Analysis of electrocardiograms in individuals with CDKL5 deficiency disorder.

CDKL5 deficiency disorder (CDD) is an epileptic encephalopathy associated with medically refractory epilepsy. We sought to determine whether prolonged corrected QT interval (QTc) or other cardiac conduction abnormalities were seen in CDD in a clinical cohort. A cohort of individuals with CDD was evaluated in the Children's Hospital Colorado's International Foundation for CDKL5 Research designated Center of Excellence clinic with routine electrocardiograms obtained as part of routine clinical care. Retrospective review of electrocardiograms was completed. ECGs from 44 individuals (7 male, 37 female, age range 0-34.5 years) with pathogenic mutations and findings consistent with CDD were evaluated. Multiple ECGs were available from the 44 individuals obtained from 1996 to 2020. Prolonged QTc was found in two individuals (4.5%) and either resolved or was not confirmed on Holter monitor; no additional interventions were performed. A total of 11 individuals had echocardiograms for a variety of indications including unexplained tachycardia and ECG abnormalities; all were normal. Two individuals in the cohort died during the study with no abnormal findings on ECG. The incidence of prolonged QTc or other significant actionable cardiac abnormalities was rare in a cohort of individuals with CDD though was higher than the prevalence seen within the general population. Further studies in a larger, confirmatory cohort over a longer period are needed.

Infectious causes and outcomes in patients presenting with cerebral spinal fluid pleocytosis.

To evaluate the infectious etiologies, clinical features, and outcomes of patients with CNS infections at a tertiary care center. Patients that present with a pleocytosis in the cerebral spinal fluid (CSF), defined as a CSF WBC count > 5 cells/mm3, from July 2015 to June 2016 at a tertiary care hospital were analyzed for this report. Data from patients with confirmed (n = 43) and presumed (n = 51) CNS infections were analyzed. CNS infection was the leading known cause of CSF pleocytosis (n = 43, 18% of all patients with a pleocytosis in the CSF), and HSV-2 was identified as the leading causative pathogen (n = 10) followed by varicella zoster virus (n = 5). Fifty-three percent of patients with a pleocytosis in the CSF did not receive a diagnosis. In the patients that did not receive a diagnosis, CNS infection was presumed to be the cause in 51 patients (21% of patients with CSF pleocytosis). The mean time to diagnosis for patients with confirmed CNS infection was 16 days, but time to diagnosis was highly variable depending on the causative pathogen. There was a significant overlap in CSF parameters and peripheral white blood cell counts in patients diagnosed with a viral, bacterial, or fungal infection. Neuroimaging changes were present in only 44% of CNS infections. The overall mortality was 7% for CNS infections, and 17% of patients with a CNS infection had a severe neurologic deficit at presentation while only 3% had a severe deficit at the last neurologic assessment. This study provides new insights into the infectious causes of disease in a cohort of patients with pleocytosis in the CSF. The study provides new insights into the time to diagnosis and outcomes in patients that present with pleocytosis in the CSF.

Cerebral Visual Impairment in CDKL5 Deficiency Disorder Correlates With Developmental Achievement.

Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder is a rare neurodevelopmental disorder characterized by infantile-onset refractory epilepsy, profound developmental delays, and cerebral visual impairment. Although there is evidence that the presence of cerebral visual impairment in CDKL5 deficiency disorder is common, the potential impact of cerebral visual impairment severity on developmental attainment has not been explored directly. Focusing on a cohort of 46 children with CDKL5 deficiency disorder, examination features indicative of cerebral visual impairment were quantified and compared to developmental achievement. The derived cerebral visual impairment severity score was inversely correlated with developmental attainment, bolstering the supposition that cerebral visual impairment severity may provide a useful early biomarker of disease severity and prognosis. This study demonstrates the utility of a cerebral visual impairment score to better capture the range of cerebral visual impairment severity in the CDKL5 deficiency disorder population and further elucidates the interaction between cerebral visual impairment and developmental outcomes.

Current neurologic treatment and emerging therapies in CDKL5 deficiency disorder.

BACKGROUND: CDKL5 deficiency disorder (CDD) is associated with refractory infantile onset epilepsy, global developmental delay, and variable features that include sleep, behavioral disturbances, and movement disorders. Current treatment is primarily symptom-based and informed by experience in caring for this population. METHODS: We describe medication and non-medication approaches to treatment of epilepsy and additional key neurologic symptoms (sleep disturbances, behavioral issues, movement disorders, and swallowing dysfunction) in a cohort of 177 individuals meeting criteria for CDD, 154 evaluated at 4 CDKL5 Centers of Excellence in the USA and 40 identified through the NIH Natural History Study of Rett and Related Disorders. RESULTS: The four most frequently prescribed anti-seizure medications were broad spectrum, prescribed in over 50% of individuals. While the goal was not to ascertain efficacy, we obtained data from 86 individuals regarding response to treatment, with 2-week response achieved in 14-48% and sustained 3-month response in 5-36%, of those with known response. Additional treatments for seizures included cannabis derivatives, tried in over one-third of individuals, and clinical trial medications. In combination with pharmacological treatment, 50% of individuals were treated with ketogenic diet for attempted seizure control. Surgical approaches included vagus nerve stimulators, functional hemispherectomy, and corpus callosotomy, but numbers were too limited to assess response. Nearly one-third of individuals received pharmacologic treatment for sleep disturbances, 13% for behavioral dysregulation and movement disorders, and 43% had gastrostomy tubes. CONCLUSIONS: Treatment for neurologic features of CDD is currently symptom-based and empiric rather than CDD-specific, though clinical trials for CDD are emerging. Epilepsy in this population is highly refractory, and no specific anti-seizure medication was associated with improved seizure control. Ketogenic diet is commonly used in patients with CDD. While behavioral interventions are commonly instituted, information on the use of medications for sleep, behavioral management, and movement disorders is sparse and would benefit from further characterization and optimization of treatment approaches. The heterogeneity in treatment approaches highlights the need for systematic review and guidelines for CDD. Additional disease-specific and disease-modifying treatments are in development.

Defining diagnostic approaches and outcomes in patients with inflammatory CSF: A retrospective cohort study.

OBJECTIVE: Define the etiologies, clinical features, time to diagnosis, and outcomes of patients that present with cerebral spinal fluid (CSF) pleocytosis. PATIENTS AND METHODS: This is retrospective cohort study of patients with CSF pleocytosis, defined as WBC count >5 cells/mm3 in the CSF, from July 2015 to June 2016 at a large tertiary care hospital. The proportion of patients within specific diagnostic categories were analyzed for differences in diagnostic testing and outcomes. RESULTS: 53% of patients had CSF pleocytosis due to an unknown etiology. The leading known cause of neuroinflammation was CNS infection (n = 43/244, 18%), followed by malignancy (n = 28/244, 11%). Mean time to diagnosis was 125 days in patients with autoimmune neuroinflammation and was 16 days in patients with an infection or malignancy. CSF parameters and peripheral white blood cell counts did not distinguish between categories of disease. The presence of CSF oligoclonal bands or a positive biopsy result most commonly supported a diagnosis of an autoimmune disease or malignancy, respectively. Neuroimaging changes were present in only 44% of infections but were found in 80-90% of other categories of neuroinflammation. Patients presenting with a severe neurologic deficit had 22.29 higher odds of a severe deficit at the last neurologic assessment, and mortality was highest (29%) in patients with malignancy-associated neuroinflammation. CONCLUSIONS: This study to defines general diagnostic categories of neuroinflammatory disease in patients and provides new insight on the value of specific diagnostic testing, time to diagnosis, and outcomes in these patient populations.