The Pharmacoresistant Epilepsy: An Overview on Existent and New Emerging Therapies

Fattorusso, Antonella; Matricardi, Sara; Mencaroni, Elisabetta; Dell’Isola, Giovanni Battista; Cara, Giuseppe Di; Striano, Pasquale; Verrotti, Alberto

doi:10.3389/fneur.2021.674483

Cited by 175 publications

(108 citation statements)

References 147 publications

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“…These patients usually need polytherapy frequently with poor efficacy due to the natural fluctuating trend of seizures and to the various cluster triggers. The management of drug-refractory patients represents a great challenge for physicians, especially for syndromes with heterogeneous seizure semeiology and course ( 58 ). Currently, different drug associations have been tested and none has definitively proven to be superior ( Table 1 ).…”

Section: Treatment Of Pcdh19-related Epilepsymentioning

confidence: 99%

“…Stiripentol may be effective especially in patients with DS-like, however, due to drug resistance, it is often necessary to use it in combination with clobazam and valproate. Aggravations of seizures were reported in connection with sodium channel blockers ( 58 ), with topiramate and valproate ( 60 ). The increasing number of antiseizure medications in the last decades has led to the development of new successful therapies.…”

Section: Treatment Of Pcdh19-related Epilepsymentioning

confidence: 99%

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The Broad Clinical Spectrum of Epilepsies Associated With Protocadherin 19 Gene Mutation

et al. 2022

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Protocadherin 19 (PCDH19) gene is one of the most common genes involved in epilepsy syndromes. According to literature data PCDH19 is among the 6 genes most involved in genetic epilepsies. PCDH19 is located on chromosome Xq22.1 and is involved in neuronal connections and signal transduction. The most frequent clinical expression of PCDH19 mutation is epilepsy and mental retardation limited to female (EFMR) characterized by epileptic and non-epileptic symptoms affecting mainly females. However, the phenotypic spectrum of these mutations is considerably variable from genetic epilepsy with febrile seizure plus to epileptic encephalopathies. The peculiar exclusive involvement of females seems to be caused by a cellular interference in heterozygosity, however, affected mosaic-males have been reported. Seizure types range from focal seizure to generalized tonic-clonic, tonic, atonic, absences, and myoclonic jerks. Treatment of PCDH19-related epilepsy is limited by drug resistance and by the absence of specific treatment indications. However, seizures become less severe with adolescence and some patients may even become seizure-free. Non-epileptic symptoms represent the main disabilities of adult patients with PCDH19 mutation. This review aims to analyze the highly variable phenotypic expression of PCDH19 gene mutation associated with epilepsy.

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Section: Treatment Of Pcdh19-related Epilepsymentioning

confidence: 99%

Section: Treatment Of Pcdh19-related Epilepsymentioning

confidence: 99%

The Broad Clinical Spectrum of Epilepsies Associated With Protocadherin 19 Gene Mutation

et al. 2022

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“…In addition, AED combinations, like ethosuximide (ETX) with valproic acid (VPA), are reported to be more effective than the monotherapy in children suffering from absence seizures. Other AED combination regimens include lamotrigine (LTG)-levetiracetam (LEV) and lacosamide (LCM)-LEV, VPA-LTG [29]. PHT-PB (phenobarbital), carbamazepine (CBZ)-VPA, vigabatrin (VIG)-LTG, tiagabin (TGB)-VIG, gabapentin (GBP)-LTG and LTG-TPM (topiramate) [30][31][32].…”

Section: Discussionmentioning

confidence: 99%

Thymoquinone Potentiates the Effect of Phenytoin against Electroshock-Induced Convulsions in Rats by Reducing the Hyperactivation of m-TOR Pathway and Neuroinflammation: Evidence from In Vivo, In Vitro and Computational Studies

et al. 2021

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Epilepsy is a chronic neurodegenerative disease characterized by multiple seizures, hereto 35% of patients remain poor responders. Phenytoin (PHT; 20 and 40 mg/kg) and thymoquinone (THQ; 40 and 80 mg/kg) were given alone and as a low dose combination for 14 days (p.o), prior to challenge with maximal electroshock (MES; 180 mA, 220 V, 0.2 s). Apart from observing convulsions, hippocampal mTOR, IL-1β, IL-6 and TNF-α levels were measured. Hippocampal histomorphological analysis was also conducted. In vitro cell line studies and molecular docking studies were run in parallel. The results revealed the synergistic potential of the novel duo-drug combination regimen: PHT (20 mg/kg) and THQ (40 mg/kg) against MES-induced convulsions. MES amplified signaling through mTOR, and inflated the levels of proinflammatory markers (IL-1β, IL-6 and TNF-α), which was significantly averted (p < 0.001) with the said drug combination. The computational studies revealed that PHT and THQ cooperatively bind the active site on Akt (upstream target of m-TOR) and establish a good network of intermolecular interactions, which indicates the sequential inhibition of PI3K/Akt/m-TOR signaling with the combination. The combination also increased cell viability by 242.81% compared to 85.66% viability from the the toxic control. The results suggest that the PHT and THQ in combination possesses excellent anticonvulsant and neuroprotective effects.

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“…Treatment is only prescribed by experts, if there is a clear diagnosis of seizures and it is important to use long-lasting video EEG in situations of uncertain significance (103). Epilepsy affects the quality of life, patients appear more tired and less responsive throughout the day, and the sedative effects of anti-epileptic therapies may also contribute to sleep disorders of older individuals (95,(107)(108)(109)(110). Insomnia is characterized by a high prevalence in subjects with neurodevelopmental disabilities but is not associated with a specific genetic risk.…”

Section: Mecp2 Cdkl5 and Foxg1 Genes And Their Proteinmentioning

confidence: 99%

Sleep Disorders in Rett Syndrome and Rett-Related Disorders: A Narrative Review

et al. 2022

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Rett Syndrome (RTT) is a rare and severe X-linked developmental brain disorder that occurs primarily in females, with a ratio of 1:10.000. De novo mutations in the Methyl-CpG Binding protein 2 (MECP2) gene on the long arm of X chromosome are responsible for more than 95% cases of classical Rett. In the remaining cases (atypical Rett), other genes are involved such as the cyclin-dependent kinase-like 5 (CDKL5) and the forkhead box G1 (FOXG1). Duplications of the MECP2 locus cause MECP2 duplication syndrome (MDS) which concerns about 1% of male patients with intellectual disability. Sleep disorders are common in individuals with intellectual disability, while the prevalence in children is between 16 and 42%. Over 80% of individuals affected by RTT show sleep problems, with a higher prevalence in the first 7 years of life and some degree of variability in correlation to age and genotype. Abnormalities in circadian rhythm and loss of glutamate homeostasis play a key role in the development of these disorders. Sleep disorders, epilepsy, gastrointestinal problems characterize CDKL5 Deficiency Disorder (CDD). Sleep impairment is an area of overlap between RTT and MECP2 duplication syndrome along with epilepsy, regression and others. Sleep dysfunction and epilepsy are deeply linked. Sleep deprivation could be an aggravating factor of epilepsy and anti-comitial therapy could interfere in sleep structure. Epilepsy prevalence in atypical Rett syndrome with severe clinical phenotype is higher than in classical Rett syndrome. However, RTT present a significant lifetime risk of epilepsy too. Sleep disturbances impact on child's development and patients' families and the evidence for its management is still limited. The aim of this review is to analyze pathophysiology, clinical features, the impact on other comorbidities and the management of sleep disorders in Rett syndrome and Rett-related syndrome.

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The Pharmacoresistant Epilepsy: An Overview on Existent and New Emerging Therapies

Cited by 175 publications

References 147 publications

The Broad Clinical Spectrum of Epilepsies Associated With Protocadherin 19 Gene Mutation

The Broad Clinical Spectrum of Epilepsies Associated With Protocadherin 19 Gene Mutation

Thymoquinone Potentiates the Effect of Phenytoin against Electroshock-Induced Convulsions in Rats by Reducing the Hyperactivation of m-TOR Pathway and Neuroinflammation: Evidence from In Vivo, In Vitro and Computational Studies

Sleep Disorders in Rett Syndrome and Rett-Related Disorders: A Narrative Review

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