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Keywords:

  • Cortical excitability;
  • Refractory seizures;
  • Seizure freedom;
  • Temporal lobe epilepsy;
  • Transcranial magnetic stimulation

Summary

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure
  8. References
  9. Biography

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).

Cortical hyperexcitability has been reported consistently in transcranial magnetic stimulation (TMS) studies of focal epilepsy (Cantello et al., 2000; Werhahn et al., 2000; Hamer et al., 2005; Badawy et al., 2007). We recently found evidence to suggest that these changes are progressive in nature and extend to involve the unaffected hemisphere in patients with chronic refractory focal epilepsy over time (Badawy et al., 2013). Temporal lobe epilepsy (TLE) is the most common focal epilepsy and perhaps the most homogeneous, and therefore provides the best available model for further elucidation of the nature of electrophysiologic changes associated with epilepsy in vivo. TLE is also one of the most common forms of focal epilepsies associated with intractable seizures (Wiebe, 2000). In many of these patients, seizures are refractory from the onset (Kwan & Brodie, 2000), perhaps providing evidence for an underlying role for pharmacogenetic interactions (Loscher et al., 2009). In others, drug resistance may develop during the course of epilepsy after an initial positive response to antiepileptic drugs (AEDs). Furthermore, seizures may persist after the surgical removal of the epileptogenic focus despite what appears to be precise localization on both scalp and even invasive electroencephalography (EEG; Tellez-Zenteno et al., 2005, 2010). On many occasions, surgery is unsuccessful owing to failure of removal of additional regions of seizure origination that were not appreciated at the initial evaluation; however, this is not always the case. This suggests that there are multifaceted disturbances associated with epilepsy, which in some cases persist even if the origin or “generator” is removed.

In the current study we used TMS to assess cohorts with TLE with different levels of seizure control (medical and postoperative). We hypothesized that the pattern of disturbance in cortical excitability will depend on the clinical course of the disease and speed/degree of responsiveness to treatment. We also anticipated to find a difference in the cortical excitability profile depending on whether the management was medical (intact generator, but modulated by medication) or surgical (the generator is gone).

Methods

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure
  8. References
  9. Biography

Participant populations

Patients

The current study included patients with a confirmed diagnosis of TLE consecutively recruited by screening the databases of the Epilepsy Clinic and Epilepsy Surgery Program at St Vincent's Hospital in Melbourne. To maintain homogeneity between the groups, only participants aged 14–45 years were included.

The diagnoses were made by at least two experienced epileptologists who were unaware of the study based on clinical history, EEG, and imaging findings.

The study protocol was approved by the St Vincent's Hospital Human Research Ethics Committee, and written informed consent was obtained from each participant including parental consent from those participants younger than 18 years.

Patients were divided into (Table 1):

Table 1. Demographics of participants included in each group
SubgroupNumber (number of females)Mean age in years (range)Mean age of onset in years (range)Seizure frequency; all types (range)AEDs
  1. CBZ, carbamazepine; GBP, gabapentin; LAC, lacosamide; LEV, levetiracetam; LTG, lamotrigine; OXC, oxcarbazepine; TPM, topiramate; VPA, sodium valproate.

Drug-naive new-onset10 (5)24 (14–32)4 (1–6)None
Early medically refractory seizures13 (7)27 (17–45)20 (12–29)7/month (2–14)CBZ, GBP, LAC, LEV, LTG, OXC, TPM, VPA
Late medically refractory seizures14 (8)25 (18–45)20 (11–27)7/month (2–14)CBZ, GBP, LAC, LEV, LTG, OXC, TPM, VPA
Early seizure-free on AEDs12 (5)26 (18–45)22 (13–30)3–4 seizures prior to AED Now noneCBZ, LTG, VPA
Late seizure-free on AEDs12 (7)26 (20–45)22 (11–30)5/month (2–12) Now noneCBZ, GBP, LAC, LEV, LTG, OXC, TPM, VPA
Postoperative refractory seizures12 (6)31 (19–45)24 (13–32)8/month (2–14)CBZ, GBP, LAC, LEV, LTG, OXC, TPM, VPA
Postoperative seizure-free12 (9)29 (21–45)22 (14–29)0CBZ, GBP, LEV, LTG, OXC, TPM, VPA
  1. Drug-naive new-onset epilepsy: These patients were recruited on presentation to the clinic and were studied with TMS within the same week and prior to any exposure to AEDs.
  2. Early medically refractory seizures: Patients who were refractory from onset and never achieved seizure control. Patients were considered refractory if they continued to have seizures for at least 3 years (despite trials of at least two different AEDs at therapeutic doses) (Kwan & Brodie, 2000; Kwan et al., 2010). This included focal seizures with loss of awareness and unequivocal focal seizures comprising visual, auditory, motor, sensory, or autonomic manifestations with retained awareness or secondarily generalized tonic–clonic seizures. Isolated infrequent nonspecific vague feelings, uneasiness, or brief déjà vu were not considered seizures.
  3. Late medically refractory: Patients with an initial seizure control (lasting at least 12 months), followed by recurrence of seizures that were refractory to medication (according to the refractory criteria described above).
  4. Postoperative refractory seizures: Patients were included in this group if they had surgery at least 1 year prior to the TMS test and continued to have seizures postoperatively for that time.
  5. Early seizure-free on AEDs: Patients who stopped having seizures after reaching the target dose of the first AED prescribed and continued to be seizure-free for at least 3 years prior to the TMS test.
  6. Late seizure-free on AEDs: Patients who did not respond to the first AED and only became seizure-free after reaching the target dose of add-on AED(s). They had to be seizure-free for at least 3 years prior to the TMS test.
  7. Postoperative seizure-free: Postoperative seizure freedom was defined as 1 year with no seizures (International League Against Epilepsy [ILAE] Class I) prior to the TMS test.
Inclusion criteria
  1. Syndromic classification required that the seizure symptomatology (specifically characteristics of the aura when consistently present) and the EEG (routine or video-telemetry) showed definite and prominent interictal sharp-slow discharges or clear ictal rhythms consistently over the temporal (T1–T3/T2/T4) region. Patients with temporal intermittent rhythmic delta activity (TIRDA) were included only if the activity was consistently recorded over one hemisphere. Nonspecific slowing or sharp waves were not considered lateralizing or localizing, even if recorded on only one side. Further localizing signs were found on brain magnetic resonance (MR) images (Table 2).
  2. Normal neurologic examination.
Table 2. Abnormalities seen on MRI in each of the groups
SubgroupFindings
Drug-naive new-onsetA patient with hypertrophied amygdala
9 patients lesion negative
Early medically refractory seizures3 patients with hippocampal sclerosis
3 patients with cortical dysplasia
1 patient with a dysembryoplastic neuroepithelial tumour
6 patients lesion negative
Late medically refractory seizures4 patients with hippocampal sclerosis
2 patients with cortical dysplasia
1 amygdala hypertrophy
7 patients lesion negative
Early seizure-free on AEDs2 patients with hippocampal sclerosis
1 patient with temporal cyst
9 patients lesion negative
Late seizure-free on AEDs4 patients with hippocampal sclerosis
9 patients lesion negative
Postoperative refractory seizures2 patients with hippocampal sclerosis
5 patients with cortical dysplasia
5 patients lesion negative
Postoperative seizure-free8 patients with hippocampal sclerosis
2 patients with cortical dysplasia
1 patient with a dysembryoplastic neuroepithelial tumour
1 patient lesion negative
Exclusion criteria
  1. Suspicion of nonepileptic events.
  2. Bilateral seizure foci.
  3. Suspicion of noncompliance to medication.
Nonepilepsy controls

Twenty healthy participants (11 female, mean age 27 years; range 18–40 years) without a personal or family history of seizures or any other neurologic conditions.

Transcranial magnetic stimulation

Both hemispheres were studied in each participant (patients and controls). Each participant was studied with TMS once only and none had a repeat study. During TMS, the participants sat in a comfortable, reclining chair. Surface electromyography (EMG) recording was made from the abductor pollicis brevis (APB) muscle. Stimuli were delivered to the contralateral cerebral hemisphere by applying the appropriate direction of coil current flow (anticlockwise for left cortical stimulation and clockwise for right cortical stimulation), using a flat circular 9 cm diameter magnetic coil (14 cm external diameter) with the center of the coil positioned over the vertex and held in a plane tangential to it using a pair of Magstim 200 magnetic stimulators (Magstim, Whitland, Dyfed, United Kingdom). Paired stimulation at various interstimulus intervals (ISIs) was performed using a Bistim module to connect 2 stimulators to the coil.

The motor evoked potentials (MEPs) were recorded and digitized online via a CED 1401 interface (Cambridge Electronic Design Ltd, Cambridge United Kingdom) and stored on computer for offline analysis. Signal software (Cambridge Electronic Design Ltd) was used for automated acquisition and marking of the recorded MEPs. Filters for the acquisition were set to low frequency of 10 Hz and high frequency of 5 KHz. Sweep speed for threshold determination and paired pulse TMS at short ISIs was 100 msec, and the sensitivity was set to 100 μV/division. For longer ISIs the sweep was adjusted to 500 msec and sensitivity to 2 mV/division. The MEP amplitude was measured from peak to peak.

The experimental session lasted for 60–90 min, and the following parameters were recorded:

  1. Motor Threshold (MT): MT was determined for each hemisphere tested while the participant was at rest, verified by continuous visual and auditory EMG feedback. Stimulation commenced at 30% of maximum output and increased in 5% increments until the MEP was established. One percent changes in intensity were then used to measure the threshold value. Motor threshold was defined as the lowest level of stimulus intensity that produced a MEP in the target muscle of peak-to-peak amplitude >100 μV on 50% or more of 10 trials (Rossini et al., 1994).
  2. Intracortical Inhibition and Facilitation: Cortical recovery curves were derived using paired-pulse TMS. For the short ISIs of 2, 5, 10, 15 msec, the first stimulus was given at 80% of MT and the second stimulus 20% above MT. Ten stimuli at 20% above MT without a preconditioning stimulus were also given. For longer ISIs, the stimulation intensity was 20% above MT using paired stimuli in 50-msec increments at ISIs of 100–300 msec. A minimum interval of 15 s was kept between the delivery of each pair of stimuli. Stimuli were given at randomly selected ISIs until a total of 10 at each ISI was achieved.

Recovery curves at short ISIs (2–15 ms) were constructed for each hemisphere using the ratio of the mean peak to peak amplitude of the response (termed test response [TR]) at each ISI following the conditioning stimulus given below MT expressed as the percentage of the mean MEP when the test stimulus was given alone without a preconditioning stimulus (TR/MEP%).

Recovery curves at longer ISIs (100–300 msec) were constructed for each hemisphere using the ratio of the mean peak-to-peak amplitudes of the response to the second stimulus termed the test response (TR) and the response to the first stimulus termed the conditioning response (CR) at each ISI measured as a percentage (TR/CR%).

To avoid any effect of diurnal variation in cortical excitability, all studies were performed between 10 a.m. and 3 p.m. Care was taken to avoid clustering of any of the participants in a group to a particular time, and the studies were spread evenly over this time interval in all groups. Similarly, to avoid any hormonal effects related to variations across the menstrual cycle, care was taken to avoid clustering of the female participants in each group to a particular phase of the cycle, and they were spread evenly across the two phases (luteal and follicular) in each group. It was requested of all participants to maintain regular sleep patterns with 7–9 h of sleep the night before the test, and the results were only analyzed after a minimum of 2 days of seizure freedom on either side of the study was confirmed. This was based on seizure diaries. No patients were excluded as a result of seizures in this cohort. In addition, no patient had a seizure during the TMS study.

Each participant was given a unique alpha numeric code. This was the only identifying feature on the TMS data acquired. The analysis was performed after all participants had been tested. This ensured that the investigator analyzing the TMS results was blinded to clinical information during the analysis.

Statistical analysis

The results from nonepilepsy controls were analyzed according to hemisphere dominance. This was assessed using the Edinburgh Handedness Inventory (Oldfield, 1971). In patients, the results were analyzed according to the ipsilateral (hemisphere with presumed seizure focus) and contralateral hemisphere. This was based on electroclinical and imaging findings.

Intergroup comparisons between clinical features (age, age at onset of seizures, gender, seizure type, and seizure frequency) and AED type and dosage were performed using the using t-tests and the chi-square test.

For cortical excitability measures (MT and ISIs) a two-way analysis of variance (ANOVA) was used. Each ANOVA had a between-participants factor “group” (drug naive, medically refractory, seizure-free on AEDs, postoperative refractory, postoperative seizure-free, nonepilepsy controls) and a within-participant factor “hemisphere” (interhemispheric comparison).

For all analyses, p < 0.05 was chosen as the significance level. Fisher's Protected Least Significant Difference post hoc tests were performed as appropriate. The analysis was performed on SPSS, 15.0 for Windows (IBM, Armonk, NY, U.S.A).

The effect size was calculated for the significant results (MT and each ISI) using the formula:

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Effect size 0.2 was considered small, 0.5 medium and ≥0.8 large (Cohen, 1969).

Results

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure
  8. References
  9. Biography

Clinical features

The only significant intergroup difference was the number of AEDs used by each patient being significantly higher in the refractory seizure groups (medical and postoperative) compared to the seizure-free groups (Table 1). This was most prominent in the patients in the early seizure-free group who were all taking a single AED.

There were no intergroup differences in age, gender, age of seizure onset, clinical features (seizure type), or seizure frequency in any of the groups.

Motor threshold

Compared to nonepilepsy controls, motor threshold (MT) was higher in both hemispheres of both refractory and seizure-free groups (medical and postoperative; p < 0.05, effect sizes 0.2–0.4).

There was no difference on comparison of either hemisphere of patients in the drug-naive new-onset state and controls.

In drug-naive patients with new-onset TLE, there was an increase in mean MT (denoting decreased excitability) in the ipsilateral hemisphere compared to the contralateral hemisphere (p < 0.05, effect size 0.3; Table 3). This interhemispheric difference in MT was not observed in any of the other groups.

Table 3. MT (mean ± SD) for each participant group (patients and controls) and their siblings
SubgroupMT (stimulus intensity %)
Nonepilepsy controls55.2 ± 5.6
Drug-naive, new-onset 
Ipsilateral hemisphere59.2 ± 5.9
Contralateral hemisphere54.3 ± 5.9
Early medically refractory seizures 
Ipsilateral hemisphere60.8 ± 5.0
Contralateral hemisphere60.9 ± 4.1
Late medically refractory seizures 
Ipsilateral hemisphere59.9 ± 4.8
Contralateral hemisphere61.0 ± 5.3
Early seizure-free on AEDs 
Ipsilateral hemisphere62.9 ± 4.9
Contralateral hemisphere61.1 ± 5.4
Late seizure-free on AEDs 
Ipsilateral hemisphere61.9 ± 6.0
Contralateral hemisphere60.9 ± 5.9
Postoperative refractory seizures 
Ipsilateral hemisphere59.3 ± 7.0
Contralateral hemisphere60.9 ± 6.4
Postoperative seizure-free 
Ipsilateral hemisphere61.2 ± 4.9

Intracortical inhibition and facilitation

Comparison with nonepilepsy controls
Drug naive, new onset

In patients with TLE, the ipsilateral hemisphere demonstrated an increase in cortical excitability at both short (2 and 5 msec; p < 0.01, effect size 0.5 and 0.4) and long (250 and 300 msec; p < 0.01, effect sizes 0.9 and 0.5) ISIs compared with the contralateral hemisphere (Fig. 1; far left).

image

Figure 1. Short and long ISI recovery curves with error bars for both hemispheres in the patients in each group. Ratios <100% indicate inhibition and ratios >100% indicate facilitation. Ipsilateral hemisphere signifies hemisphere with seizure focus. The upper boundary of the gray shaded area represents nonepilepsy controls.

Download figure to PowerPoint

Compared with nonepilepsy controls, there were increases in excitability at the 2 and 5 msec ISI (p < 0.01, effect sizes 0.8 and 0.6) and the 250 and 300 msec ISIs (p < 0.01; effect sizes 1.2–0.7) in the ipsilateral hemisphere.

There were no differences in the contralateral hemisphere compared to nonepilepsy controls at any ISI.

Early medically refractory seizures

Cortical excitability was increased in both hemispheres at the short ISIs (2 and 5 msec) (p < 0.01; effect sizes ranging from 0.5 to 0.7) and all the long ISIs (p < 0.01, effect sizes ranging from 0.7 to 1.0) compared to nonepilepsy controls (Fig. 1; left upper panel).

Late medically refractory seizures

In this group cortical excitability was also increased in both hemispheres at the short ISIs (2 and 5 msec (p < 0.01; effect sizes ranging from 0.4 to 0.5) and all the long ISIs (p < 0.01, effect sizes ranging from 0.5 to 0.8) compared to nonepilepsy controls (Fig. 1; middle upper panel).

Postoperative refractory seizures

Values in the early part of the short ISI curve (2 and 5 msec) and all the longer ISIs remained significantly increased in both hemispheres compared to nonepilepsy controls (p < 0.01, effect sizes ranging from 0.6 to 0.9) (Fig. 1; right upper panel).

Early seizure-free on AED

Cortical excitability was increased for the ipsilateral hemisphere at the long ISIs (250 and 300 msec; p < 0.05, effect sizes 0.3–0.4) compared to nonepilepsy controls (Fig. 1; left lower panel). Comparison of the short ISI recovery curve revealed that there were no differences at any of the short ISIs compared to nonepilepsy controls in the ipsilateral hemisphere.

There were no differences between the contralateral hemisphere and nonepilepsy controls at any ISI.

Late seizure-free on AED

Cortical excitability was increased in both hemispheres at the long ISI 250 msec (p < 0.05, effect sizes 0.3–0.4) compared to nonepilepsy controls. There was also an increase at the 300 msec ISI for the ipsilateral hemisphere (Fig. 1; middle lower panel).

There were no differences between either hemisphere and nonepilepsy controls at any of the short ISIs.

Postoperative seizure-free

Cortical excitability of both hemispheres was increased at the long ISIs (250 and 300 msec; p < 0.05, effect sizes 0.3–0.4) compared to nonepilepsy controls (Fig. 1; right lower panel).

There were no differences at any of the short ISIs in either hemisphere compared to nonepilepsy controls.

Intergroup comparison
Refractory seizure groups

Cortical excitability was higher across both hemispheres when comparing the early to the late medically refractory seizure group for all ISIs, but this effect was only significant for the ipsilateral hemispheres at the long ISIs of 200–300 msec (p < 0.05, effect size 0.3).

Seizure-free groups

Cortical excitability of both hemispheres tended to be reduced for the early seizure-free group on AEDs when compared to the late seizure-free groups, although this was only statistically significant when comparing the contralateral hemisphere of the early seizure-free group to the postoperative seizure-free group at the 200 and 300 msec ISIs (p < 0.05, effect size 0.4).

Across all groups

Cortical excitability was greater for both hemispheres across all refractory groups (medical and postoperative) compared to the ipsilateral hemisphere of drug-naive new-onset patients at the 100, 150, and 200 msec ISIs and to the contralateral hemisphere of the same group as well as both hemispheres of all seizure-free groups for all long ISIs (p < 0.05; effect sizes 0.3–1.0).

In addition, cortical excitability was increased across both hemispheres for the refractory groups compared to the seizure-free groups at the 2 msec ISI (p < 0.05, effect size 0.4–0.5).

Discussion

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure
  8. References
  9. Biography

In the current study we show specific cortical excitability changes in different cohorts of patients with TLE at various stages of the disease. The primary difference is a significant interhemispheric difference in patients with TLE at early onset prior to starting AEDs, with a net increase in cortical excitability in the hemisphere ipsilateral to the seizure focus, whereas the unaffected hemisphere remains normal. According to our results, the course of the illness changes this pattern into one of two archetypes, both ultimately resulting in the loss of interhemispheric differences. Refractory seizures result in increased excitability in both hemispheres even though the focus is unilateral and seizure freedom results in reduction of the hyperexcitability that was present prior to treatment whether medical or surgical.

The refractory groups were taking a significantly higher number of AEDs compared to the seizure-free groups. Despite that, cortical excitability was still higher in all refractory groups. It is known that AEDs have a prominent effect on TMS measures (Ziemann, 2004). This effect is most marked on MT and would thus explain the increase in MT compared to controls that was observed in the current study as well as previous studies on patients with chronic focal epilepsy (Cantello et al., 2000; Hamer et al., 2005). However, this effect would be expected to increase as a function of the number of AEDs used (Cantello et al., 2000), but we did not find this to be the case. Values for MT were similar in both the refractory and seizure-free groups, even though the number of AEDs used by the refractory groups was much higher. The results suggest that patients with refractory seizures are resistant to the effect of AEDs. Conversely, although cortical excitability was normal or near normal in both hemispheres in patients who were seizure-free from onset, it remained mildly elevated even in the unaffected hemisphere at the 250 msec ISI in patients where seizure freedom was more difficult to achieve. These changes occurred irrespective of the specific AED(s) used. This suggests that despite what is known about particular mechanisms of each drug; whether it works on specific channels or receptors, a common mechanism possibly exists at the level of interneuronal interactions and synapses. This is likely due to the complexity of the alterations that are associated with the epileptic process. These disturbances cause widespread functional changes that extend beyond the epileptic focus to involve the unaffected hemisphere. This interneuronal interaction is probably affected by many physiologic and acquired factors, all of which determine the course and prognosis of epilepsy.

With successful surgery, cortical excitability decreased in both hemispheres in patients who became seizure-free. Postoperative changes in the contralateral hemisphere were also reported previously, in the form of increased intracortical facilitation (the late part of the short ISI curve) in one study (Kamida et al., 2007), and reduced intracortical facilitation together with shortening of the cortical silent period (denoting increased cortical excitability) in another (Lappchen et al., 2008). Another study also found increased interhemispheric inhibition on stimulation of the unaffected hemisphere postoperatively (Lappchen et al., 2011). Such contradictory findings may be due to sample size; however, they may also be due to the fact that each of these TMS parameters reflects activity in different intracortical circuits. Intracortical facilitation is most likely mediated by excitatory interneuronal circuits, possibly glutamate mediated (Ziemann, 2003); the early part of the short ISI curve is thought to be mediated by γ-aminobutyric acid (GABA)A (Boroojerdi, 2002), and long ISIs reflect GABAB mechanisms (Florian et al., 2008). The silent period may represent GABAB circuits (Ziemann, 2003). It appears that different circuits are modulated in different ways following surgery. This perhaps depends on the operative procedure and the level of cortical hyperexcitability in that hemisphere prior to surgery, as a net increase in excitability was found mainly in the study with patients without cortical hyperexcitability changes in the contralateral hemisphere prior to surgery (Kamida et al., 2007).

Our findings show that the characteristic pattern of cortical hyperexcitability associated with TLE is influenced by the natural course of the disorder. The results indicate that this abnormality can be reversed with successful epilepsy treatment (medical or surgical), which is interesting as there is a structural difference between medication- and surgical-related seizure freedom. With medication the presumed “generator” remains, but its activity is “damped down,” whereas with surgery the generator is removed. Although it is not clear whether this effect is due to a change within the brain's predisposition to generate seizures, or simply the loss of the secondary consequences of seizures, it seems the cortical hyperexcitable network is further reinforced by recurrent seizures. Successful treatment alters this relationship; when seizures stop regardless of whether this is the effect of medication or surgery functional reorganization within the previously hyperexcitable circuits takes place. Alternatively, synaptic reorganization following disruption of the epileptic network may elevate the threshold required for seizure generation and thus can also be the reason that seizures stop. Therefore, although we cannot ascertain that when seizure freedom is achieved the “abnormal” circuits are actually gone or simply inactivated via improved control (medical or surgical), our results suggest that TMS can provide a noninvasive insight into the dynamic nature of the condition at various stages.

The next step is to investigate whether the findings represent a potential objective surrogate measure to seizure control of the underlying abnormality within individuals. This would require large scale possibly multicenter studies to overcome the known high interindividual variability in TMS measures. Such studies would further benefit if the patients were followed with repeated TMS throughout the course of the disease. This is because it is known that TMS measures do not show significant intersession or interinvestigator variability (Mills & Nithi, 1997; Boroojerdi et al., 2000; Maeda et al., 2002; Badawy et al., 2012); therefore, any differences observed in the repeat TMS study(s) will be attributable to underlying electrophysiologic changes caused by the disorder.

Acknowledgments

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure
  8. References
  9. Biography

We wish to thank Dr. Wendyl D'Souza, Dr. Michael Tan, and Dr. Karen Fuller for their help in recruiting the patients and facilitating access to their electroclinical and imaging findings; Ms. Agnes Iwasiw from JLM Accutek Health Care for providing the TMS equipment; Dr. Danny Flanagan for his incredible support during all the phases of the study; Mrs. Shireen Cook, Professor David Grayden, Mr. Tim Nelson, Mr. Richard Balson, Miss Nicola Beattie, and Mr. Dean Freestone for the administrative and technical support they provided throughout the study; and the participants for their time.

Disclosure

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure
  8. References
  9. Biography

None of the authors has any conflict of interest to disclose. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

References

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure
  8. References
  9. Biography

Biography

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure
  8. References
  9. Biography
  • Image of creator

    Radwa A. B. Badawy Radwa is a postdoctoral Epilepsy Research Fellow in the Department of Medicine at the University of Melbourne, Australia. She is a clinician and researcher with primary interests in studying epilepsy using TMS, EEG, and fMRI.