. 2024 Oct;65(10):3064-3075.

doi: 10.1111/epi.18094. Epub 2024 Aug 27.

Psychometric evaluation of clinician- and caregiver-reported clinical severity assessments for individuals with CDKL5 deficiency disorder

Jacinta M Saldaris¹, Peter Jacoby¹, Jenny Downs^{1

2}, Eric D Marsh³, Helen Leonard¹, Elia Pestana-Knight⁴, Rajsekar Rajaraman⁵, Judith Weisenberg⁶, Bernhard Suter⁷, Heather E Olson⁸, Dana Price⁹, William Hong⁸, Erin Prange³, Tim A Benke¹⁰, Scott Demarest¹¹

Affiliations

¹ Telethon Kids Institute, Centre for Child Health Research, The University of Western Australia, Perth, Western Australia, Australia.
² Curtin School of Allied Health, Curtin University, Perth, Western Australia, Australia.
³ Departments of Neurology and Pediatrics, Division of Child Neurology and University of Pennsylvania Perelman School of Medicine, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
⁴ Cleveland Clinic, Neurological Institute, Cleveland, Ohio, USA.
⁵ UCLA Mattel Children's Hospital, Los Angeles, California, USA.
⁶ St. Louis Children's Hospital and Washington University School of Medicine, St. Louis, Missouri, USA.
⁷ Department of Pediatrics & Neurology, Baylor College of Medicine, Houston, Texas, USA.
⁸ Division of Epilepsy and Clinical Neurophysiology and Epilepsy Genetics Program, Department of Neurology, Boston Children's Hospital, Boston, Massachusetts, USA.
⁹ NYU Langone Health and Department of Neurology, New York University, New York City, New York, USA.
¹⁰ Departments of Pediatrics, Neurology and Pharmacology, University of Colorado School of Medicine and Children's Hospital Colorado, Aurora, Colorado, USA.
¹¹ Departments of Pediatrics and Neurology, Precision Medicine Institute, University of Colorado School of Medicine and Children's Hospital Colorado, Aurora, Colorado, USA.

PMID: 39190322
PMCID: PMC11495992
DOI: 10.1111/epi.18094

Psychometric evaluation of clinician- and caregiver-reported clinical severity assessments for individuals with CDKL5 deficiency disorder

Jacinta M Saldaris et al. Epilepsia. 2024 Oct.

. 2024 Oct;65(10):3064-3075.

doi: 10.1111/epi.18094. Epub 2024 Aug 27.

Authors

Affiliations

¹ Telethon Kids Institute, Centre for Child Health Research, The University of Western Australia, Perth, Western Australia, Australia.
² Curtin School of Allied Health, Curtin University, Perth, Western Australia, Australia.
³ Departments of Neurology and Pediatrics, Division of Child Neurology and University of Pennsylvania Perelman School of Medicine, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
⁴ Cleveland Clinic, Neurological Institute, Cleveland, Ohio, USA.
⁵ UCLA Mattel Children's Hospital, Los Angeles, California, USA.
⁶ St. Louis Children's Hospital and Washington University School of Medicine, St. Louis, Missouri, USA.
⁷ Department of Pediatrics & Neurology, Baylor College of Medicine, Houston, Texas, USA.
⁸ Division of Epilepsy and Clinical Neurophysiology and Epilepsy Genetics Program, Department of Neurology, Boston Children's Hospital, Boston, Massachusetts, USA.
⁹ NYU Langone Health and Department of Neurology, New York University, New York City, New York, USA.
¹⁰ Departments of Pediatrics, Neurology and Pharmacology, University of Colorado School of Medicine and Children's Hospital Colorado, Aurora, Colorado, USA.
¹¹ Departments of Pediatrics and Neurology, Precision Medicine Institute, University of Colorado School of Medicine and Children's Hospital Colorado, Aurora, Colorado, USA.

PMID: 39190322
PMCID: PMC11495992
DOI: 10.1111/epi.18094

Abstract

Objective: The CDKL5 Clinical Severity Assessment (CCSA) is a comprehensive, content-validated measurement tool capturing the diverse challenges of cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD), a genetically caused developmental epileptic encephalopathy (DEE). The CCSA is divided into clinician-reported (CCSA-Clinician) and caregiver-reported (CCSA-Caregiver) assessments. The aim of this study was to evaluate the factor structure of these measures through confirmatory factor analysis (CFA) and evaluate their validity and reliability.

Methods: Participants were recruited from the International CDKL5 Clinical Research Network to take part in an in-clinic CCSA-Clinician evaluation (n = 148) and/or complete the CCSA-Caregiver questionnaire (n = 198). CFA was used to determine domains, and factor loadings and validity were assessed. For the CCSA-Clinician, inter-rater reliability was assessed by nine CDD experienced clinicians via 14 pre-recorded evaluations. Eight clinicians re-viewed and re-scored the videos after 4 weeks to evaluate intra-rater reliability. The CCSA-Caregiver was completed on a second occasion by 34 caregivers after 2-4 weeks to assess test-retest reliability.

Results: CFA resulted in three domains for the CCSA-Clinician (motor and movement, communication, vision) and four domains for the CCSA-Caregiver (seizures, behavior, alertness, feeding), with good item loadings across both measures. Structural statistics, internal consistency, discriminant validity, and reliability were satisfactory for both measures, and scores were consistent between known groups.

Significance: This study provides strong evidence that the CCSA measures are suitable to assess the clinical severity of individuals with CDD, supporting their use in clinical trials. Further evaluation of responsiveness to change in a longitudinal assessment is planned. Use may also be appropriate in similar DEEs but would require validation in those populations.

Keywords: clinical outcome assessment; confirmatory factor analysis; developmental epileptic encephalopathy; reliability; validity.

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Conflict of interest statement

• JD: Consultancy for Marinus, Ultragenyx, Acadia, Avexis, Orion and Taysha; Clinical Trials with Anavex and Newron; All consultancies are unrelated to this work and all remuneration has been made to her department.

• HL: Consultancy for Marinus, Acadia, Avexis and Orion; Clinical Trials with Anavex and Newron; All remuneration has been made to her department.

• EM: The PI for Stoke therapeutics, Zogenix Pharmaceuticals, Acadia Pharmaceuticals, Marinus Pharmaceuticals, Takeda Pharmaceuticals, Epygenix Pharmaceuticals. He has received research support from NIH, Penn Orphan Disease center, International Rett syndrome foundation, International CDKL5 Research Foundation, Curaleaf Inc., is a consultant for Acadia Pharmaceuticals, and has prepared an educational program for Medscape.

• EPK: Speaker and scientific advisory board member for Marinus pharmaceutical for which she has received compensation.

• RR: Speaker/consultant for Marinus Pharmaceuticals. Consultant for UCB Pharmaceuticals. Received funding from the International Foundation for CDKL5 Research.

• BS: Received research funding from the International Foundation for CDKL5 Research, Loulou Foundation, the National Institutes of Health, International Rett Syndrome Foundation, the Rett Syndrome Research Trust, and the Grace Science Foundation; consultancy for the IONIS pharmaceuticals, Neurogene, and Taysha; clinical trials with Acadia Pharmaceuticals Inc., Marinus Pharmaceuticals, Neurogene, and the Rett Syndrome Research Trust. All remuneration has been paid to Baylor College of Medicine.

• HO: Dr. Olson received consulting fees from Takeda Pharmaceuticals and Zogenix regarding clinical trial design, Ovid Therapeutics regarding clinical trial results, Marinus Pharmaceuticals regarding CDKL5 Deficiency Disorder, and has done consulting for the FOXG1 Research Foundation. She is site-PI for a trial with UCB Pharmaceuticals.

• DP: Consultancy for OVID therapeutics. Clinical Trials with Stoke, UCB, and Zogenix. All consultancies are unrelated to this work.

• EP: Consultant for Acadia Pharmaceuticals for which she has received compensation.

• SD: Consultancy for Biomarin, Neurogene, Marinus, Tysha, Ultragenyx, Zogenix, Capsida, Encoded and Ovid Therapeutics. He has funding from the NIH, Project 8P and Mila’s Miracle Foundation. He also serves on advisory boards for the non-profit foundations Rare X, SLC6A1 Connect, Project 8P, Ring14 USA, FamilieSCN2A and N of 1 Collaborative.

• TB: Received research funding from GRIN2B Foundation, the International Foundation for CDKL5 Research, Loulou Foundation, the National Institutes of Health, and Simons Foundation; consultancy for Alcyone, AveXis, GRIN Therapeutics, GW Pharmaceuticals, the International Rett Syndrome Foundation, Marinus Pharmaceuticals, Neurogene, Ovid Therapeutics, and Takeda Pharmaceutical Company Limited; clinical trials with Acadia Pharmaceuticals Inc., GW Pharmaceuticals, Marinus Pharmaceuticals, Ovid Therapeutics, and Rett Syndrome Research Trust; all remuneration has been made to his department.

• JS, PJ, JW and WH have no conflicts of interest.

Figures

**Figure 1:**
**(A) CCSA-Clinician Domain and Total Scores:** Following CFA, 3 domains were identified as the best fit to the data from 148 participants. **(B) CCSA-Caregiver Domain and Total scores:** Following CFA, 4 domains were identified as the best fit to the data from 198 participants.

See this image and copyright information in PMC

References

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Psychometric evaluation of clinician- and caregiver-reported clinical severity assessments for individuals with CDKL5 deficiency disorder

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Psychometric evaluation of clinician- and caregiver-reported clinical severity assessments for individuals with CDKL5 deficiency disorder

Authors

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Abstract

Conflict of interest statement

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