Proposed classification: Syndromes in Neonates and Infants

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 & Definition of Epilepsy Syndromes in the Neonate and Infant

See all four Proposed papers for Nosology and Definitions


15 July 2021


Epilepsy syndromes are divided into two major groups:

1. Self-limited epilepsy syndromes, where there is likely to be spontaneous remission
2. Developmental and epileptic encephalopathies (DEE), diseases where there is developmental impairment related to both the underlying aetiology independent of epileptiform activity and the epileptic encephalopathy DEEs are divided into
a. Early Infantile DEE: Onset under 3 months of age
b. Other syndromes which either typically present after 3 months of age or have a spectrum of age of onset which includes early and late infantile periods.


1. Classification is in a way that makes approach to neonatal and infantile epilepsy straightforward.
2. Benign has been replaced by “self limited”, the importance of which is well known.

Sheffali Gulati and Sonali Singh

15 July 2021

I would comment on several points in Dravet syndrome.

1/ Onset age: do not expand it up to 20 months.It is well established now the DS starts up to 1 yr at the latest (ref 133, Cetica et al., 2017). The 3 published cases with onset after 1yr remain the exception.

2/ Seizure types. Generalized tonic-clonic seizures exist but they are rare. In the first year seizures are more clonic than tonic-clonic while focal onset seizures with tonic-clonic bilateralization are the most frequent later in the course (ref 135, Dravet et al.,2012, and the same authors in the 6th edition of the book,2019, not cited in the list). The atonic seizures can be observed but they are not a characteristic of the syndrome.

3/ Neuroimaging. I am surprised by the rate of "about one third of hippocampal sclerosis." We cannot generalize the 7 cases among 18 found by one author (ref 149, Gaily et al, 2013) and the 10/14, without genetic analysis, by another author (Siegler et al.,2005) when other authors have reported much less : 1/58 (Striano et al.,2007, cited by ref 148, Guerrini et al., 2011), 1/18 by Catarino et al. ( Catarino CB, Liu JYW et al.,Dravet syndrome as epileptic encephalopathy: evidence from long-term course and neuropathology Brain, 2011).

4/ Table 9. Onset age. 1-12 months; alert 1-2 months and 12-20 months; exclusionary after 12 months. Imaging. exclusionary: MRI showing a causal focal lesion present at the onset..

I regret the autors have not cited the last edition of the book "Epileptic syndromes in infancy, childhood and adolescence" published in 2019 by John Libbey Eurotext.

I could not read all this new proposal for classification and definition of epilepsy syndromes in detail, but it is really an important work and I appreciate the commitment and effort of the authors who dedicated a large part of their time to it. Many thanks to them.

Charlotte Dravet

15 July 2021

The classification task force has done a great job in preparing the detailed papers for the epilepsy syndromes of different age groups as well as different etiologies. This set of papers will help all the care providers, researchers and administrators to speak on one language. The classification also provides sufficient flexibility to be applied under different conditions of minimal evaluation to more detailed genetic screening etc. I would like to submit the following comments that had come up while the papers were discussed in our epilepsy teaching forum.

Classification of Epilepsy in Neonates and Infants

Excellent classification

  1. Self-limiting neonatal and neonatal-infantile epilepsies cannot be diagnosed in the first visit and requires close follow up especially on the frequency and semiology of seizures with time, time of attainment of developmental milestones and appearance of new neurological symptoms with age. Hence the patients satisfying the mandatory and exclusionary criteria in the first visit may be classified as Self limiting Epilepsy NOS/ Probable and the diagnosis may be revised as definite self-limiting epilepsy on follow up.
  2. The protocol for neonatal brain imaging also needs to be detailed. The appropriate age for acquisition of MRI may also be clarified.
  3. In the exclusion criteria for Myoclonic Epilepsy of Infancy, identification of each of the exclusionary seizure types may be difficult.
  4. Though genetic basis has been found in many of the syndromes in the self-limiting and DEE groups, it doesn’t form a part of the diagnostic criteria
  5. Many more specific epilepsy syndromes may be added to the etiology specific group in the near future with advances in genetics.
  6. The introduction of new diagnostic criteria and its reflection to better application of precision medicine is underplayed in this position paper and hence therapeutic implications may also be highlighted.

Sanjeev V. Thomas

15 July 2021

Thanks for a very nicely written paper. From my point of view--

You can include Chromosome 15 disorders (including Inv dup 15) and Myoclonic encephalopathies in nonprogressive disorders (or myoclonic status in nonprogressive encephalopathies) under the etiology-specific syndromes.

Dr. A. R. M. Sakhawat Hossain Khan

14 July 2021

It seems that a neonate or infancy brain is unable to produce a true tonic-clonic seizure even after a focal seizure (as it happens later in life, > 2 years). However, this is described in tables and within the text. Most of time it is focal to bilateral tonic or focal to bilateral clonic.

van Rijckevorsel Kenou

14 July 2021

1. Maybe we need to mention ring Chr 20 in karyotyping, being a specific syndromic entity to be looked for, with a defined phenotype and prognosis.

2. Why do we segregate Epilepsy with Migrating focal seizures, as it is in fact an IDEE with a poor prognosis and with treatment or prognostic implications no different from other IDEEs(Ohtahara or EME)?

  • IDEE may be
  • Ohtahara
  • EME
  • Epilepsy with migrating focal seizures

Keeping in line with the methodology so well designed and used, there should be a sound reason to segregate due to diagnostic, specific genetics and treatment or prognostic reasons

In Fig 1 Pg 60:
It may be possible to add Etiological causes on the right of the figure (as in classification of seizure types)

  • genetic
  • structural
  • Metabolic
  • unknown

That may urge clinicians to pursue them in the workup and definition of IDEE .

Nandan Yardi

13 July 2021

Dans la partie "self limited epilepsy " il y 'a parfois manque de précision avec chevauchement entre l'âge de début.

Ben Nsir Sihem

12 July 2021

This is a nicely written paper. In the section of DEE, there is a mention of structural etiology. If we can elaborate this structural etiology in a separate heading, it will have more emphasis. Also, we can also include some representative MRIs of structural etiologies in the supplement.

Dr Sandeep Patil

12 July 2021

It is better to include the syndromes, if any,associated with fetal seizures. This paper should mention a few points about seizures in fetal age ,which are missing.

M. A. Aleem

12 July 2021

We read with great interest the proposed paper. We have some minor issues we wish that 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

9 July 2021

Selina Husna Banu

4 July 2021

Congratulations for the excellently written article.

  1. Good to bring EMEI and EIEE (Ohtahara ) under one umbrella of DEE.
  2. As West syndrome is a well known term (used by paediatricians as well), it should be retained, just like Dravet syndrome.
  3. Addition of newer gene based syndromes like PCDH19, CDKL5 related ones are a welcome step.
  4. It will be good to have a single table combining the self limited neonatal and infantile (familial and non familial) epilepsies, so that the differences in genetics are apparent.

Kavita Srivastava

1 July 2021

Our comments are with regard to the definition of Dravet Syndrome (starting on page 25) and the Diagnostic Criteria table for Dravet Syndrome (on page 52).

For the main definition (p25), we request to add clarification that DS is not only a paediatric syndrome. Although DS is a life-limiting condition, it is also life-long, with around 80% surviving into adulthood.

On the section relating to genetics (p27), we request to add a comment that genetic testing is recommended wherever DS is suspected as a possibility, no matter the age of the patient. For example, some older adults will have left paediatric care before modern genetic testing. There is good evidence to show improvement in adults with Dravet Syndrome once given the appropriate treatment (e.g. once sodium channel blockers are stopped).

On the table (p5) - we have the following comments:

  • Request to update the 'Mandatory' section to read ''Recurrent hemiclonic febrile and afebrile seizures...' for clarity.
  • On the 'Alerts', we have a question. Why 16-20 months, not 13-20?
  • Under 'Syndrome without laboratory confirmation': We agree it should not be mandatory to include the genetic test. However, it should be encouraged to confirm the diagnosis with the genetic test wherever possible. Could there be an amend the wording or a new paragraph added with the headline 'Genetic testing' to say: 'Genetic testing is strongly recommended wherever the possibility of Dravet Syndrome is suspected, including adult patients'.

Thank you for the opportunity to comment.
Claire Eldred

29 June 2021

Congratulations on this excellent piece of work.

As an adult neurologist I have no expertise on the contemporary management and diagnosis of these conditions, but I do have a comment that may seem strange, and I apologise if you feel this is outwith the scope of this work.

The retrospective syndromic diagnosis of adults with ID and early onset epilepsy can be challenging. Given that changes in available treatments render this question more than academic, would there be any thought given to providing criteria for retrospective diagnosis? A heavy dose of pragmatism will be needed to avoid burdening patients with unnecessary and invasive investigations, but this should be possible.The authors may feel that this is more reasonably formed as a separate paper. The same comment may of course apply to the paper on onset in childhood.

Best wishes,
John Paul Leach

15 June 2021

The Pediatric Epilepsy Research Consortium (PERC) is a group of 50+ pediatric epilepsy programs in the United States. PERC’s mission is to provide a network and infrastructure to facilitate collegial, collaborative practice-changing research that will provide answers needed to improve the care of children with epilepsy. PERC supports several special interest groups, each of which consist of clinician researchers who meet regularly to discuss active projects and opportunities to collaborate.

The PERC Early Life Epilepsies Special Interest Group (PERC ELE SIG) reviewed the ILAE’s recent Statement by the Task Force on Nosology and Definitions to classify and define neonatal and infantile epilepsy syndromes. Per this document “The principal aim … is to support clinical management and emphasise the importance of classifying epilepsy in an individual both by syndrome and etiology.” The PERC ELE SIG found this to be a very helpful and useful document, and also proposed the following recommendations:

1. A clear recommendation should be made for brain MRI for infants with neonatal and infantile epilepsy syndromes outside of resource-limited settings. Given good evidence for the high diagnostic yield of MRI in this population, and the critical importance of excluding acute brain injury as the seizure etiology, we recommend that there be an unambiguous recommendation for universal brain MRI for affected children, unless such imaging is not available due to a resource-limited setting.

Additionally, please note there is some disagreement on the need for imaging between text and tables (e.g., p.11 and p.46 Table 3 recommendations do not match; p.32 for CDKL5 the entire neuroimaging subsection is absent). We would encourage clear consistent guidance that MRI is standard of care for neonatal and infantile epilepsies.

2. Consideration should be given to adding epilepsy management recommendations, including current evidence and uncertainties, consistently across syndromes.

ILAE’s principal aim “to support clinical management and emphasise the importance of classifying epilepsy” highlights one of the major utilities of this document, which is development and appropriate implementation of specifically targeted management recommendations for these syndromes. Some sections of the present draft mention this in passing (e.g., utility of sodium channel blocking agents in SCN2A and KCNQ2-related early infantile developmental epileptic encephalopathy, p.16), though such recommendations are not provided consistently.

A separate, dedicated section for each syndrome on Evidence-Based and Preliminary Evidence Treatments would be helpful. This might also include whether the ILAE has a clear recommendation on whether a trial of pyridoxine for treatment of Ohtahara syndrome/EIDEE should be undertaken. Other examples: ezogabine data and potassium channel drugs in development for KCNQ2-related epilepsies; Dravet Syndrome gene therapies in development; and the complexity of sodium channel blocker use according to the gain or loss of function status of genetic variants.

3. The spectrum of phenotypes possible with the same genotype should be more clearly and consistently stated.

It is important that those using this document not be confused by KCNQ2 as causing both self-limited epilepsy and epileptic encephalopathy, or equate PRRT2 only with self-limited epilepsy.

4. Consider inclusion of Glut-1 transporter deficiency and tuberous sclerosis as other Etiology-Specific Syndromes due to their prevalence and specific treatment recommendations.

5. Skin exam utility should be emphasized beyond tuberous sclerosis. Neurocutaneous findings can help identify etiology for other early life epilepsies, particularly in resource-poor settings and may minimize inappropriate testing or classification.

6. Emphasis of Dravet Syndrome as a clinical diagnosis could be stronger, with reference to Hattori criteria. 

Pediatric Epilepsy Research Consortium Early Life Epilepsies Special Interest Group
Contributers: Sonal Bhatia, Krista Eschbach, Renée Shellhaas, Emily Spelbrink

15 June 2021

This is a comment on the "clinical course" part of the chapter on Infantile spasms. The authors note that developmental prognosis is poor in many children regardless of seizure outcome. I suggest pointing out that the unknown and identified etiology groups are very different with regard to developmental and seizure outcome. The prognosis is actually very good for children with unknown etiology and prompt syndrome-specific treatment. This was shown eg. by Raili Riikonen in her prospective long-term follow-up study, Brain & development. , 2001, Vol.23(7), p.683-687, by O'Callaghan et al. Epilepsia, 52(7):1359–1364, 2011 and also in our retrospective population-based study Gaily et al. Epilepsia, 57(10):1594–1601, 2016. Being aware of this may further promote early diagnosis and early medical intervention with ACTH/steroids or vigabatrin, as lead time to treatment reimains the most important prognostic factor in the unknown etiology group.

Eija Gaily

14 June 2021

Dear ILAE committee,

The Pediatric Epilepsy Research Consortium (PERC) is a group of 50+ pediatric epilepsy programs in the United States. PERC’s mission is to provide a network and infrastructure to facilitate collegial, collaborative practice-changing research that will provide answers needed to improve the care of children with epilepsy. PERC supports several special interest groups, each of which consist of clinician researchers who meet regularly to discuss active projects and opportunities to collaborate.

The PERC Infantile Spasms Special Interest Group (PERC ELE SIG) reviewed the ILAE’s recent document regarding the Proposed Classification of Syndromes in Neonates and Infants. This submission pertains only to the syndromic classification/criteria for children with infantile spasms.

Read group comment on syndromes in neonate and infant

John R. Mytinger, Sonam Bhalla, Sonal Bhatia, Fiona Baumer, Harini Chellamani, Krista Eschbach, Erin M. Fedak Romanowski, Zachary Grinspan, Shaun Hussain, Kelly Knupp, John J. Millichap, Sunil Naik, Adam Numis, Debopam Samanta, Renee Shellhaas, Rani Singh, Deepa Sirsi, Emily Spelbrink, K. Liu Lin Thio, Steven Wolf, Christopher Yuskaitis, Daniel Shrey

5 June 2021

I appreciate efforts of the Task Force.

Although the definition of “early-infantile developmental and epileptic encephalopathy” and “infantile spasms syndrome” allows inclusion of atypical cases, it may blur their concepts. I believe that the core concepts of these disorders are important, and that “West syndrome,” “Ohtahara syndrome,” and “early myoclonic encephalopathy” should remain as the core syndromes.

Katsuhiro Kobayashi

4 June 2021

First of all I wish to congratulate the commission on their hard work and detailed outline on syndromes in neonate and infant. I think this will help the clinicains across the world to define the children into the most appropirate syndromes.

My comments are related to the new terminology of Infantile Spasms Syndrome in place of previously used West syndrome. The authors indicate that this will reduce the confusion when classifying children if they do not have the triad of hypsarrhythmia, developmental regression and spasms. According to the statement of West Delphi group (2004), WS diagnosis required only two components; spasms and hypsarrhythmia. Since this consensus statement, we have defined WS based on these two criteria for over 16 years. Therefore the only additional group who would be included by changeing terminology would be those who do not have hypsarrhythmia.

Other observation regard to the new terminology:

1. The proportion with normal EEG and infantile spasms is very small

2. In this group, it is better to be certain by performing video telemetry in order to avaoid treating spasm mimickers with high dose steroids or vigabatrin. If the EEG is normal, as clinicians we do not need to rush to commence treatment either. In some cases the hypsarrhythmia appears after few days.

3. In the current terminology, ISS includes children who have spasms onset upto 24 months. Infancy is only upto first 12 months. Therefore the use of ISS upto 24 months is confusing.

4. The proposed document states that spasms occur from 3-24 months. What about those who have spasm onset > 24 months (Late onset spasms), What terminology is suggested for this condition?

5. In ISS, the seizure type is epileptic spasms. This was changed from infantile spasms based spasm onset age exceeding infancy. Use of different terminologies around the same condition i.e epileptic spasms in ISS adds to further confusion. Why not call ISS Epileptic spasms syndrome which then resonates the type of seizures in the condition and does not pose issue of using the word infantile for those who develop the condition beyond 12 months?

Regarding the course of the illness, it may be useful to include the proportion who respond to therapy and never develop other epilepsies.

Best regards,
Jithangi Wanigasinghe 

3 June 2021

Thank you for this important work.

My first comment relate to the term, Infantile Spasms.

An infant, as defined in the medical field, refers to a baby who is 0-1 year of age (less than 1 year of age). However, we know that infantile spasms exist beyond infancy. Thus, it makes little sense to specify the age when classifying a seizure. For example, we do not classify clonic seizures in an infant as “infantile clonic seizure, or tonic seizure as “infantile tonic seizure.”

2. The term, “Infantile spasms” may also refer to non-epileptic spasms after a careful video EEG analysis. Thus, it is unclear if one is referring to epileptic or non-epileptic spasms.

3. The term “epileptic spasm” should be sufficient to apply to both infants and older children with “epileptic” spasms. Any infant or child with epileptic spasms require a through work up.

My second comment relates to the proposed term, Infantile Spasms Syndrome.

It is acknowledged that a patient with epileptic spasms may be older than 1 year, may not have hypsarrythmia or have various antecedent history. The issue with age would be resolved by the use of the term, Epileptic Spasms. This term should remain a seizure semiology classification term. Indeed, it would be more informative and precise to describe presence or absence of certain EEG features (such as hypsarrhythmia and/or back ground slowing) or other antecedent or evolving clinical/EEG features.

An attempt to include clinical and electroencephalographic information in a term, such as Infantile Spasms Syndrome, would lead to over simplification of a complex presentation and evolution. The diagnostic term may and should change with evolution of electrographic and/or clinical presentation. As such, diagnostic terms like West syndrome should remain unchanged. Ultimately as the field of epilepsy genetics advances, syndromic classification terms may be replaced by genetic diagnosis.

Jun T. Park

2 June 2021

Infantile Spasms Syndrome is employed for covering West syndrome and atypical one lacking one or two characteristic features of West syndrome. It is acceptable, but the authors did not refer to the syndromic position of West syndrome, whether it is remained in the ILAE-recognized syndrome like Lennox-Gastaut syndrome or not.

Hirokazu Oguni

20 May 2021

For the developmental and epileptic encephalopathy patients, we should [include] a guidance on how to classify them into:

  1. Othahara
  2. EME
  3. MeUNCLAtabolic
  4. Migrating partial epilepsy
  5. West Syndrome
  6. LGS 6) Dravet
  7. Electrical status in sleep/LKS
  8. Unclassified

This should also help research as also to identify genes responsible for various sub types of early-onset DEE.

Also, I feel that we should include migrating partial epilepsy of infancy in the early-onset DEE as a subgroup as it is fulfilling all the criteria of being DEE( abnormal development, sequential seizures). By putting it as a separate entity unnecessary confusion might be created. As this entity of migrating epilepsy has only been separated because of its Ictal EEG finding and not due to clinical presentation which can easily fit into a type of early-onset DEE I would say it will be better to subclassify early-onset DEE into following subgroups:

  1. Otahara phenotype
  2. EME phenotype
  3. Epilepsy of migrating partial epilepsy phenotype
  4. Unclassified

Vivek Jain

10 May 2021

In the article, in the part of "Self-Limited (Familial) Infantile Epilepsy" it is so written "The interictal EEG is typically normal, but a variant with midline spikes during slow sleep has been described". Capovilla et al first published this variant, describing both the EEG marker and the ictal clinical semeiology, proposing it as a new epileptic syndrome in 2000 (Brain & Development 22 (2000) 93-98) and updated it in 2006 in another article (Brain & Development 28 (2006) 85–91). None of these articles are cited among the references. The authors should revise the text and correctly describe how this variant has been proposed to the scientific community.

Giuseppe Capovilla