Kan de nieuwe classificatie de definitie van …Kan de nieuwe classificatie de definitie van epilepsie verbeteren? • Standpunten van de “Commission on Classification and Terminology

Kan de nieuwe classificatie de definitie van epilepsie verbeteren?

D. Velis

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Kan de nieuwe classificatie de definitie van epilepsie verbeteren? • Standpunten van de “Commission on Classification and Terminology of

the International League Against Epilepsy (ILAE)”- historisch perspectief

• Bijdrage van nieuw verkregen kennis in de diagnostiek van epilepsie – in hoeverre heeft deze kennis geholpen in dezen?

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Commission on Classification and Terminology of the International League Against Epilepsy; Proposal for revised classification of epilepsies and epileptic syndromes. Epilepsia,1989;30:389–99

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(video-)EEG ~ 80 – 90%

1989 – 2014: Veranderingen bij de diagnostiek van epilepsie • Neuro-imaging

– Structureel – MRI-H, MRS, DTI

– Functioneel – fMRI – PET – SPECT/SISCOM

• EEG / MEG – ESI / MSI

• Neurogenetica / genetisch screening

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Advances in understanding the causes of epilepsy

Thomas RH, Berkovic SF. Nat Rev Neurol. doi:10.1038/nrneurol.2014.62

Presentator

Presentatienotities

Figure 1 - a | In 1975, the majority of epilepsies were characterized as 'idiopathic'. b | Today, epilepsy of unknown cause comprises a much smaller proportion, owing to the discovery of autoimmune epilepsies, epilepsies with lesions that are only detectable by MRI and, most importantly, the reclassification of many epilepsies previously considered idiopathic as having a genetic cause. The exact proportions of monogenic and complex or polygenic epilepsies remain uncertain. Data for part a were obtained from Hauser & Kurland.15 [Hauser, W. A. & Kurland, L. T. The epidemiology of epilepsy in Rochester, Minnesota, 1935 through 1967. Epilepsia. 16, 1–66 (1975)]

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(video-)EEG ~ 50 – 75%

(video-)EEG ~ 40 – 60%

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Epilepsy is a disorder of the brain characterized by an enduring predisposition to generate epileptic seizures, and by the neurobiologic, cognitive, psychological, and social consequences of this condition. The definition of epilepsy requires the occurrence of at least one epileptic seizure.

2001 - 2011 ILAE CCT: De wijzigingen • Er wordt geen onderscheid gemaakt tussen ziekte en syndroom • Concepten als “gegeneraliseerd” en “focaal” mogen niet langer worden

toegepast met betrekking tot elektro-klinische syndromen • Nieuwe terminologie en concepten naar voren gebracht omtrent oorzaak

van epileptische aanvallen (en epilepsie) • “Benigne” epilepsie vervalt als term • “Debuut” (leeftijd) wordt als basis genomen voor nadere onderverdeling

van epilepsie • Epilepsiesyndromen worden louter genoemd (naam) doch niet nader

omschreven (definitie)

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De bezwaren

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2012 - 2014 ILAE CCT: Terug bij af • Still Needed—A Proposal to Achieve a Truly Modernized

Classification

• Areas of certainties and uncertainties and of agreements and disagreements should be identified and explained. This approach may be the only way to achieve a scientifically sound and clinically meaningful organizational system for the epileptic seizures and the epilepsies—a process that would incorporate the tremendous advances in our field and would be accepted by the wider community of clinicians and scientists. 11

2014 – ILAE CCT nieuw initiatief

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(video-)EEG ~ 50%

Trends in gebruik van onderzoeksbevindingen als determinant bij classificatie / organisatie schemata • (Video-)EEG

– Gemengd beeld [enige toename in de z.g. “structural group” en de “metabolic group ”, sterk afgenomen bij de overige groepen m.u.v. specifieke elektro-klinische syndromen en bij vooral (zeer) jonge kinderen]

• Neuro-imaging (in het bijzonder MRI-H) – Zeer sterk toegenomen, vooral bij laesionele epilepsie (uitsluitend in de

“structural group”) • Genetica / genetische screening

– Aanvankelijk sterk toegenomen (Sanger sequencing) – Gestabiliseerd tussen 2008 en 2014 – Mogelijk enige toename sedert NGS sequencing

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The history of gene identifications in epilepsy research

14 Helbig I. Lowenstein D. Curr Opin Neurol. 2013;26(2):179–85.

Presentator

Presentatienotities

Fig. 2. The history of gene discovery in epilepsy began in 1995 with the discovery of CHRNA4 as the causative gene in Autosomal Dominant Nocturnal Frontal Lobe Epilepsy (ADNFLE). After a series of gene discoveries in monogenic epilepsies, it was found that most causative genes were ion channel genes, postulating the Channelopathy concept of human epilepsy. However, subsequent association studies mainly on ion channel genes have failed, and the initial hope for rapid detection of further risk variants (gray) has diminished. The field entered a period of association studies, which largely were not replicable. Finally, with the discovery of epilepsy-related microdeletions, the first risk genes for common epilepsies were identified. With the advent of Next-Generation Sequencing technologies (NGS), more gene discovery is likely. The expectations of this technology, however, parallel a typical “bubble phenomenon” and first indications from other neurodevelopmental disorders suggest that only a small subset of genes can be identified.

The dimensions of the genetic architecture of the epilepsies

15 Helbig I. Lowenstein D. Curr Opin Neurol. 2013;26(2):179–85.

Presentator

Presentatienotities

Fig. 1. Effect size refers to the increase in risk carried by a given genetic variant. While the effect size is very high for monogenic variants, common genetic variants such as Single Nucleotide Polymorphism (SNPs) usually confer a very small risk. Rare genetic variants located between both extremes currently pose a major problem for genetic research, as established frameworks to interpret this variant are still lacking. Variants can be frequent or rare in the general and patient population, and there is usually an inverse correlation between effect size and frequency. A variant with a strong effect is usually rare. This inverse correlation, however, only applies to disease risk variants, as the low frequency of the disease in the population only permits such a correlation. In genetic risk factors for medication side effects, for example, both the frequency and effect size can be high, which allows for these studies to be performed with a modest sample size.

Inheritance patterns and phenotypic heterogeneity in familial epilepsies

16 Thomas RH, Berkovic SF. Nat Rev Neurol. 2014;10:283–92 doi:10.1038/nrneurol.2014.62

Presentator

Presentatienotities

Figure 2 - a | Autosomal dominant inheritance with phenotypic homogeneity, such as in KCNQ2-related benign familial neonatal epilepsy. Blue denotes an individual with epilepsy. b | De novo SCN1A mutation leading to Dravet syndrome. Blue denotes the affected child. c | GLUT1-associated familial epilepsy (red, myoclonic–astatic epilepsy; yellow, generalized epilepsy; green, early-onset absence epilepsy; purple, focal epilepsy105) [Mullen, S. A., Suls, A., De Jonghe, P., Berkovic, S. F. & Scheffer, I. E. Absence epilepsies with widely variable onset are a key feature of familial GLUT1 deficiency. Neurology 75, 432–440 (2010). ]. d | 15q13.3 microdeletion is a risk factor rather than a cause of epilepsy: not all affected individuals have the deletion, and some unaffected individuals are carriers of it.111 [Dibbens, L. M. et al., Familial and sporadic 15q13.3 microdeletions in idiopathic generalized epilepsy: precedent for disorders with complex inheritance. Hum. Mol. Genet. 18, 3626–3631 (2009). ] Blue represents individuals with juvenile myoclonic epilepsy.

ILAE classification of the epilepsies: Position paper of the ILAE Commission for Classification and Terminology

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Epilepsia Volume 58, Issue 4, pages 512-521, 8 MAR 2017 DOI: 10.1111/epi.13709 http://onlinelibrary.wiley.com/doi/10.1111/epi.13709/full#epi13709-fig-0001

http://onlinelibrary.wiley.com/doi/10.1111/epi.2017.58.issue-4/issuetoc

http://onlinelibrary.wiley.com/doi/10.1111/epi.13709/full#epi13709-fig-0001

Wanneer is er sprake van epilepsie? • Actueel • Potentieel • Geen uitspraak mogelijk • “Resolved”

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Wanneer is er sprake van epilepsie? • Voorbeelden gebaseerd op:

– Fisher RS et al. ILAE official report: a practical clinical definition of epilepsy. Epilepsia, 2014;55:475-82.

– Fisher RS et al. Instruction manual for the ILAE 2017 operational classification of seizure types. Epilepsia, 2017;58:531-42.

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http://onlinelibrary.wiley.com/store/10.1111/epi.12550/asset/image_m/epi12550-fig-0001-m.png?v=1&s=bcdc609c44050b3241e36a2230c2f10cc7fa9b27

Operational (practical) clinical definition of epilepsy Epilepsy is a disease of the brain defined by any of the following conditions 1. At least two unprovoked (or reflex) seizures occurring >24 h apart 2. One unprovoked (or reflex) seizure and a probability of further seizures similar to the general recurrence risk (at least 60%) after two unprovoked seizures, occurring over the next 10 years 3. Diagnosis of an epilepsy syndrome Epilepsy is considered to be resolved for individuals who had an age-dependent epilepsy syndrome but are now past the applicable age or those who have remained seizure-free for the last 10 years, with no seizure medicines for the last 5 years.

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Presentator

Presentatienotities

Table 2, item 2 defines another path for diagnosing epilepsy. Its intent is to encompass circumstances for which some practitioners[9] and expert epileptologists[3] manage patients as if epilepsy is present after a single unprovoked seizure, because of a very high risk of recurrence. Such examples may include patients with a single seizure occurring at least a month after a stroke[6] or a child with a single seizure conjoined with a structural or remote symptomatic etiology and an epileptiform electroencephalography (EEG) study.[10] Another example is a patient in whom diagnosis of a specific epilepsy syndrome associated with persistent threshold alteration can be made after the occurrence of a single seizure. A first seizure might present as status epilepticus,[11, 12] but this does not in itself imply epilepsy. Recurrence risks are not known for the majority of individual cases. However, if a treating physician is aware that the lesion has generated an enduring predisposition for unprovoked seizures with a risk comparable to those who have had two unprovoked seizures (which we all agree is epilepsy), then that person too should be considered to have epilepsy. Choosing a specific threshold risk number might be excessively precise, but for general comparison, this risk is about 60–90% after two unprovoked seizures.1 A threshold level of 60% appropriately exceeds the 50% level of recurrence risk found at 5 years after a single seizure in the United Kingdom multicentre study of early epilepsy and single seizures (MESS) study.[13] It is important to note that a single seizure plus a lesion or a single seizure plus epileptiform EEG spikes does not automatically satisfy criteria for this operational definition of epilepsy, because data may vary among different studies and specific clinical circumstances. In the Dutch Epilepsy Study,[10] children with epileptiform EEG patterns after their first seizure had a 2-year risk for recurrence of 71%, but in the study by Shinnar et al.,[12] children with a first idiopathic seizure and abnormal EEG patterns had recurrence risk of 56% at 3 years. No formula can be applied for additive risks, since data are lacking on how such risks combine; such cases will have to be decided by individualized considerations. Recurrence risk is a function of time, such that the longer the time since the last seizure, the lower the risk.[14] The revised definition places no burden on the treating physician to specify recurrence risk in a particular circumstance. In the absence of clear information about recurrence risk, or even knowledge of such information, the default definition of epilepsy originates at the second unprovoked seizure. On the other hand, if information is available to indicate that risk for a second seizure exceeds that which is usually considered to be epilepsy (about 60%), then epilepsy can be considered to be present.

Eerste (en enige) epileptische aanval

• Klassiek voorbeeld:

• Spontaan ontstane focale aanval (al dan niet focaal gebleven) bij een patiënt

met een RIP in cerebro

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Kans op recidief na 2 spontaan ontstane aanvallen

• “After two unprovoked seizures, the risk of a 3rd by 60 months is 73% (59-87%, 95% CI)”.

• “60-at-60-Rule Consensus”: ~ 60% is epilepsie

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Hauser et al. Risk of recurrent seizures after two unprovoked seizures. NEJM 1998;338:429.

Wanneer is er sprake van “resolved” epilepsie?

• Klassiek voorbeeld: Volwassenen, die als kind (3-13 jaar) last van frequent optredende focale epileptische aanvallen hadden met als enige afwijking een kenmerkende stabiele, meestal asymmetrische verdeling van centro-temporale pieken in het interictale (slaap)EEG.

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Wanneer is er sprake van “resolved” epilepsie?

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Chadwick D et al. Outcomes after seizure recurrence in people with well-controlled epilepsy and the factors that influence it. The MRC Antiepileptic Drug Withdrawal Group. Epilepsia. 1996;37:1043-50.

• Hoe langer (in jaren) iemand aanvalsvrij is gebleven des de kleiner de kans op een (aanvals-) recidief

Geen uitspraak (vooralsnog) mogelijk • Gemelde doch niet gedocumenteerde gedragsveranderingen, plotseling

en spontaan ontstaan • Gebrek aan bekende etiologische factoren

• Ter discussie: criteria voor het vastleggen van “mogelijk” c.q.

“waarschijnlijk” epilepsie

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Epilepsie anno 2017 – een samenvatting • Twee voldoende gedocumenteerde spontaan ontstane epileptische

aanvallen (in > 1 etmaal) of een enkele, voldoende gedocumenteerde, spontaan ontstane epileptische aanval waarvan een oorzakelijke conditie bekend is met een hoge kans (>= 60%) voor een aanvalsrecidief.

• Geprovoceerde (reflex) aanvallen alsmede epileptische aanvallen bij een spontane mutatie behorende bij een epilepsiesyndroom of bij een overerfelijke epilepsiesyndroom.

• Epilepsie is “voorbij” (resolved) na het bereiken van een bepaalde leeftijd (bij leeftijdsgebonden epilepsiesyndromen) of na een aanvalsvrije periode van 10 jaar (5 jaar zonder AED medicatie).

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• De diagnose epilepsie – Is potentieel stigmatiserend

(vooral bij een “genetisch bepaalde” etiologie).

– Nog niet compleet aangaande de kans op recidiveren van aanvallen bij alle bekende oorzaken van epilepsie.

– Vereist multidisciplinaire expertise (schaars en soms duur).

Epilepsie anno 2017 – pros & cons • De diagnose epilepsie

– Is in toenemende mate praktijkgericht (en hopelijk breed gedragen).

– Baseert zich op meerdere diagnostische modaliteiten.

– Kan een diagnose-specifieke behandeling bevorderen.

– Houdt rekening met een voorbijgaande vorm van epilepsie.

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Documents

Kan de nieuwe classificatie de definitie van …Kan de nieuwe classificatie de definitie van epilepsie verbeteren? • Standpunten van de “Commission on Classification and Terminology