Radwa A. B. Badawy

Summary: 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).

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. Ann Neurol 2013;74:743–757

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.

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.

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.

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.

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.