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The development, content and response process validation of a caregiver-reported severity measure for CDKL5 deficiency disorder

Ziniel, Sonja I; Mackie, Alexandra; Saldaris, Jacinta; Leonard, Helen; Jacoby, Peter; Marsh, Eric D; Suter, Bernhard; Pestana-Knight, Elia; Olson, Heather E; Price, Dana; Weisenberg, Judith; Rajaraman, Rajsekar; VanderVeen, Gina; Benke, Tim A; Downs, Jenny; Demarest, Scott
BACKGROUND:CDKL5 Deficiency Disorder (CDD) is a severe X-linked developmental and epileptic encephalopathy. Existing developmental outcome measures have floor effects and cannot capture incremental changes in symptoms. We modified the caregiver portion of a CDD clinical severity assessment (CCSA) and assessed content and response-process validity. METHODS:We conducted cognitive interviews with 15 parent caregivers of 1-39-year-old children with CDD. Caregivers discussed their understanding and concerns regarding appropriateness of both questions and answer options. Item wording and questionnaire structure were adjusted iteratively to ensure questions were understood as intended. RESULTS:The CCSA was refined during three rounds of cognitive interviews into two measures: (1) the CDD Developmental Questionnaire - Caregiver (CDQ-Caregiver) focused on developmental skills, and (2) the CDD Clinical Severity Assessment - Caregiver (CCSA-Caregiver) focused on symptom severity. Branching logic was used to ensure questions were age and skill appropriate. Initial pilot data (n = 11) suggested no floor effects. CONCLUSIONS:This study modified the caregiver portion of the initial CCSA and provided evidence for its content and response process validity.
PMID: 37751639
ISSN: 1872-6844
CID: 5609382

Prevalence and Risk Factors of Neurologic Manifestations in Hospitalized Children Diagnosed with Acute SARS-CoV-2 or MIS-C

Fink, Ericka L; Robertson, Courtney L; Wainwright, Mark S; Roa, Juan D; Lovett, Marlina E; Stulce, Casey; Yacoub, Mais; Potera, Renee M; Zivick, Elizabeth; Holloway, Adrian; Nagpal, Ashish; Wellnitz, Kari; Czech, Theresa; Even, Katelyn M; Brunow de Carvalho, Werther; Rodriguez, Isadora Souza; Schwartz, Stephanie P; Walker, Tracie C; Campos-Miño, Santiago; Dervan, Leslie A; Geneslaw, Andrew S; Sewell, Taylor B; Pryce, Patrice; Silver, Wendy G; Lin, Jieru Egeria; Vargas, Wendy S; Topjian, Alexis; Alcamo, Alicia M; McGuire, Jennifer L; Domínguez Rojas, Jesus Angel; Muñoz, Jaime Tasayco; Hong, Sue J; Muller, William J; Doerfler, Matthew; Williams, Cydni N; Drury, Kurt; Bhagat, Dhristie; Nelson, Aaron; Price, Dana; Dapul, Heda; Santos, Laura; Kahoud, Robert; Francoeur, Conall; Appavu, Brian; Guilliams, Kristin P; Agner, Shannon C; Walson, Karen H; Rasmussen, Lindsey; Janas, Anna; Ferrazzano, Peter; Farias-Moeller, Raquel; Snooks, Kellie C; Chang, Chung-Chou H; Yun, James; Schober, Michelle E
BACKGROUND:Our objective was to characterize the frequency, early impact, and risk factors for neurological manifestations in hospitalized children with acute severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or multisystem inflammatory syndrome in children (MIS-C). METHODS:Multicenter, cross-sectional study of neurological manifestations in children aged <18 years hospitalized with positive SARS-CoV-2 test or clinical diagnosis of a SARS-CoV-2-related condition between January 2020 and April 2021. Multivariable logistic regression to identify risk factors for neurological manifestations was performed. RESULTS:Of 1493 children, 1278 (86%) were diagnosed with acute SARS-CoV-2 and 215 (14%) with MIS-C. Overall, 44% of the cohort (40% acute SARS-CoV-2 and 66% MIS-C) had at least one neurological manifestation. The most common neurological findings in children with acute SARS-CoV-2 and MIS-C diagnosis were headache (16% and 47%) and acute encephalopathy (15% and 22%), both P < 0.05. Children with neurological manifestations were more likely to require intensive care unit (ICU) care (51% vs 22%), P < 0.001. In multivariable logistic regression, children with neurological manifestations were older (odds ratio [OR] 1.1 and 95% confidence interval [CI] 1.07 to 1.13) and more likely to have MIS-C versus acute SARS-CoV-2 (OR 2.16, 95% CI 1.45 to 3.24), pre-existing neurological and metabolic conditions (OR 3.48, 95% CI 2.37 to 5.15; and OR 1.65, 95% CI 1.04 to 2.66, respectively), and pharyngeal (OR 1.74, 95% CI 1.16 to 2.64) or abdominal pain (OR 1.43, 95% CI 1.03 to 2.00); all P < 0.05. CONCLUSIONS:In this multicenter study, 44% of children hospitalized with SARS-CoV-2-related conditions experienced neurological manifestations, which were associated with ICU admission and pre-existing neurological condition. Posthospital assessment for, and support of, functional impairment and neuroprotective strategies are vitally needed.
PMID: 35066369
ISSN: 1873-5150
CID: 5139372

Content Validation of Clinician-Reported Items for a Severity Measure for CDKL5 Deficiency Disorder

Saldaris, Jacinta; Weisenberg, Judith; Pestana-Knight, Elia; Marsh, Eric D; Suter, Bernhard; Rajaraman, Rajsekar; Heidary, Gena; Olson, Heather E; Devinsky, Orrin; Price, Dana; Jacoby, Peter; Leonard, Helen; Benke, Tim A; Demarest, Scott; Downs, Jenny
CDKL5 deficiency disorder (CDD) results in early-onset seizures and severe developmental impairments. A CDD clinical severity assessment (CCSA) was previously developed with clinician and parent-report items to capture information on a range of domains. Consistent with US Food and Drug Administration (FDA) guidelines, content validation is the first step in evaluating the psychometric properties of an outcome measure. The aim of this study was to validate the content of the clinician-reported items in the CCSA (CCSA-Clinician). Eight neurologists leading the USA CDD Center of Excellence clinics were interviewed using the "think aloud" technique to critique 26 clinician-reported items. Common themes were aggregated, and a literature search of related assessments informed item modifications. The clinicians then participated in 2 consensus meetings to review themes and finalize the items. A consensus was achieved for the content of the CCSA-Clinician. Eight of the original items were omitted, 11 items were added, and the remaining 18 items were revised. The final 29 items were classified into 2 domains: functioning and neurologic impairments. This study enabled refinement of the CCSA-Clinician and provided evidence for its content validity. This preliminary validation is essential before field testing and further validation, in order to advance the instrument toward clinical trial readiness.
PMID: 34378447
ISSN: 1708-8283
CID: 5006192

Effect of fenfluramine on convulsive seizures in CDKL5 deficiency disorder

Devinsky, Orrin; King, LaToya; Schwartz, Danielle; Conway, Erin; Price, Dana
CDKL5 deficiency disorder (CDD) is an X-linked pharmacoresistant neurogenetic disorder characterized by global developmental delays and uncontrolled seizures. Fenfluramine (FFA), an antiseizure medication (ASM) indicated for treating convulsive seizures in Dravet syndrome, was assessed in six patients (five female; 83%) with CDD whose seizures had failed 5-12 ASMs or therapies. Median age at enrollment was 6.5 years (range: 2-26 years). Mean FFA treatment duration was 5.3 months (range: 2-9 months) at 0.4 mg/kg/day (n = 2) or 0.7 mg/kg/day (n = 4; maximum: 26 mg/day). One patient had valproate added for myoclonic seizures. The ASM regimens of all other patients were stable. Among five patients with tonic-clonic seizures, FFA treatment resulted in a median 90% reduction in frequency (range: 86%-100%). Tonic seizure frequency was reduced by 50%-60% in two patients with this seizure type. One patient experienced fewer myoclonic seizures; one patient first developed myoclonic seizures on FFA, which were controlled with valproate. Adverse events were reported in two patients. The patient with added valproate experienced lethargy; one patient had decreased appetite and flatus. No patient developed valvular heart disease or pulmonary arterial hypertension. Our preliminary results suggest that FFA may be a promising ASM for CDD. Randomized clinical trials are warranted.
PMID: 33979451
ISSN: 1528-1167
CID: 4867492

Focal nonmotor versus motor seizures: The impact on diagnostic delay in focal epilepsy

Pellinen, Jacob; Tafuro, Erica; Yang, Annie; Price, Dana; Friedman, Daniel; Holmes, Manisha; Barnard, Sarah; Detyniecki, Kamil; Hegde, Manu; Hixson, John; Haut, Sheryl; Kälviäinen, Reetta; French, Jacqueline
OBJECTIVE:To test the hypothesis that people with focal epilepsy experience diagnostic delays that may be associated with preventable morbidity, particularly when seizures have only nonmotor symptoms, we compared time to diagnosis, injuries, and motor vehicle accidents (MVAs) in people with focal nonmotor versus focal seizures with motor involvement at epilepsy onset. METHODS:This retrospective study analyzed the enrollment data from the Human Epilepsy Project, which enrolled participants between 2012 and 2017 across 34 sites in the USA, Canada, Europe, and Australia, within 4 months of treatment for focal epilepsy. A total of 447 participants were grouped by initial seizure semiology (focal nonmotor or focal with motor involvement) to compare time to diagnosis and prediagnostic injuries including MVAs. RESULTS:Demographic characteristics were similar between groups. There were 246 participants (55%) with nonmotor seizures and 201 participants (45%) with motor seizures at epilepsy onset. Median time to diagnosis from first seizure was 10 times longer in patients with nonmotor seizures compared to motor seizures at onset (P < .001). The number and severity of injuries were similar between groups. However, 82.6% of MVAs occurred in patients with undiagnosed nonmotor seizures. SIGNIFICANCE/CONCLUSIONS:This study identifies reasons for delayed diagnosis and consequences of delay in patients with new onset focal epilepsy, highlighting a treatment gap that is particularly significant in patients who experience nonmotor seizures at epilepsy onset.
PMID: 33078409
ISSN: 1528-1167
CID: 4647112

Basics of modern epilepsy classification and terminology

Varnado, Shelley; Price, Dana
BACKGROUND:The terminology and classification of seizures and epilepsy has undergone multiple revisions in the last several decades, which can lead to confusion and miscommunication amongst physicians and researchers. In 2017, the International League Against Epilepsy (ILAE) revised the classification of both seizures and epilepsy types in an effort to use less ambiguous terminology. Over time, definitions for status epilepticus, febrile seizures, and neonatal seizures have also evolved, as has the delineation of various epilepsy syndromes by age. METHODS:Review of the literature for old and new terminology and various epilepsy syndromes was accomplished using the PubMed database system. RESULTS:In the following article, we review old terminology for classifying seizures and epilepsy as compared to the new (2017) ILAE guidelines. We discuss neonatal seizures, status epilepticus, febrile seizures, autoimmune epilepsy and various epilepsy syndromes by age of onset. CONCLUSION/CONCLUSIONS:Adopting a classification system that uses plain language allows for more effective and efficient communication between individuals and across specialties. Definitions of various syndromes and seizure types have evolved over time and are reviewed.
PMID: 33153903
ISSN: 1538-3199
CID: 4668712

Recognition and Treatment of New Onset Focal Seizures in Emergency Departments [Meeting Abstract]

Pellinen, Jacob; Tafuro, Erica; Yang, Annie; Price, Dana; French, Jacqueline
ISSN: 0028-3878
CID: 4561082