Are Generalized Tonic–Clonic Seizures Really “Generalized”?

Abstract

Cortical and Subcortical Networks in Human Secondarily Generalized Tonic–Clonic Seizures. Blumenfeld H, Varghese GI, Purcaro MJ, Motelow JE, Enev M, McNally KA, Levin AR, Hirsch LJ, Tikofsky R, Zubal IG, Paige AL, Spencer SS. Brain 2009;132(Pt 4):999–1012. Generalized tonic–clonic seizures are among the most dramatic physiological events in the nervous system. The brain regions involved during partial seizures with secondary generalization have not been thoroughly investigated in humans. We used single-photon emission computed tomography (SPECT) to image cerebral blood flow (CBF) changes in 59 secondarily generalized seizures from 53 patients. Images were analyzed using statistical parametric mapping to detect cortical and subcortical regions most commonly affected in three different time periods: 1) during the partial seizure phase prior to generalization; 2) during the generalization period; and 3) postictally. We found that in the pregeneralization period, there were focal CBF increases in the temporal lobe on group analysis, reflecting the most common region of partial seizure onset. During generalization, individual patients had focal CBF increases in variable regions of the cerebral cortex. Group analysis during generalization revealed that the most consistent increase occurred in the superior medial cerebellum, thalamus, and basal ganglia. Postictally, there was a marked progressive CBF increase in the cerebellum that spread to involve the bilateral lateral cerebellar hemispheres, as well as CBF increases in the midbrain and basal ganglia. CBF decreases were seen in the fronto-parietal association cortex, precuneus, and cingulate gyrus during and following seizures, similar to the “default mode” regions reported previously to show decreased activity in seizures and in normal behavioral tasks. Analysis of patient behavior during and following seizures showed impaired consciousness at the time of SPECT tracer injections. Correlation analysis across patients demonstrated that cerebellar CBF increases were related to increases in the upper brainstem and thalamus, and to decreases in the fronto-parietal association cortex. These results reveal a network of cortical and subcortical structures that are most consistently involved in secondarily generalized tonic–clonic seizures. Abnormal increased activity in subcortical structures (cerebellum, basal ganglia, brainstem, and thalamus), along with decreased activity in the association cortex may be crucial for motor manifestations and for impaired consciousness in tonic–clonic seizures. Understanding the networks involved in generalized tonic–clonic seizures can provide insights into mechanisms of behavioral changes, and may elucidate targets for improved therapies.