|Distinct Cerebrospinal Fluid Proteomes Differentiate Post-Treatment Lyme Disease from Chronic Fatigue Syndrome.
||Schutzer SE, Angel TE, Liu T, Schepmoes AA, Clauss TR, Adkins JN, Camp II DG, Holland BK, Bergquist J, Coyle PK, Smith RD, Fallon BA, Natelson BH.
||PLoS ONE 6(2): e17287. doi:10.1371/journal.pone.0017287
Neurologic Post Treatment Lyme disease (nPTLS) and Chronic Fatigue (CFS) are syndromes of unknown etiology. They share features of fatigue and cognitive dysfunction, making it difficult to differentiate them. Unresolved is whether nPTLS is a subset of CFS.
Methods and Principal Findings
Pooled cerebrospinal fluid (CSF) samples from nPTLS patients, CFS patients, and healthy volunteers were comprehensively analyzed using high-resolution mass spectrometry (MS), coupled with immunoaffinity depletion methods to reduce protein-masking by abundant proteins. Individual patient and healthy control CSF samples were analyzed directly employing a MS-based label-free quantitative proteomics approach. We found that both groups, and individuals within the groups, could be distinguished from each other and normals based on their specific CSF proteins (p<0.01). CFS (n = 43) had 2,783 non-redundant proteins, nPTLS (n = 25) contained 2,768 proteins, and healthy normals had 2,630 proteins. Preliminary pathway analysis demonstrated that the data could be useful for hypothesis generation on the pathogenetic mechanisms underlying these two related syndromes.
nPTLS and CFS have distinguishing CSF protein complements. Each condition has a number of CSF proteins that can be useful in providing candidates for future validation studies and insights on the respective mechanisms of pathogenesis. Distinguishing nPTLS and CFS permits more focused study of each condition, and can lead to novel diagnostics and therapeutic interventions.
The article can be read in its entirety at PLos ONE.
Discussion and Analysis by the CFIDS Association of America
|A Randomized, Placebo-Controlled Trial of Repeated IV Antibiotic Therapy for Lyme Encephalopathy.
||Fallon BA, Keilp JG, Corbera KM, Petkova E, Britton CB, Dwyer E, Slavov I, Cheng J, Dobkin J, A Randomized, Placebo-Controlled Trial of Repeated IV Antibiotic Therapy for Lyme Encephalopathy.Nelson D, Sackeim HA.
||Neurology. 2008; 70 (13); 992-1003; epub 10-07
The study, titled “A Randomized, Placebo-Controlled Trial of Repeated IV Antibiotic Therapy for Lyme Encephalopathy,” was published in the journal Neurology in March 2008. The study was led by Principal Investigator Brian Fallon, M.D., M.P.H., Director of the recently established Lyme and Tick-borne Diseases Research Center at Columbia University Medical Center (http://www.cumc.columbia.edu/news/press_releases/fallon_lyme_center.html). The research was conducted jointly at the Columbia University Medical Center and New York State Psychiatric Institute and was funded by the National Institute of Neurological Disorders and Stroke (NINDS).
Dr. Fallon and his research team identified patients with cognitive problems that developed after being diagnosed with Lyme disease and which persisted or relapsed despite prior treatment, in order to determine whether patients who have already received the “standard” course of antibiotic treatment (three weeks of IV antibiotic therapy), would benefit from an additional 10 weeks of antibiotic therapy. They also set out to determine whether patients relapse when taken off antibiotics or whether the alleviation of symptoms is sustained or enhanced with time.
Study participants (57 subjects: 37 patients with a history of Lyme disease and 20 healthy volunteers) were divided into three subject groups: patients with a history of treated Lyme disease who were randomized to IV treatment with an antibiotic called ceftriaxone for 10 weeks; patients with a history of treated Lyme disease who were randomized to IV placebo for 10 weeks; and, healthy controls who were tested at the same time points as the patients to help to control for the practice effect on neuropsychological testing. All patients had to meet criteria for memory impairment at the start of the study and they were also required to have documented clinical and serological evidence of a history of Lyme disease.
Findings from this study, the first placebo-controlled study of chronic cognitive impairment after treated Lyme disease (also known as persistent Lyme encephalopathy), demonstrate that patients at the start of the study reported moderate cognitive impairment, physical dysfunction comparable to patients with congestive heart failure, and fatigue comparable to patients with multiple sclerosis. In the study, repeated intravenous (IV) antibiotic therapy was shown to have moderate short-term benefit in treating cognitive dysfunction compared to the two control groups together (healthy volunteers and Lyme patients given IV placebo), but this improvement was not sustained after the antibiotic was discontinued (p=.04). The specific drug vs placebo comparison at the primary end point of week 12 fell at the margin of significance (p=.053), raising the risk slightly that this result may have occurred by chance. Specific improvement in memory – the primary domain of interest in the cognitive battery – was not noted at either the primary end-point of week 12 or at the end point to assess longer-term sustained response (week 24).
On secondary clinical outcome planned analyses, the study investigators also found that, among those with greater impairment at the start of the study, significantly greater benefit was noted at week 12 in fatigue, pain, and physical functioning among those given IV antibiotic compared to those given IV placebo. Among these IV antibiotic treated patients with greater initial pain and physical dysfunction, the significantly greater improvement over placebo was sustained to the six month end-point (the period when patients were off antibiotics).
In a post-hoc analysis, which reanalyzed the data to determine what the results would look like if enrollment had been the same as in the Krupp study of post-treatment Lyme fatigue (Neurology, 2003), the Columbia results were comparable. The StonyBrook study reported that 64% of ceftriaxone-treated patients showed clinically meaningful improvement in fatigue compared to 18.5% of placebo-treated patients. The Columbia study similarly found that 66.7% of the ceftriaxone group vs 25% of the placebo group showed a significant improvement in fatigue (p<.05).
The investigators reported that about 19% of patients did experience potentially serious side effects associated with IV antibiotic therapy, such as thrombi, systemic infections, allergic reactions, and/or gall bladder disease.
Given the significant risk and the lack of sustained benefit, Dr. Fallon and his co-authors recommended against the use of a course of 10 weeks of IV ceftriaxone followed by 14 weeks of no antibiotics as a treatment strategy for a sustained improvement in cognition. The acute and sustained antibiotic-associated improvement in pain and physical functioning among subgroups of patients with greater severity of symptoms was notable as these are among the most disabling symptoms experienced by patients; however, because these were secondary and not primary outcome measures, conclusions regarding the benefit of repeated IV therapy for this set of symptoms must await further investigation.
This NIH-funded study was published in Neurology on-line in October 2007 and in the journal itself in March 2008.
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