Wen Wang, Lin Wan, Linyan Hu, Jian Chen, Yan Zhao, Zhichao Li, Guang Yang
Epileptic negative myoclonus (ENM) is defined as an interruption of tonic muscle activity, which is time-locked to an epileptic electroencephalogram (EEG) abnormality, without evidence of an antecedent positive myoclonia in the agonist–antagonist muscles.1, 2 CHD2-related epilepsy is characterized by notable photosensitivity and diverse seizure types,3-6 but ENM, a distinct seizure phenotype, has not been reported in this condition. We describe a child with CHD2-related epilepsy presenting with head-restricted ENM triggered by blink-induced epileptiform activity. A 6-year-11-month-old girl, firstborn to nonconsanguineous parents, presented with three sequential seizure phases: (1) at age 1 year, nocturnal focal impaired consciousness seizures—eye deviation, bilateral fist clenching, and 1-min duration—occurring every 2–8 months; (2) at 1 year 8 months, daily or near-daily generalized myoclonic-atonic, myoclonic, and atonic seizures featuring rapid bilateral upper-limb jerks followed by falls; and (3) at age 4, isolated eye blinking and head nodding, triggered by fatigue or awakening, occurring once daily to every few days—with all prior seizure types resolving. Brain magnetic resonance imaging (MRI) was normal. At 6 years 11 months, EEG showed a normal background rhythm; occipital-predominant interictal discharges; a grade III photoparoxysmal response to intermittent photic stimulation; fixation-off sensitivity-induced occipital epileptiform discharges; and bilateral occipital spike–wave discharges (SWDs) triggered by multiple eye blinks. Ictal EEG showed generalized 1.3–2.7 Hz spike-and-wave discharges with occipital predominance, triggered by blinking and correlating with ENM clinically manifesting as head drops (Video 1, Figure 1). Simultaneous EMG recordings demonstrated that eyelid EMG bursts (Figure 1B, a) preceded generalized SWD on EEG (Figure 1B, b), whereas ENM (head drop) exhibited precise temporal alignment with the slow-wave component of the spike wave complexes (Figure 1B, c). Whole-exome sequencing identified a de novo CHD2 nonsense variant (NM_001271.4:c.340C>T, p.Arg114*) classified as pathogenic per American College of Medical Genetics and Genomics (ACMG) guidelines. The child had normal intellectual and motor development before disease onset. After onset, neurodevelopmental regression occurred. At 6 years and 11 months of age, the child demonstrated severely limited expressive vocabulary, with no consistent use of two-word phrases or syntactically structured utterances. WPPSI-IV CN testing yielded an IQ of 60. Motor development and current motor skills are age-appropriate. Valproate was started for epilepsy but stopped after 2 weeks due to a rash. Subsequent treatments—levetiracetam, lamotrigine, topiramate, ketogenic diet, and perampanel—failed to achieve adequate seizure control. Following the recent recurrence of ENM, valproate was reinitiated at 200 mg twice daily, reducing ENM frequency to once weekly. Numerous studies have highlighted the prominent photosensitivity in CHD2-related epilepsy and its strong association with seizure types including eyelid myoclonia with or without absences, myoclonic-atonic, myoclonic, and atonic seizures.3-6 During seizures of eyelid myoclonia with or without absences, the eyelid EMG burst follows the spike component of SWDs, reflecting a myoclonic response directly triggered by epileptiform discharges. In this case, EEG–EMG polygraphic recording showed that the eyelid EMG burst preceded epileptiform discharges, indicating reflexive triggering by blinking. Subsequently, ENM—clinically manifesting as head drop—exhibited a precise temporal relationship with the slow-wave component of the spike–wave complexes. The ENM exhibits a fundamentally distinct causal relationship between epileptiform discharges and clinical manifestations compared to eyelid myoclonia with or without absences. EEG-fMRI studies in photosensitive epilepsy show reduced inhibitory control over alpha rhythm–generating networks in the occipital, sensorimotor, anterior cingulate, and supplementary motor cortices. Moreover, occipital, parietal, and frontal lobes show abnormally enhanced functional connectivity.7 This abnormal network allows blink-induced visual transients to trigger epileptiform discharges that spread from the occipital cortex to the frontal and parietal lobes—engaging ENM-relevant regions (premotor, primary motor, somatosensory, and supplementary motor cortices) and causing ENM manifestations.8 Blink-induced visual transients may act as microphotosensory stimuli within this hyperexcitable visual network. Only one-third of patients with epilepsy with myoclonic–atonic seizures (EMAtS) have photosensitivity; most have normal intellectual development. Ictal EEG shows generalized polyspike or spike discharges with the myoclonus, followed by a high-voltage slow-wave accompanying the atonic component.2 This child with CHD2-related epilepsy showed prominent photosensitivity, developmental delay, and intellectual disability. Eyelid EMG triggered epileptic discharges, which in turn precipitated ENM seizures—excluding this case from typical EMAtS. CHD2-related epilepsy has a broad phenotypic spectrum, reflecting a shift in epilepsy classification—from syndrome-based descriptions to genotype-driven understanding.9 As previously reported, pathogenic CHD2 variants are associated with developmental delay and intellectual disability—both present in this patient. Valproate is the first-line treatment for CHD2-related epilepsy and effectively reduces seizures in this patient. This case reveals a previously underrecognized direct association between sensory perturbations (even minor ones such as blink-induced visual transients) and ENM in genetic epilepsy, which could potentially provide further insights into the pathophysiological mechanisms of seizures in other photosensitive genetic epilepsies. Dr. GuangYang and Wen Wang had full access to all of the data in the study and took responsibility for the integrity of the data and the accuracy of the data analysis. Guang Yang: Design and conceptualization, drafting/revision of manuscript for intellectual content. Wen Wang: drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; study concept or design; analysis or interpretation of data. Lin Wan: drafting/revision of the manuscript for content, including medical writing for content. Linyan Hu: drafting/revision of the manuscript for content, including medical writing for content. Jian Chen: drafting/revision of the manuscript for content, including medical writing for content. Yan Zhao: drafting/revision of the manuscript for content, including medical writing for content. Zhichao Li: drafting/revision of the manuscript for content, including medical writing for content. We are grateful to the patient and her family for their participation in this study. This research was funded by the general project of National Key Research and Development Program of China (Reference: 2023YFC2706405, 2022YFC2705300), Beijing Natural Science Foundation (Reference: 7262121), Capital's Funds for Health Improvement and Research (Reference: 2024-2-5082), the key project of innovation cultivation fund of the Seventh Medical Center of Chinese PLA General Hospital (Reference: QZX-2023-1) and Innovation Talent Fund of Senior Department of Pediatrics, the Seventh Medical Center of PLA General Hospital (Reference: QZX-04-EKLHJH-3). The funders had no role in the design and conduct of the study; the collection, management, analysis, and interpretation of the data; the preparation, review, or approval of the manuscript; or the decision to submit the manuscript for publication. The authors report no relevant disclosures. The data that support the findings of this study are available from the corresponding author upon reasonable request. Data S1. Data S2. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. What are the characteristics of CHD2-related epilepsy? Answers may be found in the Supporting information.