TMS for the Diagnosis and Treatment of Epilepsy
TMS for the Diagnosis and Treatment of Epilepsy
Converging lines of evidence suggest that epilepsies are in general characterized by cortical hyperexcitability in a syndrome-specific manner. Recently, this concept has been extended to include asymptomatic siblings of patients with epilepsy as well.
Badawy et al. reported that cortical excitability is higher in asymptomatic siblings of patients with focal and particularly generalized epilepsy. The pattern of cortical hyperexcitability, essentially reflecting defective ICI mechanisms, was similar in siblings of patients with various epilepsy syndromes, raising the possibility that genetic factors predispose to both generalized and focal epilepsies and a complex genetic/environmental interaction determines the ultimate clinical phenotype.
In idiopathic generalized epilepsy (IGE), a study of 30 drug-naïve patients [10 patients with juvenile myoclonus epilepsy (JME), eight with juvenile absence epilepsy and 12 with generalized tonic–clonic seizures only] concluded that cortical excitability was significantly enhanced in all epilepsy syndromes as evidenced by reduced CMT values and decreased ICI at short and particularly at long ISIs. Patients with JME demonstrated significantly higher levels of cortical excitability compared with the other two groups of patients, thereby differentiating JME from other IGE syndromes. This view is also supported by a meta-analysis of 14 trials involving 265 drug-naïve IGE patients and 424 control subjects, which concluded that only patients with JME had reduced CMT values compared with controls. These observations are in line with the recently proposed construct of 'system epilepsies' and set JME as an archetype within this conceptual scheme. However, Puri et al. did not detect reduced CMT in 30 drug-naïve JME patients. These inconsistent results in well characterized IGE cohorts and in the absence of confounding factors, such as AED intake, are probably related to the small magnitude of the threshold decrease and the precision of threshold measurements. Indeed, according to the Internation Federation of Clinical Neurophysiology guidelines, adaptive methods based on threshold-tracking algorithms provide the most accurate CMT estimation and are probably the optimal method for reliably detecting subtle threshold changes in patients with epilepsy.
In certain IGE syndromes, hyperexcitability occurs in other areas of the cortical mantle, beyond the motor strip. Brigo et al. investigated corticomotor and phosphene threshold in 33 patients with IGE, a subset of which displayed photosensitivity. The authors observed decreased phosphene threshold in patients with photosensitivity implying regional hyperexcitability of the primary visual cortex. This observation provides additional evidence in favor of the construct of system epilepsies and suggests that the primary visual cortex is a 'hub' of pathophysiological importance in the 'photosensitivity system'.
With regard to progressive myoclonic epilepsies, a unique study by Danner et al. investigated 70 genetically verified EPM type 1 patients and 40 controls correlating structural and electrophysiological findings. The authors observed significant elevations of CMT, which were ascribed to medication effects and the increased scalp-to-cortex distance in the context of disease-related cortical atrophy. In addition, they reported significantly prolonged silent period durations, which were interpreted as a cortical inhibitory mechanism reactive to the underlying pathology of EPM1. In the first TMS–EEG study of EPM1 patients, Julkunen et al. reported increased amplitude of the early P30 waveform, suggesting enhanced cortico-cortical excitability and reduced amplitude of the later N100–P180 complex indicating impaired cortical inhibition. In addition, the authors investigated the event-related spectral perturbation, and observed reduced power of alpha, beta and gamma band oscillations and decreased inter-trial coherence following the magnetic stimulus in EPM1 patients, indicating malfunctioning circuits at cortical and subcortical levels.
With regard to focal epilepsy, a study by Badawy et al. in 10 drug-naive patients with new-onset temporal lobe epilepsy (TLE) disclosed an interhemispheric imbalance with hyperexcitability in the hemisphere containing the epileptogenic zone and normal excitability of the unaffected hemisphere. In addition, Wright et al. investigated 18 patients with TLE during the preictal state and described changes in cortical excitability in the form of a compound index of intracortical inhibition/facilitation that was able to predict in the short term the occurrence of epileptic seizures.
In 18 adult patients with Lennox–Gastaut syndrome, Badawy et al. reported a hypoexcitability reflected in increased CMT and ICI and decreased ICF. This finding stands in sharp contrast with the persistent hyperexcitability characterizing other refractory epileptic syndromes. It is unclear whether this hypoexcitable state is pertinent to Lennox–Gastaut syndrome only or whether it characterizes other generalized epileptic encephalopathies as well.
Investigation of Cortical Excitability
Converging lines of evidence suggest that epilepsies are in general characterized by cortical hyperexcitability in a syndrome-specific manner. Recently, this concept has been extended to include asymptomatic siblings of patients with epilepsy as well.
Badawy et al. reported that cortical excitability is higher in asymptomatic siblings of patients with focal and particularly generalized epilepsy. The pattern of cortical hyperexcitability, essentially reflecting defective ICI mechanisms, was similar in siblings of patients with various epilepsy syndromes, raising the possibility that genetic factors predispose to both generalized and focal epilepsies and a complex genetic/environmental interaction determines the ultimate clinical phenotype.
In idiopathic generalized epilepsy (IGE), a study of 30 drug-naïve patients [10 patients with juvenile myoclonus epilepsy (JME), eight with juvenile absence epilepsy and 12 with generalized tonic–clonic seizures only] concluded that cortical excitability was significantly enhanced in all epilepsy syndromes as evidenced by reduced CMT values and decreased ICI at short and particularly at long ISIs. Patients with JME demonstrated significantly higher levels of cortical excitability compared with the other two groups of patients, thereby differentiating JME from other IGE syndromes. This view is also supported by a meta-analysis of 14 trials involving 265 drug-naïve IGE patients and 424 control subjects, which concluded that only patients with JME had reduced CMT values compared with controls. These observations are in line with the recently proposed construct of 'system epilepsies' and set JME as an archetype within this conceptual scheme. However, Puri et al. did not detect reduced CMT in 30 drug-naïve JME patients. These inconsistent results in well characterized IGE cohorts and in the absence of confounding factors, such as AED intake, are probably related to the small magnitude of the threshold decrease and the precision of threshold measurements. Indeed, according to the Internation Federation of Clinical Neurophysiology guidelines, adaptive methods based on threshold-tracking algorithms provide the most accurate CMT estimation and are probably the optimal method for reliably detecting subtle threshold changes in patients with epilepsy.
In certain IGE syndromes, hyperexcitability occurs in other areas of the cortical mantle, beyond the motor strip. Brigo et al. investigated corticomotor and phosphene threshold in 33 patients with IGE, a subset of which displayed photosensitivity. The authors observed decreased phosphene threshold in patients with photosensitivity implying regional hyperexcitability of the primary visual cortex. This observation provides additional evidence in favor of the construct of system epilepsies and suggests that the primary visual cortex is a 'hub' of pathophysiological importance in the 'photosensitivity system'.
With regard to progressive myoclonic epilepsies, a unique study by Danner et al. investigated 70 genetically verified EPM type 1 patients and 40 controls correlating structural and electrophysiological findings. The authors observed significant elevations of CMT, which were ascribed to medication effects and the increased scalp-to-cortex distance in the context of disease-related cortical atrophy. In addition, they reported significantly prolonged silent period durations, which were interpreted as a cortical inhibitory mechanism reactive to the underlying pathology of EPM1. In the first TMS–EEG study of EPM1 patients, Julkunen et al. reported increased amplitude of the early P30 waveform, suggesting enhanced cortico-cortical excitability and reduced amplitude of the later N100–P180 complex indicating impaired cortical inhibition. In addition, the authors investigated the event-related spectral perturbation, and observed reduced power of alpha, beta and gamma band oscillations and decreased inter-trial coherence following the magnetic stimulus in EPM1 patients, indicating malfunctioning circuits at cortical and subcortical levels.
With regard to focal epilepsy, a study by Badawy et al. in 10 drug-naive patients with new-onset temporal lobe epilepsy (TLE) disclosed an interhemispheric imbalance with hyperexcitability in the hemisphere containing the epileptogenic zone and normal excitability of the unaffected hemisphere. In addition, Wright et al. investigated 18 patients with TLE during the preictal state and described changes in cortical excitability in the form of a compound index of intracortical inhibition/facilitation that was able to predict in the short term the occurrence of epileptic seizures.
In 18 adult patients with Lennox–Gastaut syndrome, Badawy et al. reported a hypoexcitability reflected in increased CMT and ICI and decreased ICF. This finding stands in sharp contrast with the persistent hyperexcitability characterizing other refractory epileptic syndromes. It is unclear whether this hypoexcitable state is pertinent to Lennox–Gastaut syndrome only or whether it characterizes other generalized epileptic encephalopathies as well.
