Monograph: Epilepsy Rajesh Shankar Iyer, Mugundhan Krishnan
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Epilepsy: Past, Present, and FutureCHAPTER 1

Haseeb Hassan
 
INTRODUCTION
The epilepsy is as old as mankind. The universal misbelief of the condition caused by “divine curse” and remedy directed to please the “supernatural forces” dominated till 18th century. The scientific understanding of epilepsy in last two centuries has given way to many path-breaking discoveries, developments and interventions. This chapter reviews the historical progress in field of epileptology, the present understanding, the current unmet needs in epilepsies and future developments that is likely to improve the understanding and management of epilepsies.
 
UNDERSTANDING EPILEPSY: PAST, PRESENT, AND FUTURE
The existence of epilepsy is known to human civilization from as early as 2000 BC. Descriptions of epileptic fits are available in all ancient civilization and evils, ghost and supernatural factors were believed to be the reason in almost all ancient civilization.1 In Ayurvedic texts, epilepsy has been mentioned as Apasmara or Apasmrti. There is a detailed description of epilepsy in the Charaka Samhita. It was attributed to dosa (humor) and treatment ranging from mantra (hymn), emesis, purgative, topical application and oral medications were used.2
Till 19th century, there was no serious challenge to supernatural theory, though time to time, possibility of epilepsy being disorder of body and mind was put forward by many famous ancient physicians, Hippocrates being most prominent. French and British medical schools by end of 18th century and beginning of 19th century started to understand epilepsy as brain disorder. Both observational study and animal experiments were carried out and anti-epileptic property of Bromide was discovered. John Hughling Jackson (1835–1911), Father of epileptology laid the foundation of scientific basis of epilepsy.3 Jackson studied epilepsy on a pathological 2and anatomical basis and postulated origin of epilepsy from damaged cortex in case of focal epilepsy. Gowers published his famous book The Borderlands of Epilepsy4 recognizing the mimickers of epilepsy. During the 1920s, Lennox (1884–1960) and Cobb (1887–1968) focused on the effects of starvation, ketogenic diet and altered cerebral oxygen in seizures and published their first monograph entitled “Epilepsy from the Standpoint of Physiology and Treatment”.1 In 1941, Jasper (1906–1999) and Kershman proved that the temporal lobe is the site of origin of psychomotor seizures.5 Graham Goddard demonstrated changes in hippocampus causes by electrical stimulus and mechanism of “epileptogenesis”, the process in which the normal brain is transformed into one that generates seemingly unprovoked seizure and coined the term “kindling”.6
In last few decades, tremendous progress has been made in understanding pathophysiology of epilepsy, mechanism of epileptogenesis, various etiologies and genetics of epilepsy. Role of neurotransmitters and imbalance between excitatory and inhibitory neurotransmitters is researched in last 50 years. International League Against Epilepsy (ILAE) in 1969 proposed first classification of epileptic disorders based on seizure type, electroencephalography (EEG) characteristics, anatomical substrate, etiology and the age.7 The concept of electroclinical syndrome emerged subsequently. Further exponential development in genetics led to discovery of several monogenic epilepsies and numerous susceptibility genes. These developments were incorporated by ILAE to propose new classification in 2010.8
The focus has now extended beyond “seizures”. Psychiatric and cognitive comorbidities that were earlier considered as consequence of epilepsy or anti-epileptic drugs (AEDs) is being recognized as part of disorder that can pre-exist or coexist and are probably caused by common denominator with additional influence of psychosocial factors and medications. The neurobiological mechanism of these psychiatric manifestations is still very poorly understood and its correlation with seizure seems to be poor though some correlation with interictal epileptiform discharges has been observed especially in Benign rolandic epilepsy9 and its spectrum extending to Landau-Kleffner syndrome. The understanding of complex interplay between psychiatric comorbidities and cognitive disability with epilepsy, EEG abnormalities and its underlying mechanisms is at very nascent stage and needs future research.
Understanding underlying mechanism of epileptogenesis and its evolution from cellular, molecular to level of circuits and network is another key area of future research. The term “epileptogenesis” refers to the process by which normal brain tissue is transformed into tissue capable of generating spontaneous seizures. This area is looked forward as potential target to cure epilpesy.103
 
ELECTROENCEPHALOGRAPHY AND OTHER DIAGNOSTIC TOOL FOR EPILEPSY: EVOLUTION AND FUTURE TREND
There are many references of animal experiments on effect of electrical stimulation of brain and spontaneous electrical activity of brain.1 In 1929, Berger (1873–1941), a German neurologist, reported his findings on human brainwaves. In 1932 and 1933, he described postictal changes and 3-Hz spike and wave discharges. He made important observations on patients and on healthy subjects over the next few years. His work on EEG was carried forward by Frederic Andrews Gibbs (1903–1992), an American neurologist, and Erna Leonhardt Gibbs (1904–1987), technician and wife of Frederic, who in collaboration with Lennox, established the correlation between EEG findings and epileptic convulsions.11 Gibbs couple published in 1941 their monumental monograph “Atlas of Electroencephalography”.12 Henri Jean Pascal Gastaut (1915–1995) discovered photic stimulation as activation procedure. He also described lambda waves, pi rhythm, mu rhythm, rolandic spikes and posterior theta rhythm. He described two epilepsy syndromes under his name, Gastaut-type idiopathic childhood occipital epilepsy and Lennox-Gastaut syndrome.1
The technology of EEG rapidly evolved due to technological development and digitalization. In 1960s, simultaneous video and EEG recording gave new dimension of EEG. Video EEG currently plays pivotal role in epilepsy diagnosis and presurgical workup. At present EEG is the primary tool to study epileptiform abnormality (interictal and ictal). In parallel with discovery of EEG, there was rapid development in imaging of brain, both structural and functional. With advent of computed tomography (CT) scan followed by magnetic resonance imaging (MRI) and rapid technological advancement in MRI including functional MRI, the understanding of epilepsies has increased many folds. Localization of potential epileptogenic lesion and detection of subtle MRI changes of clinical relevance has led to better surgical outcome. Functional imaging (positron emission tomography and single-photon emission computed tomography) and multimodality imaging have become important tool for clinical and research use.
Despite a substantial progress, investigations in epilepsy has significant unmet needs. The misdiagnosis of epilepsy is as high as 20–30%, mainly because of absence of diagnostic tests, abuse of EEG and other investigations and need for reliable eye-witness account.13 EEG, the main tool in epilepsy has considerable limitations. It has poor spatial resolution, lacks sensitivity and specificity, and has interobserver variability and lack objectivity. Magnetoencephalography (MEG) is another powerful tools that overcomes some of the drawbacks of EEG.14 MEG usage is currently limited to few research center, but likely to have more widespread use in future both in 4clinical and research setting. Till date, we do not have neuroimaging that can detect and differentiate active epileptogenic foci and we rely more on lesion or finding that are abnormal structurally and functionally and can be possible site of seizure origin or cause of epilepsy. The present approach of looking into imaging data along with attempt to correlate it with clinical and EEG data and sometime other ancillary tests helps us to overcome some of current limitations of imaging. However, it needs certain expertize and training and it can lead to error in diagnosis, medical and surgical treatment of epilepsy even at the level of expert. Further improvement in structural and functional neuroimaging might help us to understand epileptogenic area and network of the brain that currently cannot be determined directly.
Other area of future research is to determine reliable biomarker for epilepsy and epileptogenesis and target the process to “cure” epilepsy. Biomarker for epileptogenesis is “an objectively measurable characteristic of a biological process that reliably identifies the development, presence, severity, progression or localization of an epileptogenic abnormality”.15 The development of biomarkers will help in individualizing treatment, prognostication as well as developing strategies to prevent epilepsy by targeting epileptogenesis once potential epileptognic insult has occurred to the brain. The biomarkers that are currently under research are electrophysiological (high-frequency oscillation), genetic, molecular and imaging biomarkers.16
 
TREATMENT OF EPILEPSY: PAST, PRESENT AND FUTURE
 
Medical Treatment
The introduction of bromide potassium in the treatment of epilepsy by Edward Sieveking in 1857 marked the beginning of modern anti-epileptic treatment. In 1912, Hauptmann (1881–1948), a German physician, discovered anti-epileptic property of phenobarbital while using it as tranquilizer.1 Phenobarbitone is still widely used and is only anti-epileptic medication available in many resource-poor countries.17 Search for less-sedative drug led to research and a number of nonsedative phenyl compounds was studied and phenytoin was found to be effective.18 It was introduced in 1938. Subsequently, primidone, ethosuximide, carbamazepine and valproate were introduced. Benzodiazepines in parallel got established in acute seizure management as well as add-on chronic therapy. Subsequently, there was rapid expansion on AEDs and were termed as “newer” anti-epileptic medications. Many of these molecules had different or novel mechanism of action, giving physician a wider choice of anti-epileptic medications. This expansion of number of AEDs has given opportunity to tailor treatment and helps to minimize the adverse effects. However, despite having newer AEDs, the proportion of medically refractory epilepsy is only marginally 5change. Almost 30% of epilepsies are poorly controlled despite availability of more than 20 anti-epileptic medications.19 The increasing understanding of mechanism of drug resistance in epilepsy has also opened the new area of research in form of pharmacogenomics and targeted drug delivery by nanoparticles that may help to overcome some of the mechanism of drug resistance. The incidental observation of dramatic effect of marijuana (cannabinoid) on Dravet's syndrome (a devastating epilepsy syndrome of childhood) has opened a new front of research on anti-epileptic medications with both skepticism and hope.20
Medical treatment till date is largely “symptomatic treatment” to control seizure. There is no therapy till date that can alter epileptogenesis. None of the current treatment can prevent development of epilepsy after potential epileptogenic damage to the brain-like stroke, trauma or infections. There are a few promising progress in focal epilepsy as well as epileptogenesis at experimental level. The most widely used vector system for gene therapy in the brain is adeno-associated virus (AAV), which can transfect postmitotic cells (including neurons) with high efficiency and stability and is relatively nonpathogenic.21
Looking even further, curing epilepsy may require not only halting epileptogenic processes, but returning synaptic networks to their pre-epileptic state or by creating a compensatory balance to suppress the excess excitability. In order to achieve this target, better understanding of factors in addition to genetic and developmental factors that leads to development of seizure-prone circuits is needed. Why some individuals develop seizures after a given type of brain insult while others do not, remains a subject for future research.
 
Epilepsy Surgery
There are evidences of trephination of skull was practiced in ancient civilization including India for neurological disorder.22 However, enthusiasm of surgical treatment for epilepsy started in 19th century and in 20th century, there was rapid development in field of surgical epileptology.1 Dandy (1886–1946) introduced hemispherectomy as a neurosurgical procedure in 1923. The idea of by surgical removal of abnormal discharging area of brain was put forward by Gibbs and Lennox in 1938. Wilder Penfield (1891–1976) along with Herbert Jasper (1906–1999) and Theodore Brown Rasmussen (1910–2002) in the Neurologic Center of University of Montreal also contributed importantly to the evolution of the surgery of epilepsy. In 1954, Penfield published with Jasper one of the greatest classics in neurology, Epilepsy and the Functional Anatomy of the Human Brain.23 In 1953, Falconer, a neurosurgeon from New Zealand, introduced anterior temporal lobe resection for temporal lobe epilepsy. In later half of 20th century, epilepsy surgery was practiced at many centers, but encountered 6lot of skepticism. By the turn of century, Class I evidence for effectiveness of surgery in temporal lobe epilepsy was established24 and at present plays a very important role in medically refractory epilepsy.
In India, first epilepsy surgery in India was performed on August 25, 1952, by Dr Jacob Chandy at the Christian Medical College (CMC) in Vellore. After initial enthusiasm, there was decline in epilepsy surgery in India. The credit of resurgence of epilepsy surgery in India goes to Professor Kurupath Radhakrishnan, who established India's first dedicated and comprehensive epilepsy center in India in 1994. R Madhavan Nair Comprehensive Epilepsy Center (RMNC), at Sree Chitra Tirunal Institute of Medical Sciences and Technology (SCTIMST), Thiruvananthapuram, Kerala, became the premier center for surgical treatment of epilepsy as well as epilepsy training.25 The first epilepsy surgery (left anterior temporal lobectomy with amygdalohippocampectomy) at RMNC was conducted on March 20, 1995. Since then, more than 2,000 epilepsy surgeries have been conducted at this center. Epilepsy surgery and centers in steadily growing and average of 420 epilepsy surgery per year is conducted in India.26 However, there is still huge surgical treatment gap in India.
In future, the epilepsy surgery is likely to become more acceptable, less invasive and safer due to better presurgical localization and planning, delineation of functional areas of brain, improved surgical and postsurgical management. Minimally invasive method, like gamma knife surgery, endoscopic surgery and radiofrequency and thermal ablation method, is likely to play significant role and evolve further with technological refinement.
 
EPILEPSY AND SOCIETY
The discrimination against epilepsy emerged with belief of supernatural cause that prevails in all civilizations for century. These patients were seen as possessed by devil or demons and seen as cursed by God. This misconception was so deep rooted and prevalent worldwide, that even in 21st century, has significant influence on how society looks toward person with epilepsy (PWE). In India, stigma and taboo are highly prevalent in rural and tribal areas. Even in urban India, it is considerable, but there is steady improvement in social perception and acceptance of PWE in mainstream. Stigma related to epilepsy can lead to underutilization of medical facilities and modern treatment and can defeat the purpose of scientific development.27 There can be unnecessary restriction including restriction on education by parents or school, unemployment or underemployment leading to long-lasting social, psychological and financial consequences. There is inadequate law to protect rights of PWE in our country. The drive for better legal protection to PWE needs to be intensified. One successful example is abolition of the 7Hindu Marriage Act of 1955 and the Special Marriage Act of 1954 that stated that epilepsy at time of marriage can be ground for divorce. It took a struggle of 12 years for the Indian Epilepsy Association to have the word “epilepsy” deleted from this law. This was achieved in December 1999.28
The advancement in understanding and therapeutics alone is not enough to fight against epilepsy. We need to empower PWE with knowledge and arm them with law and legislation to protect their right and provide equal opportunity to achieve and perform to their capabilities. On the other hand, education and awareness at community level are necessary to give equal space to PWE.
 
CONCLUSION
Significant progress has been made in understanding the cause and mechanism of various epilepsies. The therapeutic armamentarium has rapidly expanded in last three decades, but we are still far away from the ideal treatment. The future prospects and upcoming development in pipeline are very promising and there are reasons to hope that epilepsy management in future will be significantly better and have new dimensions like antiepileptogenesis. Due to space limitations, all developments could not be discussed. Finally, the long social injustice to epilepsy needs to be eliminated from society to reap the benefit of rapidly improving scientific development in field of epileptology.
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