Epilepsy – Neuronal Properties In Focal and Parafocal Regions in Intractable Neocortical Epilepsy of Pediatric Patients

 

Worldwide, epilepsy afflicts 50 million patients with an incidence in developed countries of 50-70 per 100,000. Only 54% of patients with epilepsy of all age groups will gain complete seizure control, whereas the remainder develop intractable seizures. Neurological surgery becomes the last hope to control these seizures. Unfortunately not all patients who undergo surgery will achieve seizure freedom with current surgical techniques. Thus, understanding potential mechanistic differences between different patient populations to better predict those patients who will likely have a good surgical outcome is of critical importance (for more details see Marcuccilli et al. 2010). The Ramirez laboratory is interested in this clinically important issue. We tested the hypothesis that focal and parafocal neocortical tissue from pediatric patients with intractable epilepsy exhibit cellular and synaptic differences. We characterized the propensity of neocortical neurons to generate (a) voltage-dependent bursting and (b) synaptically driven paroxysmal depolarization shifts (Marcuccilli et al. 2010, Martell et al. 2010). We employ neocortical slices that are prepared from tissue resected from patients with intractable epilepsy. Multiunit network activity and simultaneous whole-cell patch recordings are made from slices that exhibit seizure-like activity and concomitant bursting in intracellularly recorded cortical neurons.  These electrophysiological characterizations reveal functional differences between focal and parafocal tissue in patients with severe cortical dysplasia.  (For a movie example, see  Human_brain_slices video.)

 

The figure to the left shows recordings from two pyramidal neurons with different intrinsic discharge properties. The neuron in B can be characterized as a regular spiking neuron, the neuron in C exhibits properties of a voltage-dependent burster. Click here fora movie that shows a bursting neuron that was recorded in the focal tissue and subsequently a non-bursting “regular spiking” neuron in the parafocal tissue of the same patient.

 

 

Rational Pharmacotherapy.  The ability to evoke seizures in the excised tissue from pediatric patients with intractable epilepsy allows us to test different anti-epileptic drugs on the tissue of an individual patient. Using this approach, the Ramirez lab can confirm that drugs that do not abolish seizures in the patient do not abolish the seizure-like activity in the slice preparation. Interestingly in some instances we were able to block seizure-like activity in the slice preparation and then confirm that this particular drug indeed abolished seizure activity in this particular patient. This is a very promising approach that can be used to develop novel approaches of rational pharmacotherapy.

The figure below depicts this approach: The seizure focus is determined using subdural cortical recordings (see ECoG on the left upper panel depicting the onset of a seizure). Subsequently the seizure focus is surgically removed (see open brain surgery with the electrodes placed on the neocortex). The excised tissue is then cut into slices. Following the preparation of a cortical slice, neuronal activity is characterized electrophysiologically and antiepileptic drugs are tested on intracellular or extracellularly recorded neocortical activity. In the example shown an antiepileptic drug abolished bursting activity in the slice and subsequently abolished seizure activity in the child (see seizure free EEG on left lower panel).