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.

Please see the Draft: ILAE Classification & Definition of Epilepsy Syndromes in the Neonate and Infant

The manuscript will be open for comments until 15 July 2021. Please use this survey to enter your comments and they will be published below.

Thank you for your help in this important effort of the ILAE.

See all four Proposed papers for Nosology and Definitions

Comments

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