1.  (Abst. 1.054), 2014
 TREATMENT OF CONVULSIVE STATUS EPILEPTICUS IN AN ANIMAL MODEL OF
GLUCOSE TRANSPORTER TYPE 1 DEFICIENCY (G1D) SYNDROME.
 Authors: Cary Trent,Levi Good, Dorothy Kelly, Saima Kayani, Juan Pascualand Karthik Rajasekaran
 Content:
RATIONALE:Convulsive status epilepticus (CSE) leads to increased energy demand and is associated
with significant hypermetabolism in the brain and up-regulation of the facilitative glucose transporter type
1 (GLUT1). Mutations in the SLC2A1 gene lead to diminished GLUT1 function causing an epileptic
encephalopathy (G1D) that may account for as many as 1% of all idiopathic generalized epilepsies (IGE).
The frequency of CSE in IGE is suggested to be low and highly responsive to therapy; however, drugs
used to treat CSE, including diazepam (DZP) and phenobarbital (PB),inhibit GLUT1 function in in
vitro assays. This suggests the possibility that in G1D patients with CSE, treatment with DIA or PB may
negatively affect prognosis by exacerbating cerebralmetabolic deficits. We investigated the efficacy of
DZP and PB to terminate CSE in a mouse model of G1D syndrome.METHODS:Adult male G1D and
age-matched wild-type (WT) mice were injected intraperitoneally (IP) with pilocarpine (PILO) and the
onset and termination of CSE was determined using the Racine scale. The efficacy of IP DZP and PB to
stop CSE was studied at two time points after CSE onset: early (<2 min) and late CSE (30 min). Total
duration of observation was 3 hours from PILO injection. Animals were considered successfully treated if
CSE was terminated for atleast 30 min without recurrence for the remaining duration of
observation.RESULTS:Threshold dose to induce CSE was determined using graded doses of PILO (100-
320 mg/kg). PILO threshold doses were 155 mg/kg for G1D and 220 mg/kg for WT mice, with ED50
values of 141.5 mg/kg and 182.5 mg/kg (p<0.05) respectively. A supra-threshold dose of PILO (270
mg/kg) with comparable latency to CSE onset in WT (10.33±1.5 min, n=7) and G1D (14.1±4 min, n=8)
mice was chosen for treatment studies. In WT mice, with increasing CSE duration, there was a 10-fold
reduction in DZP efficacy to stop CSE (ED50, 3.14 vs. 28.9 mg/kg). Early treatment with DZP (3 mg/kg)
stopped CSE in 100% of WT (n=5), but only 25% of the G1D (n=4) animals. Late treatment with DZP
(30 mg/kg) stopped CSE in 50% of WT (n=2) but none of the G1D (n=3) animals. In WT animals, early
treatment with PB at 30 mg/kg failed to stop CSE (n=4); however at 60 mg/kg, PB stopped CSE in 66.7%
of animals (n=6). The ED50 value of PB to stop CSE increased with increasing CSE duration (52 mg/kg
to 133.6 mg/kg). Similar to WT, early treatment with PB (50 mg/kg) stopped CSE in 50% of G1D
animals (n=4). However,late treatment with PB (90 mg/kg) stopped CSE in only 22% of WT (n=9) but
none of the G1D (n=5, p<0.05) animals. With PB (90 mg/kg) G1D animals (5/5) exhibited significant
respiratory depression compared to WT animals (3/8).CONCLUSIONS:G1D animals appear to be more
susceptible to CSE and less responsive to DZP and PB. While ongoing power analyses of EEG recordings
and histopathological studies will revealwhether treatment with DZP and PB aggravated CSE and its
outcomes in the G1D animals, the current data suggest the need for greater awareness and caution in
treating G1D patients who present with CSE.