan has some similarities to Alzheimer's scan - more research is needed to determine the significance. 3. Swiss cheese pattern seen in Lyme disease SPECT scan. Definitely not normal. Appears to be reversible. This is not a subtle change. 4. Lyme disease scan differs from lupus, drug abuse (cocaine); multiple infarct dementia, chronic fatigue syndrome, and AIDS. * Possible pathogenic mechanisms of Lyme disease may involve
hypoperfusion of the brain and cellular dysfunction.

*** The Antimicrobial Agent, Melittin, Exhibits powerful in vitro Inhibitory Effects on the Lyme Disease Spirochete - Claude F. Garon, Ph.D.

FROM THE ABSTRACT: * Borrelia burgdorferi has demonstrated an extraordinary capacity to resist the effects of powerful eukaryotic and prokaryotic replication inhibitors. * In contrast, however, the antimicrobial agent, melittin, a 26 amino acid, cationic, amphipathic, peptide contained in honeybee venom, showed almost immediate and profound inhibitory effects. * The extraordinary sensitivity of Borrelia burgdorferi to this small peptide may provide both a useful research reagent and important clues to the development of effective drugs against Lyme disease.

FROM THE NOTES: * Melittin effectively interrupted Bb motility by 90 to 100% within seconds. * Melittin caused increased bleb formation. * Melittin affects inner surface membrane and permeability of the outer membrane. * Melittin is highly toxic to cells and not usable as a treatment option for Lyme disease in the form used in this study. * It is hoped that the compound can be used in some way to improve the efficacy of drugs that are poorly or totally ineffective to treat the disease.

[ COMMENT: I have seen mentioned since the meeting speculation that bee pollen might be of use in Lyme disease based on the presentation. It was emphasized that Melittin is in bee *venom* not pollen. ]

*** Tetracycline Therapy of Chronic Lyme Disease - Sam T. Donta, M.D.

FROM THE ABSTRACT: * Patients with clinical symptoms compatible with chronic Lyme disease. In the absence of a reasonable alternative diagnosis, both seropositive and seronegative patients were given a trial of oral tetracycline, 500mg tid, for 3 months. If symptoms improved, therapy was continued for up to 8 months. The results were: 1) 75% of patients with specific reactions by Western blot are negative by ELISA, 2) tetracycline therapy led to cure or significant improvement in 75% of patients; improvement did not usually begin until after 4-6 weeks had elapsed (range: 2-10 weeks), 3) there were no obvious differences in therapeutic responses between seropositive and seronegative patients, 4) 30% of improved patients had relapsing symptoms 1-6 weeks after stopping therapy; these symptoms improved either spontaneously over several weeks to months or with another 1-3 month course of tetracycline, 5) treatment failures seldom responded to alternative regimes,
including IV cephalosporins.

FROM THE NOTES: * Study involved 277 patients. The study was uncontrolled. * Major symptoms reported: fatigue (90%); Musculoskeletal (80%); cognitive disorders (50%); cardiac (10%); ocular (10%). * Only 29% were positive on both ELISA and Western blot tests. * Both tests were negative in 18.5 % of the patients. * Test results were discordant in 52% of the patients. * Cure was defined as no symptoms 1 year or more after trial. * Improvement was defined as >75% improvement as accessed by the patient. * Failure was defined as no sign of improvement. * Cure rate overall was 16%. * Failure rate was higher in female patients. * Age of patient didn't appear to influence outcome. * Presence of rash was not a factor in outcome. * The longer the duration of symptoms prior to treatment the higher the failure rate. 1. Less than 1 year: 28% cure; 67% improvement; 5% failure 2. 1 to 3 years: 15% cure; 75% improvement; 10% failure 3. Greater than 3 years: 11% cure; 70% improvement; 18% failure
* Symptom duration related to time of first improvement: 1. Less than 1 year improvement began in about 2 weeks; 2. One to 3 years improvement began in about 3 weeks; 3. Greater than 3 years improvement began in about 4-6 weeks; 4. Overall it took 1 - 1.5 months to improvement; 5. By 2 months 50 to 75 % improved; 6. By 3 months > 75 % improved. * Study resulted in improvement or cure in 82% of patients. * Mean course of treatment was 4 months. * Beyond 5 months of treatment more failures which reflects the duration of disease. * Untreated patients did much better than previously treated patients. * Question whether partial treatment or unsuccessful treatment changes the organism so it is less susceptible to subsequent treatment. * Serology proved to be nearly irrelevant to what was happening with the patients. * Repeated rounds of treatment are ineffective. * Reasons for choosing tetracycline for trial included the many poor responses reported for betalactam antibiotics
* Twice daily treatment with tetracycline failed often. Three times a day treatment did better if treated long enough. * Doxycycline is better absorbed but doesn't produce any better results.

*** Intramuscular Bicillin For Persistent Pediatric Lyme Disease - Louis Corsaro, M.D.

FROM THE ABSTRACT: * We conducted a chart review and follow-up of all patients with seropositive Lyme disease treated with IM Bicillin in a private pediatric out-patient office in a Lyme endemic area between 1993 and 1995. * Methods: The diagnosis of Lyme disease was based on at least one seropositive test and typical articular or neurological symptoms. Treatment consisted of either Bicillin LA or CR 1.2-2.4 million units administered weekly. Relapse was defined as the return of any symptoms which required greater than two weeks of Abx treatment. To assess efficacy, the longest period without symptoms prior to IM Bicillin was compared to the symptom free interval after bicillin. * 61 charts were reviewed of which 25 met study criteria for seropositive Lyme disease. Mean age at time of chart review 11.9 +/- 4.4 years. Mean age at time of Lyme disease onset was 9.4 +/- 4.3 years. Mean duration of symptoms prior to the administration of antibiotics was 16 +/- 32 weeks.
* All patients failed to sustain improvement after courses of oral antibiotics. Five children received IV antibiotics and all failed to sustain improvement. Of the twenty-five patients given IM PCN (Intramuscular Penicillin), the mean duration of IM treatment was 4-38 weeks (mean 14.5 +/- 8.9 wks; median 10.5 wks). * Of the 23 children available to assess relapse after treatment, 19 were symptom free, 3 had mild symptoms that did not require treatment, and 1 relapsed and was being retreated. * Conclusion: A chart review and follow-up studies suggest that intramuscular Bicillin may be a particularly effective treatment for children with antibiotic refractory persistent Lyme disease whether previously treated orally or with intravenous antibiotics.

FROM THE NOTES: * If the patient was going to relapse it generally occurred the second week following cessation of treatment. * If relapse occurred treatment was reinstituted for another 4 weeks before trying to stop again. This cycle continued until the patient was symptom free for two weeks beyond ending of therapy.

*** Use of Vancomycin in Chronic Persistent Lyme Disease - Joseph Burrascano, Jr., M.D.

FROM THE ABSTRACT: * Vancomycin has been shown to be effective in killing Borrelia burgdorferi in vitro, and a case report demonstrated the efficacy of this agent in a patient with ongoing symptoms unresponsive to other treatments. An expansion of that trial is now reported.

FROM THE NOTES: * Why Vancomycin? 1. Bb may be resistant to Beta Lactam antibiotics. 2. Bb persists despite long term aggressive antibiotics therapy. 3. No antibiotic is universally effective. * Vancomycin is antibiotic of last resort. Use in advanced LD treatment failure cases. It can have serious side effects. Other organisms can develop resistance to it. * Vancomycin can produce "red man syndrome": caused by histamine release if given too rapidly - LD patients are especially sensitive to this. Use antihistamine and give slowly. Drug was better tolerated as treatment progressed. * Ototoxic and nephrotoxic - especially earlier formulations - seems to be less so today. * Must use central line -Vancomycin is caustic. * Pulse therapy; Standard dose based on blood levels - start low and work up - given two days in a row per week - duration of therapy based on response. * Monitor peak and trough levels. * Study statistics. ( Dr. B. stated that the statistics in the printed
abstract were in error) 1. Nineteen patients were in study. 2. The average duration of therapy was 17 weeks (34 doses). 3. There were no major adverse reactions. 4. Two of 19 had no response. (probably not treated long enough.) 5. Six of 19 had partial response. (Rx stopped before medically should have - insurance ran out and other reasons.) 6. Eight of 19 had good response. (Some of these had had 43 weeks of IV therapy previously.) 7. Three of 19 were cured. (Possibly less ill to start with.) * Cures in patients treated earlier in the course of the disease. * Longer duration of treatment correlated with better outcomes. * Vancomycin effectiveness is enhanced with penicillin. * Dosage range of Vancomycin used was 500 to 1500mg every 12 hours based on blood levels.

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