WONOEP appraisal: Biomarkers of epilepsy-associated comorbidities

Abstract

Neurologic and psychiatric comorbidities are common in patients with epilepsy. Diagnostic, predictive, and pharmacodynamic biomarkers of such comorbidities do not exist. They may share pathogenetic mechanisms with epileptogenesis/ictogenesis, and as such are an unmet clinical need. The objectives of the subgroup on biomarkers of comorbidities at the XIII Workshop on the Neurobiology of Epilepsy (WONOEP) were to present the state-of-the-art recent research findings in the field that highlighting potential biomarkers for comorbidities in epilepsy. We review recent progress in the field, including molecular, imaging, and genetic biomarkers of comorbidities as discussed during the WONOEP meeting on August 31-September 4, 2015, in Heybeliada Island (Istanbul, Turkey). We further highlight new directions and concepts from studies on comorbidities and potential new biomarkers for the prediction, diagnosis, and treatment of epilepsy-associated comorbidities. The activation of various molecular signaling pathways such as the "Janus Kinase/Signal Transducer and Activator of Transcription," "mammalian Target of Rapamycin," and oxidative stress have been shown to correlate with the presence and severity of subsequent cognitive abnormalities. Furthermore, dysfunction in serotonergic transmission, hyperactivity of the hypothalamic-pituitary-adrenocortical axis, the role of the inflammatory cytokines, and the contributions of genetic factors have all recently been regarded as relevant for understanding epilepsy-associated depression and cognitive deficits. Recent evidence supports the utility of imaging studies as potential biomarkers. The role of such biomarker may be far beyond the diagnosis of comorbidities, as accumulating clinical data indicate that comorbidities can predict epilepsy outcomes. Future research is required to reveal whether molecular changes in specific signaling pathways or advanced imaging techniques could be detected in the clinical settings and correlate with epilepsy-associated comorbidities. A reliable biomarker will allow a more accurate diagnosis and improved treatment of epilepsy-associated comorbidities.

Keywords: Cognition; Depression; Epilepsy; Imaging; Neurobehavioral comorbidities; Polymorphisms.

Figure 1.

Phosphorylated STAT3 levels in injured hippocampus correlate with injury severity and cognitive and motor performance after controlled cortical impact (CCI) in mice. (A): Representative Western blots of protein homogenates from whole ipsilateral hippocampus (relative to side of CCI) of mice at 6–72 h, 1 week, and 16 weeks after CCI probed with pSTAT3 and STAT3 antibodies. The pSTAT3 levels were higher in both the severe CCI (CCI-S) and moderate CCI (CCI-M) injured groups from 6 to 72 h postinjury when compared to sham-injured controls. Notably at 6 h post-injury, the CCI-S group had statistically higher levels of pSTAT3 than those detected in the CCI-M group. (B): Quantification of average time spent exploring the new object during Novel Object Recognition testing shows that the CCI-S injured mice performed statistically worse than the sham-injured controls or CCI-M injured mice. (C): Quantification of average time spent on the rotarod apparatus showed that the CCI-S injured mice performed significantly worse than the CCI-M injured mice or sham-injured controls. *p < 0.05, **p < 0.01.

Figure 2.

FDG-PET coregistration with MRI in a patient with ASD, intellectual disability, and epilepsy. Representative images showing the color spectrum correspondent to FDG uptake, with red indicative of high uptake and blue indicative of low uptake, in a patient with ASD, intellectual disability, and TSC. Note several areas of decreased FDG uptake in the bilateral temporal lobes (A and B).

Figure 3.

Clinical and experimental evidence showing the utility of comorbidity assessment to predict epilepsy outcomes. (A): Bar gram depicting the evidence that the presence of psychiatric problems before surgery in patients with temporal lobe epilepsy is associated with an unfavorable postsurgical seizure freedom (non-Engel class IA). (B): Cognitive performance in epileptic rats as assessed by Morris water maze. Epileptic rats not responsive to phenobarbital (PB) (Nonresponder) displayed more marked learning deficits than epileptic rats responsive to PB (Responder), as assessed by the longer escape latency measured (i.e., the time needed to reach the hidden platform). Sham-implanted rats are used as controls.