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. Author manuscript; available in PMC: 2021 May 1.
Published in final edited form as: Neuropharmacology. 2019 Aug 1;167:107735. doi: 10.1016/j.neuropharm.2019.107735

Table 2.

Molecular, imaging, and electrophysiologic prognostic/diagnostic biomarkers for epileptogenesis, severe drug-refractory epilepsy and pharmacological and surgical therapy response.

Study design Modality Tissue Analysis platform Biomarker AUC Reference
Prognostic & Diagnostic biomarker for epileptogenesis
Rats which develop epilepsy vs. rats which do not develop epilepsy after electrical stimulation - induced SE Molecular Plasma ELISA Increased total HMGB1 1.00* Walker et al. (2017)
Children with benign childhood epilepsies vs. controls Molecular Hair ECLIA Increased hair cortisol within 24 h after the 1st seizure 0.817 Stavropoulos et al. (2017)
Rats with or without epilepsy after hyperthermia-induced SE at P11 Imaging  Brain tissue - amygdala, thalamus T2 MRI T2 relaxation time ⇩ in basolateral amygdala

T2 relaxation time ⇩ in medial amygdala

T2 relaxation time ⇩ in medial thalamus
0.910


0.820


0.780
Choy et al. (2014)
Rats with or without increased seizure susceptibility in the PTZ test after TBI Imaging Brain tissue - amygdala, hippocampus, thalamus T2-w DTI MRI T1σ in S1 cortex T1σ in Prh cortex T2 in thalamus T1σ in HC 0.881
0.929
0.893
0.857
Pitkänen and Immonen (2014)
P21 rats which develop epilepsy vs. P21 rats which do not develop epilepsy after systemic pilocarpine -induced SE Imaging Septal pole of the hippocampus MRS Increased hippocampal mIns/tCr on day 72 post-SE 0.830 Pascente et al. (2016)
Patients with vs. without epilepsy after TBI Imaging Cerebral cortex Gadolinium-MRI Area of gadolinium leakage around cortical lesion after TBI 0.850 Data by A Friedman in Pitkänen et al. (2016)
Rats with epilepsy vs. no epilepsy after lateral fluid-percussion induced TBI Electrophysiology Brain Sleep-EEG Shortening of the duration of sleep spindles occurring at transition from N3 to REM 0.907 Andrade et al. (2016)
HFOs differentiate rats which develop epilepsy after intrahippocampal kainite injection or lateral fluid-percussion injury from those that will not Electrophysiology Brain EEG Presence of HFOs during the first 2 post-injury weeks no data Bragin et al. (2004, 2017)
Diagnostic biomarker for epileptogenesis

or

Prognostic biomarker for development epilepsy in rodents with brain injury
Mice with or without epilepsy after i.c.v. injection of albumin, TGF-β, or IL-6

Rats with or without epilepsy after photothrombotic stroke

Rats with or without epilepsy after bilateral hippocampal electrical stimulation - induced SE
Brain Electrophysiology

Theta dynamics in EEG on days 2-4
Absolute slope value of dynamic change in theta band

Distance from the mean control group
0.910

0.997
Milikovsky et al. (2017)
Patients with acute anterior circulation ischemic stroke developing epilepsy vs. not developing epilepsy Electrophysiology Brain EEG Background asymmetry

Interictal epileptiform activity
0.810 Bentes et al. (2018)
Three models Electrophysiology Brain EEG Decrease in non-linear dynamics dimension in EEG/ECoG ≥0.886 in different models Rizzi et al. (2019)
Prognostic/Diagnostic biomarkers for progression of epilepsy (drug-refractoriness) or epileptogenicity
Patients with high (median ≥4 sz/month) vs. low (<4) seizure frequency undergoing temporal lobectomy with amygdalohippocampectomy due to intractable TLE Molecular Lateral temporal cortex Affymetrix GeneChip Human Gene 1.0 ST Array Relative down-regulation of 35 genes and up-regulation of 5 genes in ≥4 sz/month group ≥0.904*

* logistic regression
McCallum et al. (2016)
Drug-sensitive vs. drug-refractory patients Molecular Plasma ELISA Total HBMG1 0.990 Walker et al. (2017)
Patients with benign vs. refractory mTLE Imaging Brain tissue - temporal lobe grey and white matter DTI MRI ⇧ ipsilateral MD
⇩ ipsilateral FA
⇩ ipsilateral HC vol
ipsilateral HS
FA+HS
0.670
0.770
0.670
0.660
0.768
Labate et al. (2015)
Diagnostic biomarker for localization of seizure onset zone (tissue epileptogenicity)
Intrahippocampal kainate model of TLE and lateral FPI model of PTE in rat

Seizure onset zone vs. other brain areas in humans evaluated for epilepsy surgery
Brain Electrophysiology

iHC or iECEEG scalp EEG
occurrence of HFOs

stereotypical HFOs with waveform similarity

Spikes x HFO
no data Bragin et al. (1999)

Liu et al. (2018)

Roehri et al. (2018)
Predictive biomarker for antiepileptogenic treatment effect
Post-SE rats treated with vehicle vs. anakinra+BoxA+ifenprodil polytherapy Molecular Plasma ELISA Prevention in the increase in total HMGB1 ≥0.900* Walker et al. (2017)
Predictive biomarker for cure after epilepsy surgery
Patients undergoing temporal lobectomy with amygdalohippocampectomy due to intractable TLE with seizure-free vs. non-seizure-free outcome Molecular Lateral temporal cortex Affymetrix GeneChip Human Gene 1.0 ST Array Relative down-regulation of ZNF852 CDCP2 PRRT1 FLJ41170 and 7 RNA probes in sz-free subjects

0.958*
0.941*
0.942*
0.908*

* logistic regression
Gallek et al. (2016)

Abbreviations: AUC, area under the curve; DTI, diffusion tensor imaging; ECLIA, electrochemiluminecence assay; EEG, electroencephalogram; ELISA, enzyme linked immune assay; HFO, high-frequency oscillation; HMGB1, high-mobility group box 1 protein; i.c.v., intracerebroventricular; i.p., intraperitoneal; MRI, magnetic resonance imaging; mTLE, medial temporal lobe epilepsy; P, postnatal day; PTE, post-traumatic epilepsy; PTZ, pentylenetetrazol; SE, status epilepticus; T2, a time constant for the decay of transverse magnetization arising from natural interactions at the atomic or molecular levels; TBI, traumatic brain injury; TLE, temporal lobe epilepsy