Proposed classification: Syndromes with onset at variable ages

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 Classification and Definition of Epilepsy Syndromes with Onset at a Variable Age

See all four Proposed papers for Nosology and Definitions


15 July 2021

Due to its clinical relevance, the syndrome of frontal lobe epilepsy syndrome may be addressed even in preliminary approach.

Alejandro de Marinis

15 July 2021

Our comments:

1. This paper meets its goal of providing updated diagnostic criteria for the epilepsy syndromes that have a variable age of epilepsy onset based on expert consensus of the International League

2. This paper clearly demarcates these syndromes which can have variable age of onset from those which have a classical age of onset in neonatal, infantile or childhood onset.

Sheffali Gulati and Sonali Singh

15 July 2021

1) The word hypermotor which is used in SHE Sleep related Hypermotor E was changed for hyperkinetic in the 2017 Instruction Manual : this inconsistency will be difficult to justify.

2) "In epilepsies that begin in adolescence or adulthood, after developmental milestone acquisition, the term developmental encephalopathy (DE) can be applied when there is clinical onset of a condition manifesting with cognitive, neurological or psychiatric impairment, stagnation or regression, if this is considered related directly to the underlying etiology and not to frequent epileptic activity." This is quite confusing and not consistent with the definition in the other papers!

Eliane Roulet-Perez

15 July 2021

This is a comprehensive paper.

It was mentioned about reading-induced seizures. The specific stimulus induced seizures also occur in music-induced seizures. Why it should be mentioned as specific syndrome?

I agree that sleep-related hypermotor epilepsy should be accounted as a distinct syndrome.

Thank you very much for the efforts on this paper.

Fitri Octaviana

15 July 2021

The epilepsy syndromes presenting at a variable age are broadly divided into the following groups by ILAE

  • generalized epilepsy syndromes, with presumed polygenic etiologies – the idiopathic
    generalized epilepsies (juvenile absence epilepsy (JAE), juvenile myoclonic epilepsy
    (JME) and epilepsy with generalized tonic-clonic seizures alone (GTCA)
  • focal epilepsy syndromes with genetic, structural or genetic-structural etiologies - sleep
    related hypermotor epilepsy (SHE), familial focal epilepsy with variable foci (FFEVF),
    epilepsy with auditory features (EAF)
  • a combined generalized and focal epilepsy syndrome with polygenic etiology - epilepsy
    with reading-induced seizures (EwRIS)
  • a specific group of developmental and/or epileptic encephalopathies (DEEs) -progressive myoclonus epilepsies (PME)- excellently organised frame work and every groups were well explained what I want to mention that Immune mediated epilepsies in autoimmune encephalitis although very distinct and often underdiagnosed entity with onset at variable age groups might be accomodated in etiology based classification particularly the two syndromes New Onset Refractory Status Epilepticus (NORSE), Febrile Infection Related Epilepsy Syndrome (FIRES), and Related Conditions both can happen in childhood as well as in adult,there has been debate regarding whether this represents one syndrome, multiple syndromes, and with what name(s) ,.therefore should come under new classification

G P Burman

15 July 2021

The classification is very useful and practical.

1. What are the differences between epilepsy with auditory features (EAF) and temporal neocortical epilepsy? The proposed criteria for EAF can all be satisfied by a subgroup of patients with temporal neocortical epilepsy. Kindly, clarify the same.

2. The introduction of new diagnostic criteria and its effect on better application of precision medicine is underplayed in this position paper and hence therapeutic implications may also be highlighted (e.g. mTORopathies.)

3. The importance of a positive genetic test in these syndromes and its effect on the diagnosis (in combination with other criteria mentioned) has not been discussed.

Sanjeev V. Thomas

15 July 2021

Thanks a lot for this excellent article.

* I don't know whether acquired epilepsies (for example trauma, tumor, cerebral infection or stroke etc.) should be placed here or not.

A. R. M. Sakhawat Hossain Kha

14 July 2021

It would be nice if, along with other classifications, we had a classification of syndromes according to neurochemical defect - the imbalance of which neurotransmitters cause this syndrome. This will help pharmacists develop new drugs.

Alexander Kharibegashvili

14 July 2021

Where to classify Ring 20 epilepsy?

Non-Rasmussen EPC should be added.

van Rijckevorsel Kenou

12 July 2021

This was a very clear paper and we have no further clarifications to suggest.

Päivi Nevalainen, Maria Peltola, Leena Lauronen, Jukka Vanhanen and Hanna-Reetta Lajunen

12 July 2021

Very comprehensively written paper. Can we include focal epilepsy due to structural abnormalities as a different syndrome? Most often these epilepsies are classified according to the lobe they represent. Electroclinically they can be classified in single syndrome and also they have onset at variable ages.

Sandeep Patil

9 July 2021

The mitochondrial disorders MERRF and POLG are missing. They are mentioned once as a differential for RE, and again saying that are a common cause of PME (see table 10) but then don't appear in table 10.

MELAS is missing. If you want help writing these - just ask. Similarly Leigh's is absent in the childrens' papers.

I couldn't find IPOE in any of the papers - please excuse me if it has been renamed.

Rhys Thomas

5 July 2021

This is a well written paper and tackles a complex set of epileptic conditions. Although it is not possible to cover all topics fully, I was left wanting a fuller discussion of reflex epilepsies. Discussion only reading epilepsy without mentioning the well studied photosensitive epilepsies as well as musicogenic seizures and seizures induced by thinking dos not do justice to the syndromes that involve complex neuronal network processing to set of seizures. More study of these rare but fascinating syndromes may well lead to a better understanding of the mechanics of the genesis of seizures.

One minor point in the introduction is that it should be mentioned that incidence of epilepsy in elderly is higher than in children. Wilkins AJ et al Ann Neurol 1982;11:608

Ilo Leppik

4 July 2021

No specific comments, but it will be good if an initial table is provided in the beginning of the whole document to indicate which syndromes are included in the different categories.

Kavita Srivastava

3 July 2021

Congratulations to the authors for this comprehensive converge of most of the dimension related onset at variable age.

Just a small comment about epilepsia partialis continua, it wasn't given importance in the draft, if the authors add some data about epilepsia partialis continua onset and incidence would be beneficial for clinicians.

Muhammad Liaquat Raza

12 June 2021

This is a complex paper, including a lot of valuable information on different clinical pictures. However, in the section of epilepsy syndromes of different etiologies, including some syndromes in which the only clear common basis is the electroclinical correlation (meaning ictal semiology related to location) with significant variations on natural history, prognosis and response to treatment (mostly related to very different possible etiologies) seems a bit confusing. On that line, every single putative epileptogenic zone/network could be presented as a syndrome...?

Patricia Braga

12 June 2021


Nensi Manusheva

12 June 2021

Comprehensive and well thought out.

Arun Swaminathan MD

9 June 2021

We have a few concerns regarding the chapter on “The progressive myoclonus epilepsies”.

The sentence: “The severity of the condition depending on the etiology.” is not fully correct since it is known that a marked phenotype variability may occur even in siblings carrying the same gene mutations (as in subjects with Unverricht-Lundborg disease). We suggest changing this sentence with “Phenotype severity usually depends from etiology but individual genetic background as well as unknown environmental factors may make a contribution.”

In the sub-chapter on “Unverricht-Lundborg disease”, authors state that “The EEG background may be normal at onset, but progressive slowing of the background appears over time”. We do not fully agree, since in some patients, background activity can keep stable during the course of the disease and may even appear more organized many years after disease onset (Ferlazzo et al. Epilepsy Res 2007; 73:219-27). The last sentence: “This condition is differentiated from other PME’s by notable dysarthria, dysphagia and tremor” is incorrect since it does not match literature data. Subjects with Unverricht-Lundborg disease are known to have a milder phenotype as compared to other PMEs. We suggest deleting this sentence.

In the subchapter on “Lafora Disease.” We suggest adding a sentence stating that “Peculiar EPM2B mutations are associated with milder phenotype, slower progression and longer survival”.

Edoardo Ferlazzo, Sara Gasparini, Umberto Aguglia

26 May 2021

Thank you to the authors for this paper. It summarizes important aspects for the different syndromes.

Nevertheless, I am a little bit confused by the term "onset at a variable age" since the authors include syndromes which do not have a variable age. A definition of the term is not given (e.g. in which age frame variable? How many years variable in a defined syndrome?). To summarize these syndromes and differentiate those from the other two papers you might use "syndromes with onset in youth and young adulthood."

Yvonne Weber

13 May 2021

Focal epilepsy of unknown cause (FEUC) or with its former name cryptogenic focal epilepsy is an under-investigated topic despite its remarkable frequency and importance for the patients who will face anxiety about their prognosis labeled as “unknown”.

About 40% of adult-onset epilepsies are diagnosed as FEUC, thus they constitute an important subgroup among all types of epilepsies [1, 2]. Therefore, I certainly believe that this ignored but frequent heading should not be neglected in this pioneering paper to promote well-designed prospective future researches on FEUC.

Our recent study emphasized that the initial diagnosis of FEUC always needs further diagnostic evaluation such as genetic testing, immunological studies, advanced imaging which might illuminate the underlying hidden etiology in only 6.6% of patients even in a tertiary center. We also conclude that when appropriately treated, FEUC has a benign subgroup with the favorable course, lower drug resistance and higher 5 years of terminal remission rates. Clinicians must be aware of the related factors regarding drug response and long-term remission in FEUC and enlighten the patients at the pretreatment phase to give an insight into their epilepsy and diminish the anxiety of having an unclarified diagnosis.

1) Berg AT, Berkovic SF, Brodie MJ, Buchhalter J, Cross JH, van Emde BW, Engel J, French J, Glauser TA, Mathern GW, Moshé SL, Nordli D, Plouin P, Scheffer IE (2010) Revised terminology and concepts for organization of seizures and epilepsies: report of the ILAE Commission on Classification and Terminology, 2005–2009. Epilepsia 51:676–685

2) Shorvon SD (2011) The etiologic classification of epilepsy. Epilepsia 52:1052–1057

3) Atalar AÇ, Vanlı‑Yavuz EN, Yılmaz E, Bebek N, Baykan B. Long‑term follow‑up of a large cohort with focal epilepsy of unknown cause: deciphering their clinical and prognostic characteristics Journal of Neurology 2020; 267: 838-847.

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