scholarly journals RHEB/mTOR-hyperactivity causing cortical malformations drives seizures through increased axonal connectivity

2020 ◽  
Author(s):  
Martina Proietti Onori ◽  
Linda M.C. Koene ◽  
Carmen B. Schafer ◽  
Mark Nellist ◽  
Marcel de Brito van Velze ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Mammalian Target Of Rapamycin ◽  
Malformations Of Cortical Development ◽  
Cortical Malformation ◽  
Unknown Mechanism ◽  
Generalized Seizures ◽  
Physiological Abnormalities ◽  
Generalized Epilepsy ◽  
New Evidence ◽  
Focal Expression

ABSTRACTDominant-active mutations in Ras Homolog Enriched in Brain 1 (RHEB), such as the recently identified RHEBp.P37L mutation, can cause malformations of cortical development (MCD) with associated epilepsy and intellectual disability through a yet unknown mechanism. We found that focal expression of RHEBp.P37L in mouse somatosensory cortex results in an MCD-like phenotype, with increased mammalian target of rapamycin (mTOR) signaling, ectopic localization of neurons and generalized seizures. In addition, the RHEBp.P37L expressing neurons showed increased axonal length and branching. By temporally controlling RHEBp.P37L expression, we found that the cortical malformation by itself was neither necessary nor sufficient to generate seizures. Rather, seizures were contingent on persistent mTOR activation and enhanced axonal connectivity of RHEBp.P37L expressing neurons, causing hyperexcitability of distally connected neurons. These results provide new evidence of the extent of anatomical and physiological abnormalities caused by mTOR hyperactivity, beyond local malformations, that can lead to generalized epilepsy.

scholarly journals RHEB/mTOR hyperactivity causes cortical malformations and epileptic seizures through increased axonal connectivity

PLoS Biology ◽  
2021 ◽  
Vol 19 (5) ◽  
pp. e3001279
Author(s):  
Martina Proietti Onori ◽  
Linda M. C. Koene ◽  
Carmen B. Schäfer ◽  
Mark Nellist ◽  
Marcel de Brito van Velze ◽  
...  
Keyword(s):  
Mammalian Target Of Rapamycin ◽  
Epileptic Seizures ◽  
Mtor Pathway ◽  
Vesicle Release ◽  
Generalized Seizures ◽  
Malformation Of Cortical Development ◽  
Physiological Abnormalities ◽  
Generalized Epilepsy ◽  
New Evidence ◽  
Focal Expression

Hyperactivation of the mammalian target of rapamycin (mTOR) pathway can cause malformation of cortical development (MCD) with associated epilepsy and intellectual disability (ID) through a yet unknown mechanism. Here, we made use of the recently identified dominant-active mutation in Ras Homolog Enriched in Brain 1 (RHEB), RHEBp.P37L, to gain insight in the mechanism underlying the epilepsy caused by hyperactivation of the mTOR pathway. Focal expression of RHEBp.P37L in mouse somatosensory cortex (SScx) results in an MCD-like phenotype, with increased mTOR signaling, ectopic localization of neurons, and reliable generalized seizures. We show that in this model, the mTOR-dependent seizures are caused by enhanced axonal connectivity, causing hyperexcitability of distally connected neurons. Indeed, blocking axonal vesicle release from the RHEBp.P37L neurons alone completely stopped the seizures and normalized the hyperexcitability of the distally connected neurons. These results provide new evidence of the extent of anatomical and physiological abnormalities caused by mTOR hyperactivity, beyond local malformations, which can lead to generalized epilepsy.

scholarly journals Prenatal treatment with rapamycin restores enhanced hippocampal mGluR-LTD and mushroom spine size in a Down’s syndrome mouse model

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Jesús David Urbano-Gámez ◽  
Juan José Casañas ◽  
Itziar Benito ◽  
María Luz Montesinos
Keyword(s):  
Intellectual Disability ◽  
Pyramidal Neurons ◽  
Metabotropic Glutamate Receptor ◽  
Therapeutic Potential ◽  
Mammalian Target Of Rapamycin ◽  
Memory Deficits ◽  
Prenatal Treatment ◽  
Hippocampal Pyramidal Neurons ◽  
Metabotropic Glutamate ◽  
Mushroom Spines

AbstractDown syndrome (DS) is the most frequent genetic cause of intellectual disability including hippocampal-dependent memory deficits. We have previously reported hippocampal mTOR (mammalian target of rapamycin) hyperactivation, and related plasticity as well as memory deficits in Ts1Cje mice, a DS experimental model. Here we characterize the proteome of hippocampal synaptoneurosomes (SNs) from these mice, and found a predicted alteration of synaptic plasticity pathways, including long term depression (LTD). Accordingly, mGluR-LTD (metabotropic Glutamate Receptor-LTD) is enhanced in the hippocampus of Ts1Cje mice and this is correlated with an increased proportion of a particular category of mushroom spines in hippocampal pyramidal neurons. Remarkably, prenatal treatment of these mice with rapamycin has a positive pharmacological effect on both phenotypes, supporting the therapeutic potential of rapamycin/rapalogs for DS intellectual disability.

Medical Management in Focal versus Generalized Epilepsy

2021 ◽  
Vol 10 (02) ◽  
pp. 081-087
Author(s):  
Kumar Sannagowdara ◽  
Nadir Khan
Keyword(s):  
Broad Spectrum ◽  
Side Effect ◽  
Seizure Control ◽  
Therapeutic Effects ◽  
Side Effect Profile ◽  
Genetics Research ◽  
Generalized Seizures ◽  
Technological Advances ◽  
Generalized Epilepsy ◽  
New Compounds

AbstractAbout 70% of children with new-onset epilepsy have the potential to become seizure-free on antiepileptic drug (AED) monotherapy with appropriately selected first-line medication. In ideal world, physician is expected to achieve best possible seizure control without impacting the quality of life. There is rapid increase in number of AEDs available over last couple of decades. Although not necessarily all of them are superior to old generation drugs in terms of seizure control, certainly there is change in landscape from perspective of tolerability and side-effect profile. Physicians must therefore be familiar with safety, tolerability, therapeutic effects, synergistic combinations as well as AEDs to avoid in specific circumstances. The article attempts to give general overview of available AEDs under broad umbrella of effectiveness against focal and generalized seizures as well as drugs with “broad spectrum.” The emergence of newer AEDs with broad spectrum and favorable side-effect profile is welcome. However, the future lies in better understanding of underlying diverse pathophysiology of clinical symptom “epilepsy” and developing new compounds acting on molecular targets as well as individualizing therapy. Technological advances in molecular genetics research are bringing precision medicine to the fore.

scholarly journals Retention Rate and Efficacy of Perampanel with a Slow Titration Schedule in Adults

2020 ◽  
pp. 1-7
Author(s):  
Mazen Basheikh ◽  
R. Mark Sadler
Keyword(s):  
Seizure Frequency ◽  
Retention Rate ◽  
Responder Rate ◽  
Dose Titration ◽  
Seizure Freedom ◽  
Chart Audit ◽  
Generalized Seizures ◽  
Included Patient ◽  
Generalized Epilepsy

ABSTRACT: Rationale: The manufacturer of perampanel (PER) suggests an initial adult dose of 2–4 mg/day and an upward dose titration of 2 mg at no more frequently than 1- or 2-week intervals when used with enzyme-enhancing antiepileptic drugs (AEDs) or nonenzyme-enhancing AEDs, respectively. The general practice in our clinic is an initial dose of PER 2 mg/day and titrated by 2 mg/4 weeks to an initial target of 6 mg/day. Methods: Retrospective chart audit of patients starting PER in an adult epilepsy clinic between September 2013 and November 2016 with at least one 6-month follow-up visit was reviewed. Data collection included patient demographics, seizure characteristics, past and concurrent therapy, monthly seizure frequency before PER and at 6-month visit, and characteristics of PER discontinuation. Efficacy of treatment was assessed with the Engel classification and 50% responder rate. Results: N = 102 patients; mean age = 40 years and 54% females. Focal onset seizures 85%, generalized 13%, and unknown 2%. Median prior AED exposure = 6 (range 3–20); median concomitant AED use = 2 (range 1–5). Follow-up range was 6–37 months. The median seizure frequency/month prePER treatment was 6 (range 0–30) for focal onset seizures and 1 (range 0–6) for generalized seizures. The retention rate amongst all patients at 6 months was 78.4%. At 6-month follow-up, 36% of all patients achieved Engel class I (seizure freedom) (30.7% of patients with focal onset seizures and 63.6% with generalized epilepsy). The 50% responder rate was 52% and 82% for focal and generalized epilepsy, respectively. Conclusion: PER has a good retention rate when titrated slowly and thus encouraging seizure freedom results in an otherwise medically refractory epilepsy population.

Potassium Bromide in the Treatment of Pediatric Refractory Epilepsy

2019 ◽  
Vol 34 (10) ◽  
pp. 582-585 ◽  
Author(s):  
Kazuo Kodama ◽  
Taku Omata ◽  
Yoshimi Watanabe ◽  
Hiromi Aoyama ◽  
Yuzo Tanabe
Keyword(s):  
Adverse Effects ◽  
Seizure Frequency ◽  
Refractory Epilepsy ◽  
Focal Epilepsy ◽  
Dravet Syndrome ◽  
Generalized Seizures ◽  
Clonic Seizures ◽  
Moderate Effect ◽  
Generalized Epilepsy ◽  
Free Status

Objective: We evaluated potassium bromide’s (KBr’s) efficacy and tolerability for pediatric refractory epilepsy. Methods: We retrospectively reviewed the records of 42 patients treated with KBr in our hospital between 2008 and 2016 (age: 4 months to 19 years; mean: 6.2 years). Thirteen of them had 2 seizure types. The treatment durations ranged from 1 month to 6 years (mean: 15.0 months). Results: KBr had an excellent effect (seizure-free status) in 3 patients (7.1%), a moderate effect (>50% reduction in seizure frequency from the pretreatment baseline) in 21 patients (50.0%), and no effect (<50% reduction in seizure frequency from the pretreatment baseline) in 18 patients (42.9%). The effective daily doses ranged from 20 to 80 mg/kg (mean: 50.0 mg/kg). KBr was effective in 59.1% patients with generalized epilepsy (n = 22), 55.6% patients with focal epilepsy (n = 18), and both patients with Dravet syndrome. An excellent or moderate effect was found in 72.2% patients with tonic seizures (n = 18), 66.6% patients with generalized tonic-clonic seizures (n = 6), 75.0% patients with secondary generalized seizures (n = 4), 46.2% patients with focal seizures (n = 13), and 20% patients with infantile spasms (n = 10) but no patients with myoclonic seizures (n = 2). Adverse effects including drowsiness, excitement, and rashes were reported in 13 patients (31.0%). Conclusions: These findings suggest that KBr is particularly effective for tonic seizures, generalized tonic-clonic seizures, and secondary generalized seizures. Although the adverse effects need further attention, KBr should be considered for pediatric refractory epilepsy.

scholarly journals Copy number variants are frequent in genetic generalized epilepsy with intellectual disability

Neurology ◽  
2013 ◽  
Vol 81 (17) ◽  
pp. 1507-1514 ◽  
Author(s):  
S. A. Mullen ◽  
G. L. Carvill ◽  
S. Bellows ◽  
M. A. Bayly ◽  
S. F. Berkovic ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Copy Number ◽  
Copy Number Variants ◽  
Generalized Epilepsy

Author response for "New evidence that bi‐allelic loss of function in EEF1B2 gene leads to intellectual disability"

2019 ◽  
Author(s):  
Lise Larcher ◽  
Julien Buratti ◽  
Bénédicte Héron‐Longe ◽  
Brigitte Benzacken ◽  
Eva Pipiras ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Author Response ◽  
Allelic Loss ◽  
Loss Of Function ◽  
New Evidence ◽  
I Gene

Use of Lamotrigine in Lennox-Gastaut and Related Epilepsy Syndromes

1997 ◽  
Vol 12 (1_suppl) ◽  
pp. S23-S28 ◽  
Author(s):  
Olivier Dulac ◽  
Anna Kaminska
Keyword(s):  
Drug Therapy ◽  
Pediatric Epilepsy ◽  
Mental Deterioration ◽  
Clinical Observations ◽  
Generalized Seizures ◽  
Antiepileptic Medication ◽  
Generalized Epilepsy ◽  
Diagnostic Work ◽  
Work Up ◽  
Diagnostic Work Up

Lennox-Gastaut syndrome, a combination of various generalized seizures including atypical absences and tonic seizures with generalized slow spike waves and mental deterioration, is often difficult to distinguish from a subgroup of myoclonic-astatic epilepsy, other generalized epilepsy syndromes, and various symptomatic generalized epilepsies. Conventional antiepileptic medication is poorly effective in this condition, particularly because various types of seizures respond differently to each given drug. Lamotrigine is effective in the various types of generalized seizures and efficacy has been demonstrated in Lennox-Gastaut syndrome. Given the potential of major mental deterioration within a matter of months in this condition, and the need of slow dose escalation in order to prevent skin rash, lamotrigine should be administered as soon as the diagnosis of Lennox-Gastaut syndrome is suspected. In addition, there is growing evidence that lamotrigine is also most useful in the subgroup of myoclonic-astatic epilepsy beginning in childhood, and that these patients should benefit from the drug like those affected by Lennox-Gastaut syndrome, as soon as the diagnosis is suspected. However, this drug may worsen other cases of myoclonic-astatic epilepsy beginning in infancy. These clinical observations add to the evidence for the need of clear diagnostic work-up before appropriate drug therapy is decided in pediatric epilepsy. (J Child Neurol 1997;12(Suppl 1):S23-S28).

scholarly journals The clinical spectrum of malformations of cortical development

2007 ◽  
Vol 65 (2A) ◽  
pp. 196-201 ◽  
Author(s):  
Maria Augusta Montenegro ◽  
Fernando Cendes ◽  
Iscia Lopes-Cendes ◽  
Carlos A.M. Guerreiro ◽  
Li M. Li ◽  
...  
Keyword(s):  
Magnetic Resonance Imaging ◽  
Magnetic Resonance ◽  
High Resolution ◽  
Cortical Development ◽  
Malformations Of Cortical Development ◽  
Resonance Imaging ◽  
Imaging Diagnosis ◽  
Epileptic Syndromes ◽  
Different Types ◽  
Generalized Epilepsy

BACKGROUND: Malformations of cortical development (MCD) usually manifest in childhood with epilepsy, developmental delay and focal neurological abnormalities. OBJECTIVE: To evaluate the presentation and severity of epilepsy in the different types of MCD. METHOD: We evaluated the first 100 consecutive patients with a neuroimaging diagnosis of MCD. They were identified among all the high resolution magnetic resonance imaging exams performed at our service between 1997 and 2001. The causes of referral were diverse, according to the routine of the neurology outpatient clinic. After magnetic resonance imaging diagnosis of the subtype of MCD a detailed clinical assessment was performed. RESULTS: There were 55 females and 45 males, with ages ranging from five months to 71 years old (mean=15.2 years). Seventy-seven patients presented with epilepsy. Sixty-one had partial epileptic syndromes, 13 secondary generalized syndromes, and in three, the type of epileptic syndrome could not be established. Epilepsy was less frequent in patients with the MCD subtypes of polymicrogyria and schizencephaly (p<0.001). Patients with schizencephaly and polymicrogyria had their seizures more easily controlled by antiepileptic drugs (p<0.001). CONCLUSION: That the frequency of epilepsy is lower and seizures are more easily controlled in the setting of polymicrogyria and schizencephaly. Patients with MCD frequently present with secondary generalized epilepsy early in childhood.

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