Annual Meeting Abstracts: View

<< Back to Search Results

(Abst. 1.084), 2019

Increased Spindle Density Coincides with Cognitive Recovery in a Child with an Epileptic Encephalopathy
Authors: Sally Stoyell, Massachusetts General Hospital; Bryan Baxter, Massachusetts General Hospital; Dhinakaran Chinappen, Massachusetts General Hospital; Lin Zhu, Massachusetts General Hospital; John McLaren, Massachusetts General Hospital; Julie A. Grieco, Massachusetts General Hospital; Amy Morgan, Massachusetts General Hospital; Britt C. Emerton, Massachusetts General Hospital; Mark Kramer, Boston University; Dara Manoach, Massachusetts General Hospital; Catherine J. Chu, Massachusetts General Hospital
Content: Rationale: Epileptic encephalopathies are devastating developmental epilepsy syndromes characterized by abundant spikes during NREM sleep and progressive declines in cerebral function. Previous work has not been able to establish a relationship between spike activity and the cognitive symptoms. There is no known pathophysiological mechanism to explain the cognitive deficits characteristic of these syndromes and consequently no proven treatment. Epileptiform spikes and sleep spindles, bursts of sigma band (10-16 Hz) oscillations during NREM sleep, can be generated by the same thalamocortical circuit, where spikes may reflect a pathological hijacking of spindle circuitry. As spindles are essential for sleep-dependent learning, we hypothesized that a disruption in spindles required for normal learning could contribute to cognitive dysfunction in epileptic encephalopathies. Here we present a proof of concept case of a child with an epileptic encephalopathy followed from diagnosis through successful treatment. Methods: A 5-year-old girl was incidentally found to have near-continuous spike and wave discharges on EEG during NREM sleep. Detailed neuropsychological testing revealed cognitive delay and she was followed carefully over the next several years with paired overnight EEGs and neuropsychological testing. At 8 years of age, she was found to have cognitive regression and formally diagnosed with an epileptic encephalopathy. She was treated with high dose diazepam and had follow up EEG and neuropsychological testing 4 months after treatment. Her pre- and post- treatment neuropsychology evaluations and EEGs were analyzed for spikes and spindles. To determine spindle density, we used a validated automated spindle detector that was modified to account for spurious spindle detections produced by spikes. To determine spike rate, we applied the Persyst 13 spike detector (Persyst Development Corporation, San Diego) to the same data. These measures were compared to improvements in neuropsychological performance. Results: Annual neuropsychological testing revealed stable impairments in multiple cognitive domains from ages 5 to 7 years. Testing at ages 8 and 9 years revealed initially subtle and then dramatic cognitive regressions. Following treatment with high-dose diazepam, her parents noted immediate improvement which was confirmed by follow-up neuropsychological testing at age 10 years. From ages 5-7, spindle density ranged from 1.7-3.3 spindles per minute. This improved dramatically after treatment with high-dose diazepam, with a 90% increase in spindle density from the previous night (3.0 to 5.8 spindles/min). Spike rate followed a waxing and waning course and there was with a non-significant negative correlation between spike rate and spindle density (-0.78, p=0.12). Conclusions: We found a dramatic increase in spindles that coincided with cognitive improvement in a child with epileptic encephalopathy. Spindles are well-established in neuroscience literature as critical for memory consolidation during NREM sleep and offer a direct, established pathophysiological mechanism for the cognitive deficits observed in childhood epileptic encephalopathies. Future work will evaluate spindle density in children with epileptic encephalopathies and relate these findings to cognitive performance. As sleep spindles can be modulated with pharmacologic and neuromodulatory approaches, this work identifies a novel biomarker and mechanism for cognitive dysfunction and new opportunities for research and treatment of cognitive deficits in epileptic encephalopathies. Funding: NINDS K23-NS092923
Figure 1