Dr. Baker: Well thank you very much Dr. Sood and we have Dr. Ken Liegner please come to the podium for his presentation.

Dr. Liegner: Thank you very much. I’d like to very much thank the IDSA panel for accepting my submission of evidence and for inviting me to present today. I’d like to ask you all as in the Joe South lyric to walk a mile in my shoes. In college my concentrations were in Ancient History and History of Science with Prof. Lauren Graham at Columbia. While in college I worked as an orderly in the Neurologic Institute of New York and Director of Nursing Martha Haber I saw a lot and I learned a lot while there. Between college and medical school I worked as a research assistant for Malcolm Carpenter author of the renowned text Human Neuroanatomy. During this time I also precepted Columbia and P & S students in their neuroanatomy lab. At my exit interview from New York Medical College where I graduated [Inaudible] 00:01:07] urged me to aim high, that is what I have tried to do in both my personal and professional life. During my post graduate training I did one year of anatomic pathology including some 20 to 30 complete autopsy my department chair at New York Medical College [Inaudible] 00:01:25] and my chief at Westchester Medical Center William Fillmore taught me how to work up cases and how to analyze them. After completing a residency in Internal Medicine I trained in critical care medicine in the Department of Surgery at Westchester Medical Center under Lewis R.M Dargacio a pioneer of surgery critical care and John Sovino who ran the surgery critical care unit. They taught me how to care for individuals with serious multi system illness and the principles of titrate therapies. Three months in the Medical Center with Jane Pitro and Rogers Salisbury taught me never to give up and that where there is life, there is hope. At Westchester Medical Center I became acquainted with and friends with Garry Wimeser and we have maintained cordiality despite our diametrically opposed positions on Lyme disease in fact Garry critiqued for me my first published article on Lyme disease concerning the use of Minocycline. After completion of my fellowship I worked a few miles from here at Washington Hospital Center under Howard Champion and Austin Andre in Hospital Surgical Critical Care and Med Star units. I then returned to Westchester where I opened a private practice in Armonk, I knew virtually nothing about Lyme disease. Unwittingly though, I had planked myself down smack in the middle of a virgin epidemic of Lyme disease and like any internist I couldn’t help but see patients with Lyme disease. I found that many of these patients did not behave the way the books said they should, I would treat them with antibiotics and they would get better but when antibiotics stopped the symptoms would bounce right back. If I resumed antibiotics the symptoms would improve but often returned once again when treatment was stopped, it was very puzzling. I became friendly with medical entomologist Jolene Fish whose office at the time was about half a mile away from mine. He introduced me to colleagues from the CDC Wayne Gubler, David Dennis Roy Campbell, Joe Pizemann, Tom Kuan, Gary Muffin and Leonard Mayer among others. They knew that I was seeing patients with Lyme disease and they asked me to send them specimens of urine, serum and CSF from the patients I was seeing, it was an honor to be able to collaborate with such fine scientists. Unbeknown to me CDC forwarded some of my patients’ specimens onto Claude Garang and David Derwood at the NID’s Rocky Mountain in Hamilton Montana. Garang, Derwood and Cowan had done fundamental on the basic biology Borrelia burgdorferi including what they published in scanning

microscopy. They discovered that although the number of Borrelia in tissues might be few these spirochetes collaborated zillions of membranous blebs. Garang, Derwood and Tom Schwann went on to develop an antigen capture method of detecting these blebs using immuno electron microscopy. They published their meticulous work which included negative controls in the journal of clinical microbiology in 1989 applied to serum, urine and tissues from infected ticks mice and dogs to humans. Claude Garang forwarded these grid of distributed test results on my patients comparing RML antigen capture method and urine to 3 CDC antibodies and serum, I call your attention to this line which showed the largest group of patients 37 out of 51 which tested positive under direct antigen detection using the RML antigen capture and negative online antibody serum. We reported these results in an abstract at the 5th International Congress on Lyme Borreliosis in Arlington Virginia. There was an incredible diversity of syndromes in the patients who tested positive one of them was a young woman from Southern Cali who had eruption consistent with Erythema-migrans who are known to develop fatal hypertension. Study results in these direct antigen detection method suggests seronegative Lyme Borreliosis is not rare and support the hypothesis that burgdorferi can persist in human host despite intensive antibiotic regiments. The RML antigen capture essay was very labor-intensive requiring electron microscopy and was not suitable as a high through put method for commercial or clinical purposes. Results suggested there was a deep complexity to Lyme disease not adequately reflected by antibody testing alone. The journal of the American Academy of Dermatology published of a 60 year old social worker from the Bronx who developed erythema migraines in her right thigh 3 weeks after returning from a trip to Bear Mountain. She consulted me after treatment with 10 days of Tetracycline by her regular physician failed to resolve her rash other symptoms. I treated her with 3 months of Minocycline the rash faded and her other symptoms resolved. 3 months later her original rash reappeared and a new circular rash developed on the opposite thigh biopsy on her left thigh and [Inaudible] [00:06:35] the findings were consistent with Erythrema Migrans and silver stains showed a spirochetal compatible structure. Lyme PCR was positive in her blood and Lyme western block showed bans of high [Inaudible] [00:06:48] the Lyme spirochete. She was treated with 10 months of Minocycline with fading of both rashes and resolution of her symptoms. She seemed to remain basically well thereafter, if you’ve read Thomas Eskoon’s Structure of Scientific Revolutions it’s the anomalous case that doesn’t fit the theory which often comes with assessment of a reigning paradigm. In 1989 39 year old pediatric ICU nurse Vicky Logan consulted me because of progressive paralysis with spinal fluids cytosis. She had grown up in Golden Bridge in New York’s Westchester county she gave no history of tick attachment at any time nor of a rash suspicious for Lyme disease. I studied her carefully for one year and was unable to establish a diagnosis all tests for Lyme disease were negative. Because I could not completely rule out Lyme disease despite negative tests and since no other treatable diagnosis could be made I decided to treat her for the possibility of Lyme disease with 21 days of intravenous Cefotaxime. Spinal tap before and after treatment showed no change in her lupus cytosis and her condition did not improve. Additional treatment with four months of oral Minocycline yielded no benefit and I backed off. About one year later she contacted me again and begged me to do another spinal tap at that time I was working with The Centers for Disease Control and when I tapped her I placed a few CCs of spinal fluid into [Inaudible]

[00:08:11] media. A few weeks later I received a phone call from an excited David Dennis at the CDC Port Collins advising me that spirochete was growing from a CSF. This is the original report in Port Collins with a notation from Roy Campbell that a PCR confirmed these spirochete to be iral key to be burgdorferi. This is reported with colleagues from the CDC at the 5th International Congress on Lyme Borreliosis in Arlington and it says [Inaudible] [00:08:45] Minocylcine and in the case of Lyme Meningoencephalomyelitis in the United States and I would like you to please note that co-authors included Roy Campbell, Tom Schwann and David Dennis from the CDC. Culture VCS specimen and VCS K2 yielded a strain of burgdorferi culture confirmed treatment failures had been previously reported with three Lyme neuroborreliosis cases in Europe. The present case apparently is the first case of this type to be reported from the United States. This made the front page of the New York Times Science Time and also prompted me to author a guest commentary in the journal of Clinical Microbiology and I also reported her case in detail along with the cases of three other cases of chronic Lyme Meningoencephalomyelitides in the journal in tick borne diseases if any body likes re-prints they can contact me, I do have some here. Now knowing she had Lyme disease I treated her with high dose post Cefotaxime for 13 weeks with complete resolution of lymphocytic which she had for years and with improvement in her clinical condition. I sent her to the male clinic for consideration of placement of a matronic pump in her [Inaudible] [00:10:05] to control her severe sparcicity she was deemed she had lupus because she did have some markers of audio immunity treated with high dose cotical steroids she developed cardio effusions she returned to Westchester severely deteriorated and required hospitalization at Northern Westchester Hospital Center a plural cardio window had to be created to avert the risk of her cardio tempo node and for diagnostic purposes intravenous Cefotaxime for 109 continuous days resolved to pluracal cardio effusion reversed severe and allowed [Inaudible] [00:10:40] with plasma cells was found NIH found spirochetes consistent with [Inaudible] [00:10:40] stains and on this touch preparation hope you can see that. Over the next several years whenever she could be treated with several months of intravenous Cefotaxime her condition improved but when treatment was discontinued she then seriously deteriorated she was her own and of one trial. In 2000 I was able to send about 129 specimens of frozen spinal fluid from 108 patients for testing to the research laboratory of Dr. [Inaudible] [00:11:17] where CDC funded research was being conducted concurrently with two other collaborating research labs using four research assays with spinal fluid antigen capture and IDG and IGM borrelius of immune complex. These research acids were based on published research by Pat Coyle and Steve Shusta. This is a printout of the results of testing prepared by Priscilla Munyos who is the research supervisor and administrator at Dr. Wiler’s lab she highlighted all positive results in yellow. On the left are results of standard antibody assays on spinal fluid only 2% tested positive, on the right are results of the four research assays 61% of the spinal fluids tested positive on one or more of the spinal fluid assays. Three of these specimens that were submitted were from my patient Vicky Logan from 1999, 2000 and 2001, all of them tested positive. The latest one that was available from June 2001 tested positive on antigen capture at a level more than seven times greater than the positive cutoff and also tested positive for IDG and IGM the really specific immune complexes. In 1998 it became non-feasible to reinstitute intravenous antibiotics and the patient progressively deteriorated. In 2003 she suffered a series of grandma seizures and

a myocardial infraction which led to her demise. Anyone interested in the circumstances leading up to her death should read Pam Wysher’s book Cure Unknown. Autopsy was performed which showed primary diagnosis of chronic meningoencephalomyelitis acute myocardial and fraction was the approximate cause of her death. Brain tissues showed some ringal vasculitis with prominent plasma cells for those who have not studied pathology plasma cells frequently are a clue to the presence of spirochete you see this in syphilis and you see it in Lyme. Claude Andegri was kind enough to apply his chemical methods to characterize and identifying Lyme spirochetes in the skin to Vicky’s brain tissue with uptake localized to the vicinity of the cerebral vascolitis in haematoma. This case is still under study and has not yet been submitted for publication. Martin Eisenhardt an outdoors man and resort manager in the mountain regions in New York State developed a great red option on one thigh followup 1985 he developed severe headache low grade fever chronical instability and spinal fluid lymphocytosis, although his wife kept asking if he could possibly have Lyme disease Lyme disease was first ruled out because Lyme screening tests were negative he was treated with steroide and Cefotaxime for diagnosis of vascolities progressively deteriorating to a primitive level of neurologic functioning. His wife Marylou contacted me and asked me if I would take his case and I agreed to do so, he was admitted to Northern Westchester Hospital Center in April of 1982, this is a CAT scan of his head on admission showing massive Hydrocephalus he was found to be on standard epillepticus and seizures were controlled with [Inaudible] [00:14:33] spinal fluids tested positive for detection of OspA antigen and Lyme specific immune complexes on Pat Coller’s research assays. He was treated with one month of intravenous Cefotaxime in a hospital and for one year with [Inaudible] [00:14:46] at home although he was severely neurologically damaged at the time I first saw him his condition did improve modestly after intravenous antibiotics therapy was discontinued he succumbed to his disease and an autopsy was performed. On the upper left is a section through his brain again showing massive hydrocephalus ex vaccuo on the right is a brain of someone dying from other causes showing the normal cleft like ventricular spaces. The picture on the bottom is a picture through the cerebellum showing a floored Meningoencephalomyelitis shoulder surround to his colleagues neuropathology section of the NIH Clinical Center and what he told me is that they had never seen anything like this right Paul?

Paul: True

Dr. Liegner: I also sent his tissue to the reference laboratory of the Czech Republic where Professor Dagmar Hulinska performed electron microscopy and she identified structures that she believed were consistent with Borellia burgdorferi cross section, she also did tissue PCR on brain tissue showing reaction products when tested against primers from a Northern American isolate. Does this scenario only happen in adults? Unfortunately not, Dr. Charles Ray Johns and I reported a tragic similar case that was fatal in a child developing after the pediatrician refused a mother’s plea to treat preventively with antibiotics for fully engorged due to tick attachment. Many other workers worldwide have reported similar cases in the worldwide period literature and this list I have up here is by no means exhaustive. Clinicians treating people with Lyme disease are often faced with very seriously ill individuals as you heard before Clinton

found patients in his study had ability comparable to persons with chronic congested heart failure. Think about that for a moment. On top of that it is not rare for persons with Lyme disease to have one, two or even three tick-borne color infections testing for these as for Lyme disease is not always reliable. Additionally both Proctanela and Bibizia have been reported to have the potential to survive recommended antimicrobial treatment regiments one of the unexpected findings in Dr. NIAD study was the high percentage of persons with Lyme disease having serological evidence of exposure to proctanella. Overall this leads to quite a challenging and a complex situation requiring maximum flexibility and innovation on the part of the treating physician for successful outcomes the treating physician must have discretion regarding choice of anti microbial agent, singly or in combination and as to duration of therapy they need access to the full therapeutic armentarium of FDA approved agency including off label usage, some of the agents we had said with Lyme disease one of my pharmacology professors in med school invented vaccilin for the use of treatment in syphilis it’s been reported by Smear to be useful and I’ve used it with excellent results I have had patients who are allergic to penicillum who required intravenous agents and I’ve used azithromycine with good results [Inaudible] [00:18:10] Charlie Cavier in Garry’s own department and myself Garry is a specialist in Hospital and Dr. Nio invitro in a mass model showing definitely reduced numbers of Borrillia so my mind is a rationale as far as not exceeding IDSA recommended doses what do they recommend for Maxillin 500mg 3 times a day that might be suitable for it is completely and adequate for treating essential nervous infection and is good literature to demonstrate that. Patients with chronic Lyme disease and their families endure profound suffering. Marylou Eisenheardt submitted this letter to Richard Godfrey the chair of New York Assembly Committee on Health November 2001 when he convened hearings on Lyme disease. I do not have time to read this, I wish the panel and others would read this at their leisure I also recently asked Marylou to send me a photograph of Martin when he was well and I had never seen this photograph previously it was very moving to me when I saw it. I’d also like to play this short clip from Vicky Logan. I think of Vicky whenever I pass the Golden Bridge about Inter State 684, although the cases I have presented represent an extreme end of a spectrum of Lyme disease they include some of the best documented cases in the United States they offer shed light on what should be operative in many other patients suffering from chronic Lyme disease. They also illustrate the disaster consequences of over reliance on antibody methods of testing which do not adequately characterize the phenomology of Lyme disease.

Dr. Baker: Dr. Liegner you’ll have to finish up please.

Dr. Liegner: Okay, in a letter to me Claude Garang referred to burgdorferi as a formidable pathogen although burgdorferi may trigger immune mediated or post infectious syndromes Lyme disease is first and foremost an infectious disease. In my opinion chronic persistent infection is the underlying pathology in many individuals who remain or become ill while following an encounter with Lyme disease. General reassessment of everything that is assumed to be true about Lyme disease is necessary as well as clinical availability of a validated highly sensitive direct protection method. I don’t think that long term antibiotic therapy is the solution for chronic Lyme disease however it’s the best approach we presently have for many patients. We could have

better methods of treatment but until the problem is acknowledged for what it is we will not. I’ve said it before and I’ll say it again if we can put a man on the moon we can solve the problem of Lyme disease but we all have to work together to accomplish this goal. In closing I’d like to quote Sharpe Cole father of modern neurology, disease is very old and nothing about it has changed, it is we who change as we learn to recognize what was formerly imperceptible. Thank you so much for your attention.

Dr. Baker: Thank you for your testimony, are there questions from the panel? Dr. Sanders.

Dr. Sanders: Those are obviously striking severe cases, I have been looking forward to your testimony to ask you to go back to some of what has been talked about earlier today and to severe in respect as well given what you perceive as great limitations on our testing ability how do you distinguish between cases of Lyme versus in the severe end lupus were other atromune diseases or in the more chronic end chronic fatigue syndrome and others. What clinical measures are you putting out there to make those distinctions?

Dr. Liegner: I think you use all the tools that you have available and I tend to evaluate my patients very thoroughly usually you can get clues ultimately it does require very careful and repeated study of the patient over time and usually of course it’s important to identify other treatable conditions so you don’t treat them incorrectly but it does boil down to clinical judgment with careful study of the patient but it’s difficult.

Dr. Baker: Yes, Dr. Moro.

Dr. Moro: Yes Dr. Liegner question about you presented one case, please correct me if I’m wrong about the failure of treatment in the case of a nurse a fellow treated this lady with a spinal tap and then a year later her knee was isolated.

Dr. Liegner: That’s correct

Dr. Moro: I didn’t read the paper but it would you consider that it was maybe a case of re-infection in this case?

Dr. Liegner: That’s an excellent question, anybody who lives in a Lyme endemic area there’s always risk of re-infection, at this point in her life she was to a large degree confined to a wheelchair she did not have any pets I think it’s highly unlikely that she was re-infected or it’s hard to 100% exclude that but this is the same patient who later after all kinds of treatment spirochetes were found in her pericardium so this has been demonstrated in numerous occasions over the course. Yes sir.

Dr. Moro: How do you suggest that we apply catastrophic and exceptional cases to a practice guideline that is targeted towards more likely presentation or more common presentations this is not just [Inaudible] [00:24:27] but any clinical phenomenon for which we have guidelines in an evidence basis?

Dr. Liegner: Well like many illnesses Lyme has a spectrum of presentations and like I said this is the extreme end of the spectrum and because I’m critical care trained I tend to see some of these more patients but I think they can provide a window to what may be happening in other patients who are not as seriously ill and what’s very frustrating to me is to know that some of these methods of direct attachment have been developed more than a decade ago and for reasons I can’t fully [Inaudible] [00:25:05] is not suitable for high if it had been supported that could have been used at the Rocky Mountain lab for example at least for research purposes to help us understand the disease better. I think qualitative methods those should be out there, those are not rocket science, those could be made available clinically so I think we need both antigen and oxygen and that would settle a lot of the controversy and it wouldn’t be so much matter of opinion we would have some hard science.

Dr. Baker: Third person.

Dr. Parsonnet: A quick question you described the isolation of your organism after many types of treatment how many times have you tried to reproduce this or have others tried to reproduce this and not the organism, I mean is this truly an exceptional case or is only one of few patients whose actually the loophole.

Dr. Liegner: Well this is the abstract I said this is the first case in the United States.

Dr. Parsonnet: Are there many negatives or you tried to culture it after all?

Dr. Liegner: Yeah I mean it’s very hard to culture from the spinal fluid I made many other attempts I stopped the CDC when no one was interested in further culturing at a certain point. In Europe there have been many reports of positive cultures from spinal fluids and other tissues.

Dr. Parsonnet: After treatment, I’m talking about.

Dr. Liegner: After treatment yes [Inaudible] [00:26:25] in 1989 published a landmark study of 10 cases and there’ll be many other cases since. I think we all have to come to terms as Claude Garang said this is a formidable pathogen and there’s still a lot that we don’t understand about it and I think we have to be humbled before this disease.

Dr. Baker: I have one last question.

Dr. Liegner: Yes ma’am.

Dr. Baker: In Europe, isn’t the species different, the dominant species?

Dr. Liegner: There are several straits but there’s also burgdorferi as well which is the same as in the States.

Dr. Baker: Thank you very much.