Prognosis and management of acute symptomatic seizures: a prospective, multicenter, observational study

Abstract

Background: Acute symptomatic epileptic seizures are frequently seen in neurocritical care. To prevent subsequent unprovoked seizures, long-term treatments with antiseizure medications are often initiated although supporting evidence is lacking. This study aimed at prospectively assessing the risk of unprovoked seizure relapse with respect to the use of antiseizure medications. It was hypothesized that after a first acute symptomatic seizure of structural etiology, the cumulative 12-month risk of unprovoked seizure relapse is ≤ 25%.

Methods: Inclusion criteria were age ≥ 18 and acute symptomatic first-ever epileptic seizure; patients with status epilepticus were excluded. Using telephone and mail interviews, participants were followed for 12 months after the acute symptomatic first seizure. Primary endpoint was the occurrence and timing of a first unprovoked seizure relapse. In addition, neuro-intensivists in Germany were interviewed about their antiseizure treatment strategies through an anonymous online survey.

Results: Eleven of 122 participants with structural etiology had an unprovoked seizure relapse, resulting in a cumulative 12-month risk of 10.7% (95%CI, 4.7%-16.7%). None of 19 participants with a non-structural etiology had a subsequent unprovoked seizure. Compared to structural etiology alone, combined infectious and structural etiology was independently associated with unprovoked seizure relapse (OR 11.1; 95%CI, 1.8-69.7). Median duration of antiseizure treatment was 3.4 months (IQR 0-9.3). Seven out of 11 participants had their unprovoked seizure relapse while taking antiseizure medication; longer treatment durations were not associated with decreased risk of unprovoked seizure relapse. Following the non-representative online survey, most neuro-intensivists consider 3 months or less of antiseizure medication to be adequate.

Conclusions: Even in case of structural etiology, acute symptomatic seizures bear a low risk of subsequent unprovoked seizures. There is still no evidence favoring long-term treatments with antiseizure medications. Hence, individual constellations with an increased risk of unprovoked seizure relapse should be identified, such as central nervous system infections causing structural brain damage. However, in the absence of high-risk features, antiseizure medications should be discontinued early to avoid overtreatment.

Keywords: Acute symptomatic seizure; Antiseizure medication; CNS infection; Cerebrovascular accident; Ischemic stroke; Mortality; Secondary seizure prophylaxis; Seizure risk; Structural brain damage; Unprovoked seizure.

Fig. 1

Flowchart of participant recruitment for the PROSE register. The multicenter recruitment phase was preceded by a monocenter pilot phase at Charité – Universitätsmedizin Berlin. During that monocenter pilot phase, eligible but not successfully recruited patients (‘screening failures’) were not documented. Otherwise, the study protocol was identical

Fig. 2

Durations of antiseizure treatment following acute symptomatic seizures. Durations of initial treatment with antiseizure medication (ASM; dark color) followed by time without antiseizure medication (bright color) in individual participants with acute symptomatic seizure of structural etiology (purple, n = 122) vs. non-structural etiologies (green, n = 19). Grey and black, ASM intake could not be determined because of loss to follow-up (FU) or death. Yellow rhombus, unprovoked seizure relapse. Black vertical lines, median durations of initial ASM treatment were 4.0 months in cases with structural etiology (n = 106) and 0 months in cases with non-structural etiology (n = 14)

Fig. 3

Cumulative risk of unprovoked seizure relapse – reverse Kaplan–Meier plots. A cumulative risk of unprovoked seizure relapse within 12 months of acute symptomatic first seizure. Purple, structural etiology with 95%CI; green, non-structural etiology. Uncorrected log-rank test, p = 0.22. Dashed horizontal line, a cumulative risk of ≤ 25% was initially hypothesized. B cumulative risk of unprovoked seizure relapse depending on the underlying structural pathology. Double line, combined infectious and structural pathology (e.g., cerebral abscess or meningoencephalitis with MR-visible affection of brain tissue; n = 14); dotted line, cerebral venous thrombosis and/or intracerebral hemorrhage (n = 37); dashed line, ischemic stroke (n = 37). Uncorrected log-rank test, p = 0.097

Fig. 4

Results of the online survey on antiseizure treatment strategies. In an anonymous online survey, 122 participating physicians working in neurology, neurosurgery, and/or intensive care were given three fictitious cases of a first acute symptomatic seizure (purple) due to eclampsia/posterior reversible encephalopathy syndrome (PRES), ischemic stroke, and herpes simplex virus (HSV) type-1 encephalitis, plus one fictitious case of a first unprovoked seizure (yellow) following traumatic brain injury. A Recommendations for durations of treatment with antiseizure medication. B Demand for acute (above) and/or follow-up EEG (below) to guide decisions on treatment duration. ^# In case of HSV encephalitis, the ‘1 week’ option was replaced by ‘as long as anti-infective treatment is given’. * Uncorrected Wilcoxon test, p < 0.05 in pairwise comparisons to all other cases