Chronic Lyme Disease: a discussion of the epidemiological data

I’ve decided to take a closer look at the evidence for chronic Lyme disease. I’ve chosen to skip issues relating to the persistence of the bacterium Borrelia burgdorferi and the use of prolonged antibiotic therapy, to focus on basic epidemiology. The main question I wanted to answer is whether there is an increased incidence of chronic debilitating symptoms such as fatigue, pain and cognitive difficulties following Lyme disease compared to a control group that didn’t experience Lyme disease. In my view, if the answer to this question is no, all other discussions on the etiology and treatment of chronic Lyme disease become redundant as the diagnosis might not be the correct one. For those who might not be able to read through the whole text, my conclusion is that the current epidemiological evidence for chronic Lyme disease is conflicting and unconvincing.

Post-treatment Lyme disease syndrome (PTLDS): the question not the answer
When I explain my question people usually refer me to studies on Post-Treatment Lyme Disease Syndrome (PTLDS) such as the one by Rebman and colleagues [1]. But this isn’t exactly what I’m looking for. These studies often show that patients who receive a PTLDS diagnosis are severely disabled, but don’t demonstrate that this disability is related to Lyme disease. The problem with many studies on PTLDS is that they start by defining the syndrome and then recruit patients to study it, which results in selection bias. It’s a bit like defining ‘post-vaccine autism syndrome’, then recruiting persons who developed autism following vaccination and declaring that the syndrome is real if persons meet the definition. What I would like to know is whether having Lyme disease increases the risk of developing the type of severe disability seen in those PTLDS-studies. To answer that question we need proper epidemiological studies that look at representative samples of patients with Lyme disease and that follow these patients in a longitudinal design to see if they develop more disabling symptoms than a matched control group.

The Nancy Shadick studies in Boston: some evidence suggestive of PTLDS
There are a few studies like that and the early ones did suggest a connection between experiencing Lyme disease and subsequent chronic symptoms. The first prominent study was published in 1994 in Annals of Internal Medicine by Nancy Shadick and colleagues. [2] It was a study conducted in Boston, Massachusetts where they followed up on 38 Lyme patients and matched controls for a period of more than 6 years. The authors reported that patients who had Lyme disease experienced more symptoms than the controls, including arthralgia, concentration difficulties and difficulty sleeping.

There were some interpretation problems though. No correction for multiple comparisons was performed and it’s possible that the difference for prominent symptoms such as fatigue (26% compared with 9%; P = 0.04) would no longer be statistically significant if such corrections were applied. Another problem is recall bias: the tendency to report symptoms could be affected by the history of patients. The patients in this study contracted Lyme disease in the 1980s when the recognition of the illness was poor. Few received the recommended antibiotic therapies and some had months to years of disease before treatment. As one commenter noted: “patients in this study, informed that they received treatment for Lyme disease before optimal treatment protocols were established, might recall aches and pains that others might dismiss.” Finally, the result focused on the prevalence of reported symptoms in the Lyme versus control group, without indicating the impact of those symptoms. The symptoms were corroborated by neurocognitive testing (the Lyme group had more neurocognitive deficits than the control group) but the SF-36 global health scores seem to indicate differences in functional capacity were rather small (although I find it hard to interpret those scores, which I assume are raw scores on a scale of 30?)

The sample size of this first study was also quite small. In 1999 Shadick et al. published a larger study where they followed up on 186 persons who had a history of Lyme and 167 controls that did not. [3] Once again the former reported more symptoms than the latter. The main problem with this study, however, is that it is retrospective: patients weren’t examined clinically and then followed up, instead the authors mailed random persons to find a sample that did and didn’t experience Lyme disease based on medical records. As the authors note, this design “lacked the clinical certainty of case status that is seen in a prospective analysis.”

And that’s a bigger issue than it might seem because blood tests for Lyme disease are often false positive, especially before 1995 when U.S. Public Health Service recommended both two-tier testing and the use of evidence-based criteria for interpreting immunoblots. So what might have happened is that some patients with chronic fatigue syndrome, fibromyalgia or other conditions that resemble Lyme disease were misdiagnosed because of a false positive blood test.

The study recruited patients from Nantucket Island, one of the highest reported incidences of Lyme disease in the United States. So it’s not unlikely that physicians thought of Lyme disease when a patient presents with unexplained symptoms of fatigue, pain or cognitive dysfunction. In some cases, this could have resulted in a false positive serology. These patients will not have gotten better with antibiotic treatment and thus give a false impression of persistent Lyme disease.

Although the two Shadick studies are frequently cited, they aren’t convincing evidence that more people remain significantly disabled following Lyme disease. At the time there was also the report by Wang et al. that 26 children with prior Lyme disease did not have a higher prevalence musculoskeletal or neurological symptom than controls. [4] So what was needed were larger and better-conducted studies.

The Eugene Shapiro study in Connecticut
The next important study was published in 2000 in JAMA by the research team of Eugene Shapiro. [5] It followed-up on a random subsample of 212 patients selected from a large sample of all reports of Connecticut residents with suspected Lyme disease submitted to the Department of Public Health from 1984-1991. There is a risk of selection bias because for a large proportion contact information was not available and there’s a problem with the control group having more females (66% versus 49%). Despite these shortcomings, this study seems like one of the best in its kind. The results showed that 9.0% of patients believed they were still not cured of Lyme disease. When researchers made the comparison with the healthy group, however, there were practically no differences in impairment. The authors report:

“Although many patients who had been diagnosed as having Lyme disease reported increased symptoms or increased difficulties with typical daily activities, the proportions were similar to those reported by the matched controls, except that there were statistically significant differences between the groups in the categories of ‘joint or muscle pain’ and ‘ability formulating ideas.’ Likewise, there were no significant differences in the entire cohort between the cases and the controls in the results of the SF-36 or the CES-D.”​

So the results of the highest quality study suggested that while there might be lingering symptoms these did not lead to a clear increase in disability compared to a control group, as one would expect.

Allen Steere and the patients from Lyme
Following reports of chronic disability after Lyme Disease, Allen Steere, the man who gave the disease its name, decided to contact some of the original study patients from the Lyme, Connecticut, region. He randomly selected 84 patients so that there were three Lyme groups characterized by either facial palsy, Lyme arthritis or confirmed erythema migrans. These were then compared to a control group of 30 healthy persons. There were some mild residual deficits in facial nerve function and bodily/joint pain in the facial palsy group but overall, the three Lyme groups and the control group did not differ significantly in current symptoms or neuropsychological test results. On the 8 scales of mental and physical health of the SF-36 questionnaire, the three patient groups and the control group had similar results that compared favorably with normative data scores from the general US population. [6]

The Gary Wormser study in New York
The next important study comes from the research team of Gary Wormser in New York. What is remarkable about this study is that it had very strict selection criteria: patients not only had to have erythema migrans, the characteristic rash associated with Lyme disease but they also took skin or blood samples to culture the B. burgdorferi and make sure the spirochetes were really there. This way the problem with false-positive antibody testing is out of the way.

The first results were published in 2003. [7] Only 8 of the 81 cases who were followed for 1 year were symptomatic at their last visit. The patients were described as follows:

“Their symptoms tended to be intermittent, with only 3 patients (4%) consistently symptomatic at each follow-up visit. Symptoms were also generally mild; in 5 (71%) of the 7 evaluable cases, individual symptoms at the last follow-up visit scored less than 3 (out of 8) on the visual analog scale.”​

So while this study did not have a sex- and age-matched control group, it does provide some evidence against the hypothesis that persons who experienced Lyme disease are at increased risk of long-term disability as usually seen in patients diagnosed with PTLDS or chronic Lyme disease.

In 2015 results were reported of a 15.4 years follow-up of 100 patients of the same cohort. In separate publications, the authors explain that there was no increased incidence of severe fatigue [8] or fibromyalgia [9] and that the SF-36 scores were similar to those of the general population. [10] One might think that the patients who developed severe fatigue and disability due to Lyme disease might be too ill to participate in the study but patients with severe fatigue due to other reasons than Lyme did show up at assessments, so I’m not sure that this could explain the results.

The Wisconsin study by Kowalski and colleagues:
Then there’s the study by Todd Kowalski and colleagues in Wisconsin, published in 2010. [11] This was the biggest study with 607 patients involved, but just like the Shadick et al. 1999 study it was also retrospective: the authors simply looked at the charts for ICD-9 diagnosis of Lyme disease and then sent up SF-36 questionnaires to see how these patients were doing. Patients with late Lyme disease (eg, arthritis and late neurologic disease) were excluded from this study. The results showed, in short, that treatment failure was rare and participants had a good prognosis.

In a separate publication (Jares et al. 2014) [12] where patients from this cohort with a reinfection were studied more closely, there was a comparison of a sample of 60 Lyme patients (15 reinfected and 45 infected only once) and a healthy control group, showing no major differences in the reported frequency of symptoms. Unfortunately, the comparison we are interested in is somewhat obscured because the authors had split up the Lyme group.

The large Slovenian treatment trial
Also published in 2010 was a large Slovenian treatment trial of Lyme disease where the authors were smart enough to include a healthy control group. [13] 285 patients with adult patients with erythema migrans were included in the study. The results showed that “at both 6 and 12 months, the frequency of new or increased symptoms in patients with erythema migrans did not exceed the frequency of such symptoms in a control group of individuals of similar gender and age without a clinical history of Lyme disease.” And: “Of the 5 patients with new or increased symptoms at 12 months, none qualified to have “post-Lyme disease syndrome,” because the reported symptoms were not severe enough to result in a reduction in previous levels of patient activities.”

 

Eikeland and colleagues in southern Norway
There were also two decent studies that did provide some evidence for PTLDS. The first one was conducted in southern Norway and followed up on 50 patients with Lyme neuroborreliosis. [14] The results were reported as follows:

“Lyme neuroborreliosis-treated patients scored lower than control persons in the SF-36 domains physical component summary (PCS) (44 vs 51 P < 0.001) and mental component summary (MCS) (49 vs 54 P = 0.010). They also scored lower than control persons in all the SF-36 subscales, except for bodily pain, and on FSS (3.5 vs 2.1 P < 0.001), but not on MMS (28 vs 29 P = 0.106).”​

One possible bias, however, is that patients selected their controls themselves, which could have led to a selection of more healthy controls than how a representative sample of the general population would look like.

Aucott and colleagues from John Hopkins: a foundation for PTLDS?
Another prominent study was conducted by Aucott and colleagues from John Hopkins and published in 2013. [15] They followed up on 74 patients with confirmed erythema migrans and 14 controls for a period of 6 months. The authors report that eight (11%) patients met the operationalized definition of PTLDS, which included self-reported symptoms of fatigue, widespread musculoskeletal pain or cognitive complaints, and functional impairment. The results are a bit confusing though. The authors compare the SF-36 scores of the PTLDS, healthy Lyme group and the healthy control group. So the Lyme-group is already split when making a comparison with the control group. The authors note that none of the healthy controls met the impairment criteria of PTLDS but that could also be because that control group was 5 times smaller than the Lyme group and the impairment criteria aren’t very strict (less than half a standard deviation from the general population mean). Nonetheless, their data, displayed in the graph below, does suggest that more people in the group that experienced Lyme disease, was suffering from severe disability.




Two studies on children with Lyme disease complications
Then there are two studies on children with Lyme disease complications. The group of Eugene Shapiro looked (retrospectively) at 43 children with facial nerve palsy attributable to Lyme disease, according to CDC criteria. [16] For each case, 2 controls without Lyme disease, matched by age, were selected by sequential digit dialing technique. The results were as follows:

“Overall, 79% believed they were cured of Lyme disease, 9% believed they were not cured, and 12% did not know. The proportions of patients and of matched controls that reported increased problems with normal daily activities (eg, exercise, academic performance, word recall, sleeping) were similar”​

A Swedish study looked at the prognosis of 177 children with suspected Lyme Neuroborreliosis, recruited from 5 pediatric clinics. [17] The findings were reported as follows:

“Persistent nonspecific symptoms, such as headache and fatigue, were not more frequently reported in patients than in controls. [...] Affected daily activities were reported in 24% of patients and 38% of controls.”​

So in this study, the controls reported more disability (which is probably a statistical fluke).

There’s also a large treatment trial conducted by the research team of Gary Wormser where they included a control group to interpret the results of neurocognitive testing. The authors reported that” There were no significant differences in the results of neurocognitive testing among the three treatment groups and a separate control group without Lyme disease” but unfortunately no further information is given about this in the paper. [18]

The many studies without a control group
There are also quite a few prospective studies that reported persistent symptoms following Lyme disease, which are commonly cited as evidence for PTLDS or chronic Lyme disease. The most prominent one is the study by Ash et al. from 1994, [19] but there are quite a few others. [20-27]

I’m not convinced by these studies as they have no healthy control group, were small or not population-based and thus subject to selection bias. Given that many are quite old it’s possible that some of the Lyme cases were a misdiagnosis of other chronic conditions that do not respond to antibiotic therapies.

But the main reason for not discussing them in-depth is that there’s a similarly large collection of studies showing excellent prognosis following Lyme disease [28-34] including the enormous database on 10.936 participants enrolled in a phase III trial of the Lyme disease vaccine. [35] The most prominent of these studies is probably the one performed by Adriana Marques at the NIH. They found that patients who had Lyme disease reported normal quality of life at follow-up, with SF-36 scores just above the national average. [36]

Conclusion
We could go deeper into the results of all these studies. Each has its problems which I didn’t discuss in full. But I think the overall trend is clear that the current evidence for PTLDS and consequently for chronic Lyme disease is not that strong. The evidence that chronic and debilitating symptoms of fatigue, widespread pain, and cognitive problems are associated with Lyme disease isn’t very convincing. Therefore, I think it’s wrong for physicians to give a diagnosis that does suggest such a connection. Even for patients whose symptoms started following a confirmed Lyme infection, it remains uncertain if there really is a connection between the initial Lyme infection and the subsequent development of chronic and debilitating symptoms.

Please don’t get me wrong! I’m not saying the evidence shows that PTLDS isn’t real. The evidence is too weak and conflicting either way. It’s not unreasonable to believe that some of the major studies might have missed something, for example, because the most severely affected might not be able to participate in follow-up assessments. Most studies looked at the frequency of symptoms of SF-36 scores in the whole sample that experience Lyme disease and only reported averages. If most people fully recovered then it might be possible that very low scores of some of the participants are overlooked. None of the studies really looked at the prevalence of chronic and debilitating symptoms at follow-up, which is the question we’re really interested in. Many studies also focused on early Lyme disease, so it could be that there is a higher risk of PTLDS following neuroborreliosis or late and disseminated Lyme disease. There is a lack of data and some methodological weaknesses that prevent us from making strong conclusions.

But in my view, the burden of evidence is on those making the diagnosis of PTLDS or chronic Lyme disease. To justify such a diagnosis there should be strong epidemiological data in that direction which currently isn’t the case. Even if for some reason you think that all the studies that couldn’t find evidence for PTLDS are flawed (or corrupted or whatever) and you want to ignore them, the evidence still wouldn’t be that strong. The studies of Shadick et al. 1994, Eikeland et al. 2011 and Aucott et al. 2011 were fairly small and the one by Shadick et al. 1998 was retrospective. So the evidence for PTLDS would still be rather weak and unconvincing to justify diagnosing patients as such.

I would love to hear what others here on the forum think of this. I’m also interested in hearing the thoughts of Lyme advocates on this. If you could invite some to have a look at this discussion, that would be very much appreciated. I suspect that sometimes so much energy is going into discussions on persistent borrelia and antibiotic treatment that these more basic epidemiological data might be under-discussed. I have to mention that I have no particular expertise in Lyme disease and because of my chronic illness I was limited in how deeply I could dissect the studied mentioned above. So it’s certainly possible that I made some mistakes or overlooked some important studies. Please let me know and I will try to correct my writing.

 

References
[1] Rebman AW, Bechtold KT, Yang T, Mihm EA, Soloski MJ, Novak CB, et al. The Clinical, Symptom, and Quality-of-Life Characterization of a Well-Defined Group of Patients with Posttreatment Lyme Disease Syndrome. Front Med (Lausanne). 2017 Dec 14;4:224.

[2] Shadick NA, Phillips CB, Logigian EL, Steere AC, Kaplan RF, Berardi VP, et al. The long-term clinical outcomes of Lyme disease. A population-based retrospective cohort study. Ann Intern Med. 1994 Oct 15;121(8):560-7.

[3] Shadick NA, Phillips CB, Sangha O, Logigian EL, Kaplan RF, Wright EA, et al. Musculoskeletal and neurologic outcomes in patients with previously treated Lyme disease. Ann Intern Med. 1999 Dec 21;131(12):919-26.

[4] Wang TJ, Sangha O, Phillips CB, Wright EA, Lew RA, Fossel AH, et al. Outcomes of children treated for Lyme disease. J. Rheumatol. 1998, 25(11):2249-2253.

[5] Seltzer EG, Gerber MA, Cartter ML, Freudigman K, Shapiro ED. Long-term outcomes of persons with Lyme disease. JAMA. 2000 Feb 2;283(5):609-16.

[6] Kalish RA, Kaplan RF, Taylor E, Jones-Woodward L, Workman K, Steere AC. Evaluation of study patients with Lyme disease, 10-20-year follow-up. J Infect Dis. 2001 Feb 1;183(3):453-60.

[7] Nowakowski J, Nadelman RB, Sell R, McKenna D, Cavaliere LF, Holmgren D, Long-term follow-up of patients with culture-confirmed Lyme disease. Am J Med. 2003 Aug 1;115(2):91-6.

[8] Wormser GP, Weitzner E, McKenna D, Nadelman RB, Scavarda C, Nowakowski J. Long-term assessment of fatigue in patients with culture-confirmed Lyme disease. Am J Med. 2015 Feb;128(2):181-4.

[9] Wormser GP, Weitzner E, McKenna D, Nadelman RB, Scavarda C, Farber S, Prakash P, Ash J, Nowakowski J. Long-Term Assessment of Fibromyalgia in Patients with Culture-Confirmed Lyme Disease. Arthritis Rheumatol. 2015 Mar;67(3):837-839.

[10] Wormser GP, Weitzner E, McKenna D, Nadelman RB, Scavarda C, Molla I, et al. Long-term assessment of health-related quality of life in patients with culture-confirmed early Lyme disease. Clin Infect Dis. 2015 Jul 15;61(2):244-7.

[11] Kowalski TJ, Tata S, Berth W, Mathiason MA, Agger WA. Antibiotic treatment duration and long-term outcomes of patients with early lyme disease from a lyme disease-hyperendemic area. Clin Infect Dis. 2010 Feb 15;50(4):512-20.

[12] Jares TM, Mathiason MA, Kowalski TJ. Functional outcomes in patients with Borrelia burgdorferi reinfection. Ticks Tick Borne Dis. 2014 Feb;5(1):58-62.

[13] Cerar D, Cerar T, Ruzić-Sabljić E, Wormser GP, Strle F. Subjective symptoms after treatment of early Lyme disease. Am J Med. 2010 Jan;123(1):79-86.

[14] Eikeland R, Mygland A, Herlofson K, Ljøstad U. European neuroborreliosis: quality of life 30 months after treatment. Acta Neurol Scand. 2011 Nov;124(5):349-54.

[15] Aucott JN, Crowder LA, Kortte KB. Development of a foundation for a case definition of post-treatment Lyme disease syndrome. Int J Infect Dis. 2013 Jun;17(6):e443-9.

[16] Vázquez M, Sparrow SS, Shapiro ED. Long-term neuropsychologic and health outcomes of children with facial nerve palsy attributable to Lyme disease. Pediatrics. 2003 Aug;112(2):e93-7.

[17] Skogman BH, Croner S, Nordwall M, Eknefelt M, Ernerudh J, Forsberg P. Lyme neuroborreliosis in children: a prospective study of clinical features, prognosis, and outcome. Pediatr Infect Dis J. 2008 Dec;27(12):1089-94.

[18] Wormser GP, Ramanathan R, Nowakowski J, McKenna D, Holmgren D, Visintainer P, et al. Duration of antibiotic therapy for early Lyme disease. A randomized, double-blind, placebo-controlled trial. Ann Intern Med. 2003 May 6;138(9):697-704.

[19] Asch ES, Bujak DI, Weiss M, Peterson MG, Weinstein A. Lyme disease: an infectious and postinfectious syndrome. J Rheumatol. 1994 Mar;21(3):454-61.

[20] Steere AC, Hutchinson GJ, Rahn DW, Sigal LH, Craft JE, DeSanna ET, Malawista SE. Treatment of the early manifestations of Lyme disease. Ann Intern Med. 1983 Jul;99(1):22-6.

[21] Berglund J, Stjernberg L, Ornstein K, Tykesson-Joelsson K, Walter H. 5-y Follow-up study of patients with neuroborreliosis. Scand J Infect Dis. 2002;34(6):421-5.

[22] Szer IS, Taylor E, Steere AC. The long-term course of Lyme arthritis in children. N Engl J Med. 1991 Jul 18;325(3):159-63.

[23] Treib J, Fernandez A, Haass A, Grauer MT, Holzer G, Woessner R. Clinical and serologic follow-up in patients with neuroborreliosis. Neurology. 1998 Nov;51(5):1489-91.

[24] Ljøstad U, Mygland A. Remaining complaints 1 year after treatment for acute Lyme neuroborreliosis; frequency, pattern and risk factors. Eur J Neurol. 2010 Jan;17(1):118-23.

[25] Vrethem M, Hellblom L, Widlund M, Ahl M, Danielsson O, Ernerudh J, Forsberg P. Chronic symptoms are common in patients with neuroborreliosis -- a questionnaire follow-up study. Acta Neurol Scand. 2002 Oct;106(4):205-8.

[26] Cimperman J, Maraspin V, Lotric-Furlan S, Ruzić-Sabljić E, Strle F. Lyme meningitis: a one-year follow up controlled study. Wien Klin Wochenschr. 1999 Dec 10;111(22-23):961-3.

[27] Gustaw K, Beltowska K, Studzińska MM. Neurological and psychological symptoms after the severe acute neuroborreliosis. Ann Agric Environ Med. 2001;8(1):91-4.

[28] Neumann R, Aberer E, Stanek G. Treatment and course of erythema chronicum migrans. Zentralbl Bakteriol Mikrobiol Hyg A. 1987 Feb;263(3):372-6.

[29] Gerber MA, Zemel LS, Shapiro ED. Lyme arthritis in children: clinical epidemiology and long-term outcomes. Pediatrics. 1998 Oct;102(4 Pt 1):905-8.

[30] Salazar JC, Gerber MA, Goff CW. Long-term outcome of Lyme disease in children given early treatment. J Pediatr. 1993 Apr;122(4):591-3.

[31] Hansen K, Lebech AM. The clinical and epidemiological profile of Lyme neuroborreliosis in Denmark 1985-1990. A prospective study of 187 patients with Borrelia burgdorferi specific intrathecal antibody production. Brain. 1992 Apr;115 ( Pt 2):399-423.

[32] Müllegger RR, Millner MM, Stanek G, Spork KD. Penicillin G sodium and ceftriaxone in the treatment of neuroborreliosis in children--a prospective study. Infection. 1991 Jul-Aug;19(4):279-83.

[33] Peltomaa M, Saxen H, Seppälä I, Viljanen M, Pyykkö I. Paediatric facial paralysis caused by Lyme borreliosis: a prospective and retrospective analysis. Scand J Infect Dis. 1998;30(3):269-75.

[34] Dattwyler RJ, Luft BJ, Kunkel MJ, Finkel MF, Wormser GP, Rush TJ, et al. Ceftriaxone compared with doxycycline for the treatment of acute disseminated Lyme disease. N Engl J Med. 1997 Jul 31;337(5):289-94.

[35] Smith RP, Schoen RT, Rahn DW, Sikand VK, Nowakowski J, Parenti DL, et al. Clinical characteristics and treatment outcome of early Lyme disease in patients with microbiologically confirmed erythema migrans. Ann Intern Med. 2002 Mar 19;136(6):421-8.

[36] Wills AB, Spaulding AB, Adjemian J, Prevots DR, Turk SP, Williams C, Marques A. Long-term Follow-up of Patients With Lyme Disease: Longitudinal Analysis of Clinical and Quality-of-life Measures. Clin Infect Dis. 2016 Jun 15;62(12):1546-1551.

 

@Michiel Tack, Thank you for compiling this. There is too much information for me to process at present.

My initial response is to want to disagree with you, but I can not hold onto the threads of my arguments long enough to know if this is a rational or an emotional response. I will return to this again, when hopefully I can come up with a more coherent response.

(It is potentially interesting that the restrictions on my thinking seem to relate to the amount of a line of reasoning I can hold in my brain at once, which, when such a logico-deductive process fails, results in falling back on associations and emotional responses.)

 

Interesting work, @Michiel Tack. Methodology is everything!

Edit to add: same as @Peter Trewhitt, my brain is hurting at the moment. But there is an additional layer of difficulty when patients get tested with labs that are not deemed reliable, both in the US and in Germany. Oh dear. Did I open a can of worm?

 

Thanks for doing this, @Michiel Tack.

Like @Peter Trewhitt , I'll admit my initial reaction is to disagree but I have not read it yet and will.

In the meantime, have you seen the 2018-2020 reports of the US HHS Tick-borne diseases advisory committee. Maybe there's some useful information or additional references in there.

https://www.hhs.gov/ash/advisory-co...reports/clinical-aspects-lyme-2020/index.html

 

Providing a glance of a mechanism instead of an epidemiological study:

I happen to know two impacts on my health, one being borrelia.

I remember now that when I was four years old I had at least two ticks. In later summer I felt dizzy, fell over and broke a bone. Since then I had lost quite some high life. When I was thirty I got EBV, which lasted for one year instead of the predicted three months, and this then brought the catastrophy about.

Whereas I don´t know why the acute EBV infection lasted longer, quite sufficient other mechanism can be reconstructed.

• Aguirre et al 2013 (A manganese-rich enviroment supports superoxide dismutase activity in a Lyme disease pathogen, Borrelia Burgdorferi) found tremendous high amounts of manganese accumulated in borrelia (two times of magnitude more than in most other cells). A first guess has been made (article is not open access though) by Posey and Gheradini 2000 when they discovered that borrelia don´t contain any iron. Another finding reported about six times higher manganese, I think, compared to most other cells.
• Yenemandra et al 2010 found: Epstein-Barr virus encoded EBNA-3 binds to vitamin D receptor and blocks activation of its target genes.
• One target gene being: Vitamin D3 transactivates the zinc and manganese transporter SLC30A10 via the Vitamin D receptor. (da Silva et al 2016) " ... in a VDR dependent manner, resulting in increased ZnT10 protein expression." So, again manganese.

I conclude now that high manganese in the presence of some infection has caused my ME/CFS. And indeed, I not only can follow the course of my illness and even life through manganese intakes, but also do improve from a low manganese diet since 2015.

After waiting for a year, it took me until now to have figured out additional influences on that mess of illness. Next to manganese some other helpful stuff can readily be associated with the basal ganglia: GABA, taurin, tyrosin. Most important are zinc (cf possibly: Thalamic distribution of zinc-rich terminal fields and neurons of origin in the rat, Mengual 2001), in a somehow strange way nickel (cf possibly: Nickel block of three Cloned T-type Calcium Channels: Low Concentrations Selectivily Block alpha1H, Lee 1999, among similar findings), chromium, and some Vit B´s all of which serve for energy production in the mitochondria - so not B9 and B12 anyway - but B6 tends to be bad.
I conclude that the preferences with which neurons connect to each other in the basal ganglia and the (related) thalamus have gotten altered by two impacts, and that different actions might be coded by different metals and different Vit B´s.


This observation may go to show that post Lyme problems (caused by borrelia) can occure without ongoing infection and without possibility to get diagnosed properly. Therefore one should expect that borrelia should play some statistical powerful role, and one may look for it again.

 

Very interesting. Thanks, Michiel. Are you thinking of publishing something based on this research?

What jumps out at me is how many studies there are out there with such obviously poor methodology. (I noticed the same thing when I looked up research on hypnosis for pain relief which I discussed here.) It appears that across medicine vast amounts of time and money are wasted on studies which don’t tell us very much because they haven’t been designed properly. I wonder if this is due to ignorance or something else. And I wonder what can be done about it.

If the answer to Michiel’s question was that there is an increased incidence of chronic debilitating symptoms following Lyme disease compared with healthy controls, a second question I would be interested to know the answer to is whether there is an increased incidence of chronic debilitating symptoms in post-Lyme patients compared with age/sex matched controls who had similar antibiotic treatments for acute non-Lyme infections at the same time as the Lyme patients.

IF Lyme disease was just one of many possible triggers for ME/CFS (and PTLDS was indistinguishable from ME/CFS) then one might expect to see a slightly higher incidence of people with chronic debilitating symptoms among post-Lyme patients compared with healthy controls, as some of those controls might not have had any of the type of infections which might trigger ME/CFS – unless the potential triggers for ME/CFS are so common that most people are exposed to them. In other words, it would seem to be possible that post-Lyme patients could have higher incidences of chronic debilitating symptoms compared to healthy controls even if PTLDS was indistinguishable from ME/CFS.

NB I’m not suggesting that PTLDS isn’t distinguishable for ME/CFS or even that ME/CFS is necessarily triggered by infection. I’m just speculating on hypothetical possibilities, as someone who isn't qualified or knowledgeable enough to make a judgement.

 

The History of Lyme disease spans scores of years, and hundreds of studies. This is a snapshot that even imo mischaracterizes the most recent Aucott studies - and I'm not an Aucott fan.

This discussion is little more than a scratch of the surface. A tip of a toe in an endless ocean. There isn't even mention of Willy's work, and without that, everything kinda is without basis. And citing Shapiro and Wormser makes me shudder.

I kindly recommend more homework. Go back to the beginning, if you can figure out where that is...

You glance at some what's when you need to parse down on the why's and the who's and the when's.

 

@Trish , yes, but not now. I'm going to sleep. Later.

Willy = willy burgdorfer.

 

Thanks to @Michiel Tack for this work...and thanks to @Peter Trewhitt for elucidating how my brain works!

I'm frustratingly unsure whether I or not was exposed to Lyme, but because of that, I'm interested in the topic. I've always found debates about post-Lyme syndrome a bit suspect – so little hard evidence, so much anecdote – but I haven't the mental clarity to attempt what Michiel is doing.

(My anecdote: I saw a bullseye rash whilst spending the hot summer of 1976 hiking through upland sheep country, but although the image is clear in my memory, I can't recall whether it was on my leg or my schoolfriend's. At the time it was nothing more than a curiosity to a teenager; the friend and I both still have ME, so even that can't help determine who owned said limb. She doesn't remember it at all, and neither of us had acute symptoms at the time.)

 

I realize that this is a controversial issue and it's certainly not my intention to throw oil on a fire. I hoped that a focus solely on epidemiology would provide an interesting perspective because that seems to be the foundation of all else. I hope people will take no offence at the autism/vaccine analogy; this was merely the simplest way to explain the issue with selection bias. It certainly is not my intention to compare the research into PTLDS to the flawed research of Wakefield and others.

I would also like to emphasise again that in my view the current evidence also doesn't refute that hypothesis that there is an increased incidence of chronic debilitating symptoms such as fatigue, pain and cognitive difficulties following Lyme disease compared to controls.

As I mentioned before, few studies looked at this. Most compared all persons who experienced Lyme disease in the past to controls who didn't. If the vast majority of patients with Lyme disease fully recovers, the average may hide a tiny minority of people who remain severely disabled because of their exposure to Lyme disease. To study researchers would have to make a definition of PTLDS disability in advance for example with SF-36 physical function or other questionnaires scores below a certain level and then test how many people who experienced Lyme disease meet that definition at follow-up compared to a control group. Thus far only the Aucott et al. 2013 study did this (and their disability criterium of 0.5 standard deviations from the population mean doesn't seem stringent enough). If there are 300.000 cases of Lyme Disease a year in the US as more recent estimates suggest, then even a very low percentage of PTLDS might result in lots of patients that remain chronically ill. So the sample size of prospective PTLDS-studies would need to be really large to pick up on subtle differences in persons meeting the predefined disability criteria.

Another argument is that most of the studies that couldn't find evidence of severe and chronic PTLDS focused on early and well-recognized Lyme disease. Perhaps PTLDS is mostly an issue in more difficult cases which aren't properly recognized or treated and where patients develop late Lyme, disseminated Lyme disease or neuroborreliosis. The Norwegian study by Eikeland and colleagues focused on neuroborreliosis, had a reasonable methodology and did find evidence of PTLDS. So it seems recommended that future epidemiological not only need to be large, have pre-specified disability criteria for PTLDS, but also focus on these more difficult cases such as neuroborreliosis.

My conclusion is mostly that the current evidence isn't strong enough to diagnose patients with a label that suggest Lyme disease is the cause or trigger of their chronic symptoms. This hypothesis may turn out to be right after all but, given the current data we have, it could also turn out to be wrong and this would have huge implications for advocacy, treatment and scientific research of patients currently diagnosed with PTLDS or chronic Lyme disease.

 

That is interesting. Presumably at the time this would have been Erythema migrans. One wonders what the acknowledged incidence of it, and of Erythema chronicum migrans, was in the UK at that time. My recollection of WB's reports is that he was never actually specific as to when it was that he remembered the details of the European literature on the subject, though his knowledge was apparently only of mention in a lecture given in 1948 or so.

There must have been a growing awareness of tick borne infection at about that time (1976). I recall the concern of my climbing partner upon finding a tick attached to his leg. I think that would have been in 1978.

 

Well, welcome to Lyme.

This can only be done if you look at all the epidemiological efforts, and do so chronologically. Context not only matters; it is essential to a thorough understanding of what has been/is going on with Lyme and Company. You appear to only have explored Steere and progeny. this will unfortunately generate what many would consider as a biased perspective. To help you balance that, it might be a good thing to read divergent studies. Researchers like Sapi and Miklossi and Middleveen(sp) and...there's a lot. I would be happy to name some authors, but curiously, if you read early (around 1976 - 1983) Steere and company you will see him often espousing what appears to me as similar themes to ILADS researchers.

This sentence assumes Lyme is eliminated. Nobody has proven that happens reliably in all treated patients.

Start looking back around 1982. 1983 was a watershed year. That's the year they redefined what qualified symptoms as major and minor. Remember how Pace authors redefined "recovery"? Similar story that actually influenced future Lyme studies, including epidemiological ones.

WIDELY acknowledged estimate is that 10 - 20 % of Lyme victims remain sick after IDSA-recommended treatment protocols. Even Aucott promotes this number. Many believe the percent cured is even lower. That hardly qualifies as "the vast majority." As for the "tiny minority" who become disabled. current US numbers are roughly 400,000 infected per year. If 10 - 20 % remain sickened, year after year, how many chronically ill and disabled people are there attributable to Lyme in the US alone right now?

No, they have to study late stage Lyme. PTLDS is a political construct. Now, technically, this has been studied by the NIH since circa 1999 or so. Check out Marques et al. But you won't find much on that particular study, even though it's been up and running 20 years.

You need to rethink this. Aucott is an infectious disease specialist turned rheum (I think) whose specialty is all things PTLDS. Many believe this is about as real as FND's. You are effectively pigeon-holing yourself. Expand to late stage Lyme and, yes, chronic Lyme. And your estimates are dated.

Yes, it's not just another argument, it's a key point. Look at almost all diagnostic efforts generated by the NIH over the last 25 years. They almost all are for acute cases. When it was first released around 2000, the C6 was touted for its ability to, among other things, determine late stage cases with solid reliability. But this capability was retracted later. Personally, I have wondered if it had something to do with the C6 still showing patients remained infected with late stage Lyme after multiple treatments, but I cannot say for sure.

Sorry, but a bit of circular reasoning here.

There is an entire medical community of well-qualified doctors, and literally hundreds of thousands of patients who would disagree.

 

There is also a much larger medical community of well-qualified and well-informed doctors who agree with Michiel's conclusions.

 

An inexorably shrinking majority. Too much new data appearing. You see it happening in the US, not just in terms of new revealing studies (like the persister studies out of Johns Hopkins and NorthEastern and Tulane), but in legislation and law suits , state by state. It will happen in Europe, too, I suspect. I hope so for the Lyme patients there.

Interestingly, one of the good things that Aucott has done was help validate patients' reports, after some old Lyme researchers had mischaracterized the patient experience. That is contributing to the positive change as well.

 

The most raw scores for the SF-36 are on a 20-point scale. If I recall correctly, 10-30. So subtract by 10 and multiply by 5 to get non-normalized scores.

 

Yes, possibly. I didn't even know ticks existed until years later, and it was probably the early 2000s before I'd heard of Lyme disease. If one of us had found a tick, we might have asked about it; as it was, I assumed the rash was a scrape from scrambling hillside scree or climbing up rock formations with bare legs.

 

Sticking once more to details rather going through epidemiologics:

Late Disseminated Lyme Disease
Assocoated Pathology and Spirochate Persistence Posrtreatment in Rheusu Macaques
Crossland et al 2018

As I said, borrelia have been shown to accumulate possibly very huge amounts of manganese.

Speaking short, I don´t see how dissence is going to continue, even if it will. Manganese has been shown to influence the immunesystem.

brain-wise: Manganese-induced potentation of in vitro proinflammatory cytokine production by activate microglia cells is associated with persistent activation of p38 MAPK Crittenden anad Filipov 2008, with a summary.

a preview on Wang et al 2018 Innate Immune Cells speak Manganese Haase 2018