White matter and cerebellar involvement in alternating hemiplegia of childhood

Abstract

Objective

To determine whether brain volumetric and white matter microstructural changes are present and correlate with neurological impairment in subjects with alternating hemiplegia of childhood (AHC).

Methods

In this prospective single-center study, 12 AHC subjects (mean age 22.9 years) and 24 controls were studied with 3DT1-weighted MR imaging and high angular resolution diffusion imaging at 3T. Data obtained with voxel-based morphometry and tract-based spatial statistics were correlated with motor impairment using the International Cooperative Ataxia Rating Scale (ICARS) and Movement and Disability sub-scales of Burke-Fahn-Marsden Dystonia Rating Scale (BFMMS and BFMDS).

Results

Compared to healthy controls, AHC subjects showed lower total brain volume (P < 0.001) and white matter volume (P = 0.002), with reduced clusters of white matter in frontal and parietal regions (P < 0.001). No significant regional differences were found in cortical or subcortical grey matter volumes. Lower cerebellar subvolumes correlated with worse ataxic symptoms and global motor impairment in AHC group (P < 0.001). Increased mean and radial diffusivity values were found in the corpus callosum, corticospinal tracts, superior and inferior longitudinal fasciculi, subcortical frontotemporal white matter, internal and external capsules, and optic radiations (P < 0.001). These diffusion scalar changes correlated with higher ICARS and BFMDS scores (P < 0.001).

Interpretation

AHC subjects showed prevalent white matter involvement, with reduced volume in several cerebral and cerebellar regions associated with widespread microstructural changes reflecting secondary myelin injury rather than axonal loss. Conversely, no specific pattern of grey matter atrophy emerged. Lower cerebellar volumes, correlating with severity of neurological manifestations, seems related to disrupted developmental rather than neurodegenerative processes.

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Abbreviations

AD:

Axial diffusivity

AHC:

Alternating hemiplegia of childhood

BFMDS:

Disability subscale of the Burke–Fahn–Marsden Dystonia Rating Scale

BFMMS:

Movement subscale of the Burke–Fahn–Marsden Dystonia Rating Scale

CSF:

Cerebrospinal fluid

DTI:

Diffusion tensor imaging

FA:

Fractional anisotropy

GLM:

General linear model

ICARS:

International Cooperative Ataxia Rating Scale

MD:

Mean diffusivity

MNI:

Montreal neurological institute

RD:

Radial diffusivity

TBSS:

Tract-based spatial statistics

VBM:

Voxel-based morphometry

WM:

White matter

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Acknowledgements

We are grateful to the members of the Italian AHC Family Association AISEA for participating in this study. This work was supported by funds from “Ricerca Corrente sui Disordini Neurologici e Muscolari (Linea 5)” of the Italian Ministry of Health. The IBAHC Consortium: Members of the IBAHC (Italian Biobank and Clinical Registry for Alternating Hemiplegia) Consortium and Working Group: 1. Maria Teresa Bassi, IRCCS Eugenio Medea, Bosisio Parini, Lecco, Italia; 2. Claudio Zucca, IRCCS Eugenio Medea, Bosisio Parini, Lecco, Italia; 3. Edvige Veneselli, IRCCS Istituto Giannina Gaslini, University of Genoa, Genova, Italia; 4. Filippo Franchini, AISEA (associazione italiana sindrome dell’emiplegia alternante) Onlus, Milano, Italia; 5. Maria Rosaria Vavassori, IAHCRC (International Consortium for the Research on Alternating Hemiplegia of Childhood) Consortium; 6. Melania Giannotta, IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italia; 7. Giuseppe Gobbi, IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italia; 8. Tiziana Granata, IRCCS Foundation Neurological Institute Carlo Besta, Milano, Italia; 9. Nardo Nardocci, IRCCS Foundation Neurological Institute Carlo Besta, Milano, Italia; 10. Francesca Ragona, IRCCS Foundation Neurological Institute Carlo Besta, Milano, Italia; 11. Fiorella Gurrieri, Servizio di Genetica Medica, Fondazione Policlinico Universitario IRCCS Agostino Gemelli, Istituto di Medicina Genomica Università Cattolica del S. Cuore, Rome, Italia; 12. Giovanni Neri, Servizio di Genetica Medica, Fondazione Policlinico Universitario IRCCS Agostino Gemelli, Istituto di Medicina Genomica Università Cattolica del S. Cuore, Rome, Italia; 13. Francesco Danilo Tiziano, Servizio di Genetica Medica, Fondazione Policlinico Universitario IRCCS Agostino Gemelli, Istituto di Medicina Genomica Università Cattolica del S. Cuore, Rome, Italia; 14. Federico Vigevano, Alessandro Capuano, Bambino Gesù Children's Hospital, IRCCS, Rome, Italia; 15. Stefano Sartori, Neurology and Neurophysiology Unit, Department of Women's and Children's Health, University Hospital of Padua, Padova, Italy

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Contributions

MS, LP, EDG, The IBAHC Consortium participants: conception and design of the study; MS, LP, EDG, DT, BT, GM, MS, RC, AZ, SK, CZ: acquisition and analysis of data; MS, LP, EDG, DT, BT, GM, MS, RC, AZ, SK, CZ, GM, AR: drafting a significant portion of the manuscript or figures.

Corresponding author

Correspondence to Elisa De Grandis.

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The authors report no financial disclosure/conflict of interest concerning the research related to the manuscript.

Ethical standards

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all individual participants involved in the study.

Additional information

Members of the IBAHC Consortium and Working Group are listed in the acknowledgement section.

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Severino, M., Pisciotta, L., Tortora, D. et al. White matter and cerebellar involvement in alternating hemiplegia of childhood. J Neurol 267, 1300–1311 (2020). https://doi.org/10.1007/s00415-020-09698-3

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Keywords

  • Alternating hemiplegia of childhood
  • Brain MRI
  • Voxel-based morphometry
  • Tract-based spatial statistics
  • White matter