Does the region of epileptogenicity influence the pattern of change in cortical excitability?

OBJECTIVE: To investigate whether cortical excitability measures on transcranial magnetic stimulation (TMS) differed between groups of patients with different focal epilepsy syndromes. METHODS: 85 Patients with focal epilepsy syndromes divided into temporal and extra-temporal lobe epilepsy were studied. The cohorts were further divided into drug naïve-new onset, refractory and seizure free groups. Motor threshold (MT) and paired pulse TMS at short (2, 5, 10, 15 ms) and long (100-300 ms) interstimulus intervals (ISIs) were measured. Results were compared to those of 20 controls. RESULTS: Cortical excitability was higher at 2 & 5 ms and 250, 300 ms ISIs (p<0.01) in focal epilepsy syndromes compared to controls however significant inter-hemispheric differences in MT and the same ISIs were only seen in the drug naïve state early at onset and were much more prominent in temporal lobe epilepsy. CONCLUSION: Disturbances in cortical excitability are more confined to the affected hemisphere in temporal lobe epilepsy but only early at onset in the drug naïve state. SIGNIFICANCE: Group TMS studies show that cortical excitability measures are different in temporal lobe epilepsy and can be distinguished from other focal epilepsies early at onset in the drug naïve state. Further studies are needed to determine whether these results can be applied clinically as the utility of TMS in distinguishing between epilepsy syndromes at an individual level remains to be determined.

On the midway to epilepsy: is cortical excitability normal in patients with isolated seizures?

Paired pulse transcranial magnetic stimulation was used to investigate differences in cortical excitability between patients with isolated (unrecurrent, unprovoked) seizures and those with epilepsy. Compared to controls, cortical excitability was higher in the isolated seizure group at 250-300 ms. Compared to epilepsy, cortical excitability was lower in patients with isolated seizures also at 250 and 300 ms. Lowered seizure threshold caused by disturbances within inhibitory circuits is present in patients who experience a seizure even if no further seizures occur.

TMS, cortical excitability and epilepsy: the clinical impact.

Paired-pulse transcranial magnetic stimulation (ppTMS) is a well-established method for non-invasive measurement of cortical excitability, alterations of which are the core background of epilepsy. For the past 20 years this technique has been extensively used to assess patients with epilepsy. We present here a critical overview of these studies, with emphasis on their translation to the clinical practice.

Exercise-induced seizures and lateral asymmetry in patients with temporal lobe epilepsy.

OBJECTIVE: The objective of this case report is to better characterize the clinical features and potential pathophysiological mechanisms of exercise-induced seizures. METHODS: We report a case series of ten patients from a tertiary epilepsy center, where a clear history was obtained of physical exercise as a reproducible trigger for seizures. RESULTS: The precipitating type of exercise was quite specific for each patient, and various forms of exercise are described including running, swimming, playing netball, dancing, cycling, weight lifting, and martial arts. The level of physical exertion also correlated with the likelihood of seizure occurrence. All ten patients had temporal lobe abnormalities, with nine of the ten patients having isolated temporal lobe epilepsies, as supported by seizure semiology, EEG recordings, and both structural and functional imaging. Nine of the ten patients had seizures that were lateralized to the left (dominant) hemisphere. Five patients underwent surgical resection, with no successful long-term postoperative outcomes. CONCLUSIONS: Exercise may be an underrecognized form of reflex epilepsy, which tended to be refractory to both medical and surgical interventions in our patients. Almost all patients in our cohort had seizures localizing to the left temporal lobe. We discuss potential mechanisms by which exercise may precipitate seizures, and its relevance regarding our understanding of temporal lobe epilepsy and lateralization of seizures. Recognition of, as well as advice regarding avoidance of, known triggers forms an important part of management of these patients.

The cortical excitability profile of temporal lobe epilepsy.

PURPOSE: Transcranial magnetic stimulation (TMS) was used to characterize measurable changes of cortical excitability in patients who were undergoing medical and surgical management of temporal lobe epilepsy (TLE) to investigate whether these alterations depended on timing of achieving seizure control throughout the course of illness and method of management. METHODS: Eighty-five patients with TLE divided into (1) drug naive-new onset, (2) early medically refractor, and (3) late medically refractory, (4) early seizure-free on antiepileptic drugs, and (5) late seizure-free on antiepileptic drugs, (6) postoperative refractory, and (7) postoperative seizure-free groups were studied. Motor threshold (MT) and paired-pulse TMS at short (2, 5, 10, and 15 msec) and long (100-300 msec) interstimulus intervals (ISIs) were measured. Results were compared to those of 20 controls. KEY FINDINGS: A significant interhemispheric difference was observed early at onset prior to starting medication, with higher cortical excitability in the hemisphere ipsilateral to the seizure focus, whereas the unaffected hemisphere was normal. After that, cortical excitability was higher in both hemispheres in the refractory groups (medical and postoperative) compared to the seizure-free and drug-naive groups (p < 0.05). This effect was most prominent at the long ISIs. SIGNIFICANCE: Changes in cortical excitability seen in patients with TLE are influenced by the course of the disease. The alterations that occur due to epilepsy are closely related to course of illness and degree/timing of seizure control. Successful management leads to resolution of this cortical hyperexcitability in a similar fashion regardless of method: medication (intact generator, but modulated by drugs) or surgery (generator removed).

Networks underlying paroxysmal fast activity and slow spike and wave in Lennox-Gastaut syndrome.

OBJECTIVE: To use EEG-fMRI to determine which structures are critically involved in the generation of paroxysmal fast activity (PFA) and slow spike and wave (SSW) (1.5-2.5 Hz), the characteristic interictal discharges of Lennox-Gastaut syndrome (LGS). METHODS: We studied 13 well-characterized patients with LGS using structural imaging and EEG-fMRI at 3 tesla. Ten patients had cortical structural abnormalities. PFA and SSW were considered as separate events in the fMRI analysis. RESULTS: Simultaneous with fMRI, PFA was recorded in 6 patients and SSW in 9 (in 2, both were recorded). PFA events showed almost uniform increases in blood oxygen level-dependent (BOLD) signal in "association" cortical areas, as well as brainstem, basal ganglia, and thalamus. SSW showed a different pattern of BOLD signal change with many areas of decreased BOLD signal, mostly in primary cortical areas. Two patients with prior callosotomy had lateralized as well as generalized PFA. The lateralized PFA was associated with a hemispheric version of the PFA pattern we report here. CONCLUSION: PFA is associated with activity in a diffuse network that includes association cortices as well as an unusual pattern of simultaneous activation of subcortical structures (brainstem, thalamus, and basal ganglia). By comparison, the SSW pattern is quite different, with cortical and subcortical activations and deactivations. Regardless of etiology, it appears that 2 key, but distinct, patterns of diffuse brain network involvement contribute to the defining electrophysiologic features of LGS.

Subcortical epilepsy?

In the past, the cortex has for the most part been considered to be the site of seizure origin in the different forms of epilepsy. Findings from histopathologic, electrophysiologic, and brain imaging studies now provide ample evidence demonstrating that like normal cerebral function, epileptic seizures involve widespread network interactions between cortical and subcortical structures. These studies show that different forms of generalized and focal epileptiform discharges and seizures engage various subcortical structures in varying ways. This interaction has been the subject of many reviews and is not the focus of the current work. The aim of this review is to examine the evidence suggesting the possibility for some of the subcortical structures to initiate seizures independently and the clinical implications of this.

Are patterns of cortical hyperexcitability altered in catamenial epilepsy?

OBJECTIVE: We used transcranial magnetic stimulation to determine menstrual cycle-related changes in cortical excitability in women with and without catamenial epilepsy and investigated whether these changes differed between ovulatory and anovulatory cohorts. METHODS: Healthy nonepilepsy women and women with generalized and focal epilepsy were investigated during ovulatory (n=11, 46, and 43, respectively) and anovulatory (n=9, 42, and 41) cycles. Patients were divided based on seizure pattern into catamenial (C1=perimenstrual, C2=periovulatory, C3=luteal seizure exacerbation), noncatamenial, and seizure free. Cortical excitability was assessed using motor threshold (MT) and paired pulse stimulation at short (2-15 milliseconds) and long (100-300 milliseconds) interstimulus intervals twice, at the (1) late follicular and (2) mid luteal phases of the menstrual cycle. RESULTS: In controls, cortical excitability was greatest in the follicular study, where intracortical facilitation was increased (p<0.05). The opposite was seen in women with epilepsy, where intracortical facilitation was greatest and intracortical inhibition was least in the luteal studies (p<0.05). There were no differences between the ovulatory and anovulatory groups in any of the cohorts. No changes were observed in MT. INTERPRETATION: Nonhormonal factors are involved in the cyclicity of cortical excitability across the menstrual cycle. Normal menstrual cycle variations in cortical excitability are altered in a similar pattern in ovulatory and anovulatory women with epilepsy regardless of seizure patterns. The underlying neural changes associated with epilepsy may alter responses to sex hormones. This may be an important underlying mechanism for catamenial seizure clustering.

Cortical excitability changes correlate with fluctuations in glucose levels in patients with epilepsy.

OBJECTIVE: We used transcranial magnetic stimulation (TMS) to investigate motor cortical excitability changes in relation to blood glucose levels. METHODS: Twenty-two drug-naïve patients with epilepsy [11 generalized and 11 focal] and 10 controls were studied twice on the same day; first after 12h of fasting and then 2h postprandial. Motor threshold and paired-pulse TMS at a number of short and long interstimulus intervals were measured. Serum glucose levels were measured each time. RESULTS: Decreased long intracortical inhibition was seen in patients and controls during fasting compared to postprandial studies. This effect was much more prominent in patients with generalized epilepsy (with effect sizes of up to 0.8) in whom there was also evidence of increased intracortical facilitation (effect size: 0.3). CONCLUSION: Cortical excitability varies with fluctuations in blood glucose levels. This variation is more prominent in patients with epilepsy. Decreased glucose levels may be an important physiological seizure trigger.

Patterns of cortical hyperexcitability in adolescent/adult-onset generalized epilepsies.

PURPOSE: To investigate whether using transcranial magnetic stimulation (TMS) to derive if measures of cortical excitability changes can distinguish between various adolescent/adult-onset generalized epilepsy syndromes at different phases of the disorder. METHODS: One hundred thirty-seven patients with adolescent/adult-onset generalized epilepsy divided into juvenile myoclonic epilepsy, juvenile absence epilepsy, and generalized epilepsy with tonic-clonic seizures only were studied. The cohorts were further divided into drug naive-new onset, refractory, and seizure-free groups. Motor threshold (MT) and paired pulse TMS at short (2, 5, 10, 15 msec) and long (100-300 msec) interstimulus intervals (ISIs) were measured. Results were compared to those of 20 controls. KEY FINDINGS: In the drug-naive cohorts MT was reduced (p < 0.05) and cortical excitability increased at 2 and 5 msec and 150, 250, and 300 msec ISIs (p < 0.01) in juvenile myoclonic epilepsy compared to other generalized epilepsy groups and controls. Cortical excitability increased to a lesser degree in other generalized epilepsy syndromes compared to controls, but those two syndromes were not distinguishable from one another. The changes in paired pulse TMS were more prominent in the groups with refractory seizures and very small in the groups who were seizure free. SIGNIFICANCE: There are syndrome specific changes in cortical excitability associated with generalized epilepsy. These changes are also dependent on seizure control with medication. Juvenile myoclonic epilepsy has a higher cortical excitability profile compared to other adolescent/adult-onset generalized epilepsy syndromes and can be clearly distinguished from them during all phases.

Capturing the epileptic trait: cortical excitability measures in patients and their unaffected siblings.

We used transcranial magnetic stimulation to investigate whether the cortical excitability changes observed amongst the different generalized and focal epilepsy syndromes are reflected in their asymptomatic siblings and if these changes depended on the clinical phenotype. We studied 157 patients with epilepsy (95 generalized and 62 focal) and their asymptomatic siblings (138 and 82, respectively). Motor threshold and paired pulse transcranial magnetic stimulation at short (2, 5, 10 and 15 ms) and long (100-300 ms) interstimulus intervals were measured. Results were compared to those of 12 control subjects and 20 of their siblings. There were no differences in cortical excitability between healthy control subjects and their siblings. Compared with control subjects, cortical excitability was higher in siblings of patients whether generalized (P < 0.05; short and long interstimulus intervals) or focal (P < 0.05; long interstimulus intervals). Compared with epilepsy, motor threshold was lower (P < 0.05) in patients with juvenile myoclonic epilepsy compared with their siblings only early at onset in the drug naïve state. In all groups (generalized and focal) cortical excitability was lower in siblings only at the long interstimulus intervals (250 and 300; P < 0.05). Cortical excitability is higher in asymptomatic siblings of patients with generalized and focal epilepsy in a similar manner. The disturbance seems to involve intracortical inhibitory circuits even in the siblings of patients with a structural abnormality (acquired epilepsy). This implies there are certain genetic factors that predispose to both generalized and focal epilepsies and a complex genetic/environmental interaction then determines the clinical phenotype.

Cortical excitability and refractory epilepsy: a three-year longitudinal transcranial magnetic stimulation study.

Transcranial magnetic stimulation was used to study the effect of recurrent seizures on cortical excitability over time in epilepsy. 77 patients with firm diagnoses of idiopathic generalized epilepsy (IGE) or focal epilepsy were repeatedly evaluated over three years. At onset, all groups had increased cortical excitability. At the end of follow-up the refractory group was associated with a broad increase in cortical excitability. Conversely, cortical excitability decreased in all seizure free groups after introduction of an effective medication.

Cortical excitability decreases in Lennox-Gastaut syndrome.

PURPOSE: We used transcranial magnetic stimulation (TMS) to investigate cortical excitability changes in Lennox-Gastaut syndrome (LGS), anticipating we would find a marked increase in excitability compared to other patients with refractory epilepsies. METHODS: Eighteen patients with LGS were studied. Motor threshold (MT), short intracortical inhibition (paired pulse TMS at 2 and 5 msec interstimulus intervals [ISIs]), intracortical facilitation (10 and 15 msec ISIs), and long intracortical inhibition (100-300 msec ISIs) were measured. Results were compared to those of 20 patients with chronic refractory idiopathic generalized epilepsy (IGE), 20 patients with chronic refractory focal epilepsy, and 20 healthy nonepilepsy controls. KEY FINDINGS: A significant decrease in cortical excitability was observed in LGS compared to the other two groups with refractory epilepsy as evidenced by increased MT and intracortical inhibition at both short (2, 5 msec ISIs), and long (100-300 msec ISIs) as well as decreased intracortical facilitation (10, 15 msec ISIs), (p < 0.01; effect sizes ranging from 0.3 to 1.8). Cortical excitability was also lower in LGS compared to nonepilepsy controls (increased MT and decreased intracortical facilitation; p < 0.05; effect sizes ranging from 0.5 to 0.9). SIGNIFICANCE: Interictal cortical excitability is decreased in LGS; a feature that distinguishes it from other refractory epilepsy syndromes. This decrease may be an important mechanism for the neurobehavioral comorbidities associated with LGS.

Cortical excitability in migraine and epilepsy: a common feature?

OBJECTIVE: There is evidence for comorbidity of migraine and epilepsy. We used transcranial magnetic stimulation (TMS) to assess cortical excitability in migraine compared with control subjects and patients with epilepsy. METHODS: Twenty-six patients drug-naive patients with newly diagnosed migraine were studied. These were compared with 19 healthy control subjects and 50 patients with new onset epilepsy. Motor threshold (MT) and responses to paired pulse stimulation at short (2, 5, 10, and 15 milliseconds) and long (50-400 milliseconds) interstimulus intervals (ISIs) were measured. RESULTS: Compared with control subjects, cortical excitability was higher in migraine only at 250 milliseconds (P < 0.05; effect size 0.7), while in epilepsy, it was higher at 2, 5, 250, and 300 milliseconds. Compared with epilepsy, cortical excitability was lower in migraine only at 250 milliseconds (P < 0.05; effect size 0.6 compared with focal epilepsy and 1.1 compared with idiopathic generalized epilepsy [IGE]). CONCLUSIONS: Cortical excitability increases in migraine suggesting the involvement of intracortical inhibitory circuits. This may be a common feature underlying some of the similarities observed in migraine and epilepsy.

A mechanistic appraisal of cognitive dysfunction in epilepsy.

A strong relationship between the clinical characteristics of epilepsy and the nature of cognitive impairments associated with the condition has been found, but the nature of this relationship appears to be quite complex and not well understood. This review presents a summary of the research on the interaction between cognition and epilepsy, surveyed from a mechanistic perspective with the aim of clarifying factors that contribute to the co-existence of both disorders. The physiological basis underpinning cognitive processing is first reviewed. The physiology of epilepsy is reviewed, with emphasis placed on interictal discharges and seizures. The nature of the impact of epilepsy on cognition is described, with transient and prolonged effects distinguished. Finally, the complexity of the co-morbidity between cognitive dysfunction and epilepsy is discussed in relation to childhood and adult-onset epilepsy syndromes and severe epileptic encephalopathies. Structural and functional abnormalities exist in patients with epilepsy that may underpin both the cognitive dysfunction and epilepsy, highlighting the complexity of the association. Research, possibly of a longitudinal nature, is needed to elucidate this multifactorial relationship between cognitive dysfunction and epilepsy.

Cortical excitability and neurology: insights into the pathophysiology.

Transcranial magnetic stimulation (TMS) is a technique developed to non-invasively investigate the integrity of human motor corticospinal tracts. Over the last three decades, the use of stimulation paradigms including single-pulse TMS, paired-pulse TMS, repetitive TMS, and integration with EEG and functional imaging have been developed to facilitate measurement of cortical excitability.Through the use of these protocols, TMS has evolved in-to an excellent tool for measuring cortical excitability.TMS has high sensitivity in detecting subtle changes in cortical excitability, and therefore it is also a good measure of disturbances associated with brain disorders. In this review, we appraise the current literature on cortical excitability studies using TMS in neurological disorders.We begin with a brief overview of current TMS measures and then show how these have added to our understand-ing of the underlying mechanisms of brain disorders.

Inter-session repeatability of cortical excitability measurements in patients with epilepsy.

PURPOSE: Previous studies have evaluated the inter-session variability of motor thresholds (MT), short intracortical inhibition and intracortical facilitation using paired pulse transcranial magnetic stimulation (TMS) in normal individuals. Here we evaluate the reproducibility of a range of measures of cortical excitability in patients with epilepsy. METHODS: Twenty-four drug naïve patients with newly diagnosed epilepsy (13 idiopathic generalised epilepsy [IGE], 11 focal epilepsy) and seventeen non-epilepsy controls were studied. Motor threshold (MT) at rest and recovery curves constructed using paired pulse stimulation at short (2-15 ms) and long (50-400 ms) interstimulus intervals (ISIs) were analysed on two separate occasions, 4-20 weeks apart. The Lin's concordance correlation coefficient test was used to measure agreement between the two sessions. RESULTS: Significant levels of agreement between the two sessions were observed at MT and all the ISIs measured. This was highest in non-epilepsy controls. CONCLUSION: Cortical excitability measures are repeatable over time in both patients with epilepsy and healthy controls. Increased motor cortex excitability is a stable feature in epilepsy without significant inter-session variability.

A blinded comparison of continuous versus sampled review of video-EEG monitoring data.

OBJECTIVE: While there are well-established guidelines for optimum video-EEG monitoring (VEM), the process of reviewing VEM data varies amongst centres. In this study, we compared continuous with sampled reviewing of VEM data to assess whether their diagnostic yield differs. METHODS: VEM data acquired from 50 consecutive patients (31 females) admitted for VEM were reviewed by two independent electroencephalographers, one using the continuous review method, and the other sampling the first five minutes of each hour together with events identified by push buttons and automated spike detection software. Overall agreement between reviewers was calculated using the Kappa statistic. Comparison between the total number of clinical events detected by the two methods was done by Pearson's correlation coefficient. RESULTS: A substantial number of events were missed using sampled review. Despite this, there was excellent agreement between the two methods on the final electro-clinical diagnosis for each patient (Kappa=0.89). CONCLUSION: In our laboratory, continuous VEM more comprehensively captured information of interest, but it did not substantially alter the final electro-clinical diagnosis. SIGNIFICANCE: Sampled review of VEM data captures sufficient data to reliably make accurate clinical decisions. It may be considered as a more cost and labor efficient alternative to continuous review.

Selecting patients for epilepsy surgery: identifying a structural lesion.

One of the most important components of presurgical evaluation of patients with epilepsy is structural imaging, predominantly using magnetic resonance imaging. This study is now part of the basic assessment of patients with epilepsy and is as important as the electroencephalogram. Epilepsy protocol magnetic resonance imaging studies must be part of the overall assessment of the patient. To understand the basis of the epileptic disorder, interpretation of these investigations relies on knowledge of the clinical details and features of the seizures, the functional abnormality in the brain as shown on the electroencephalogram, and structural assessment of the brain with a magnetic resonance imaging study optimized for epilepsy. This review considers the essential elements of this issue and gives a broad overview of what imaging options are available for the investigation of the patient with epilepsy from the perspective of the practicing epileptologist.