Natural History of Alternating Hemiplegia of Childhood: Vulnerabilities in Early Childhood and Predictive Factors for Long‐Term Outcomes

ABSTRACT Objective The natural history of the most common ATP1A3 ‐related disease, alternating hemiplegia of childhood (AHC), has not been determined. We investigated three hypotheses: (1) AHC worsens over time; (2) several novel factors correlate with long‐term outcomes; and (3) AHC manifests high mortality. Methods In a large cross‐sectional study with a nested period of prospective 1–3‐year follow‐up, 115 patients (0.3–46.0 years old, 9 centers/5 countries) were evaluated using across‐center‐standardized protocol and validated scales. Univariable and multivariable linear‐mixed‐effects models with random intercepts and random slopes for age, adjusted for confounding variables, allowed for the determination of the effect of age throughout the total age range of patients studied. Results Course: We identified a distinction between two periods, namely the period of early childhood (age 1–5 years) and the period of later childhood to mid‐adulthood. Intellectual and non‐paroxysmal disability indexes (IDS, NPDI) scores as well as the Vineland Adaptive Behavior Composite and its subscales worsened during early childhood, but not in the period after that. The extent of motor skills impairment did not differ with age in either period. Within the PDI (paroxysmal disability index) scores, dystonia severity scores did not differ with age in either period; however, plegia severity scores did improve with age after 5 years of age. Prognostic variables included the following: (1) Epilepsy was associated with worse NPDI, intellectual, and fine and gross motor skills. (2) Worse early life PDI and NPDI scores were significantly associated with worse respective scores at the latest follow‐up. (3) Worse early life NPDI scores were also associated with worse IDS and fine and gross motor scores at the latest follow‐up. (4) D801N mutation was associated with worse PDI. (4) E815K mutation was associated with worse IDS. Mortality was 1.12 deaths/100 patient‐years and 6.5 sudden unexpected death in epilepsy (SUDEP) deaths/1000 patient‐years. Interpretation AHC is a progressive disease, and early childhood is the vulnerable period. We identified several novel prognostic indicators and a mortality rate, which provide critical information not only regarding prognostication, counseling, and underlying pathophysiology but also for planning therapeutic studies.

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Journal
Annals of the Child Neurology Society
Published
2025-11-11
DOI
https://doi.org/10.1002/cns3.70037
Primary Topic
Cerebral Palsy and Movement Disorders
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article
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article

Natural History of Alternating Hemiplegia of Childhood: Vulnerabilities in Early Childhood and Predictive Factors for Long‐Term Outcomes

Judith Helen Cross, Shital Patel, Lyndsey Prange, Maria T. Papadopoulou et al.
Annals of the Child Neurology Society
Cerebral Palsy and Movement Disorders
article

Natural History of Alternating Hemiplegia of Childhood: Vulnerabilities in Early Childhood and Predictive Factors for Long‐Term Outcomes

Judith Helen Cross, Shital Patel, Lyndsey Prange, Maria T. Papadopoulou, M. Papathanasiou, Francesca Ragona, Elisa Tosi, Francesco Fortunato, Aikaterini Vezyroglou, Andrey Megvinov, Giacomo Garone, Claudio Zucca, Alexis A. Arzimanoglou, Mohamad A. Mikati, Carmen Fons, Sigurdur H. Johannesson, Eleni Panagiotakaki, Marion Comajuan, Joan Jasien, Jeffrey Narayan, Simona Balestrini, Jeffrey Wuchich, Hwanhee Hong, Rosaria Vavassori, Michela Stagnaro, Sanjay M. Sisodiya, Beiyu Liu, Julie Uchitel, Giosuè Lo Bosco, April Boggs, Elisa De Grandis, Jennifer Anticona
article en

Abstract

ABSTRACT Objective The natural history of the most common ATP1A3 ‐related disease, alternating hemiplegia of childhood (AHC), has not been determined. We investigated three hypotheses: (1) AHC worsens over time; (2) several novel factors correlate with long‐term outcomes; and (3) AHC manifests high mortality. Methods In a large cross‐sectional study with a nested period of prospective 1–3‐year follow‐up, 115 patients (0.3–46.0 years old, 9 centers/5 countries) were evaluated using across‐center‐standardized protocol and validated scales. Univariable and multivariable linear‐mixed‐effects models with random intercepts and random slopes for age, adjusted for confounding variables, allowed for the determination of the effect of age throughout the total age range of patients studied. Results Course: We identified a distinction between two periods, namely the period of early childhood (age 1–5 years) and the period of later childhood to mid‐adulthood. Intellectual and non‐paroxysmal disability indexes (IDS, NPDI) scores as well as the Vineland Adaptive Behavior Composite and its subscales worsened during early childhood, but not in the period after that. The extent of motor skills impairment did not differ with age in either period. Within the PDI (paroxysmal disability index) scores, dystonia severity scores did not differ with age in either period; however, plegia severity scores did improve with age after 5 years of age. Prognostic variables included the following: (1) Epilepsy was associated with worse NPDI, intellectual, and fine and gross motor skills. (2) Worse early life PDI and NPDI scores were significantly associated with worse respective scores at the latest follow‐up. (3) Worse early life NPDI scores were also associated with worse IDS and fine and gross motor scores at the latest follow‐up. (4) D801N mutation was associated with worse PDI. (4) E815K mutation was associated with worse IDS. Mortality was 1.12 deaths/100 patient‐years and 6.5 sudden unexpected death in epilepsy (SUDEP) deaths/1000 patient‐years. Interpretation AHC is a progressive disease, and early childhood is the vulnerable period. We identified several novel prognostic indicators and a mortality rate, which provide critical information not only regarding prognostication, counseling, and underlying pathophysiology but also for planning therapeutic studies.

Annals of the Child Neurology SocietyVol. 3(4)
Université Claude Bernard Lyon 1 (FR), Centre National de la Recherche Scientifique (FR), Hospital Sant Joan de Déu Barcelona (ES), Inserm (FR), Duke University (US), Great Ormond Street Hospital (GB), Istituto Giannina Gaslini (IT), Epilepsy Research UK (GB), Centre de Recherche en Neurosciences de Lyon (FR), Counseling Center (US), Hospices Civils de Lyon (FR), Meyer Children's Hospital (IT), Bambino Gesù Children's Hospital (IT), IRCCS Eugenio Medea (IT), Duke University Hospital (US), European Patent Organisation (DE), Icelandic Heart Association (IS), The Icelandic Physiotherapy Association (IS), Istituto Euro Mediterraneo di Scienza e Tecnologia (IT), Fondazione IRCCS Istituto Neurologico Carlo Besta (IT), ERN EpiCARE (FR), University of Florence (IT), University College London (GB), Epilepsy Society (GB), University of Genoa (IT), University of Palermo (IT), HCL Technologies (India) (IN)
Openalex Percentile: Top 60%
Cerebral Palsy and Movement Disorders
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