Proposed classification: ILAE Definition of the Idiopathic Generalized Epilepsy Syndromes
Members of the Nosology and Definitions Task Force of the ILAE have developed four position papers on syndrome definitions at various ages. The ILAE guideline process requires obtaining feedback and comments from its members on the proposed paper. These comments from our international community will be reviewed by the working group before finalizing the paper.
The revised version of the manuscript is being reviewed by the ILAE and will then be submitted for publication. Review comments below.
Draft: ILAE Definition of the Idiopathic Generalized Epilepsy Syndromes
See all four Proposed papers for Nosology and Definitions
1. It delineates the syndromes that comprise the IGEs.
2. Provides updated diagnostic criteria for the 4 syndromes.
3. Current updated information regarding genetics has been incorporated in current position
Sheffali Gulati and Sonali Singh
I truly enjoyed reading this excellent and comprehensive paper about IGE definition. There are a few points that come to my mind:
1- Maybe the authors can elaborate more on the EEG findings. The epileptiform discharges are generalized but the maximum negativity potentials are usually localized to the bifrontal regions and sometimes to cz or in younger ages to the bioccipital regions. The EEG fragments are more likely to be seen in the right or left frontal or paracentral regions. However, If a there is a sustained focal finding is encountered, neuroimaging investigations are needed to rule out a concomitant focal lesion.
2- Maybe some more description can be added to the semiology part: There may be focal clinical findings occasionally like unilateral myoclonus or head version right before GTCs that can shift from right to left in each seizure.
3- In the differential diagnosis, I think it would be helpful to mention progressive myoclonic epilepsies, since at times, patients with PME may be mistaken for IGE at the beginning.
Sanaz Ahmadi Karvigh
I am thankful for the access to this education. These are excellent papers and need several times reading to absorb the information and apply in our daily practice and then to educate future neurologists. It will take some time but the faster the better as all of us in the community including the patients will benefit. I appreciate highly this tremendous effort to enhance our understanding of epilepsy.
An excellent work. Just a few queries:
1. There are only few details on the psychiatric profile of patients with IGE;
2. JAE, first para: Personally, I don't agree on the need for a lifelong therapy; I suggest changing the sentence "... lifelong treatment is tipically required ..." into "... lifelong treatment might be required ...";
JAE, para "Natural history": Here also, I suggest changing "... lifelong in the majority of cases ..." into " ... lifelong in several cases ..."; in the same para, the sentence on Ethosuximide should end with a reference;
GTCA, first para: Here too, I suggest changing the sentence " ... lifelong treatment is usually required ..." into "... lifelong treatment might be required ...".
The overall framework of the classification is great, simple, and easy to follow.
1. In the figure 1 (Concept of Genetic Generalized Epilepsy versus Idiopathic Generalized Epilepsy) , epilepsy with eyelid myoclonia and epilepsy with myoclonic absences have overlap with IGE which should be depicted clearly
2. Myoclonic epilepsy in infancy has been added under self-limiting epilepsies of infancy and an addition of the same entity under GGEs may create confusion.
Sanjeev V. Thomas
Much good can be said about this proposal but a definition of generalized epilepsies is missing. Most experts today agree that the term “generalized” is a misunderstanding and misleading. If a better term had been found, it would probably long have been replaced. In the 2017 Seizure Classification, this has been recognized by the (hesitant) introduction of the term “bilateral” as a step forward. Something similar should be attempted in the Syndrome Classification. At least, the problems with the term need to be discussed.
Juvenile myoclonic epilepsy: I fully agree with Patricia Braga that the occurrence of focal seizures in this syndrome along with generalized seizures needs to be more emphasized to make people aware of them. Nothing is gained by disguising them as “unilateral myocloni”. Their neglect may have contributed to the frequent relapses in attempts to terminate treatment in patients considered seizure free. Some probably had ongoing small focal seizures, so the "relapse" was not really a relapse.
Generalized tonic-clonic seizures alone: It is difficult to understand how this proposed entity made it into the present official document. Together with Guido Rubboli, I just had to write it up for the new edition of the Engel textbook so I am reasonably updated. There is not a single scientific study that ever established and described GTCS alone as a syndrome. It could just as well be a random collection of cases that did not fulfill the criteria for one of the established IGE syndromes. The only official comment existing until now is in the final report of the “Classification Core Group” of the ILAE (Engel J Jr. Report of the ILAE Classification Core Group. Epilepsia 2006; 47:1558-1568). It says: “Epilepsy with GTCS only is not a syndrome, and the Core Group was unable to agree on any syndrome with this feature.” Since then, no new data have been generated. The present description gives no reason why it should be considered a syndrome. The minimum requirement for that would be two independent features habitually occurring together. This requirement is missing. The specification that “remission rate is low and life-long treatment is usually required” appears to be taken out of the air. Nobody has ever investigated this question. The initial remark in parenthesis that this entity was “originally called epilepsy with grand mal seizures on awakening” seems to suggest that data from EGMA may have been interpolated. However, that would be a scientifically highly dubious procedure as the two concepts are by no means identical.
I agree with the definition of IGE and its distinction from de GGE. I think the assumption of lifelong treatment should be used with caution in some cases and would prefer more optimistic research focused statements like: Lifelong treatment is nowadays standard, but ASM withdrawal has been described in some cases and more long term follow-up studies regarding ASM response, dosing and withdrawal are necessary.
I also miss, as in other definitions, the proper names of epilepsy syndromes. Development in epilepsy and in neurology occured through timeless observation, dedication and analysis. The most important way we have to honor worldwide those great persons is to mention them in one or two sentences in official papers. Otherwise they will be forgotten or neglected to historic books and anecdotal cultural speeches in seminars and may be a congress. I feel the names of Janz, Panayiotopoulos, Otahara, Watanabe, Lafora, Fejerman beside many others, are withering in these new classifications. Maybe in 10 years we should not mention West, Lennox, Gastaut and Dravet. Perhaps we should also change later on the name of the Babinski sign.
Classifications and definitios are important because they will help a lot of persons interested in epilepsy, but they got important because of the (lifelong) commitment of those "observers" on those affected persons. Gabriel Garcia Marquez wrote in his book of "One Hundred Years of Solitude" about a time when due a pandemia of insomia people forgot their origins and the names of the daily used things. I really hope we are not approaching those times.
Thank you Nosology and Definitions Task Force of the ILAE for such an excellent summary on IGEs, especially the diagnostic criteria of IGEs using table 3,4,5 and 6.
IGEs consists of 4 syndrome, CAE, JAE, JME and GTCA, which carry prognostic and therapeutic implication.
Figure 1 demonstrates IGEs as a sub-group of GGE. GGE includes:
- Patients with one or a combination of the following generalized seizure types: absence, myoclonic, tonic-clonic and myoclonic-tonic-clonic with 2.5-5.5 Hz generalized spike wave.
- A variety of genetic generalized syndromes which have genetic overlap with IGEs syndrome, associated with DEEs.
The term “Idiopathic” is used in IGEs under GGE. So the question arises, whether the cause of IGEs is unknown or genetic. Although IGEs does have genetic basis like monogenic cause (GABA receptor subunit gene eg.GABRG2 GABRA1 and gene encoding glucose transporter 1, recurrent copy number variants such as microdelations and microduplications.
This may happen either in de novo mutation or inherited as all IGEs patient do not have family history.
Kazi Jannat Ara
On the page 5, 7th paragraph (second paragraph in description of EEG) you have mentioned that "A photoparoxysmal response may occur with intermittent photic stimulation in a minority of patients with IGE" and I do not agree with that statement.
According to litterature in almost 40-50% of cases of JME, the response to IPS is marked (Appleton and Acomb 2000, Covanis 2005). The positive response to IPS increases to 83% in patients with JME with onset under the age of 12 years. (Covanis A. Photosensitivity in Idiopathic Generalized Epilepsies. Epilepsia 2005, 46(Suppl. 9):67–72.
Others have reported photosensitivity rates in JME ranging from 30% to 54% (Harding GFA, Jeavons PM. Photosensitive epilepsies. London: MacKeith Press, 1994; Covanis A. Photosensitivity and photosensitive epilepsy. Epileptologia 2002, 10:205–22). In eyelid absences with myoclonia photosensitivity was seen in 92% and marked in 76%. (Covanis A. Eyelid myoclonia and absences.
In: Delgado-Escueta AV, Guerrini R, Medina MT, et al., eds. Myoclonic epilepsies.advances in neurology. Phildelphia, PA: Lippincott Williams& Wilkins, 2005;95:185–96 In JAE photosensitivity occursin 7.5% of the cases (Wolf P, Goosses R. Relation of photosensitivity to epileptic syndromes. J Neurol Neurosurg Psychiatry 1986;49:1386–91).
Therefore is better to devide IGE in subgroup and speak about photosensitivity in particular group of IGE.
Second, I am wondering that you did not mention Absences seizure with perioral myoclonia (POMA or PMA) as subgroup in IGE or in Absences subgroup. POMA is an IGE with onset in childhood or early adolescence and is characterized by frequent typical absence seizures with variable impairment of consciousness and ictal rhythmic myoclonus of the perioral facial or masticatory muscles (Panayitopulous 2001). (Panayiotopoulos CP, Ferrie CD, Giannakodimos S, et al. Perioral myoclonia with absences: a new syndrome. In: Wolf P, ed. Epileptic seizures and syndromes. London: JohnLibbey & Company Ltd, 1994: 143-53 Panayiotopoulos CP. Absence epilepsies. In: Engel JJ, Pedley TA, editors. Epilepsy: a comprehensive textbook. Philadelphia(PA): Lippincott-Raven, 1997: 2327-46).
Third, why do you make our life more difficult with new terminology?
Bosanka Jocic Jakubi
We read with great interest the proposed paper. We have some minor issues we hope could be clarified.
Chapter 4 is about GEFS+, but Table 4 is about FS+. This is a bit confusing as all other Chapter headings are aligned with the Table headings. In addition, it says in the text : “Children with FS+ may have several different presentations: the most frequent is where typical febrile seizures continue beyond the age of 6 years”. Then on the other hand it says in the table “Febrile seizures persisting after 6 years of age and/or afebrile seizures” is a mandatory feature. So do all other presentations also include FS continuing after 6 y? E.g. are FS beginning before 6 mo not considered FS+? Furthermore, we suggest that the text in the Table would be modified to “Febrile seizures persisting after 6 years of age and/or afebrile seizures in addition to FS”. (The current sentence indicates that afebrile seizures alone could also be FS+.)
Chapter and Table 8 on infantile spasms: We think that subtle spasms with corresponding EEG findings (typical ictal and interictal EEG) should be brought up more clearly. At the moment one gets the impression that infantile spasm syndrome diagnosis demands flexor/extensor spasms, but aren’t subtle spasms with typical EEG enough to make the diagnosis? The figure 7B displaying an epileptic spasm should preferably have deltoid EMG electrodes and it would also be beneficial to have two spasms in the figure to get an idea of the events occurring in series.
Many of the EEG figures are missing a scale bar, and it would beneficial if the phenomena of interest would be pointed out with e.g. arrows in the figures.
Many of the figures are of poor quality (perhaps this will be corrected for the final version), e.g. fig 10 has an extra “pointer” in the left upper corner.
There are some abbreviations in the tables that are not present in the text: e.g. Tables 1-3 have SeLNE, SeLNIE and SeLIE. Do you plan to launch these Abbreviations or should they be omitted from the Tables as well?
Päivi Nevalainen, Maria Peltola, Leena Lauronen, Jukka Vanhanen and Hanna-Reetta Lajunen
This is a compilation of human knowledge about epilepsy syndrome! However, why not include the examples of EEG in a separate article? I don't think that the examples of EEG are an essential part of this article. It's just to gild the lily in my view. As you know, there already are many EEG-related books.
Keun Tae Kim
1. The lines between IGE and GGE are blurred. Though the authors have tried to define a subset of patients with CAE/JAE/GTCA/JME as IGE versus all others with generalised discharges as GGE; this seems to be more doable in adults and whether this differentiation can be applied to the children remains doubtful.
2. Most children with first GTCS and normal EEG will rightfully remain unclassified, even if there is a prior history of febrile seizures or family history of any type of epilepsy. It will be helpful to mention this category somewhere in the text, as this forms a large chunk of new onset epilepsy patients that we see in our practice.
Thank you inviting to review the draft and comment on it. It was wonderful job done by all authors to define the criteria and parameters for IGES.
One of the points, which I've felt is not much considered in this classification; is the in depth utilization of EEG wave patterns in relation to various syndrome. Such as on the basis of specific type of spikes or waves pattern, we may more precisely categorize or group together these syndromes.
For instance, patterns such as late recurrent discharges, rippling, sharp ripples, complex mixed spikes with low and high amplitudes, multiple ripples coupled with spikes (slow/fast/poly), short recurrent discharges etc.
Utilizing the micro details of these spikes and waves pattern along with the amplitude, would definitely further facilitate the classification.
Muhammad Liaquat Raza
23 June 2021
Thank you very much for this special document on Classification.
It is a pleasure to see that the name IGE is rescued, but now as a subgroup of the genetic epilepsies. At the same time it raises the question what Idiopathic actually means (please a current definition, although the history of it is explained in the discussion) and whether the name will change when a causal genetic background is determined in the near future. Text from the Discussion could be transferred to the Introduction. In this important document references related to statements are now and then missing. For example after “ drug-responsive, with about 80% of the IGEs responding to appropriate ASMs”, “However, the IGE syndromes differ in their likelihood to remit, and the age of remission” and “A photoparoxysmal response may occur with intermittent photic stimulation in a minority of patients with IGE”.
This brings me to the importance of photosensitivity in especially this group of four syndromes. Photosensitivity is found between 10-75% percent in these IGE categories. Percentages of the PPR positive patients in the various syndromes are given by Silvana Franceschetti and Maurizio Elia (Chapter 8: Epileptic syndromes with photosensitivity) and Carmen Baba and Renzo Guerrini (Chapter 14: How to interpret Photoparoxysmal EEG results) in the recently published Book on The Importance of Photosensitivity for Epilepsy by Springer/Nature, ISBN 978-3-319-05079-9.
Instead of “A photoparoxysmal response may occur with intermittent photic stimulation in a minority of patients with IGE”, I propose the wording “substantial number up to 75 % , dependent on the syndrome and IPS methodology applied (Kasteleijn-Nolst Trenité D, Rubboli G, Hirsch E, Martins da Silva A, Seri S, Wilkins A, Parra J, Covanis A, Elia M, Capovilla G, Stephani U, Harding G. Methodology of photic stimulation revisited: updated European algorithm for visual stimulation in the EEG laboratory. Epilepsia 2012 Jan;53(1):16-24 and https://www.ilae.org/files/ilaeGuideline/PhoticStimulation-2012-.1528-1167.2011.03319.pdf)
“IPS triggers generalized spike-wave in 15% of CAE but does not induce seizures”- no reference is given and it is unclear what is meant by this. Do seizures mean GTC only? A nice IPS study in patients with CAE and photosensitivity is done by Baykan et al., Epilepsia, 46(1):159–163, 2005.
There are inconsistencies in % PPR between text and Tables.
I am certainly very willing to help!
Dorothee Kasteleijn- Nolst Trenité
23 June 2021
Congratulations for the summary on IGE. I would appreciate more information about the Natural History of each syndrome. Specially about treatment discontinuation (when to consider ,and factors that should be considered).
In the description of JAE I would include in the genetic studies the determination of the GLUT1 gene in patients with atypical features or drug resistance.
14 June 2021
I wish to raise two points in the IGE paper; both are about JAE
The first is about the role of hyperventilation in JAE: it is quite true that hyperventilation in CAE= childhood absence epilepsy may prove or disprove absences in untreated cases BUT its effects in JAE in our practice is not that much and it may not initiate absences even in untreated patients for reasons like the age factor and the original number of spells being quite lesser than in CAE.
Secondly the myoclonic jerks according to our education is not exclusionary in JAE since occasional jerks may be encountered in the course of of the disease, but they are not consistent and not prominent and are definitely not the presenting sign or symptom
12 June 2021
Congratulations for a concise and complete summary on IGE.
Regarding JME, it would be worth mentioning that a subset of patients may present focal ictal features, particularly head version without loss of awareness. Being an understandable "red flag", they would not exclude the diagnosis if all the remaining picture and clinical-EEG correlation is typical for the syndrome. This point is relevant due to the pharmacological choice implications.
12 June 2021
12 June 2021
Well defined and certainly adds useful guidance on classifying these seizures with some room for personal expert judgement.
Arun Swaminathan MD
12 June 2021
I follow one comment that title used should be "Generalized Genetic Epilepsies" in which "genetic" is on second place. Be careful with such classification - in some societies - the stigma against genetic diseases could influence not only the individuals but also their familial and social relationship.
Antonio Martins da Silva
7 June 2021
Dear colleagues of the ILAE chapter on Idiopathic Generalized Syndromes,
I am a co-worker of Pr. Hirsch in Strasbourg and we have discussed this pivotal article, which is very interesting. However, I would like to comment on the main Figure, Figure 1, which will be reproduced manifold in the years to come. The blue triangles on the right side of the figure are very confusing. They suggest a scale of intelectual disability, but they do not give a normal range (all patients classified 'encephalopathy'). Furthermore, it is not clear whether the triangles correspond to a scaling for the entities in the dashed squares or only for the entities given in green (Myoclonic-atonic epilepsy etc) or none (!). Is there really neurpsychological data that allows the placement of 'Epilepsy with Eyelid myoclonia' onto such a range of intellectual disability?
This figure is highly important and will be used to resume the work in slide shows all around the world, I would therefore recommend to revise it.
Thank you very much in advance.
29 May 2021
I’m working in a area with migrant from Middle East, North Africa, and Africa
Some patients report that the term Generalized Genetic Epilepsy could be better or more appropriate:
1) Use of "Genetic" as the second word (i.e., Generalized Genetic) could be less stigmatizing (control study?)
2) In some countries and communities, it might be difficult to get married if you have a genetic disease. In such countries could we encourage expanding the use of Idiopathic to mean “disease by itself”?
29 May 2021
Should we consider an MRI negative patient -- male 25 years (onset) no developmental encephalopathy with generalized epileptiform EEG trait and only Generalized Tonic Clonic seizures occurring 80% during sustained sport activities and 20% 2 hours after awakening -- as GTCA.
1) Physical activity induced GTC should be considered as “Red Flag”.
2) If it is a GTCA, genetic diagnostic test could or should be performed: Genetic (SCN1A, K channel, Long QT...)
3) Mild Mitochondriopathy should be seek
4) Lamotrigine, Lacosamide, Carbamazepine should be avoided until there is rare SUDEP case in GGE
22 May 2021
From a conceptual point of view it is bizarre, if not incorrect, to want to insert a group of syndromes without etiology ("Idiopathic": adj. Denoting a disease or condition the cause of which is not known or that arises spontaneously [Oxford Medical Dictionary]) in a broader grouping defined by a specific etiology (Genetic), even if only presumed.
P.S. E. Hirsch appears twice in the disclosures (with different attributions).
18 May 2021
Generalized seizure types -- absence, myoclonic, tonic-clonic and myoclonic-tonic-clonic seizures, with 2.5-5.5 Hz generalized spike wave -- should be classified as having GGE, fully agreed and the frame work is excellent.
However, few idiopathic generalised epilepsies with normal brain imaging study using epilepsy protocol have genetic origin. Birth hypoxia and subtle hypoxic ischemic injury might be the etiopathogenesis for epilepsy in those cases.
13 May 2021
Comments on the prominent motor symptoms related to 3 Hz spike-waves (absences), like the perioral, or those involving head movement should also be inserted to help new beginners.
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