Abstracts

Rationale:
POLG gene mutations are associated with intractable epilepsies that have a bimodal peak of onset in early childhood (2-4 years) and late adolescence/early adulthood (17-24 years). A wide spectrum of epilepsy phenotypes and presentations have been described, including fulminant cases of RSE and NORSE (defined as de novo RSE without an identifiable cause). The goal of this study was to define the spectrum of age of onset of seizures and RSE in POLG gene variant-associated RSE, and latency from incident seizure to RSE onset.




Methods:
We performed a systematic review of peer-reviewed studies that described individual cases of children or adults with RSE found to have identifiable POLG gene variants. The protocol was registered in PROSPERO. PubMed, Scopus and Embase were used to identify publications through April 2024 that included the search terms “POLG” and “status epilepticus”, “NORSE”, or “FIRES” . Exclusion criteria included absence of individual case data, age of onset of seizure or RSE was unavailable or unclear, or a specific POLG gene variant was not mentioned. Two authors independently screened the title, abstract, and body of each study to identify individual cases of POLG-related RSE and collect age of RSE onset (for all) and age of seizure onset (when available).




Results:
From a total of 166 screened articles, 61 met eligibility criteria for data extraction. Of the 97 RSE cases with age of RSE specified, 90 (92.8%) also specified incident seizure onset. Of the 90 with latency data, median age of seizure onset was 9.5 yrs (Interquartile range [IQR] 1.56-17yrs, full range [FR] 7mo-68yrs) and median RSE onset was 11 yrs (IQR 2-19, FR 7mo-71yrs) [Figure 1]. Median RSE onset latency from incident seizures was 0 (IQR 0-0.156, FR 0-50) [Figure 2]. 72cases (80%) were pediatric-onset (age< 18yrs) and 18 (20%) were adult-onset (age 18yrs+). Latency between seizure and RSE onset was similar between peds and adults [median 0 (IQR 0-0.14, FR 0-50) vs median 0 (IQR 0-1.5, range 0-19), respectively]. 65 cases of NORSE were identified (67% of RSE cases), 13 (20%) of which presented as adults. Median age of onset for all NORSE cases was 7 (FR 7 mos-31 yrs) and RSE onset latency was < 6 months for all NORSE cases by definition.




Conclusions:
This study confirms POLG-associated epilepsy can have a fulminant presentation: incident RSE occurred within 1 year of incident seizure in 75% of published cases of POLG-associated RSE. Moreover, at least 65 cases of POLG-associated NORSE and/or FIRES have been published to date, representing a third of RSE cases detailed in the scientific literature, 20% (n=13) of which presented in adulthood. These findings have important implications for clinical practice: genetic testing should be sent on all cases of NORSE/FIRES, regardless of age of onset.




Funding: No funding to disclose.