Original Article Citation: Global modified Delphi consensus on diagnosis, phenotypes, and treatment of SCN8A-related epilepsy and/or neurodevelopmental disorders
G. Conecker, M. Y. Xia, J. Hecker, C. Achkar, C. Cukiert, S. Devries, et al. Epilepsia 2024 Vol. 65 Issue 8 Pages 2322-2338 Global modified-Delphi consensus on comorbidities and prognosis of SCN8A-related epilepsy and/or neurodevelopmental disorders G. Conecker, M. Y. Xia, J. Hecker, C. Achkar, C. Cukiert, S. Devries, et al. Epilepsia 2024 Vol. 65 Issue 8 Pages 2308-2321
Original Article Abstract: OBJECTIVE: We aimed to develop consensus for diagnosis/management of SCN8A-related disorders. Utilizing a modified Delphi process, a global cohort of experienced clinicians and caregivers provided input on diagnosis, phenotypes, treatment, and management of SCN8A-related disorders. METHODS: A Core Panel (13 clinicians, one researcher, six caregivers), divided into three subgroups (diagnosis/phenotypes, treatment, comorbidities/prognosis), performed a literature review and developed questions for the modified Delphi process. Twenty-eight expert clinicians, one researcher, and 13 caregivers from 16 countries participated in the subsequent three survey rounds. We defined consensus as follows: strong consensus, ≥80% fully agree; moderate consensus, ≥80% fully/partially agree, <10% disagree; and modest consensus, 67%-79% fully/partially agree, <10% disagree. RESULTS: Early diagnosis is important for long-term clinical outcomes in SCN8A-related disorders. There are five phenotypes: three with early seizure onset (severe developmental and epileptic encephalopathy [DEE], mild/moderate DEE, self-limited (familial) infantile epilepsy [SeL(F)IE]) and two with later/no seizure onset (neurodevelopmental delay with generalized epilepsy [NDDwGE], NDD without epilepsy [NDDwoE]). Caregivers represented six patients with severe DEE, five mild/moderate DEE, one NDDwGE, and one NDDwoE. Phenotypes vary by age at seizures/developmental delay onset, seizure type, electroencephalographic/magnetic resonance imaging findings, and first-line treatment. Gain of function (GOF) versus loss of function (LOF) is valuable for informing treatment. Sodium channel blockers are optimal first-line treatment for GOF, severe DEE, mild/moderate DEE, and SeL(F)IE; levetiracetam is relatively contraindicated in GOF patients. First-line treatment for NDDwGE is valproate, ethosuximide, or lamotrigine; sodium channel blockers are relatively contraindicated in LOF patients. SIGNIFICANCE: This is the first-ever global consensus for the diagnosis and treatment of SCN8A-related disorders. This consensus will reduce knowledge gaps in disease recognition and inform preferred treatment across this heterogeneous disorder. Consensus of this type allows more clinicians to provide evidence-based care and empowers SCN8A families to advocate for their children. OBJECTIVES: We aimed to develop consensus on comorbidities (frequency, severity, and prognosis) and overall outcomes in epilepsy, development, and cognition for the five phenotypes of SCN8A-related disorders. METHODS: A core panel consisting of 13 clinicians, 1 researcher, and 6 caregivers was formed and split into three workgroups. One group focused on comorbidities and prognosis. All groups performed a literature review and developed questions for use in a modified-Delphi process. Twenty-eight clinicians, one researcher, and 13 caregivers from 16 countries participated in three rounds of the modified-Delphi process. Consensus was defined as follows: strong consensus ≥80% fully agree; moderate consensus ≥80% fully or partially agree, <10% disagree; and modest consensus 67%-79% fully or partially agree, <10% disagree. RESULTS: Consensus was reached on the presence of 14 comorbidities in patients with Severe Developmental and Epileptic Encephalopathy (Severe DEE) spanning non-seizure neurological disorders and other organ systems; impacts were mostly severe and unlikely to improve or resolve. Across Mild/Moderate Developmental and Epileptic Encephalopathy (Mild/Moderate DEE), Neurodevelopmental Delay with Generalized Epilepsy (NDDwGE), and NDD without Epilepsy (NDDwoE) phenotypes, cognitive and sleep-related comorbidities as well as fine and gross motor delays may be present but are less severe and more likely to improve compared to Severe DEE. There was no consensus on comorbidities in the SeL(F)IE phenotype but strong consensus that seizures would largely resolve. Seizure freedom is rare in patients with Severe DEE but may occur in some with Mild/Moderate DEE and NDDwGE. SIGNIFICANCE: Significant comorbidities are present in most phenotypes of SCN8A-related disorders but are most severe and pervasive in the Severe DEE phenotype. We hope that this work will improve recognition, early intervention, and long-term management for patients with these comorbidities and provide the basis for future evidence-based studies on optimal treatments of SCN8A-related disorders. Identifying the prognosis of patients with SCN8A-related disorders will also improve care and quality-of-life for patients and their caregivers.
Commentary
The past 15 years of progress in gene discovery have changed the practice of clinical epilepsy. New causative genes for various epilepsies, developmental and epileptic encephalopathies (DEE) and neurodevelopmental disorders (NDD) have been discovered. Most practicing clinicians, especially in a tertiary care center, have now seen patients with DEE caused by mutations in KCNT1, SCN2A, SCN8A, CDKL5, STXBP1, DNM, SLC6A1, and other genes.
I can relate to this change in a very personal way: over a decade ago, each index case in my practice with a new genetic diagnosis was accompanied with a small sense of relief and accomplishment that we had ended the diagnostic odyssey. However as new genetic diagnoses became more commonplace, the clinic visits became bittersweet and frustrating for the families and clinician (myself) alike because a mere label to the disease was only the first step we had taken; not much was known about the clinical phenotype, prognosis, disease-specific (and available) treatments of these rare conditions. As the clinician of record, I was left to do the best I could with limited published information. Suboptimal treatments were often discovered through trial and error and continue to be realized today after the incorrect antiseizure medications are prescribed and seizure control is poor/worsens in a rare disease.
Another notable change over the past several years is the increased availability of information to patients through social media, which in turn has bolstered the shared care model of practice where well-intentioned parents have started blog posts/advocacy groups and this partnership is mutually beneficial to the clinician due to access to databases through patient partnerships and to the parents due to the support and access to latest research/trials. Those of us involved in the care of sick patients with DEE have seen this in action with examples like SLC6A1 Connect, PCDH19 advocacy, and Dravet Foundation.
with the Above in Mind- What is Special About the Companion Articles on SCN8A- Chosen for this Commentary
Authorship
The first 3 authors of both these papers are nonclinician members of advocacy groups.1,2 A quick look at the author contributions of this work indicates that authors: Conecker, Xia, and Hecker were either equal or leading contributors to the conceptualization, funding acquisition, investigation, project administration, resource procurement, software related tasks, curation of data, original draft writing and editing, and methodology.
In the acceptance of this article, the editorial board of Epilepsia has validated the strength and value of these parent-clinician relationships in the medical community.
The Delphi Methodology
SCN8A is a rare condition with no established standards of care. SCN8A-related DEE was first described in 2012 in a single patient with severe DEE.
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Over the next 7 years less than 50 patients were described in the published literature.4,5 The most severely affected patients came to clinical attention earlier. Centers with the ability to perform high throughput analysis of the SCN8A gene were able to expand on the phenotype to identify mildly affected patients with SCN8A. While informing treating physicians about the broad phenotype and initial treatment signals, this initial work could hardly be considered robust evidence to guide long-term therapies. More than a decade later, although there is increased experience in this DEE worldwide with geographically dispersed areas of local expertise, we still do not have standard guidelines for clinicians to follow and for patients to refer to. National and International advocacy groups for SCN8A have been established and there is a push for treatment trials. Thus, a unified “expert consensus” became necessary to fully elucidate disease spectrum, identify gaps in knowledge and inform best practices.
Consensus methodologies are used in research to generate innovative ideas, solve existing problems and raise priorities. The Delphi Methodology generates an expert consensus providing class IV evidence in the absence of higher classes of evidence in rare DEE. While consensus could also be obtained through focus groups or other methods like the nominal group technique—both the above methods require a meeting in person and consensus is achieved at the end of the meeting. However, in person attendance can be a challenge and also risks the presence of a dominant voice that drowns out other opinions in the absence of strict facilitators.
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A Delphi study that is well-executed assures (a) an initial thorough literature search of the condition; (b) a balanced and optimal choice of “experts” to include various perspectives across geographic regions and levels of expertise (recruiting parents and clinicians in various stages of their career); (c) well-rounded questions that balance and respect autonomy; (d) a questionnaire/survey strategy that does not force a conclusion; and (e) accomplishes a sufficient number of rounds without attrition of experts over time.7–9
Latest Consensus Information About SCN8A Important for the Reader
Phenotypes including age of onset and common seizure types:
There are 5 different phenotypes of SCN8A. SCN8A manifests in infancy in the form of severe (ages 0-6 m) or moderate (ages 4-12 m) DEE and in the form of self-limited benign (familial) infantile epilepsy. However, it can manifest as NDD with generalized epilepsy (NDDwE) or without generalized epilepsy (NDDwoE) in toddlerhood (ages 24-48 m). The charts provided in the papers show that focal seizures are a common presenting feature of NDD with epilepsy related to SCN8A in toddlerhood. Most practitioners would want to investigate for a focal cortical dysplasia in the setting of focal seizures and NDD. It remains important for the clinician to continue to seek out genetic causes for any child under 3 years with epilepsy of unknown etiology.
Best and worst in the treatment for seizures:
In patients with gain of function (GOF) mutations (GOF are common in the severe DEE phenotype) carbamazepine and oxcarbazepine are preferred first-line treatment. In patients with the NDDwE phenotype, valproic acid, ethosuximide, and lamotrigine were considered first-line treatments. Supratherapeutic doses of sodium channel blockers should be considered if they are well tolerated. Patients with GOF mutations will do poorly with the use of levetiracetam. Considering that most patients who present to an emergency department with new onset seizures are likely to be sent home on levetiracetam—this information is important to disseminate.
Prognosis of epilepsy and role of surgery:
The early onset phenotypes are unlikely to attain seizure freedom. While there was strong consensus among caregivers that LOF patients were more likely to attain seizure freedom, there was only modest consensus among clinicians for the same. Keeping in mind the fact that LOF patients might present with focal seizures in toddlerhood (NDDwE) and keeping in mind the strong consensus among clinicians that there is not a role for resective surgery in SCN8A patients, best treatment for patients with medication-resistant NDDwE needs more research.
Partnership with caregivers and care coordination:
All SCN8A patients with seizures or at risk of seizures should have a seizure action plan. Clinicians should partner with caregivers and remain open and respectful to new research findings that sometimes only parents might be aware about and value caregiver preferences while balancing seizure control versus medication side effects.
Varying perceptions of goals between clinicians and caregivers:
This SCN8A Delphi project recruited parents as experts and this process highlighted some of the differences in clinician perception versus caregiver perception in goals of treatment and outcomes of importance to caregivers. Despite the strong clinician consensus of improbability of seizure freedom in the severe and moderate DEE group, and despite clinician agreement of ideally not wanting polypharmacy for their patients, most caregivers felt that their child was on too many medications. Additionally, while there was a strong feeling among clinicians that severe DEE patients might have emotional and behavioral challenges, parents did not perceive such challenges in their children.
Comorbidities and prognosis for improvement of comorbidities
: A total of 17 comorbidities were identified across the spectrum of SCN8A. It was recognized that there was limited exposure among clinicians to the full-lived experience of the patient. However, 7 comorbidities were identified as occurring uniformly across all SCN8A phenotypes. This insight once again underscores the importance of the lived experience of the patient and that in a DEE; success of treatment is not all about seizure control. There was a strong consensus from clinicians and caregivers alike that multidisciplinary care is needed, access to various resources including complex care and hospice care where applicable is important. Caregivers felt strongly that there is value of engagement in community and family advocacy groups to gain more insight into opportunities for research in its various forms (including surveys and brain donation).
Conclusion
This is an exciting time in the world of DEE. Parents are no longer passive participants in their children's healthcare planning. This degree of support and engagement will surely bolster the medical community to work with renewed determination to find best treatments while focusing on patient-related outcomes that are important for research.
