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Seizure induction by high frequency transcranial magnetic stimulation (TMS) has been reported in normal subjects and by single pulse TMS close to the epileptic focus in patients with epilepsy.1
We report an 18 year old patient with right frontal lobe epilepsy due to paramedian focal cortical dysplasia (FCD). The patient’s usual seizure semiology consisted of a somatosensory aura of the left hand followed by a tonic seizure of the left arm which evolved to a bilateral asymmetrical tonic seizure without loss of consciousness. In the two years preceding the study (see below) he had rare night-time seizures only. His antiepileptic medication consisted of levetiracetam 500 mg, phenobarbital 25 mg, and carbamazepine 1600 mg daily.
During presurgical videoelectroencephalogram (video-EEG) monitoring, interictal EEG showed right frontotemporal spikes. Ictal EEG revealed seizure patterns with a right frontal onset. Magnetic resonance imaging (MRI) showed FCD in the right superior frontal gyrus extending into the right precentral gyrus (fig 1A). Neurological examination was normal.
Transcranial magnetic stimulation
The patient participated in a TMS study using a protocol described previously2 to evaluate intracortical excitability of both motor cortices (M1). The study was approved by the local ethics committee, and the patient gave written informed consent.
We used a focal 70 mm figure of eight coil connected to two magnetic stimulators via a BiStim module (Magstim Company, Dyfed, UK). Surface electromyography (EMG) was recorded from the contralateral abductor digiti minimi muscle (ADM) of the hand.
TMS commenced over the left M1 contralateral to the epileptic focus with the coil placed over the M1 hand area. First, motor thresholds (RMT, AMT) and cortical induced silent period at an intensity of 110% RMT were evaluated. Next, paired pulse TMS (conditioning stimulus set at 38% of maximum stimulator output, second stimulus 60% of stimulator output) was started on the left M1 with a train of paired pulses with ISI 2, 3, 10, and 15 ms in a random order.
After 65 stimuli, the patient noticed that his habitual somatosensory aura of the left hand followed by myoclonic jerks of the left forearm (mainly biceps brachii muscle and forearm flexor muscles) was triggered by each stimulus, contralateral to the epileptogenic zone but ipsilateral to the cortical stimulation. The jerks were triggered by both single and paired stimuli at all ISI and rapidly involved both arms. These motor phenomena were different from the typical seizure semiology. EMG recordings of the ADM showed movement artefacts 63–75 ms after the MEP (fig 1B). The TMS was immediately interrupted, which aborted the myoclonus at once.
The TMS data of the left hemisphere showed increased motor thresholds, prolonged cortical induced silent period, markedly decreased intracortical inhibition, and increased facilitation compared with 20 controls2 (percentiles of the patient’s measures within the control group: >99% for ISI 2 and CSP, >95% for motor thresholds and ISI 15, >90% for ISI 10, and >85% for ISI 3).
After the TMS experiment, the patient was again free of daytime seizures until the last follow up visit six months later.
Transcallosal seizure induction by paired pulse TMS
In patients with epilepsy, all reported cases of seizure induction by TMS have occurred during ipsilateral stimulation and near to the epileptic focus. Therefore, it has been assumed that direct stimulation of the epileptogenic tissue was required to trigger a seizure.1 We used a focal coil placed over the left M1 hand area more than 5 cm away from the midline. Thus, it is unlikely that the right epileptogenic zone or mesial frontal cortex of the present patient was stimulated directly, and we assume that an indirect transcallosal activation of the epileptogenic zone provoked the aura. The latency of 65–75 ms of the myoclonic jerks after the MEP may reflect polysynaptic pathways in addition to a direct transcallosal connection of both M1. It is still not clear whether involvement of additional cortical areas such as the ipsilesional and contralesional sensory cortices or basal ganglia contributed to the seizure provocation. Despite the patient’s statement that the jerks were not volitional, this cannot be completely ruled out. The preceding somatosensory aura, however, represented his typical seizure semiology. We hypothesise that transcallosal activation of the epileptic focus was promoted by the increased excitability of M1, which was due to the underlying FCD. This, in turn, led to the aura and peri-ictal changes in M1 excitability facilitating TMS driven myoclonic jerking. It has been previously reported that FCD is intrinsically epileptogenic and promotes reflex seizures.3
There is a possibility that ipsilateral pathways of movement activation could underlie our observations. In a child with extensive cortical dysplasia, TMS of the unaffected hemisphere evoked MEPs in both ADM muscles implying bilateral corticospinal connections from one cortex.4 Histological studies on severe brain damage in early development have revealed collateral sprouting into denervated areas of cortex or spinal cord.4 Ipsilateral activation under maximum muscle contraction has been observed in healthy volunteers and in patients with acute stroke.5 Our patient, however, presumably had congenital but circumscribed FCD, no motor deficits, and was investigated at rest. This and the fact that his habitual somatosensory aura occurred before the myoclonic jerks strongly argue against the activation of ipsilateral corticospinal tracts. Activation of a silent mirror focus in the left hemisphere with subsequent spread to the right is also unlikely because exclusively right sided ictal and interictal epileptiform discharges were recorded during the video-EEG monitoring.
Changes in motor cortex excitability
Our patient’s higher motor thresholds compared with controls are very likely due to his ion channel blocking anticonvulsant medication.6
The loss of intracortical inhibition and increased intracortical facilitation in the left hemisphere contralateral to the epileptogenic zone may reflect synaptic reorganisation of the ipsilesional and contralesional motor cortices. These distant functional cortical changes associated with malformations of cortical development have also been described previously.7 The prolongation of the cortical induced silent period seen in the present patient may be independent of the phenobarbital intake6 and confirms similar findings from previous studies as a remote effect of FCD on the motor cortex in untreated patients with cortical dysgenesis.7
Unilateral epileptogenic FCD involving M1 can induce complex bilateral alteration of motor cortex excitability resulting in a net increase of excitability. In such cases, transcallosal seizure induction appears to be possible with paired pulse TMS using a focal coil away from the epileptic focus.
Competing interests: none declared
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