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Multicenter Study
. 2025 Jun;66(6):1975-1987.
doi: 10.1111/epi.18329. Epub 2025 Mar 4.

Dravet syndrome: From neurodevelopmental to neurodegenerative disease?

Arunan Selvarajah  1 , Andrea Sabo  2 , Carolina Gorodetsky  3 , Paula T Marques  1 , Ilakkiah Chandran  1   4 , Miles Thompson  1 , Quratulain Zulfiqar Ali  4 , Mary Pat McAndrews  5 , Maria Carmela Tartaglia  6 , Victor S T Lira  7 , Linda Huh  8 , Mary Connolly  8 , Arezoo Rezazadeh  9 , Farah Qaiser  4 , Tadeu A Fantaneanu  9 , Monica Duong  1 , Karen Barboza  7 , Lysa Boissé Lomax  10 , Luciana Inuzuka Nakaharada  11 , Kette Valente  12 , Jack Arbinuch  13 , Mariana Espindola  14 , Eliana Garzon  15 , Gianluca Sorrento  16 , Mary Anne Meskis  17 , Nicole Villas  17 , Veronica Hood  17 , Marta Gonzalez  18 , Elena Cardenal-Muñoz  18 , Jose Angel Aiba  18 , Lauraine McKenna  18 , Christine Linehan  19 , Sophine Hohn  20 , Stéphane Auvin  21 , Orrin Devinsky  22 , Ryan Yuen  23 , Anne T Berg  24   25 , Babak Taati  2 , Alfonso Fasano  26 , Danielle M Andrade  1   4   27
Affiliations
Multicenter Study

Dravet syndrome: From neurodevelopmental to neurodegenerative disease?

Arunan Selvarajah et al. Epilepsia. 2025 Jun.

Abstract

Objective: Dravet syndrome (DS) is a severe developmental and epileptic encephalopathy caused by SCN1A haploinsufficiency in the majority of cases. Caregivers of adults with DS often complain about the loss of previously acquired skills. We set out to explore these perceptions and determine whether abnormalities reported were detectable in validated tests. We also investigated possible correlations between symptoms, age, and exposure to sodium channel blockers (SCBs).

Methods: This cross-sectional, multicenter study used the Vineland Adaptive Behavior Scales, 3rd edition (raw scores) for behavior analyses and Moss-Psychiatric Assessment Schedules checklist to screen for psychiatric symptoms. The Social Communication Questionnaire screened for social communication deficits. Parkinsonian features were evaluated with the modified Unified Parkinson's Disease Rating Scale. For gait evaluation, we validated the use of home videos, using instrumental gait analysis in a subgroup of patients, and then used the home videos for the remainder.

Results: A total of 92 patients were enrolled (age range = 18-51 years, mean = 27.93 ± 8.59 years). Sixty percent of caregivers observed a decline in previously acquired skills, including intelligence, speech, interaction with others, ability to climb stairs and walk without support, and hand coordination. Adaptive skills, parkinsonian symptoms, and gait were worse in older patients and those exposed to SCBs for longer periods of time. Fourteen percent of patients screened positive for affective disorders, 11.6% for dementia, and 10.5% for a psychotic disorder. Fifty-three percent screened positive for social communication deficits.

Significance: This is the largest group of adults with DS to be systematically evaluated. They had severe nonseizure symptoms. Older age and longer use of SCBs were associated with worse adaptive skills, gait, and parkinsonism. Some older adults screened positive for depression and dementia. Caregivers identified functional decline in activities of daily living (ADLs). Taken together, the risk of dementia, parkinsonian gait, and decline in ability to perform previously mastered ADLs support that some adults with DS may be developing a neurodegenerative disorder.

Keywords: SCN1A; Accelerated ageing; Dravet syndrome; Neurodegeneration; Sodium channel blockers; adult; dementia; natural history; parkinsonism.

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Conflict of interest statement

D.M.A. has received grant support from the Dravet Syndrome Foundation; has received trial support from Epygenix and Zogenix (UCB); has done consultancy for Eisai, Encoded, Biocodex, and Jazz; and serves on the medical advisory board for the Dravet Syndrome Foundation. O.D. has equity in and/or has received compensation from the following companies: Tilray, Tevard Biosciences, Regel Biosciences, Script Biosciences, Actio Biosciences, Empatica, Ajna Biosciences, Blackrock Neurotech, Emotiv, and Praxis Precision Therapeutics. He has received consulting fees or equity options from UCB Pharma, Ultragenyx, LIN, UCB, Praxis, and Abbott. J.A.A. is the President of the Dravet Syndrome Foundation Spain (DSF), and he and/or DSF have received grants and/or financial support from Jazz Pharma, UCB, Ovid Therapeutics, Encoded, Stoke, Takeda, Biocodex, Praxis, and StrideBio to help carry out some of DSF's founding activities or to provide consulting services. J.A.A.'s honoraria have always been donated directly or indirectly to the DSF. K.V. serves on the board of the São Paulo Research Foundation and receives support from Biocodex, Takeda, UCB, Praxis, Abbott, Prati‐Donaduzzi, ACHE, and Eurofarma. The remaining authors have no conflicts of interest. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

Figures

FIGURE 1
FIGURE 1
A decreasing trend of worsening adaptive skills across all Vineland Adaptive Behavior Scales, 3rd edition (VABS‐III) subdomains.14 This figure demonstrates the worsening of adaptive skills across the subdomains assessed using the VABS‐III as it relates to older age.
FIGURE 2
FIGURE 2
Validation of vision‐based gait assessments using home‐recorded videos. We display the Openpose, Detectron, and Alphapose pose tracking software comparisons between manual annotation and Density‐Based Spatial Clustering of Applications with Noise (DBSCAN) automatic annotation for (A) cadence and (B) number of steps for 13 participants.
See this image and copyright information in PMC

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