Different pharmacoresistance of focal epileptic spasms, generalized epileptic spasms, and generalized epileptic spasms combined with focal seizures

Abstract

Objective: Among standard treatments for infantile spasms, adrenocorticotropic hormone (ACTH) is reported as the best treatment, but ACTH is ineffective in one-half of the patients. To establish precision medicine, we examined pharmacoresistance of focal epileptic spasms (ES), generalized ES, and generalized ES combined with focal seizures, diagnosed based on the revised seizure classification of ILAE in 2017.

Methods: We conducted a retrospective nationwide study in Japan on the long-term seizure outcome of ES. Long-term seizure outcome was evaluated by seizure-free rate, seizure-free period, and Kaplan-Meier curve. Seizure-free was defined as seizure control for longer than 2 months.

Results: From the medical history of 501 patients, 325 patients had generalized ES only (GES group) at the start of the first treatment, 125 patients had generalized ES after focal seizure onset (FS-GES group), seven patients had focal ES after focal seizure onset (FS-FES group), and 24 patients had generalized ES combined with focal seizures after focal seizure onset (FS-GES + FS group). Seizure-free period of ES (generalized ES and focal ES) [mean (95% confidence interval)] was 2.7 (0.0-5.4) months in GES group, 1.1 (0.1-2.2) months in FS-GES group, 1.0 (0.2-1.9) months in FS-GES + FS group, and 0.1 (-0.2-0.5) months in FS-FES group. Seizure-free rate, seizure-free period, and Kaplan-Meier curve of generalized ES were almost the same in GES group and FS-GES group, with characteristics of superior response to ACTH. Mean seizure-free period of generalized ES combined with focal seizures was significantly shorter in FS-GES + FS group than in GES group. Mean seizure-free period of focal ES in FS-FES group was extremely short with exceedingly early relapse.

Significance: Pharmacoresistance was different in generalized ES, focal ES, and generalized ES combined with focal seizures. ES with focal features or with focal seizures may have focal lesions, thus consider surgical options earlier in the course.

Keywords: combined generalized epileptic spasms; focal epileptic spasms; generalized epileptic spasms; infantile spasms; seizure outcome.

FIGURE 1

Selection of patients and definition of groups based on seizure evolution and seizure type in this study. A, Patient recruitment. Among patients receiving care in eleven hospitals nationwide, 526 patients with a history of epileptic spasms were registered. B, Diagnosis of seizure types. Seizure types at the start of ES were diagnosed in the majority of patients by video‐EEG monitoring and in a few patients by clinical semiology of seizures. AAB, atypical absence; ES, epileptic spasms; FES, focal epileptic spasms; FS, focal seizure; GES, generalized epileptic spasms; GTC, generalized tonic‐clonic seizure

FIGURE 2

Seizure outcome of ES (generalized or focal ES) in all groups. A, Seizure‐free period of ES. SFP of ES in the first treatment. Bars show mean with 95% confidence interval of SFP after the start of the first treatment for ES. B, Kaplan‐Meier curves of ES. Probability of control of ES by various drugs is shown. ACTH, ACTH therapy; B6, vitamin B6 (pyridoxal phosphate hydrate); CBZ, carbamazepine; CZP, clonazepam; ES, epileptic spasms; PB, phenobarbital; SFP, seizure‐free period; VPA, valproate; ZNS, zonisamide

FIGURE 3

Comparison of seizure outcome of ES (generalized or focal ES) among four groups. A, Seizure outcome of ES. ES + denotes no control of ES and ES‐denotes control of ES. B, Seizure‐free period of ES. Seizure‐free periods (months) of ES are compared between four groups. Bars show mean with 95% confidence interval of seizure‐free period after the start of treatment for ES. C, Kaplan‐Meier curves of ES. Probabilities of control of ES in four groups are shown. ES, epileptic spasms; GES, generalized ES only at epilepsy onset; FS‐GES, focal seizures at epilepsy onset evolving to generalized ES; FS‐FES, focal seizures at epilepsy onset evolving to focal ES; FS‐GES + FS, focal seizures at epilepsy onset evolving to generalized ES and focal seizures

FIGURE 4

Seizure outcome of four groups treated by various drugs. Bars show mean with 95% confidence interval of seizure‐free period (SFP) after the start of first treatment for ES (A, C, E, and G). Probabilities of control of ES by ASMs in four groups are shown (B, D, F and H). FS‐FES, focal seizures at epilepsy onset evolving to focal ES; FS‐GES, focal seizures at epilepsy onset evolving to generalized ES; FS‐GES + FS, focal seizures at epilepsy onset evolving to generalized ES and focal seizures; GES, generalized ES only at epilepsy onset; ACTH, ACTH therapy; B6, vitamin B6 (pyridoxal phosphate hydrate); CBZ, carbamazepine; CLB, clobazam; CZP, clonazepam; DZP, diazepam; IVIg, intravenous immunoglobulin therapy; KBr, potassium bromide; LEV, levetiracetam; NZP, nitrazepam; PB, phenobarbital; PRM, primidone; TRH, thyroid hormone‐releasing hormone; VPA, valproate; ZNS, zonisamide

FIGURE 5

Seizure outcome of generalized epileptic spasms (GES) and focal seizures (FS) at the last observation of first treatment in FS‐GES + FS group (focal seizures at epilepsy onset evolving to generalized ES and focal seizures). A, Seizure‐free period of focal seizures. Bars show mean with 95% confidence interval of SFP after the start of first treatment for ES. B, Seizure‐free periods of GES and focal seizures in individual patients. ACTH, ACTH therapy; B6, vitamin B6 (pyridoxal phosphate hydrate); CLB, clobazam; DZP, diazepam; KBr, potassium bromide; PB, phenobarbital; VPA, valproate; ZNS, zonisamide