History and Classification of “Myoclonic” Epilepsies: From Seizures to Syndromes to Diseases



History and Classification of “Myoclonic” Epilepsies: From Seizures to Syndromes to Diseases


Pierre Genton*

Joseph Roger*

Renzo Guerrini

Marco T. Medina

Michelle Bureau*

Charlotte Dravet*

Antonio V. Delgado-Escueta§


*Centre Saint-Paul, Hôpital Henri Gastaut, Marseille, France

Department of Child Neurology and Psychiatry, University of Pisa and Research Institute ‘Stella Maris’ Foundation, Pisa, Italy

Neurology Training Program, Postgraduate Direction, National Autonomous University of Honduras, Tequcigalpa, Honduras

§Comprehensive Epilepsy Program, David Geffen School of Medicine at UCLA and Epilepsy Center of Excellence at VA GLAHS, Los Angeles, CA.



Introduction

The word “paramyoklonus multiplex” was first introduced by Professor Nikolaus Friedreich (1) in Heidelberg, and the shorter term “myoclonus” was used thereafter in various clinical settings. All through the years of the 19th and 20th centuries, clinicians had to cope with a concept of “myoclonic epilepsies,” which covered mostly cases that were difficult to classify and even more difficult to treat.

This volume contains detailed descriptions and discussions of a large number of rare and common epilepsies associated with myoclonias. Our aim in this chapter is to review the evolution of attitudes and concepts in this large domain of epileptology and their molecular genetics. We feel that they can be summarized into three separate and successive (but overlapping) stages:



  • The first stage, which stretches over more than 2 centuries, corresponds to the description of different forms of epilepsy characterized by a specific seizure type that included a myoclonic component: The seizure type was synonymous with the epilepsy type, which was named accordingly.


  • The second stage, which began a few decades ago, saw the introduction of a syndromic approach to the problem of myoclonic epilepsies, with a new importance given to the electroencephalogram (EEG), and to elements of etiology and prognosis; for example, using qualifications like “benign” or “severe,” the definition of epilepsy types along such lines was sometimes complex and could not be summarized in a brief denomination. Therefore, eponymic designations, which pay tribute to the major contributor(s) of the original description of such syndromes, were often (and are still) used.


  • The third and present stage is a continuation of the second but is now also based on other findings, especially on molecular genetics. The aim, currently, is to define forms of epilepsy by their seizure-causing molecular mechanisms, that is, to speak about epilepsies as diseases. The potential inclusion, among diagnostic criteria, of descriptive genetics, on the one hand, for example, epilepsy phenotypes, mode of inheritance, and chromosomal locus, versus their molecular lesions, on the other hand have challenged the syndromic concepts. Indeed, recent data have pointed to the complexities of the relationship between phenotype and genotype and the complexities of epilepsy inheritance. Unraveling these complexities will undoubtedly lead to novel and curative treatments.


When a Seizure Type Defines an Epilepsy Type

The first use of the word “myoclonus” to describe an epileptic entity can be ascribed to Unverricht, who published, in 1891, a monography entitled “Die Myoklonie” (2). This constituted the first comprehensive description and discussion of a familial epilepsy disease. In 1903, H. Lundborg described 10 families and wrote a review of “Die progressive Myoklonus–Epilepsie.” Since then, this rare, but spectacular and recognizable inherited neurological disease with seizures and myoclonus has been called Unverricht–Lundborg disease. In 1911, Lafora and Glueck described a separate and more rapidly progressive and fatal dementing myoclonus epilepsy with periodic acid Schiff’s procedure (PAS)-positive “amyloid bodies” distributed throughout the central nervous system at autopsy. In 1921, Ramsay Hunt described six cases of action myoclonus and cerebellar ataxia, four of whom also had epilepsy. Ramsay Hunt coined the term “dyssynergia cerebellaris myoclonica.” These descriptions of myoclonus epilepsies in the early 20th century produced the concept of progressive myoclonus epilepsies, (refer to Chapter 4).

There were, however, much more common epilepsy forms that presented with myoclonic jerks as their most prominent symptom. Already fairly well characterized by its epileptic “secousses” or “impulsions” by Herpin in 1857, and later by its “myoclonie épileptique” by Rabot in 1899, (3) (Fig. 1-1) a form of epilepsy that has a high prevalence worldwide was formally described nearly simultaneously from two sources in the middle of the 20th century. In Germany, Janz, as a clinician, and Christian, as the electroencephalographer, reported a series of patients with “Impulsiv Petit Mal.” The denomination was chosen because of the characteristic occurrence of minor seizures (hence, “Petit Mal”) in the form of brief, forward directed jerks (4,5). From Uruguay came the description, in exactly the same vein, of a “bilateral myoclonic and conscious epilepsy” that had the same general features (6). In France, the condition was thought to be very uncommon and was characterized as “massive bilateral myoclonic jerks of adolescence” (7,8).






FIG. 1-1. Facsimile of the cover of Dr. Rabot’s doctoral thesis on “The Epileptic Myoclonia,” Paris, 1899.

In contrast to this nonfatal form of epilepsy with onset in adolescence less common, but much more severe cases, characterized by very debilitating drop attacks with frequent injuries, affecting young children were observed. From Germany came the description based on the spectacular falls that were its trademark. Doose (9) called them “myoclonic-astatic” epilepsy. The falls, which were due to a combination of a massive jerk and a brutal atonia, were the only seizure type, at least initially, in many cases. The context of this epilepsy was highly variable: Most of these children had previously developed normally, many had a family history of epilepsy, and, although the ictal EEG correlates were fairly homogenous, the interictal findings were variable. This description met with little success outside of the German-speaking world, mostly because this entity was not associated with a clear prognosis: Some cases did, indeed remit, without sequel after a short period, whereas others evolved into a severe epilepsy with multiple seizure types, dramatic EEG changes, and mental deterioration. Although a “core” of such patients may have a typical “myoclonic-astatic” epilepsy, most had a condition that clearly went beyond this single seizure type. The definition by Doose of an epilepsy by a seizure type was thus judged to be insufficient: However, by a sort of twist of history, a more comprehensive approach, based on a syndromic diagnosis of severe epilepsies, finally led to the recognition of a genetic form of myoclonic astatic epilepsy.

Among cases with childhood absence epilepsy (CAE), a subgroup with absence seizures that were very typical on the EEG, with regular, 3-Hz spike-and-wave discharges, had particular clinical correlates in the form of both increased axial muscular tone and rhythmic jerks, especially apparent in the upper limbs. The first identification of “epilepsy with myoclonic absences”(10) was justified by this particular neurophysiology, but the identification of this seizure type as a distinct epilepsy syndrome emerged by reason of a particularly poor prognosis, with drug resistance and mental deterioration, setting it clearly apart from typical CAE (11). Here again, a very specific seizure type apparently sufficed to qualify for a distinct epilepsy syndrome.

There were other forms of absence epilepsies that were tentatively individualized on the basis of associated myoclonic features that seemed to define another form of epilepsy [review in Capovilla et al. (12)]. The syndrome of eyelid myoclonias with absences, first mentioned by Jeavons in 1977 (13), has been recognized by many as an uncommon, yet easily identifiable entity. The syndrome of absences with perioral myoclonias was first reported by Panayiotopoulos et al. in 1994 (14). This entity has not been accepted by all as an independent and distinct disorder, as it is not necessarily associated with a prognosis that sets it apart in general, from CAE. Recent studies have also stressed the fact that typical absences with very early onset, before age 3, may be associated with ictal myoclonic manifestations (15). Such cases are highly heterogenous and cannot be gathered into one single entity or grouped on the basis of myoclonic features.

The description of an epilepsy by a single seizure type has thus met with some limited success. Currently, only few epilepsy syndromes retain a denomination that is based only and mainly on the seizure type: Epilepsy with myoclonic absences and epilepsy with myoclonic-astatic seizures have both been officially sanctioned by the International League Against Epilepsy (ILAE), whereas the syndrome of “eyelid myoclonias with absences” has not.


Beyond the Seizure Type: The Syndromic Approach

By the 1970s, the evolution of concepts and classifications in epilepsy, with better use of the EEG and video-EEG, together with more concerns about prognosis, drug efficacy, and overall impairment, led to a different approach of diagnosis and classification of epilepsies, in general, and myoclonic epilepsies, in particular. Although the broad concept of “myoclonic epilepsies” was still used, usually in circumstances where there was no deep awareness of the plurality and complexity of the field, diversification occurred with a need for more informative and practical knowledge. A seizure type was no longer judged sufficient to define a form of myoclonic epilepsy and to distinguish it from the others.

A good example can be drawn from the history of “Impulsiv Petit Mal,” the early stages of which have been reported previously. This condition was first christened as “juvenile myoclonic epilepsy” in Denmark, where, under the influence of the German school, it was already well recognized and where studies were done on its social and psychological consequences (16). The latter denomination was very successful and was used when this “new” disease was rediscovered in North America and thus internationally acknowledged (17) and rightly ascribed as “the Janz syndrome.” The change of denomination is significant. Whereas the first denominations stressed the seizure type (“impulsion” or “bilateral and conscious myoclonia”), the latter introduced the age of appearance of symptoms, and, for some authors, the notion of benign prognosis, which was later dropped. It is also of significance that the most comprehensive and successful denomination was produced by those who were actually interested in the social consequences of epilepsy. The social outcome is, indeed, part of the syndromic approach.

Another significant example of the same process occurred in the case of more severe epilepsies of childhood, which are often characterized by drop attacks and mental deterioration. The EEG marker was, in many cases, a slow variant of the 3-Hz generalized spike-and-wave discharge of petit mal, and a “Petit Mal variant” of the severe type was thus reported (18) and accepted by some as the “Lennox syndrome.” However, the description remained partial. Various denominations focusing on the seizure type and on the EEG terminology were used in various parts of the world. Some focused on possibly myoclonic features, for example, childhood epileptic encephalopathy with slow spike-waves (19), or severe myokinetic epilepsy of early childhood (20). Some light was shed on this by the epochal work of Drs. Gastaut and Dravet (21,22), who defined the restrictive diagnostic criteria of what was later finally called the Lennox–Gastaut syndrome (LGS). These criteria include the coexistence of several seizure types with typical EEG features and cognitive deterioration. The modern, restrictive definition of the LGS (23,24) has stressed that myoclonias are not major features of this syndrome. There was clearly an overlap (and there were, indeed, many lively discussions) between the LGS and the aforementioned entity described by Doose as “myoclonic-astatic epilepsy” (9). Only in recent years have these syndromes been more accurately separated, as discussed elsewhere in this volume, with emphases on the “symptomatic” and acquired nature of LGS and on the “idiopathic” and genetically determined nature of myoclonic-astatic epilepsy. Recent neurophysiological data have stressed their differences showing, in particular, bilateral synchrony in the former versus truly generalized changes in the latter (see Chapter 3).

In the 1970s, infants with various seizure types and, especially, a large spectrum of outcomes led Dravet and Bureau (26) to establish new electroclinical correlations that differentiated two groups of infants who presented with myoclonic seizures and did not fulfill the criteria for the LGS. Some had febrile seizures, long clonic seizures during sleep, and later myoclonus, a variety of other seizure types and mental deterioration leading to severe retardation. They did not have tonic seizures and the prominent sleep-related EEG changes so characteristic of LGS. They had a “severe” myoclonic epilepsy in infancy (25). Other infants had isolated myoclonic jerks and a good prognosis and were thus logically described as having a “benign” myoclonic epilepsy in infancy (26). These descriptions thus included age of onset and overall prognosis and were also typical of the syndromic approach to hitherto difficult-to-define epileptic entities.


Present Developments: Toward Epilepsy Diseases

The 1989 classification of epilepsies (27) listed epilepsies with myoclonic components among various categories, within the generalized, focal, and undetermined categories, and also into various etiological subgroups (Table 1-1). Positive and negative myoclonias can occur in a variety of epilepsies—focal and generalized; however, the conditions that this volume focuses on are mostly in the categories of idiopathic generalized epilepsies (IGE). A notable exception is represented by severe myoclonic epilepsy in infancy, which was considered to have both generalized and focal features.








TABLE 1-1. Myoclonic Epilepsies: Recent Changes in ILAE Classification









International classification (27)


Proposed diagnostic scheme (Task Force, 2001: Table IV) (28)




  • Idiopathic focal epilepsies




    • Benign rolandic epilepsies (negative myoclonus)



    • Primary reading epilepsy



  • Symptomatic focal epilepsies




    • Epilepsia partialis continua (type I and II)



  • Idiopathic generalized epilepsies (IGE)




    • Benign myoclonic epilepsy in infancy



    • Juvenile myoclonic epilepsy



    • Other syndromes (including IGE with photosensitivity)



  • Symptomatic or cryptogenic generalized epilepsies




    • Myoclonic-astatic epilepsy (Doose syndrome)



    • Lennox–Gastaut syndrome (myoclonic form)



    • Epilepsy with myoclonic absences



  • Symptomatic generalized epilepsies




    • Progressive myoclonus epilepsies



  • Epilepsies undetermined whether generalized or focal




    • Severe myoclonic epilepsy in infancy




  • List of syndromes




    • Benign myoclonic epilepsy in infancy



    • Dravet’s syndrome (severe myoclonic epilepsy in infancy)



    • Epilepsy with myoclonic absences



    • Epilepsy with myoclonic-astatic seizures



    • Lennox–Gastaut syndrome



    • Progressive myoclonus epilepsies



    • IGE with variable phenotypes, including juvenile myoclonic epilepsy



    • Reflex epilepsies, including primary reading epilepsy



  • Syndromes in development




    • Myoclonic status in nonprogressive encephalopathies



    • Generalized epilepsies with febrile seizures plus


A new diagnostic scheme was recently proposed (28) that introduced the possibility of classifying epilepsies according to different axes. Syndromes are simply listed according to age at onset. The changes from the 1989 classification are minimal concerning the myoclonic epilepsies, and mostly cosmetic:



  • Given the larger than initially expected range of clinical presentations in severe myoclonic epilepsy, with many patients failing to exhibit prominent myoclonic features, it was suggested to rename this syndrome “Dravet syndrome.”


  • Other syndromes not included in the 1989 classification (27) were admitted, or admitted pending confirmation.


  • Due to the possible overlap among the phenotypes of juvenile myoclonic epilepsy, juvenile absence epilepsy, and epilepsy with grand mal seizures on awakening, it was decided to gather all three syndromes as idiopathic generalized epilepsy (IGE) with variable phenotypes.


  • A concept of “epileptic encephalopathies” was introduced that may gather various epilepsy types associated with severe and progressive cognitive and neurological decline. Dravet syndrome and some cases with myoclonic-astatic epilepsy may fit into this new category as well.

However, the recently proposed 2001 diagnostic scheme and classification lags far behind the rapid advances in molecular genetics of the epilepsies. A transformation of our global understanding of the nosology of “idiopathic” epilepsies will need to consider their defined molecular lesions and their acceptance as epilepsy diseases. Recent data, which have emerged from genetic work, have shown the importance of a disease-based approach to epilepsies. Almost 10 years have passed since Steinlein et al. (29) showed the α4 subunit of the nicotinic acetylcholine receptor (nACH) as the epilepsy mutation in autosomal dominant nocturnal frontal lobe epilepsy in chromosome 20q13, and 7 years have passed since the identification of potassium (KCNQ2, KCNQ3) ion channels as epilepsy-causing genes in benign familial neonatal convulsions in chromosomes 20q13 and 8q24 (30,31). These reports clearly showed that mutations in receptors or ion channels can cause epilepsies (32,33). They have led to discoveries of other receptoropathies and channelopathies, such as SCN1A (34), SCN1B (35), and SCN2A (36), in generalized epilepsy with febrile seizures plus (GEFS+; chromosomes 19q13 and 2q21), and the α1 and γ2 subunits of the GABA-A receptor (37,38,39) in autosomal dominant juvenile myoclonic epilepsy (JME) and (GEFS+) (chromosome 5q34). More recently, a novel glial membrane gene has been associated with autosomal dominant temporal lobe epilepsy with auditory symptoms (40). Thus, there has been ample time for the ILAE commission on classification to incorporate genetic advances in their classification schema.

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Jul 27, 2016 | Posted by in NEUROLOGY | Comments Off on History and Classification of “Myoclonic” Epilepsies: From Seizures to Syndromes to Diseases

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