Investigating the root causes of multiple sclerosis using systems analysis and dynamics, developing an integrated treatment strategy

摘要

By applying the methods of systems analysis to the problem of what causes multiple sclerosis, we have been able to show that it is a systemic illness, with multiple interacting causes and mechanisms. The results were obtained by synthesizing state-of-the-art research on parts into a whole systemic picture of the whole. These main components make up the illness system: 1. The root cause: A Permeable blood-brain barrier (BBB) and transmission of provocative substances, antibodies and leucocytes into the brain. This may be caused by chronic cerebro-spinal vascular insufficiency (CCSVI, and associated microclotting due to stagnant cerebro-venous blood flow), latent infections that cause a Th1-dominated immune response and release of matrix metalloproteases (MMPs) which can alter the BBB, or a general pro-inflammatory state created due to dietary factors. 2. Triggers are antibodies to myelin and oligodendrocytes from ⅰ. Infections by certain bacteria and viruses; ⅱ. Peripheral allergenic attacks ⅲ. Myelin and oligodendrocyte debris in the blood stream 3. Reinforcing loops: a. Feedback system involving iron in the autocatalytic Fenton cycle and production of oxidants, prominently peroxynitrite, reinforcing the increased permeability of the BBB; keeping the BBB compromised b. Autoimmune feedback loop involving immune system and myelin sheath breakdown, leading to damages to the BBB, by oxidative denaturalization of the myelin surfaces. c. Oxidative stresses, leading to scaring at damaged sites and impairment of the ability to repair myelin sheaths, making the physical damage permanent The partial mechanisms were linked together into one large integrated model leading to the disease. Multiple sclerosis has no single cause, but a number of interacting of causes in a feedback system. The model is capable of describing the untreated progress of the illness as it has been observed. Multiple sclerosis is initiated by an opening of the blood-brain-barrier, combined with provocative substances in the blood, which initiate a vicious cycle of oxidative stresses and immune attack. The conceptual model was used to investigate the dynamics of the illness and understand its initiation and subsequent illness progression qualitatively. With the model we can start to analyse how treatment for multiple sclerosis must be approached in a multi-disciplinary way in order to be successful. The conceptual model was developed into a systems dynamics model in the STELLA environment. The simulation model is capable of reconstructing the basic outline of the illness, with the onset at 25 years of age, and the transition to secondary progressive disease at 45-55 years of age. This appears to confirm the validity of the fundamental features of our model.