Treatment outcomes in drug resistant juvenile myoclonic epilepsy: Valproate resistance may not be the end of the road

Baheti, Neeraj N; Rathore, Chaturbhuj; Bansal, Atma Ram; Shah, Saumya; Veedu, Hari Kunhi; Prakash, Sanjay; Kanhere, Kalyani; Jaiswal, Shyam K; Jukkarwala, Anis; Murthy, J. M. K.; Radhakrishnan, Kurupath

doi:10.1016/j.seizure.2021.08.019

Cited by 6 publications

(6 citation statements)

References 28 publications

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“…Valproic acid (VPA) is an old AED that has been used in clinics for over 50 years due to its high efficacy and tolerability and is currently considered the first‐line therapy for absence epilepsy by the National Institute for Health and Care Excellence 5,6 . However, previous studies have shown that almost one‐third of the patients are nonresponsive to VPA 7–9 . Interestingly, resistance to VPA is usually associated with genetic generalized forms of epilepsy 10,11 .…”

Section: Introductionmentioning

confidence: 99%

“… 5 , 6 However, previous studies have shown that almost one‐third of the patients are nonresponsive to VPA. 7 , 8 , 9 Interestingly, resistance to VPA is usually associated with genetic generalized forms of epilepsy. 10 , 11 Hence, it is imperative to elucidate the mechanism underlying VPA efficacy to improve the therapy of pharmacoresistant epilepsy.…”

Section: Introductionmentioning

confidence: 99%

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Overexpression of Homer1b/c induces valproic acid resistance in epilepsy

Wang

et al. 2022

CNS Neurosci Ther

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Aims: Resistance to valproic acid (VPA) is a major challenge for epilepsy treatment.We aimed to explore the mechanism underlying this resistance.Methods: Pentylenetetrazol-induced chronic epileptic rats were administered VPA (250 mg/Kg) for 14 days; rats with controlled seizure stages (seizure score 14th-before ≤0) and latent time (latent time 14th-before ≥0) were considered VPA-responsive, while the others were considered nonresponsive. Differentially expressed genes (DEGs) between the VPA-responsive and nonresponsive rat hippocampus transcriptomes were identified, and their functions were evaluated. The roles of postsynaptic density (PSD) and Homer1 were also determined. Furthermore, a subtype of Homer1 (Homer1b/c) was overexpressed or silenced in HT22 cells to determine its effect on VPA efficacy.Moreover, the membrane levels of mGluR1/5 directly bound to Homer1b/c were assessed.Results: Overall, 264 DEGs commonly enriched in the PSD between VPA-responsive and nonresponsive rats. Among them, Homer1 was more highly expressed in the hippocampus of nonresponses compared to that of responses. Overexpression of Homer1b/c interrupted VPA efficacy by increasing reactive oxygen species production, lactate dehydrogenase release, and calcium content. Furthermore, it induced the overexpression of mGluR1 and mGluR5. Conclusion:Overexpression of Homer1b/c influenced VPA efficacy, revealing it could be a target to improve the efficacy of this treatment.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Overexpression of Homer1b/c induces valproic acid resistance in epilepsy

Wang

et al. 2022

CNS Neurosci Ther

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“…These studies did not compare different ASM combinations of drugs, not allowing a comparison between different combination therapies. Another study 23 evaluating drug-resistant juvenile myoclonic epilepsy patients suggested that the best combination therapy is valproate and lamotrigine.…”

Section: Discussionmentioning

confidence: 99%

Seizure control in mono- and combination therapy in a cohort of patients with Idiopathic Generalized Epilepsy

Pipek

Castro

2022

Sci Rep

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Idiopathic Generalized Epilepsy (IGE) patients may not achieve optimal seizure control with monotherapy. Our goal was to evaluate the efficacy of combination therapy in a retrospective series of IGE patients receiving different antiseizure medication (ASM) regimens. We retrospectively identified all patients with adolescence onset IGE with typical clinical and EEG features from a single epilepsy specialist clinic from 2009 to 2020. We evaluated long-term seizure control, for VPA, LEV, LTG mono and combination therapy. We studied 59 patients. VPA was more commonly used in men (84%) than in women (44%) (p < 0.05). VPA was the initial drug of choice in 39% of patients, followed by LEV (22%) and LTG (14.9%). Thirty-nine patients (66.1%) achieved complete seizure control for at least one year. Fifty patients (84.7)% had partial control, without GTC occurrence, for at least one year. VPA was superior to LTG for complete seizure control (p = 0.03), but not for minor seizure control or pseudoresistance (p > 0.05). Combination therapy was superior to LEV and LTG monotherapy for complete control (p = 0.03), without differences for minor seizures and pseudoresistance outcomes (p > 0.05). Combination therapy not including VPA was also non-inferior to VPA monotherapy in all settings. Combination therapy was superior to LTG and LEV monotherapy in IGE, and may be equally effective including or not VPA. Combination therapy including LTG, LEV, and/or VPA is an effective treatment option after monotherapy failure with one of these ASM in IGE. Dual therapy with LEV–LTG should be considered in monotheraphy failure, to avoid fetal effects of in utero VPA exposure.

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“…[ 58 ] There is also growing evidence that valproate has a synergistic effect with lamotrigine and low-dose valproate combined with lamotrigine may be an option in selected patients with drug-resistant IGEs. [ 59 ]…”

Section: Ige S In W Omen Of R ...mentioning

confidence: 99%

“…In patients who do not respond to valproate, the only effective combination is valproate with lamotrigine and this combination should be tried in all the patients with difficult to control IGEs. [ 59 ] Chances of seizure freedom in patients not responding to a combination of valproate and lamotrigine are remote. Few small series have demonstrated the efficacy of vagus nerve stimulation as palliative therapy in selected patients with drug-resistant IGEs.…”

Section: T Reatment R Esistant ...mentioning

confidence: 99%

Current Concepts in the Management of Idiopathic Generalized Epilepsies

Rathore

Patel

Satishchandra³

2022

Annals of Indian Academy of Neurology

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Idiopathic generalized epilepsies (IGEs) are a group of epilepsies characterized by an underlying genetic predisposition and a good response to antiseizure medicines (ASMs) in the majority of the patients. Of the various broad-spectrum ASMs, valproate is the most effective medicine for the control of seizures in IGEs. However, with the availability of many newer ASMs and evidence showing the high teratogenic potential of valproate, the choice of ASMs for IGEs has become increasingly difficult, especially in women of the child-bearing age group. In this article, we review the current evidence regarding the efficacy and safety of various ASMs in patients with IGEs and provide practical guidelines for choosing appropriate ASMs in various subgroups of patients with IGEs.

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Treatment outcomes in drug resistant juvenile myoclonic epilepsy: Valproate resistance may not be the end of the road

Cited by 6 publications

References 28 publications

Overexpression of Homer1b/c induces valproic acid resistance in epilepsy

Overexpression of Homer1b/c induces valproic acid resistance in epilepsy

Seizure control in mono- and combination therapy in a cohort of patients with Idiopathic Generalized Epilepsy

Current Concepts in the Management of Idiopathic Generalized Epilepsies

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