Through the Looking Glass: What Epilepsy Tells Us About the Future of Medicine

In 1871 Louis Carroll published his classic sequel to Alice's Adventures in Wonderland entitled Through the Looking Glass and What Alice Found There.1 This book, although not as popular as the original, became a literary classic, spawning numerous plays and musicals. The narrative reflects on a mirror image of Wonderland, with frequent use of plot devices such as changes in time and spatial directions. One of the central themes of the story is mirror scenes, with an emphasis on opposites. In the current issue of Mayo Clinic Proceedings,2,3 epilepsy serves as a looking glass in which projections of seemingly paradoxical ideas emerge and the future of medicine is foretold. Epilepsy is defined as a condition characterized by repeated unprovoked seizures. It affects 2.7 million Americans and 2% of the world's population.4 An estimated 60 million people worldwide have had seizures at one time in their life. In about 18 million individuals worldwide, medications do not control their seizures, and alternative therapies are required.5 For patients with epilepsy and the physicians who treat them, the condition is a public health scourge with a significant stigma. To neuroscientists, epilepsy is an entry zone, a “looking glass” if you will, for understanding the final common pathways and mechanisms by which seizures occur and for reflecting on other similar channelopathies and diseases with related underpinnings that may contribute to the cause of an illness via the same mechanism. The 2 articles in this issue of the Proceedings are presented with seemingly dissimilar themes and approaches but converge around the concept of epilepsy. In their review of functional neuromodulation for psychiatric disorders, Tye et al3 describe how electrical stimulation therapies (which are now part of the standard of care of epilepsy) may be the new frontier for a number of psychiatric conditions, including depression, anxiety, obsessive-compulsive disorder, and Tourette syndrome. This electrical stimulation is accomplished by implantation of a pacemaker-like pulse generator with an attached lead or electrode. The pulse generator is implanted near the clavicle with an electrode encircling the left vagus nerve for the vagal nerve stimulator system or a lead targeted to the thalamus or other subcortical structure for deep brain stimulation. Modern neuromodulation, which has its roots in the treatment of seizures, may have considerable behavioral applications given that epilepsy neurologists have long noted that psychiatric comorbidities improved with neurostimulation. Tye et al explore several anatomic targets for treatment of resistant psychiatric disorders indicative of systemwide effects of neuronal network-level dysfunction. These anatomic areas contain portions of neuronal pathways that modulate emotional and cognitive disturbances. The authors also examine anatomic models of psychopathology, including therapeutic mechanisms of deep brain electrical stimulation, and provide a modern prospectus for the management of medically refractory psychiatric conditions. They suggest that the modern era of neuromodulation may provide the key that unlocks many of the mysteries pertaining to the biological basis of disordered emotional neural circuitry and presage the future of psychiatric therapeutics. See also pages 495 and 522 Meanwhile, a renewed health care debate has begun. Regardless of the outcome, patients' quality of life and its measurement will be increasingly emphasized, including patients who have baseline aberrations of brain electrical activity and those who will benefit from artificial alterations of brain electrical activity to improve their performance. One aspect of this continuum of thought involves expanding the use of high-intensity observation units to better characterize and more effectively diagnose epileptic attacks. These observation units are termed video electroencephalography monitoring units (VEMUs). VEMUs are hospital-based clinical laboratories equipped with video electroencephalography recording equipment where patients are electively admitted for recording of typical spells and seizures. Often, seizure medications are discontinued, and other activating procedures are performed with the intent of trying to precipitate a typical attack. Recently, there have been outcries in the media about deaths that have occurred in VEMUs while precipitating a seizure.6 The article by Noe and Drazkowski2 presents a novel quality analysis of VEMU safety that sheds light on VEMU risks. The investigation consisted of a 2-year retrospective review of the medical records of 149 consecutive adult patients with epilepsy who were admitted to a VEMU at Mayo Clinic's site in Arizona. No deaths, transfers to the intensive care unit, falls, dental injuries, or pulmonary complications occurred. However, risks are inherent during observation in a VEMU. The authors found potentially serious ictal electrocardiographic abnormalities, postictal psychosis, vertebral compression fractures, generalized convulsions, and seizure clusters. This is important information. It is essential that all health care practitioners and patients understand that epilepsy monitoring has risk. VEMU evaluation is a bit of a paradox given that confirming a diagnosis and assessing the anatomic location of seizures means having patients experience the one condition (ie, seizures) they are seeking medical help to stop. Yet, observation within a VEMU is generally safe, and its benefits outweigh the risks as long as quality monitoring standards and procedures are in place to mitigate potential complications that may occur during clinical observation. Thus, these 2 articles in the current issue of the Proceedings present opposite perspectives as they relate to disordered neural circuitry. Tye et al discuss the history, techniques, and consequences of preventing abnormal neural circuits from firing (as applied to neuromodulation of psychiatric disorders), whereas Noe and Drazkowski discuss the effects and potential consequences of allowing pathological neural circuits to fire when seizure disorders are being evaluated. However, understanding the link between epilepsy and neuropsychiatric disorders is difficult. Whether the primary defect is due to failure of facilitatory networks, overexpression of facilitatory networks, or underactivation of inhibitory networks is unknown. Finally, both articles discuss the commonality in trying to understand the neural network pathology in both psychiatric and epilepsy disorders. The similarities and potential links between epilepsy and psychiatric disorders have been noted7,8 and are not surprising given the potential for common pathology (overactivation or underactivation of neural networks). Just as neuroimaging has been a helpful diagnostic tool for understanding both epilepsy and psychiatric disorders, neuromodulation via stimulation is finding common ground for these same disorders. Advances in microcircuit technology and implantation techniques with computer-assisted stereotaxis will continue to play a role in the evolution of treatment options for both these conditions. Thus, although epilepsy is a terrible condition for many people, understanding its basic mechanisms may lead to a greater good by ultimately improving quality of life not only for those with seizures but also for many others.