Rationale: Patients with severe motor and intellectual disabilities (SMID) have very frequent
tonic or tonic-clonic seizures, which are very resistant to various anti-seizure medicines (ASMs) and polytherapy. The author reported that LTG, PER, ZNS and potassium bromide (KBr) showed
> 50% responder rate (RR) for focal onset tonic or tonic-clonic seizures in
> 80% of the treated patients (annual meetings of 2021 Japan Epilepsy Society and 2019 Japanese Society of Child Neurology). The major mechanism of action (MOA) of LTG includes inhibition of sodium channels (Na-Ch), N-type calcium channels (Ca-Ch) and glutamate (GLU) release. ZNS inhibits Na-Ch, T-type Ca-Ch and GLU release and potentiate GABA-mediate inhibition. PER strongly inhibits AMPA-induced response. KBr hyperpolarizes postsynaptic membrane. It seems that ASMs with three MOA (inhibition of NA-Ch, CA-Ch and GLU release) or hyperpolarization of postsynaptic membrane or strong inhibition of AMPA response are most effective for tonic or tonic-clonic seizures. Regarding interaction of ASMs, add-on or dose-up of VPA raises LTG and PB levels, and CLB raises VPA level. PB, PHT and CBZ reduce VPA、LTG、PER and ZNS levels, which, in turn, discontinuation or reduction of PB, PHT or CBZ raise these ASMs level. Seizure reduction can be expected by rationale polytherapy based on these MOA and interaction.
Methods: Thirty-three resident patients with SMID in our institute, aged 4 to 64 years, who had average 2 to 78 tonic or tonic-clonic seizures per month despite taking 2 to 5 SAMs, were applied to rationale polytherapy based on above MOA and interaction. Average monthly seizure frequency during 3 months before the intervention between February 2018 and March 2021 and average monthly seizure frequency during the latest 3 months between January and March 2022 were compared.
Results: Based on MOA, original ASMs were switched to new ASMs with above MOA in 41 cases: 23 cases to LTG（from LEV7，VPA4, CZP3, CBZ2, ZNS2, PHT2, PB1, CLB1 and GBP), 14 cases to PER (from VPA2, CZP2, CBZ2, ZNS2, PB２, LEV1, PHT1, CLB1 and LTG1), 2 cases to KBr (from CLB1 and PRM1) and 2 cases to PB2 (from VPA1 and CBZ1). New ASMs with above MOA were added to original ASMs in 6 cases (LTG2､PER1､KBr1 and VPA1). Original ASMs were increased in 2 cases (VPA1 and LTG1). To increase target ASM level, original ASMs were changed based on interaction in 37 cases. Original ASMs were discontinued in 28 cases: PHT in 13 cases to raise LTG 5, PER 5 and VPA 3 cases, PB in 11 cases to raise LTG 6, PER 2, VPA 2 and TPM 1 case, and CBZ in 4 cases to raise LTG, PER, PB and VPA. New ASM was added in 4 cases: CLB in 3 cases to raise VPA and VPA in 1 case to raise LTG. Original ASMs were increased in 3 cases of VPA to raise LTG. Original ASMs were decreased in 2 cases of PB to raise LTG and VPA. Average monthly seizure during 3 months before intervention, 2~78 times（mean, 15.5), resulted in 0~10 times (mean, 1.4) during the latest 3 months.
Conclusions: Rationale polytherapy based on MOA and interaction of ASM is effective for drug resistant tonic or tonic-clonic seizures in patients with SMID.
Funding: None