Diagnostic challenges and evolving criteria

In our cohort, diagnostic uncertainty emerged as a prominent concern: 46% of respondents perceived LGS as both over- and underdiagnosed, and only 5% expressed confidence that most patients are accurately identified. This apparent paradox underscores the intrinsic complexity of the syndrome, characterized by heterogeneous clinical presentations, evolving seizure semiology over time, and diverse etiologies, all of which contribute to diagnostic ambiguity. ^{Reference Wolf, Boyce and Pena9}

Recent refinements to diagnostic criteria further underscore these challenges. The 2022 ILAE classification mandates the presence of tonic seizures in addition to multiple drug-resistant seizure types and requires characteristic EEG features (slow spike-wave or paroxysmal fast activity) prior to 18 years of age. ^{Reference Specchio, Wirrell and Scheffer3} Encouragingly, most respondents were familiar with the updated criteria and considered clinical assessment combined with EEG findings necessary for diagnosis. Moreover, 72% reported often or sometimes re-evaluating LGS diagnoses in patients with DRE, suggesting that evolving guidelines may have prompted greater diagnostic scrutiny. However, re-examining the diagnosis may also be impacted by access to therapies or trials that are specifically approved for LGS. For example, a United States study reported a temporary increase in newly diagnosed LGS cases coinciding with the U.S. Food and Drug Administration (FDA) approval of Epidiolex. ^{Reference Marcinski Nascimento, Li and Lin10}

Diagnosis of LGS in adulthood was identified as particularly challenging, with 46% reporting greater difficulty compared to pediatric diagnosis. Hallmark pediatric features, multiple seizure types and 1.5–2.5 Hz slow spike-wave discharges, often attenuate or transform over time. ^{Reference Oguni, Hayashi and Osawa11–Reference Yagi14} The transition from pediatric to adult care may also result in incomplete transfer of critical historical data, including early EEG findings and developmental history. ^{Reference Kerr, Kluger and Philip15} Reduced tolerance for EEG testing in adulthood can further limit diagnostic confirmation. ^{Reference Arzimanoglou, French and Blume16} Additionally, comorbidities that emerge or intensify in adolescence and adulthood, such as behavioral disturbances, cognitive impairment, and sleep disorders, may obscure the underlying epilepsy syndrome. ^{Reference Kerr, Kluger and Philip15–Reference Pina-Garza, Boyce and Tworek17}

Most clinicians also reported that an LGS diagnosis influences treatment selection in refractory epilepsy of known etiology, with 51% describing a moderate impact and 36% a significant impact. These findings suggest that syndrome-based diagnosis retains clinical relevance beyond etiologic classification alone. In the absence of accurate syndrome recognition among adults with DRE, implementation of LGS-specific therapeutic strategies may be delayed, with potential implications for long-term outcomes. ^{Reference Montouris, Aboumatar and Burdette18,Reference Resnick and Sheth19}

Etiologic investigation and genetic testing

The etiologic heterogeneity of LGS further complicates diagnosis. An underlying cause is identified in approximately 75% of cases and may be structural, genetic, metabolic, or combined (e.g., coexisting genetic and structural abnormalities). ^{Reference Asadi-Pooya20} Determining etiology is often critical to selecting optimal therapy and in the realm of precision medicine. As genetic testing technologies advance and clinician expertise in variant interpretation improves, the proportion of cases without a defined cause continues to decline. Recent developments in genomic testing have substantially expanded understanding of LGS biology. Consistent with other DEEs, LGS demonstrates both genetic heterogeneity (multiple genes producing a similar phenotype) and allelic heterogeneity (different variants within a single gene resulting in distinct phenotypes).

In our cohort, approximately 70% of respondents routinely pursued genetic testing when etiology was unknown, and only 4% cited access limitations, indicating broad availability across practice settings. Pediatric neurologists were significantly more likely than adult neurologists to consistently pursue genetic testing in cases of unknown etiology, likely reflecting differences in training, practice patterns, and access to genetic services between pediatric and adult care environments. The high rates of genetic testing in this cohort are significant, because the identification of a genetic etiology may inform prognosis, recurrence risk counseling, and, increasingly, precision treatment strategies.

Pharmacological management: Gaps between evidence and practice

Novel agents and barriers to access

The therapeutic landscape for LGS has broadened with agents targeting novel mechanisms, yet uptake remains variable. Cannabidiol demonstrated efficacy in two placebo-controlled RCTs in LGS. ^{Reference Devinsky, Patel and Cross26,Reference Thiele, Marsh and French27} Following Canadian approval in November 2023, clinicians were divided on timing: 43% favored earlier use (after fewer than five prior ASMs), whereas 42% preferred later introduction. Reported barriers included limited experience (14%), accessibility (10%), and cost (7%).

Fenfluramine showed efficacy for LGS in a Phase 3 placebo-controlled RCT ^{Reference Knupp, Scheffer and Ceulemans28,} and 45% of respondents supported Canadian approval to expand treatment options, although it is not currently available for LGS in Canada. However, concerns regarding cost (16%) and cardiac monitoring requirements (11%) tempered enthusiasm. Real-world data for cenobamate in LGS have recently emerged, ^{Reference Aguilar-Amat Prior, Alonso Singer and Oliva Navarro29,Reference Samanta30} with off-label use reported by 53% of respondents, informed by data suggesting responder rates of approximately 50%. ^{Reference Aguilar-Amat Prior, Alonso Singer and Oliva Navarro29} Cost remained a constraint (34%). However, additional larger studies are needed to confirm the effectiveness of cenobamate in LGS and to guide management. Adult neurologists were significantly more likely than pediatric neurologists to prescribe cenobamate for LGS, reflecting greater adoption of this therapy in adult practice. In contrast, pediatric neurologists were significantly more likely to identify limited accessibility as a barrier to its use, highlighting challenges in access to cenobamate within pediatric care settings.

Together, these findings highlight the interplay between emerging evidence, regulatory status, and practical barriers, particularly cost and access, in shaping prescribing decisions. Despite therapeutic expansion, 66% of respondents considered current treatment options inadequate. The lack of comprehensive, evidence-integrated treatment algorithms incorporating trial data, real-world outcomes, comorbidities, drug interactions, and patient preferences leaves clinicians without clear comparative guidance.

Although several novel agents are in development, ^{Reference Hahn, Jiang and Villanueva31,Reference Dell’isola, Verrotti and Sciaccaluga32} half of respondents (50%) were uncertain whether ongoing trials will meaningfully alter the long-term trajectory of LGS, reflecting cautious optimism shaped by decades of incremental progress.

Balancing efficacy and tolerability

Therapeutic goals in LGS are increasingly expanding beyond seizure reduction to encompass cognition, behavior, and quality of life. Furthermore, beyond seizure pathogenesis, ASMs are associated with systemic and central nervous system adverse effects, including psychiatric, cognitive, and sleep disturbances. ^{Reference Strzelczyk and Schubert-Bast33} Accordingly, when prescribing ASMs, clinicians prioritized minimizing treatment-related functional impairment, particularly psychiatric or behavioral adverse effects (76%) and sedation (59%).

Epilepsy comorbidities remain difficult to measure systematically and are incompletely evaluated in ASM trials. Cannabidiol has been associated with caregiver-reported gains in alertness, executive function, and quality of life, although other studies show no significant quality-of-life change. ^{Reference Lamonarca, Mintz and Bayarres34–Reference Rosenberg, Louik and Conway36} Fenfluramine may improve executive function at higher doses but requires vigilance for serotonin-related adverse effects. ^{Reference Lamirault and Simon37,Reference Hagena and Manahan-Vaughan38} Together, these data highlight the need for standardized assessment of cognitive, behavioral, and quality-of-life outcomes to better inform individualized treatment decisions.

Sex-specific considerations

Most respondents (65%) reported sex-specific differences in LGS management, with 11% describing substantial differences. Although valproic acid is commonly recommended as first-line therapy, its use in women of childbearing potential requires careful, individualized risk–benefit assessment due to its well-established teratogenic risk. ^{Reference Pack, Oskoui and Williams Roberson39} While many females with LGS may be unlikely to pursue pregnancy given the severity of disease, management decisions must still account for reproductive potential, hormonal considerations, and adverse effects such as valproate-associated polycystic ovary syndrome. ^{Reference Duncan40}

Non-pharmacological interventions

Ketogenic diet

The ketogenic diet has been shown to reduce seizure frequency and is generally well tolerated in individuals with LGS, although sustained seizure freedom remains uncommon. ^{Reference Lemmon, Terao and Ng49,Reference Skrobas, Duda and Brylinski50} In our cohort, perceptions of its role reflected a balance between recognized clinical benefit and practical implementation challenges. Many clinicians acknowledged that the ketogenic diet can meaningfully improve outcomes in selected patients; however, concerns regarding accessibility, institutional support, and long-term feasibility appeared to limit broader adoption. Pediatric neurologists were more likely to report that the diet could significantly benefit patients and was feasible to offer in practice (36% vs. 16%), whereas adult neurologists more frequently acknowledged potential benefit while citing limitations related to accessibility and feasibility (35% vs. 14%). Collectively, these findings suggest that despite supportive evidence, logistical and structural barriers continue to impede the integration of dietary therapy into routine LGS management, particularly within adult practice settings.

Comorbidity management: recognition without resources

LGS imposes a substantial burden beyond seizures alone. Patients frequently experience cognitive impairment, physical disability, behavioral disturbances (e.g., hyperactivity, aggression, autistic traits), and sleep disorders, all of which significantly affect quality of life. ^{Reference Kerr, Kluger and Philip15,Reference Cross, Auvin and Falip41,Reference van Rijckevorsel51} Neurodevelopmental impairment reflects a complex interaction between underlying etiology, recurrent seizures, and ASM-related adverse effects, with downstream consequences for cognition, communication, attention, behavior, and sleep. ^{Reference Cross, Auvin and Falip41} In our survey, management of comorbidities was identified as one of the three most challenging aspects of LGS care (37%), underscoring its central role in long-term management.

Although clinicians widely acknowledge the importance of screening for “non-seizure” symptoms, implementation remains inconsistent. Approximately half reported screening for behavioral and psychiatric symptoms at every visit, and fewer did so routinely for sleep disorders. Adult neurologists reported more frequent routine screening for behavioral and psychiatric comorbidities than pediatric neurologists, suggesting differences in screening practices across care settings. The reasons for this finding are unclear and were not directly explored in the survey. However, pediatric neurologists were more likely to report that the utility of screening is limited by challenges in effectively managing identified symptoms. This finding may indicate that barriers to accessing appropriate behavioral health resources influence screening practices and perceptions of the value of routine screening. Future studies are needed to better understand the factors that shape screening behaviors and the availability of supports for managing behavioral and psychiatric comorbidities in individuals with LGS. Time constraints emerged as the predominant barrier, followed by limited resources to address identified concerns. Additional challenges included uncertainty regarding optimal screening approaches, limited availability of validated tools, particularly for sleep, and difficulty managing comorbidities once detected. Only a small minority reported no barriers, indicating that these obstacles are systemic rather than site-specific.

Validated instruments for behavioral assessment, ^{Reference Schader, Schmidlechner and Cornell52,Reference von Wrede, Witt and Jessen53} as well as sleep measures, ^{Reference Arvin, Taebi and Khazaeipour54} are available but not uniformly integrated into practice. Comorbidities profoundly influence patient and family well-being and should inform ASM selection to avoid exacerbating cognitive or behavioral symptoms. The pervasive structural barriers identified highlight the need for streamlined screening tools and improved access to multidisciplinary resources to optimize comprehensive LGS care.

Transition: A critical gap in continuity

Access to structured transition programs was highly variable: only 23% of respondents reported formal epilepsy transition processes, 29% identified no adequate pathway, and 38% described inconsistent quality depending on geography. These findings point to significant regional disparities during a critical phase of LGS care.

As LGS typically persists into adulthood, effective transition planning is essential. This period is particularly vulnerable for individuals with intellectual disability and behavioral comorbidities, who may experience heightened anxiety when leaving established pediatric providers, potentially destabilizing behavior and disrupting continuity of care. ^{Reference Nabbout and Camfield55,Reference Goselink, Eklund and Olsson56} System-level factors further complicate transition: overstretched pediatric services may transfer adolescents prematurely, while adult systems are often less equipped to manage complex neurodevelopmental disorders and operate under different care models. ^{Reference Nabbout and Camfield55,Reference Borlot, Tellez-Zenteno and Allen57} This structural mismatch creates a gap at a developmentally sensitive time marked by evolving autonomy and legal responsibilities. ^{Reference Borlot, Tellez-Zenteno and Allen57}

The limited availability of formalized transition programs represents a clear and modifiable gap in care. Structured, collaborative pediatric–adult transition pathways could enhance continuity, reduce distress, and support sustained, syndrome-specific management into adulthood.

Counseling, prognosis, and natural history

Reported mortality rates range from 3% (median follow-up period: 8.5 years) to 7% (median follow-up period: 9.7 years), most commonly due to seizure-related accidents, ^{Reference Glauser58} and may be as high as 25% (median follow-up period: 20 years) in patients with severe underlying neurological conditions. ^{Reference Camfield and Camfield59} Notably, a recent German 10-year insurance database study reported a mortality rate of 2.88% among patients meeting strict LGS criteria. ^{Reference Strzelczyk, Schubert-Bast and Simon60} This apparent decline may reflect improvements in diagnostic accuracy and the availability of broader therapeutic options that enhance seizure control and reduce the risk of injury.

In our cohort, most clinicians proactively addressed SUDEP: 50% introduced it after establishing rapport, 40% during the initial consultation, and only 1% never discussed it. This reflects growing recognition of the importance of transparent communication about mortality risks, enabling families to make informed decisions regarding treatment and seizure management. ^{Reference Whitney, Jones and Sharma61}

Natural history studies showing that while electroclinical features evolve over time, LGS generally carries poor long-term outcomes, with only occasional cases achieving complete seizure freedom. ^{Reference Hancock and Cross62} However, respondents expressed uncertainty about LGS remission: 49% were unsure, 14% believed remission never occurs, and 40% considered rare remission possible before age 50.