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Evaluation of the long-term inflammation in neuroborreliosis:
Duration of therapy

by

Joachim Gruber

Overview: A Tentative Interpretation of Lyme Flare Cycles and a Corresponding Therapy
A more detailed analysis can be found in my draft "Lyme Disease: Statistical Evaluation of a Symptom Log and an Empirical Theory of Flare Cycles"

Abstract

A simple model of the immune response to an infection with B. burgdorferi (Lyme disease) is presented. During the first part of the therapy the immune system performs feedback control oscillations in the attempt to eliminate the pathogen. Towards the end of the successful therapy this oscillation stops and the immune system response becomes synchronous with the menstrual cycle. The working hypothesis persented here interpretes this switch of the frequency of oscillation to be a result of the niches for B. burgdorferi having become depleted. Accordingly, a conservative assumption is that the therapy needs to be continued until this switch is observed.

Introduction

In his "Guidelines" Joseph J. Burrascano recommends patients to keep a symptom log on a daily basis and specifies how he has used it as a guide for specifying the antibiotic treatment:
"It has been observed that symptoms will flare in cycles every four weeks. .... If the antibiotics are working, over time these flares will lessen in severity and duration. The very occurrence of ongoing monthly cycles indicates that living organisms are still present and that antibiotics should be continued.

....

"In general, I.V. therapy is given until there is a clear positive response, then treatment is changed to IM or po until free of signs of active infection for 4 to 8 weeks. "

This type of monitoring is customary in the therapy of e.g. HIV infections and cancer. The framework in which it is used there is the mathematical immune response model. To demonstrate the equivalence of both approaches (Burrascano's and mathematical modeling), I have

Immune Response Model

Detailed microbiological and immunological processes (as e.g. reviewed by Rupprecht et al., 2008) work together in such a way as to produce the globally observable symptom cycles. Similarly as the treating physician does not need to consider the host of elementary processes that produce the patient's body temperature or immune globulin dynamics, for our conservative decision on the therapy end we do not necessarily need to link the symptom cycles to detailed individual microbiological and immunological processes. In principle it suffices to model the resulting global processes as orchestrated by the latter.

The following figure describes those processes incorporated in the model. The control loop depicted with heavy lines (on the left) represents the ability of the immune system to enter self-organized feedback control oscillations the period of which is determined by parameters intrinsic to the immune system. The immune system can also oscillate with a period given by the menstrual cycle (loop drawn in medium heavy lines on the right).


FIGURE: A simple compartment system and an immune system control scheme that produces oscillations between an inflamed state and a symptom free state. Steps 1 - 6 and states 1 - 4 are explained in detail in Fig. 10 of the draft report.
  • Upper part: the simplest possible compartment model displaying oscillations consists of a compartment under immune observation (on the right) and a compartment poorly visible to the immune system (the " niche", on the left side, literature supporting the particular concept of the intracellular niche).
  • Lower part specifies the system behavior as a funtion of the Bb -or Bb fragment- concentrations within the compartment under immune surveillance.
    I and E are the threshold levels at which the immune system is triggered into inflammation and elimination, respectively. They are functions of the menstrual-endocrine system parameters, e.g. the proinflammatory prostaglandin E2 level (PGE2), and other immune system parameters, e.g. levels of modulating pleiotropic, redundant and antagonistic cytokines (J. Kuby, Immunology, 3rd Ed., WH Freeman and Co, New York, 1997, Chapter 13, p 315).
Mechanisms at work
  1. Cycle 1: As long as niche injects part of its content into compartment under immune surveillance, immune system performs self-organized feedback control cycles, periodically reducing Bb (fragment) level below threshold E. When Bb (fragment) level is below E and thus immune system at rest, Bb (fragment) level rises due to ongoing infiltration of Bb (fragments) from niche.
  2. Cycle 2: Antigen elimination is turned on and off by menstrual - endocrine system. When influx from niche is negligible, each cycle continues to reduce Bb (fragment) level.
  3. Cycle 3: Inflammation threshold I is switched down and up again by prostaglandin E2 level going up (in luteal) and down (in follicular phase), respectively. Thus, inflammation surfaces periodically in luteal phase of menstrual cycle where prostaglandin E2 level is elevated.
It is possible that presence of cycles 2 and 3 is an indication of a low pathogen level in the niche.

Caveat added: According to Marylynn Barkley, women with Lyme have an exacerbation of their symptoms around menses. She associates the worsening of women's Lyme symptoms with the decline of both estrogen and progesterone at the end of the menstrual cycle. (Marylynn S. Barkley, Ph.D., M.D., Associate Professor, Neurobiology, Physiology, and Behavior, The University of California at Davis, Davis, CA 95616, USA, E-Mail: msbarkley@ucdavis.edu, WWW: http://www.npb.ucdavis.edu/)

Results

  1. Immune system is locked into oscillations during the severe phase of the disease.
  2. Fluctuation of the immune system's susceptibility to the pathogen with the clock frequency of the menstrual cycle might indicate low pathogen levels.
  3. Monitoring of the post-iv phase.

The address of this page is http://www.lymenet.de/symptoms/cycles/evalsum.htm.

The home page of this website is http://www.lymenet.de.
Send your comments to Joachim Gruber.
version: 4 December 2015.