Abstract & Commentary
Is it Possible to Have Idiopathic Epilepsy Without Seizures?
By Douglas Labar, MD, PhD
Professor of Neurology, Weill Cornell Medical College
Dr. Labar reports no financial relationships relevant to this field of study.
SYNOPSIS: In a functional MRI study, it appears that healthy siblings of patients with juvenile myoclonic epilepsy have hyper-connectivity between motor brain regions that may result in hyper-excitable responses.
SOURCE: Wandschneider B, et al. Motor co-activation in siblings of patients with juvenile myoclonic epilepsy: An imaging endophenotype? Brain 2014;137:2469-2479.
While a history of recurrent seizures is obligate for the diagnosis of idiopathic generalized epilepsies (IGE), one may now wonder whether seizures are only the tip of the iceberg of atypical brain functional organizational features in these syndromes, for which a polygenetic underlying etiology seems likely.
Functional magnetic resonance imaging (fMRI) has recently revealed a pattern of motor cortex activation with a working memory paradigm that differs significantly between normal subjects and unaffected siblings of patients with juvenile myoclonic epilepsy (JME), a sub-type of IGE.1 Study participants were asked to move a joystick to a randomly presented baseline dot position on a computer screen ("0-back" condition) or, to test working memory, either move the joystick to the immediately prior presented dot position ("1-back" condition) or to the position before that ("2-back" condition). fMRI activity with the "0-back" baseline task was subtracted from the "1-back" or "2-back" task activities, thus isolating the fMRI changes associated with the working memory components of the later tasks. Because all the tasks required hand movements of the joystick, motor cortex activation was always seen in all test conditions in normal subjects and JME siblings. On both working memory tasks (compared with the baseline task), prefrontal and parietal areas were activated similarly in normal subjects and JME siblings. However, with the "1-back" memory test, the normal subjects deactivated primary motor cortex more than the JME siblings, and with the "2-back" memory task, the normal subjects deactivated primary motor and supplementary motor cortices more than the JME siblings. Stated differently, when deploying working memory, the JME siblings failed to deactivate primary and supplementary motor areas in the expected manner. Similar findings had previously been seen in JME patients.2 The authors propose that abnormal hyper-connectivity between prefrontal cognitive and motor system cortical areas may contribute to the occurrence of cognitively triggered myoclonic jerks in JME patients.
Several other studies also have demonstrated a variety of unique ways in which unaffected siblings of patients with IGE differ from normal subjects. In the IGE siblings, these include: 1) increased motor cortex excitability as demonstrated by transcranial magnetic stimulation (TMS),3 2) deficient nonverbal reasoning, attention, and working memory,4 and 3) presence of electroencephalographic (EEG) spikes (in 17%) and high amplitude somatosensory evoked potentials (in 21%).5 Some authors have suggested that these findings may be considered endophenotypes of IGE.
Endophenotypes are intermediate conditions more common in family members of ill patients than in the general population. Such endophenotypes are biological phenotypes which, while often requiring extra targeted testing to be demonstrated, may be closer to the genotypes than the more severe clinical epilepsy syndromes. Identification of endophenotypes thus may contribute significantly to the identification of underlying susceptibility genes. Finally, more and better characterization of IGE endophenotypes may influence our overall concepts concerning these illnesses. While we would never diagnose an unaffected IGE sibling who has abnormal fMRI motor cortex connectivity, TMS cortical motor hyper-excitability, working memory deficits, or EEG spikes as having "IGE without seizures," it would be hard to dispute that such a clinical-epilepsy-unaffected IGE sibling does have some degree of atypical brain functional organization attributable to susceptibility genes shared with the their clinical-epilepsy-affected sibling.
- Wandschneider B, et al. Motor co-activation in siblings of patients with juvenile myoclonic epilepsy: An imaging endophenotype? Brain 2014;137:2469-2479.
- Vollmar C, et al. Motor system hyper-connectivity in juvenile myoclonic epilepsy: A cognitive functional magnetic resonance imaging study. Brain 2011;134:1710-1719.
- Badawy R, et al. Capturing the epileptic trait: Cortical excitability measures in patients and their unaffected siblings. Brain 2013;136(Pt 4):1177-1191.
- Chowdhury F, et al. Impaired cognitive function in idiopathic generalized epilepsy and unaffected family members: An epilepsy phenotype. Epilepsia 2014;55:835-840.
- Atakli D, et al. Somatosensory evoked potentials and EEG findings in siblings of juvenile myoclonic epilepsy patients. Epileptic Disord 1999;1:173-177.