Encephalopathy is a term that has long been in use in many fields of medicine and the origin of which is difficult to determine exactly. Encephalopathy covers a multitude of afflictions of the entire brain, not only parts of it. A Wikipedia article (http://en.wikipedia.org/wiki/Encephalopathy) retrieved in March 2013 listed 17 heterogeneous types of encephalopathies (including hepatic, hypoxic-ischemic, uremic, Wernicke's, and toxic-metabolic), even without including epileptic encephalopathies. Whereas the etiology and severity may vary, the term usually implies morphologic changes in the brain. An altered mental state is considered the hallmark of encephalopathies, and is usually accompanied by a variety of neurologic signs and symptoms. Epileptic seizures are possible symptoms of encephalopathies, and antiepileptic drugs are possible causes of toxic encephalopathies. The term epileptic encephalopathy (EE), however, as explained in subsequent text of this article, is reserved for conditions in which the epileptic activity itself contributes to mental and neurologic decline.
The first description of epileptic encephalopathies dates back to Dr. West who, in 1857, described the syndrome that took his name. In addition to West syndrome, in the last century other epileptic syndromes entered into the chapter of epileptic encephalopathies. Henry Gastaut has the virtue of having created the modern concept of epileptic encephalopathy and entering it into the official terminology of the International League Against Epilepsy (ILAE). After the first proposal, it was further defined and refined over time.
Brief History of the Syndromes Included in the Concept of EE
The first EE described was West syndrome, the characteristic clinical features of which were first described by Dr. W.J. West of Tunbridge, United Kingdom, in 1841. In his letter addressed to the editor of The Lancet (West, 1841) he wrote “Sir: I beg…to call the attention of the medical profession to a very rare and singular species of convulsions peculiar to young children. As the only case I have witnessed is in my own child, I shall be grateful to any member of the medical profession who can give me information on the subject….” Hypsarrhythmia, the distinguishing electroencephalographic feature of West syndrome, was first described by Gibbs and Gibbs (1952). When both spasms and hypsarrhythmia are confirmed in an infant, the diagnosis of West syndrome will be established. After the first original description by Dr. West, according to Jeavons and Bower (1964), there were only two reports (Newnham, 1849; Barnes, 1873) in the United Kingdom until 1955, when Illingworth reported 12 cases of “sudden mental deterioration with convulsions in infancy” (Illingworth, 1955). In contrast to a long period of silence in the United Kingdom, soon after West's letter this new entity was introduced to the European continent, where the interest in this particular seizure ensued rather actively, especially in France and Germany, and a considerable number of original articles had been published, although intermittently, over a period of 100 years since 1850. Literature review of Gastaut and Poirier (1964) was particularly exhaustive and included a number of articles so rare that the authors could not confirm or locate all the original sources, despite their best efforts. Therefore, the authors were able to collect copies of only 23 articles published between 1841 and 1945. According to Gastaut and Poirier (1964), however, 57 articles had been published between 1841 and 1940. In the period from the first description to 1920, there were about four articles per decade; the articles increased to about 18 per decade in the period from 1920 to 1950, and after 1950, the number of articles abruptly and dramatically increased to more than a dozen per year. In 1974, Jeavons and Bower (1964) stated that the most recent term was West syndrome, but the term was never used in their first monograph (Jeavons & Bower, 1974). Therefore, the author assumes that Gastaut and his colleagues are the first authors who used the term of West syndrome officially, because the monograph they compiled in 1964 (Gastaut & Poirier, 1964) carries a subtitle of “syndrome de West” (Fukuyama, 2001).
The first description of the Landau and Kleffner syndrome dates back to William Landau and Frank Kleffner, who in 1957 reported six children with different types of convulsive seizures and acquired aphasia (Dulac, 2001). No other descriptions are present in the literature until the 1980s, when, in various parts of the world, different authors described some new cases. Curiously, many descriptions are found in journals of otology. The epileptologists started to describe the syndrome extensively in the 1990s, when the Strasbourg school published various articles on the syndrome.
The first descriptions of the Lennox-Gastaut syndrome date back to the 1960s when Gastaut and colleagues and Sorel recognized the syndrome and published the first reports about it (Gastaut et al., 1963, 1966; Sorel, 1964). Gastaut et al. suggested generously that the syndrome be named “Lennox syndrome” because earlier cases had been reported by Lennox and Davis (1950). The term “Lennox-Gastaut syndrome” was introduced later, and the final definition of Lennox-Gastaut syndrome was proposed by Beaumanoir (1985) and adopted by the International League Against Epilepsy (ILAE) Classification Commission in 1989 (Commission on Classification & Terminology of the International League Against Epilepsy, 1989; Arzimanoglou et al., 2009).
The term myoclonic-atonic (or astatic) epilepsy (MAE) was used by Doose (Doose & Baier, 1987; Doose, 1992a) to describe an epilepsy of childhood characterized by primarily generalized myoclonic and/or astatic seizures as the main clinical manifestations (Doose, 1992b; Doose & Baier, 1997). Initially this term was applied by Doose to a large subgroup of idiophatic epilepsies with atonic and myoclonic seizures. After the ILAE Classification of epileptic syndromes (Commission on Classification & Terminology of the International League Against Epilepsy, 1989), MAE was included in the “cryptogenetic and symptomatic epilepsy syndromes,” and then, subsequently, in the group of generalized epilepsy (Engel, 2001).
The terms electrical status epilepticus during sleep (ESES) and continuous spikes and waves during sleep (CSWS) are often considered synonymous, but ESES, first described by Tassinari (Patry et al., 1971; Tassinari et al., 1977a) refers to the electroencephalographic pattern (continuous spike-wave complexes exclusively during non–rapid eye movement [NREM] sleep, with a spike-wave index accounting for at least 80–85% of slow sleep), whereas CSWS indicates both electroencephalographic features and clinical neuropsychological characteristics of this EE (Galanopoulou et al., 2000; Holmes & Lenck-Santini, 2006; Parisi et al., 2010).
In 1977, additional cases were described, and it was proposed that “status epilepticus during sleep” or SES was responsible for the associated psychotic behavior and “mental deterioration”; the condition was then qualified as an “encephalopathy” with SES or ESES (Tassinari et al., 1977b). Kellerman was the first to make, in 1978, a specific connection between “recurrent” aphasia and “subclinical bioelectric status epilepticus during sleep.”
Early infantile epileptic encephalopathy (EIEE) or Ohtahara syndrome was first described by Ohtahara et al. (1976) and reviewed in Ohtahara and Yamatogi (2008; Nordli, 2012). After the first Japanese published reports, other authors from all over the world provided descriptions of the syndrome.
Aicardi and Chevrie (1971) first reported myoclonic epilepsy in a group of children with nonprogressive encephalopathy. The term “minor epileptic status” was proposed by Brett (1966). He reported 22 patients with “pseudo pseudodementia” and “pseudo-ataxia,” previously healthy or, more frequently, epileptic and with normal or slowed developmental milestones. In 1980 this description was confirmed by other authors (Dalla Bernardina et al., 1980), who described a peculiar clinical and electroencephalographic picture of myoclonic epilepsy in seven children presenting cerebral palsy caused by severe prenatal or neonatal cerebral damage. These authors called this new entity “myoclonic status in nonprogressive encephalopathies” (MSNEs), characterized by early appearance and recurrence of long-lasting myoclonic status in infants and young children with nonprogressive encephalopathy and poor prognosis (Elia, 2009).
In 1978, Charlotte Dravet described severe myoclonic epilepsy in infancy (SMEI), which, in 2001, was included in the first historical group of EEs (Engel, 2001). Recently, Dravet herself discussed whether the syndrome can be considered as an EE in the strict sense, since “it is not proven that the cognitive decline observed in the first stages of the disease is simply the direct consequence of epilepsy.” She proposed the hypothesis that channelopathy per se can play an important role in the pathogenesis of mental and neurologic deterioration (Dravet et al., 2011).
The History of the Concept of EE
The clinical descriptions of entities during the last century which we now consider EEs contributed to the delineation of the concept. This happened because the idea that not only seizures but also apparently subclinical epileptic activity could interfere with cognition was in place at that time in the scientific epilepsy community. A direct consequence of this is the notion that control of epileptic activity could improve the cognitive profile. In addition to West syndrome, this concept has been largely used in Lennox-Gastaut syndrome. Henri Gastaut considered mental retardation as a mandatory symptom of the syndrome and a consequence of the interictal electroencephalographic epileptic activity. The concept that a neuropsychological deficit could be determined by continuous or subcontinuous interictal electroencephalographic paroxysmal activity was also present in 1957 in the first description of the syndrome by Landau and Kleffner (1957). The concept was further developed by Dulac (2001) in the 1990s, and it was finally included in the proposal of the ILAE classification in 2001 (Engel, 2001), where the term of epileptic encephalopathy was used for conditions in which “the epileptiform abnormalities themselves are believed to contribute to the progressive disturbance in cerebral function.” Subsequently, in 2006, Engel defined EEs as conditions where “evidence suggests or supports the notion that there is an epilepsy-dependent neurodevelopmental or neurodegenerative process involved in the evolution of the syndrome (as opposed to an underlying metabolic, degenerative, or encephalitic process),” thereby excluding these progressive specific etiologies from the causative spectrum of EE. Engel also writes that “it is important to distinguish between deficits that are due to the cause of the epilepsy, those that are due to pharmacotherapy, and those that are due to the epilepsy itself (EE). Unfortunately, this can be difficult and many EE[s] remain theoretical.”
The ILAE Task Force report of 2010 (Berg et al., 2010) noted that “the concept of epileptic encephalopathy has grown in acceptance and use. Epileptic encephalopathy embodies the notion that the epileptic activity itself may contribute to severe cognitive and behavioral impairments above and beyond what might be expected from the underlying pathology alone (e.g., cortical malformation), and that these can worsen over time. These impairments may be global or more selective and they may occur along a spectrum of severity. Although certain syndromes are often referred to as EE, the encephalopathic effects of seizures and epilepsy may potentially occur in association with any form of epilepsy.” For a better understanding of this important conceptual distinction. We can refer to the ILAE proposal of 2001 (Engel, 2001) that differentiated epileptic disease (“a pathologic condition with a single specific, well-defined etiology”) from epilepsy syndromes that can have multiple etiologies. “Thus progressive myoclonus epilepsy is a syndrome, but Unverricht-Lundborg is a disease.” So, it is important to differentiate between epileptic encephalopathies and encephalopathies with epilepsy. During the Sicilian Workshop held in Sciacca in April 2012, Capovilla proposed the new term of epileptogenic encephalopathies. These are progressive conditions with various etiologies that can produce both deterioration (per se) and epilepsy. They can have different etiologies, such as brain tumors, neurodegenerative (e.g., Alpers) or metabolic (e.g., non–ketotic-hyperglycinemia) diseases and presumed inflammatory or autoimmune conditions (e.g., devastating epilepsy in school-age children fever-induced refractory epileptic encephalopathy (DESC-FIRES) and Rasmussen syndrome).
In “epileptogenic” encephalopathies, deterioration is independent from epilepsy, even if epilepsy can aggravate the clinical picture; they can produce an epileptic encephalopathy, but they are not pure epileptic encephalopathies. In some cases the same etiology can give encephalopathy without epilepsy. This distinction is of fundamental value because if we remember the concept of EE, in these conditions the treatment should be aggressive but if deterioration occurs due to the specific etiology, there is a danger of unjustified overtreatment. It is well known that drugs, in particular aggressive polytherapy, can worsen the neuropsychological profile, and this aggravation can be considered as a consequence of an EE, thereby provoking further pharmacologic overtreatment and a detrimental vicious cycle.
None of the authors has any conflict of interest to disclose. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.