Wednesday, April 27, 2011

0 IOM Summary Report: Neuroborreliosis Notes #2

This is Part 2 of part 1, IOM Summary Report: Neuroborreliosis Notes...
(Read that first...)

After Dr. Stephen Barthold's presentation, the following discussion came up:

"Another participant questioned how neurologic symptoms occur if the bacterium is just in collagen,even if it is associated with neural tissue. Barthold noted that mice do not get central nervous system disease, possibly because they don’t have much connective tissue in their brain. However, central nervous system disease is seen in larger mammalian species that have more collagen in their meninges and perivascular spaces. Under those circumstances, Barthold has observed spirochetes in the collagenous areas and along the perivascular spaces into the brain. Because there is a dearth of good analysis of human neuroborreliosis cases, it is not known if the spirochetes are located in other areas.  He noted that a tissue bank or biorepository would be very valuable to allow for these types of analysis."

Has Dr. Barthold talked to Dr. Alan MacDonald at all? I have to wonder... aren't there other tissue banks out there which already have neuroborreliosis samples?

So all these people - a portion of which knew they were bitten by ticks - have cognitive and neurological symptoms, but there is little good analysis of human neuroborreliosis cases.

Why is that?

Does it have anything to do with how difficult it is to determine whether or not a patient has neuroborreliosis, especially once you're read the European data on testing the CSF for IgG antibodies and realize that the initial positive rate is at it's best within two weeks of clinical presentation (assuming this means symptom onset)?

When they say there isn't enough data on human neuroborreliosis... let's start with this chart:

No news is good news?

I note that there also is no independent measurement for Late disease-Neuroborreliosis  in this table, either. Just arthritis and the measure for culture is labeled "anecdotal". So data is lacking there, too. (I have to wonder why the author used "ancedotal".)

But then there is always two-tier testing, which is indirect detection testing (does not test for the organism itself, but tests for antibodies to it):

As you can see from this chart, depending on which kind of testing you use (ELISA, two-tier Western Blot, or this other proposed test), supposedly serological testing for early Lyme disease is poor, and early disseminated neurological infection is better. Not perfect, but better.

Is that late neurological and arthritis disease detection rate correct? I want to see the cited research (this requires finding the original full text publication) before commenting more on it. But I will say that even with the correct distribution of findings here,  neuroborreliosis that occurs within the first week after being bitten is not going to show up in the early group, and 13-37% of early disseminated neuroborreliosis cases are missed, depending on the test set.

Note on page 7-4 that:

"The C6 testing protocol has performed comparably in accurately detecting the presence of antibodies to B. burgdorferi in sera of patients with acute EM, but was slightly less effective in the case of neurological Lyme disease."

And also, this is an important point, related to the first chart at the top and information in my previous neuroborreliosis notes post:

"One scientific gap is the testing of cerebrospinal fluid for antibodies. Europeans measure intrathecal production of antibodies by measuring antibodies in CSF and comparing these results against the concentration of antibodies in the serum to produce a ratio. U.S. Scientists have not had a sufficiently large population in which to evaluate the efficacy of this approach because fewer cases of neuroborreliosis are documented in the United States as compared to Europe and CSF sampling is not routinely done in patients with Lyme disease. The absence of this type of testing is a gap in diagnostics for neuroborreliosis caused by B. burgdorferi in the United States."

Is this the case - that the gap in diagnostics for neuroborreliosis is to be blamed on the bacteria? I think that's unfair to the bacteria. As far as I can see, what's happened is that the fact of neuroborreliosis is not something that has been discussed or emphasized when pathogenic Borrelia are neurotropic to varying degrees. Neurological symptoms should be included when educating doctors, nurses, and patients about the disease, and not sidelined to "that only happens in European strains". It doesn't, and besides, Americans do sometimes visit Europe. And hey, if B. garinii and B. afzelii are beginning to show up in southern ticks, well, maybe in a while you'd be seeing more cases of early neuroborreliosis anyway.

I don't know about you, but many Lyme disease patients I've spoken with only got an ELISA test for Lyme disease from their primary care physician, and when that came back negative, there was no further testing.

CSF testing when I had early neurological symptoms is not something I was offered, either.

Which is ludicrous when early serological testing is especially prone to not detecting an infection. What should happen is if the person has a lot of neurological symptoms shortly after a tick bite, they should have a LP. And also the Western Blot. Repeated Western Blot testing which shows an increasing and changing serological profile would be useful in demonstrating antibody response.

It is also stated elsewhere in the summary report:

"An increment in immunoreactive bands is observed in the IgG immunoblots of sera of patients with neuroborreliosis and Lyme disease arthritis."

Saying that Borrelia burgdorferi doesn't cause neuroborreliosis isn't true. Saying it's rare isn't a helpful statement, and aside from utility, it's not even clear how rare it is because we simply lack that data. We don't know. What we have is a guess.

Referring to some studies (there are more studies on neuroborreliosis in the paper):

Page 7-15

"Turning to the literature pertaining to patients with chronic persistent symptoms, Fallon noted a number of areas need additional research. A European study compared patients with neurologic Lyme disease to those with erythema migrans 3 years later and found that 50 percent of those with neuroborreliosis experienced persistent symptoms versus 16 percent of the EM patients (Vrethem et al., 2002). These results suggest that follow up studies on chronic symptoms, rather than focusing solely on early EM, should focus on the subpopulation of patients who present with neurologic or other disseminated symptoms."

Page A-94:

"In a study of 60 U.S. patients with neuroborreliosis (16 with early and 44 with late neuroborreliosis), the sensitivity of PCR in CSF was 38% in early and 25% in late neuroborreliosis, and an inverse correlation was found between duration of antimicrobial treatment and PCR results (Nocton et al., 1996)."

So clearly, PCR isn't so great at detecting neuroborreliosis in early or late stage infection.

Page 7-16
"With respect to pathophysiology, Borrelia act directly and can invade neural cells in vitro (Livengood and Gilmore, 2006); there are also indirect actions, such as the induction of local cytotoxins or inflammatory mediators (reviewed in Fallon et al., 2010). European studies show that pro-inflammatory cytokines are increased, and chemokines, excitotoxin, and quinolinic acid are increased in patients with neuroborreliosis (Weller et al., 1991; Halperin and Heyes, 1992; Widhe et al., 2004; Rupprecht et al., 2005)."

(An aside: For all of those readers getting excited about the excitotoxin, it's not produced by the Lyme Borrelia spirochete - it's produced by your own body. If you're thinking about detoxing that, I'll be discussing it in a different post.)

A discussion item on this was noted at some point during the workshop:

"...Dumler noted that large-scale human clinical studies that have sufficient statistical power are needed. As discussed by previous panelists, such studies would allow the acquisition of large numbers of subjects and potentially bring together all of the involved communities — patients,advocate groups, physicians, academicians—to address research uncertainties on a large scale. These clinical trials for tick-borne diseases could easily be assimilated into modern high-throughput methods that may make whole genome surveys feasible.There would need to be some discussion on how many patients would be needed for a single-nucleotide polymorphism (SNP) analysis for neuroborreliosis. A large-scale clinical study would be intense and difficult, but it would rely on the communities coming together. These clinical trial groups could provide critical corroborated subjects and a biorepository of samples for pathogenesis studies. Within the group, one could create and validate the next generation of diagnostics. It would also provide a critical structure for the assessment of the new diagnostics, clinical interventions, and therapeutics.

Here's one action item: Organize a large-scale human clinical study involving single-nucleotide polymorphism (SNP) analysis.

But is this the most relevant test for people who are ill and have persistent symptoms? I wish Dumler would outline the process for patients as to what he sees in the future for patient treatment using this data.


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