Infantile Spasms: An Update on Pre-Clinical Models and EEG Mechanisms

Janicot, Remi; Shao, Li; Stafstrom, Carl E.

doi:10.3390/children7010005

Cited by 19 publications

(17 citation statements)

References 98 publications

(113 reference statements)

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“…There are several animal models and investigated cellular pathways of epileptic spasms that are out of the scope of this review, but they are covered in‐depth in several other reviews 26–31 …”

Section: Resultsmentioning

confidence: 99%

Epileptic spasms in individuals with Down syndrome: A review of the current literature

2020

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Epilepsy can occur in individuals with Down syndrome (DS), with epileptic spasms representing the most frequent seizure type in this population. Epileptic spasms can have devastating consequences on the development of individuals with the condition. This review sought to explore the lifetime prevalence and underlying mechanism of epileptic spasms in this population. We also aimed to review the response rate to various treatments, the relapse rate, and the development of subsequent epilepsy or autism in this population. A comprehensive literature search was conducted for articles discussing the lifetime prevalence, diagnosis, treatment, outcomes, or underlying etiology of epileptic spasms in animal models or individuals with DS. According to available literature, the global clinic‐based lifetime prevalence of epilepsy in individuals with DS ranged from 1.6% to 23.1%, with epileptic spasms representing 6.7%‐66.7% of these cases. Response rate to treatment with adrenocorticotropic hormone/corticosteroids was highest (81%) and has the most literature supporting its use, with other regimens, including vigabatrin and other antiepileptic drugs, having lower response rates. Epileptic spasms occur more frequently in children with DS than in the general population, though more studies are needed to determine the true lifetime prevalence of epileptic spasms in this population. Generally, children with DS and epileptic spasms tend to be more responsive to treatment and have better outcomes than children with epileptic spasms of unknown etiology (ie, without DS), in terms of response and relapse rates as well as the development of intractable epilepsy (eg, Lennox‐Gastaut syndrome).

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Section: Resultsmentioning

confidence: 99%

Epileptic spasms in individuals with Down syndrome: A review of the current literature

2020

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“…30,58 Moreover, recent reexamination of clinical EEG data and in vitro slice results have led to computer models that implicate layer V pyramidal cells in the generation of epileptic spasms. 59,60 Our analysis of MUA also shows robust activity in the deep cortical layers at ictal onset that precedes unit activity in more superficial layers. These results are consistent with the idea that recurrent excitatory networks located infragranularly initiate ictal events but activity can quickly spread supragranularly through local excitatory synaptic pathways.…”

Section: Discussionmentioning

confidence: 60%

Neocortical Slow Oscillations Implicated in the Generation of Epileptic Spasms

Lee

Ballester-Rosado

et al. 2020

Annals of Neurology

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Objective Epileptic spasms are a hallmark of severe seizure disorders. The neurophysiological mechanisms and the neuronal circuit(s) that generate these seizures are unresolved and are the focus of studies reported here. Methods In the tetrodotoxin model, we used 16‐channel microarrays and microwires to record electrophysiological activity in neocortex and thalamus during spasms. Chemogenetic activation was used to examine the role of neocortical pyramidal cells in generating spasms. Comparisons were made to recordings from infantile spasm patients. Results Current source density and simultaneous multiunit activity analyses indicate that the ictal events of spasms are initiated in infragranular cortical layers. A dramatic pause of neuronal activity was recorded immediately prior to the onset of spasms. This preictal pause is shown to share many features with the down states of slow wave sleep. In addition, the ensuing interictal up states of slow wave rhythms are more intense in epileptic than control animals and occasionally appear sufficient to initiate spasms. Chemogenetic activation of neocortical pyramidal cells supported these observations, as it increased slow oscillations and spasm numbers and clustering. Recordings also revealed a ramp‐up in the number of neocortical slow oscillations preceding spasms, which was also observed in infantile spasm patients. Interpretation Our findings provide evidence that epileptic spasms can arise from the neocortex and reveal a previously unappreciated interplay between brain state physiology and spasm generation. The identification of neocortical up states as a mechanism capable of initiating epileptic spasms will likely provide new targets for interventional therapies. ANN NEUROL 2021;89:226–241

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“…Several animal models of epileptic spasms have been developed, and these have been reviewed elsewhere. 50,51 One major advantage of the TTX model is that compared to other models, it faithfully recapitulates the electrophysiological features of human patients during both ictal and interictal periods. Taking advantage of and extending these features, we have been able to routinely record MUA and HFA during different brain states in freely moving animals.…”

Section: Discussionmentioning

confidence: 99%

Brain state‐dependent high‐frequency activity as a biomarker for abnormal neocortical networks in an epileptic spasms animal model

Lee

Swann

2021

Epilepsia

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Objective Epileptic spasms are a hallmark of a severe epileptic state. A previous study showed neocortical up and down states defined by unit activity play a role in the generation of spasms. However, recording unit activity is challenging in clinical settings, and more accessible neurophysiological signals are needed for the analysis of these brain states. Methods In the tetrodotoxin model, we used 16‐channel microarrays to record electrophysiological activity in the neocortex during interictal periods and spasms. High‐frequency activity (HFA) in the frequency range of fast ripples (200–500 Hz) was analyzed, as were slow wave oscillations (1–8 Hz), and correlated with the neocortical up and down states defined by multiunit activity (MUA). Results HFA and MUA had high temporal correlation during interictal and ictal periods. Both increased strikingly during interictal up states and ictal events but were silenced during interictal down states and preictal pauses, and their distributions were clustered at the peak of slow oscillations in local field potential recordings. In addition, both HFA power and MUA firing rates were increased to a greater extent during spasms than interictal up states. During non‐rapid eye movement sleep, the HFA rhythmicity faithfully followed the MUA up and down states, but during rapid eye movement sleep when MUA up and down states disappeared the HFA rhythmicity was largely absent. We also observed an increase in the number of HFA down state minutes prior to ictal onset, consistent with the results from analyses of MUA down states. Significance This study provides evidence that HFA may serve as a biomarker for the pathological up states of epileptic spasms. The availability of HFA recordings makes this a clinically practical technique. These findings will likely provide a novel approach for localizing and studying epileptogenic neocortical networks not only in spasms patients but also in other types of epilepsy.

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Infantile Spasms: An Update on Pre-Clinical Models and EEG Mechanisms

Cited by 19 publications

References 98 publications

Epileptic spasms in individuals with Down syndrome: A review of the current literature

Epileptic spasms in individuals with Down syndrome: A review of the current literature

Neocortical Slow Oscillations Implicated in the Generation of Epileptic Spasms

Brain state‐dependent high‐frequency activity as a biomarker for abnormal neocortical networks in an epileptic spasms animal model

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