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Published on: June 12, 2018
Epilepsy in young Tsc1(+/-) mice exhibits age-dependent expression that mimics that of human tuberous sclerosis
Svetlana Gataullina1,2,3,4, Eric Lemaire5,6, Fabrice Wendling7,8
1INSERM U1129 "Infantile Epilepsies and Brain Plasticity", Paris, France.
Insights
Tsc1(+/-) mice pups show age-dependent seizures mirroring early human tuberous sclerosis complex (TSC) epilepsy. Early spike clusters in TSC indicate a first epilepsy stage, supporting preventive antiepileptic treatment.
Area of Science:
- Neuroscience
- Genetics
- Epileptology
Background:
- Tuberous sclerosis complex (TSC) is a genetic disorder characterized by the growth of benign tumors in various organs.
- Epilepsy is a common and often debilitating symptom of TSC, with early-onset seizures posing significant challenges.
- Understanding the early epileptic phenotype in TSC is crucial for developing effective therapeutic strategies.
Purpose of the Study:
- To characterize the electroencephalographic (EEG) seizure patterns in Tsc1(+/-) mice pups.
- To compare the observed seizure phenotypes in mice with age-related epilepsy progression in human TSC.
- To evaluate the potential of early intervention strategies for TSC-associated epilepsy.
Main Methods:
- Intracranial EEG recordings were performed in Tsc1(+/-) and control mice from postnatal day 8 to 33.
- Ictal events were classified based on distinct EEG patterns and their temporal evolution.
- Retrospective analysis of EEG data from infants with prenatally diagnosed TSC, with a focus on vigabatrin treatment outcomes.
Main Results:
- Tsc1(+/-) mice exhibited spontaneous seizures starting at postnatal day 9, with three distinct age-dependent ictal patterns identified: 'spike clusters,' 'spasm-like,' and 'tonic-clonic like' seizures.
- 'Spike clusters' were observed early (P9-12) and were often unilateral, while later patterns ('spasm-like' and 'tonic-clonic like') were bilateral with faster interhemispheric propagation.
- In human infants with TSC, pre-seizure EEG showed sharp wave/spike clusters; vigabatrin prevented seizure development when administered before onset, whereas post-onset treatment led to pharmacoresistant epilepsy.
Conclusions:
- Tsc1(+/-) mice present an age-dependent seizure sequence that accurately models early human TSC epilepsy.
- The identification of 'spike clusters' as an early stage of epilepsy in TSC supports the rationale for initiating preventive antiepileptic therapy.
- Early intervention with vigabatrin in TSC is critical for preventing seizure development and improving long-term outcomes.
Objective:
To describe the epileptic phenotype of Tsc1(+/-) mice pups in comparison with age-related seizures in human tuberous sclerosis complex (TSC).
Methods:
Tsc1(+/-) and control mice underwent intracranial electroencephalography (EEG) recording at postnatal ages (P)8 to P33, with linear silicon probe implanted in the somatosensory cortex of one or both hemispheres for 8-24 h. Ictal events were classified visually by independent analyzers; distinct EEG patterns were related to age and analyzed to quantify field potential characteristics and signal dynamics between hemispheres. We collected retrospectively 20 infants with prenatally diagnosed TSC and EEG before seizure onset, and analyzed the electroclinical course of epilepsy, taking into account a first-line treatment by vigabatrin.
Results:
Spontaneous seizures were disclosed in 55% of Tsc1(+/-) mice at P9-18. Three ictal patterns were identified: from P9 to P12 "spike clusters" consisted of recurring large spikes without clinical correlate; "spasm-like" discharges dominated from P13 to P16 consisting of high amplitude large field potential superimposed with or followed by fast activity repeated every 2-10 s for at least 20 s, accompanied by rhythmic limb contractions; from P14 to P18 a "tonic-clonic like" pattern comprised rhythmic spikes of increasing amplitude with tonic-clonic movements. Early onset "spike clusters" were mainly unilateral, whereas "spasm-like" and "tonic-clonic like" patterns were bilateral. Interhemispheric propagation was significantly faster for "tonic-clonic like" than for "spasm-like" events. In infants diagnosed prenatally with TSC, clusters of sharp waves or spikes preceded the first seizure, and vigabatrin prevented the development of seizures. Patients treated after seizure onset developed spasms or focal seizures that were pharmacoresistant in 66.7% of cases.
Significance:
Tsc1(+/-) mice pups exhibit an age-dependent seizure pattern sequence mimicking early human TSC epilepsy features. Spike clusters before seizure onset in TSC should be considered as a first stage of epilepsy reinforcing the concept of preventive antiepileptic therapy.
