Doman Glenn, Pelligra Ralph
The Institutes for the Achievement of Human Potential, 8801 Stenton Avenue, Wyndmoor, PA 19038, USA.
Med Hypotheses. 2004;62(5):740-5. doi: 10.1016/j.mehy.2003.10.020.
Recent discoveries in molecular biology and human genetics have contributed greatly to an understanding of the nature of seizure (ictal) activity. However, two questions of fundamental clinical importance continue to resist scientific inquiry: when and why does a seizure begin; and when and why does a seizure end? This paper cites evidence from the medical literature in support of two counterintuitive concepts that address this issue. First, that despite the diversity of conditions that are associated with seizures, the ictal response results from disturbances of a mitochondrial metabolic pathway that is common to them all. Second, that the seizure is not inherently harmful but is, instead, associated with massive intracerebral circulatory changes that are intended to restore impaired mitochondrial function. We hypothesize that the protogenic pathophysiological condition leading to neuronal hyperexitability and seizures results from inadequate mitochondrial energy production due to hypoxia or a hypoxia-equivalent state. Failure to generate sufficient adenosine triphosphate compromises ionic pump function and the ability to maintain neuronal homeostasis and stability. The seizure cascade is a heroic effort to perfuse the brain when local mechanisms fail to restore energy production and ionic equilibrium. In summary, a seizure starts when the neuron's aerobic machinery fails to maintain effective ionic pump function and terminates when increased cerebral perfusion, associated with the seizure response, restores adequate supplies of metabolic nutrients required for mitochondrial respiration. This unorthodox unifying concept that views ictogenesis as part of a restorative process rather than as a life threatening event may provide the basis for a much needed paradigm shift in the management of seizures. Current antiepileptic drugs are associated with many serious side effects, including death, and fail to control seizures in 20% of patients with primary generalized epilepsy and 35% of patients with partial epilepsy. We propose that efforts to prevent and control seizures should be directed away from pharma-chemical suppression towards removing the causes of disturbed neuronal energy production and developing methods and bioactive agents that promote an optimized physiological milieu within the brain.
分子生物学和人类遗传学领域的最新发现极大地促进了人们对癫痫发作（发作期）活动本质的理解。然而，两个具有根本临床重要性的问题仍然难以通过科学探究得到解答：癫痫发作何时以及为何开始；癫痫发作何时以及为何结束？本文引用医学文献中的证据来支持两个有悖直觉的概念，以解决这一问题。其一，尽管与癫痫发作相关的病症多种多样，但发作期反应是由它们共有的线粒体代谢途径紊乱所致。其二，癫痫发作本身并非有害，相反，它与旨在恢复受损线粒体功能的大规模脑内循环变化有关。我们假设，导致神经元兴奋性过高和癫痫发作的原发性病理生理状况是由于缺氧或类似缺氧状态导致线粒体能量产生不足所致。无法产生足够的三磷酸腺苷会损害离子泵功能以及维持神经元内环境稳定和稳定性的能力。当局部机制无法恢复能量产生和离子平衡时，癫痫发作级联反应是一种灌注大脑的英勇努力。总之，当神经元的有氧机制无法维持有效的离子泵功能时，癫痫发作开始；而当与发作反应相关的脑灌注增加恢复线粒体呼吸所需的足够代谢营养供应时，癫痫发作结束。这种非正统的统一概念将癫痫发作的产生视为恢复过程的一部分而非危及生命的事件，可能为癫痫管理中急需的范式转变提供基础。目前的抗癫痫药物有许多严重的副作用，包括死亡，并且在20%的原发性全身性癫痫患者和35%的部分性癫痫患者中无法控制癫痫发作。我们建议，预防和控制癫痫发作的努力应从药物化学抑制转向消除神经元能量产生受干扰的原因，并开发促进大脑内优化生理环境的方法和生物活性剂。
