Toward new paradigms of seizure detection

Abstract

Great effort has been made toward defining and characterizing the pre-ictal state. Many studies have pursued the idea that there are recognizable electrographic (EEG-based) features which occur before overt clinical seizure activity. However, development of reliable EEG-based seizure detection and prediction algorithms has been difficult. In this review, we discuss the concepts of seizure detection vs. prediction and the pre-ictal "clinical milieu" and "EEG milieu". We proceed to discuss novel concepts of seizure detection based on the pre-ictal "physiological milieu"; in particular, we indicate some early evidence for the hypothesis that pre-ictal cell swelling/extracellular space constriction can be detected with novel optical methods. Development and validation of optical seizure detection technology could provide an entirely new translational approach for the many patients with intractable epilepsy.

Figure 1. In vivo cortical surface photobleaching detects pre-ictal ECS constriction

Top left. In vivo loading of brain ECS by fluorescein-dextrans. a. Brain surface exposure following craniectomy showing cortical blood vessels and intact dura. b. Transdural loading of brain ECS with ACSF solution of fluorescein-dextran. c. Fluorescence image of cortical surface after dye loading (scale bar, 1 mm). d. Coronal 300 μm brain slice obtained ex vivo following loading demonstrates fluorescence loading of cortex (scale bar, 1 mm). Arrowhead, cortical blood vessel; asterisk, white matter. Top right. Photobleaching apparatus. A laser beam is modulated by an acousto-optic modulator and directed onto the surface of the cortex using a dichroic mirror and objective lens. Emitted fluorescence is focused through a pinhole and detected by a gated photomultiplier (PMT). Bottom. Upper traces: Electroencephalographic recordings before and after intraperitoneal injection of PTZ (100 mg/kg). Lower traces: Fluorescence recovery curves for 70-kD fluorescein-dextran before PTZ administration, after PTZ but prior to electroencephalographic seizure activity, and following seizure activity. Note the change in fluorescence recovery signal prior to EEG seizure onset, suggesting ECS constriction prior to seizure onset and providing the potential for seizure detection. Modified from [45].

Figure 2. Spatial frequency domain imaging (SFDI) detects pre-ictal reduction in optical scattering

Left: SFDI system. BPF, bandpass filter. CCD, charge-cooled device. DMD, digital micromirror device. M, mirror. Middle: Optical scattering coefficient (blue) and simultaneous EEG demonstrates a reduction in optical scattering coefficient (at 850 nm) (dashed blue line, 2 S.D. reduction in scattering coefficient) following convulsant administration (PTZ) but prior to electrographic seizure onset (dashed green line, 2 S.D. increase in EEG power). SFDI-derived total hemoglobin concentration (red) demonstrates cortical hyperperfusion following seizure onset. Right: optical lead time defined as time at optical “trigger” (2 S.D. change in optical scattering from baseline) to time of EEG seizure onset (analyzed blindly and by power analysis of EEG epochs). Mean optical lead time was 118 sec (n=5). Courtesy of Owen et al. (unpublished data).

Figure 3. Spectral domain OCT setup for in vivo OCT imaging of mouse brain

Left: schematic of SD-OCT setup. The light source, super luminescent diodes centered at 1310 nm, is split between the sample and reference arm. The reflected light from these arms recombines in the detector arm and the resulting spectrum is imaged onto the detector array. A Fourier transform of the spectrum generates the depth profile information. Middle: OCT imaging of mouse cortex can be done through a thinned-skull preparation and does not require craniectomy. Right: sample sagittal OCT image of mouse cortex (image dimension: 3×2 mm). The entire depth of the cerebral cortex and some subcortical structures lie within the optical interrogation volume and can be observed serially for reflectance intensity changes in vivo. Courtesy of Eberle et al. (unpublished data).

Figure 4. Reduction in OCT scattering signal prior to seizure onset

Stable baseline OCT images were obtained for 5 minutes prior to administration of PTZ (red line). Inset shows region of interest (ROI) in brain cortex OCT image in which near-infrared (NIR) backscatter intensity was analyzed at every time point (every 5 seconds or 0.2 Hz) indicated by the blue circles. Approximately 10% reduction in intensity was observed prior to generalized seizure onset at 10 minutes (black line). These data provide proof-of-principle for real-time OCT-based seizure detection with excellent optical stability, sensitivity and temporal resolution. Courtesy of Eberle et al. (unpublished data).