Motor evoked potential polyphasia

Objective: We compared the motor evoked potential (MEP) phases using transcranial magnetic stimulation in patients with idiopathic generalized epilepsy (IGE), their relatives, and healthy controls, hypothesizing that patients and their unaffected relatives may share a subtle pathophysiologic abnormality. Methods: In a cross-sectional study, we investigated 23 patients with IGE, 34 first-degree relatives, and 30 matched healthy controls. Transcranial magnetic stimulation was performed to produce a series of suprathreshold single-pulse MEPs. A semiautomated method was used to count phases. We compared between groups the mean number of MEP phases, the stimulus-to-stimulus variability in MEP phases, and the proportion of polyphasic MEPs within subjects. Results: Patients with IGE and their relatives had a significantly increased number of MEP phases (median for patients 2.24, relatives 2.17, controls 2.01) and a significantly higher proportion of MEPs with more than 2 phases than controls (median for patients 0.118, relatives 0.088, controls 0.013). Patients had a greater stimulus-to-stimulus variability in number of MEP phases than controls. There were no differences between patients and relatives. Conclusion: Increased MEP polyphasia in patients with IGE and their first-degree relatives may reflect transient abnormal evoked oscillations. The presence of polyphasic MEPs in relatives as well as patients suggests that MEP polyphasia is not related to treatment, and is in isolation insufficient to predispose to epilepsy. Polyphasic MEP may be a novel endophenotype in IGE. Neurology® 2015;84:1301–1307 GLOSSARY AED 5 antiepileptic drug; ALS 5 amyotrophic lateral sclerosis; FDI 5 first dorsal interosseus; IGE 5 idiopathic generalized epilepsy; IQR 5 interquartile range; MEP 5 motor evoked potential; TMS 5 transcranial magnetic stimulation. The excessive, synchronous discharges characterizing most seizures may arise through cortical hyperexcitability. Idiopathic generalized epilepsy (IGE) presents with complex genetics and distinct phenotypes. Transcranial magnetic stimulation (TMS) is a noninvasive technique for measuring cortical excitability; using TMS, abnormalities of cortical excitability have been reported in drug naive and medicated IGE. A little-studied phenomenon in TMS not previously reported in epilepsy is the occurrence of polyphasic oscillations within the motor evoked potential (MEP) (figure 1). In amyotrophic lateral sclerosis (ALS), they may reflect central corticospinal abnormality, and in myoclonus dystonia, they may reflect abnormal variability in the patterning of descending corticospinal volleys evoked by TMS (so-called I waves) and hence alteration in the pattern and timing of recruitment of spinal motor neurons. Polyphasic responses have also been observed in healthy children becoming less polyphasic with age. Asymptomatic relatives of patients with IGE may share an endophenotype that alone is not sufficient to cause seizures. EEG abnormalities have been found in unaffected siblings, and *These authors contributed equally to this work. From the Department of Clinical Neuroscience (F.A.C., A.D.P., B.C., M.P.R.) and Centre for Epilepsy (L.N., R.D.C.E.), King’s College London, UK. Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article. The article processing charge was paid by King’s College London from their RCUK block grant. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2015 American Academy of Neurology 1301 a 2015 American Academy of Neurology. Unauthorized reproduction of this article is prohibited. TMS has revealed altered cortical excitability in patients with IGE and their asymptomatic relatives, in particular an impairment of intracortical inhibition. Thus, a neurophysiologic marker present in patients and unaffected relatives might be useful in characterizing a genetically inherited predisposition to epilepsy. Based on the observation of polyphasic MEPs in other patient groups, and that this may be a central phenomenon, we hypothesized that polyphasic MEP activity would be more prominent in IGE compared with controls, and would be present as an endophenotype in asymptomatic first-degree relatives. METHODS Subjects. We studied 23 right-handed patients with IGE (12 women, mean age 29 years, range 18–59, SD 11.14), 34 first-degree relatives (13 women, mean age 35.4 years, range 18–68, SD 14.8), and 30 ageand sex-matched healthy controls (17 women, mean age 29.3 years, range 18–52, SD 8.69) with no history of neurologic illness. In this exploratory study, we chose group sizes to allow detection of a large effect size (0.8) with 80% power and a of 0.05. Patients were recruited from outpatient clinics at several London hospitals, controls from a local research volunteer database. Diagnoses of IGE were made by experienced epileptologists (L.N., R.D.C.E., M.P.R.), based on a combination of clinical presentation, EEG, and neuroimaging data. Patients were subdivided into clinical syndromes: 5 with juvenile myoclonic epilepsy, 1 with juvenile absence epilepsy, 4 with childhood absence epilepsy, 9 with generalized tonic-clonic seizures only, 1 with eyelid myoclonia and absences, and 3 IGE unclassified. Basic clinical and demographic data are shown in table 1. This cohort has been previously described. No relatives had a diagnosis of epilepsy; 2 had generalized discharges on EEG. Standard protocol approvals, registrations, and patient consents. The study was approved by the research ethics committee at King’s College Hospital (ethics reference 08/H0808/ 157). All participants gave written informed consent. Procedure. TMS recordings were obtained in a single session. All subjects were seated, relaxed, and alert. EMG was recorded by positioning silver/silver chloride EMG disc electrodes in a belly-tendon montage on the first dorsal interosseus (FDI) muscle bilaterally. TMS pulses were delivered by a figure-of-8 coil (9-cm external loop diameter) using a Magstim BiStim unit (Magstim Company, Dyfed, UK) connected to 2 Magstim 200 stimulators. EMG signals were filtered and amplified (CED 1902; Cambridge Electronic Design, Cambridge, UK) using a sampling rate of 15 kHz, a bandwidth of 10–5,000 Hz, and a gain of 1,000 (CED 1401), and traces were recorded using data capture and signals processing software (Signal 3.10; Cambridge Electronic Design). The coil was placed tangentially to the scalp with the handle facing backward and angled at approximately 45° to the midline so as to provide an optimal posterior-to-anterior current flow across the motor cortex, as per previously established methods. The optimal site for stimulating the FDI was established for each hemisphere and marked on the scalp to ensure consistency during recording. Resting motor threshold was recorded according to previously established protocols. The threshold is defined as the lowest stimulator output capable of eliciting an MEP of at least 50 mV amplitude in 50% of pulses. Resting motor threshold was recorded with patients completely relaxed whereas active motor threshold was recorded during voluntary contraction of the FDI. Contraction force was standardized using a manometer, with subjects squeezing at 20% of their maximum voluntary contraction. These data were collected as part of a larger dataset, and for the measurement of polyphasic activity, the unconditioned single pulses from a larger paired-pulse dataset were analyzed. These pulses were delivered at 120% of resting motor threshold to ensure anMEPwould be consistently evoked across the trials. A total of 20 unconditioned MEPs were recorded for each subject. Data analysis. MEPs were analyzed for polyphasic activity in Signal 3.13 using a semiautomated custom script. First, every MEP in every subject was visually inspected for the presence of 50-Hz line noise. If present, the maximum and minimum values of the 50-Hz oscillation were determined in the EMG data beyond the termination of the MEP. These maximum and minimum threshold values were entered into the automated analysis of MEP phases. The analysis script was designed to first identify the highest peak (the point of Figure 1 Motor evoked potential (MEP) from single transcranial magnetic stimulation pulse over contralateral motor cortex, recorded using surface EMG from first dorsal interosseus muscle (A) A polyphasic MEP from a patient with idiopathic generalized epilepsy with a count of 4 phases. (B) A normal MEP from a healthy control subject. 1302 Neurology 84 March 31, 2015 a 2015 American Academy of Neurology. Unauthorized reproduction of this article is prohibited. maximum amplitude) of the MEP waveform. Then, a time window was automatically placed around the peak during which polyphasic activity would be detected. Based on a prior analysis of all MEPs across all subjects, a time window of 7.5 milliseconds before and 15 milliseconds after the peak was chosen because it encompassed 100% of the observable polyphasic activity in every subject. Within this time window, peaks and troughs of the waveform were automatically counted if they exceeded the thresholds set according to the amplitude of the line noise, or if the peak/trough had an amplitude exceeding 0.4 mV if no visible line noise was present. It is conceivable that some peaks and troughs may, in some instances, have had an amplitude less than the line noise, and therefore not detected, but it should be noted that in such case our estimate of MEP phases may be conservative. It should also be noted that the presence of line noise was similar between groups of subjects. We did not use a 50-Hz notch filter. This is because the MEP has frequency components in this range, and hence using a notch filter creates very prominent ringing in the MEP waveform, which would artifactually create a polyphasic signal. Although we did everything feasible to reduce line noise, the presence of some line noise in some subjects’ data is inevitable given that we did not have access to an electrically shielded recording room or to a Faraday cage. We emphasize that line noise was always of very low amplitude and was not visually detectable in many subjects. Once a count of phases was obtained for each MEP, the total number of phases was averaged for all 20 MEPs for each subject; this meanMEP phase count was used for between-group comparisons. We also calculated the within-subjects interquartile range (IQR) of the number of MEP phases to assess whether the presence of polyphasic responses in patients and relatives was more variable from trial to trial than in control participants. Finally, we examined the proportion of all MEPs in each subject that demonstrated polyphasic activity (i.e., the number of frames that showed more than 2 phases as a proportion of the total number of MEPs recorded per subject). All data were analyzed using SPSS 21.0 (IBM UK, London). Nonparametric Kruskal–Wallis test was adopted to compare groups for each measure (mean number of phases; betweentrials IQR of the number of MEP phases; proportion of polyphasic MEPs), and post hoc nonparametric Mann–Whitney test was used to further explore the data if a significant effect was found for Kruskal–Wallis test. RESULTS There were no significant differences in polyphasic activity between hemispheres in any subject group; therefore, the number of phases was Table 1 Description of the patient group Age, y Sex Epilepsy syndrome Age at onset Seizure frequency/y Medication EEG MRI 53 F IGE GTCS 3 y ABS 5–10 daily, GTCS SF Nil GSW (with Ph1) Normal 20 F JME 13 y SF VAL GSW (front max) Normal 20 F IGE GTCS 6 mo SF Nil — 39 F IGE GTCS 22 y GTCS SF CBZ GSW Normal 18 F JME 15 y MJ LEV, LTG, ZON GSW — 18 F CAE 7 y GTCS 12, ABS ETX, LTG GSW Normal 21 F JAE 10 y GTCS, ABS SF LTG, ETX GSW Normal 32 F CAE 4 y ABS (weekly) NA GSW — 19 F IGE GTCS 15 y GTCS 6 LEV GSW Normal 45 F IGE GTCS 2 y GTCS SF Nil — — 21 F AEM 6 y 52 LTG PSW — 28 M GTCS 8 y 1 VAL GSW — 31 M IGE 8 y GTCS SF VAL Normal Normal 28 M CAE 4 y GTCS SF, ABS SF VAL, LEV, LTG GSW — 30 M IGE 11 y ABS SF Nil — — 28 M JME 17 y GTCS 12, MJ frequent VAL Frequent GSW Normal 25 M JME 14 y GTCS 3 MJ VAL GSW Normal 25 M IGE GTCS 11 y GTCS 24 VAL GSW Normal 59 M JME 14 y MJ1, GTCS SF Nil — — 26 M CAE 5 y SF VAL, TOP, LTG GSW — 28 M IGE 20 y SF CBZ Normal Normal 31 M GTCS (Ph1) 8 y GTCS 6 VAL, ZON, LEV, LTG GSW Ph1 — 45 M CAE 3 y SF VAL, LEV GSW — Abbreviations: ABS 5 absence seizures; AEM 5 absences with eyelid myoclonia; CAE 5 childhood absence epilepsy; CBZ 5 carbamazepine; ETX 5 ethosuximide; GSW5 generalized spike and wave; GTCS5 generalized tonic-clonic seizures; IGE5 idiopathic generalized epilepsy; JAE5 juvenile absence epilepsy; JME 5 juvenile myoclonic epilepsy; LEV 5 levetiracetam; LTG 5 lamotrigine; MJ 5 myoclonic jerks; ph1 5 photic stimulation; SF 5 seizure free (if .12 months without any seizure); TOP 5 topiramate; Val 5 valproate; ZON 5 zonisamide. Neurology 84 March 31, 2015 1303 a 2015 American Academy of Neurology. Unauthorized reproduction of this article is prohibited. averaged within subjects between hemispheres. Age was not significantly different between groups. There was a significant difference in the average number of MEP phases between groups (Kruskal– Wallis p 5 0.027). Patients with epilepsy had a significantly increased average number of phases compared with controls (Mann–Whitney p 5 0.010; median for patients 2.24, controls 2.01) (see figure 1, and tables 2 and 3). Relatives also had a significantly increased number of phases compared with controls (Mann–Whitney 0.048; median 2.18). There was a significant difference in the variability of the number of MEP phases between the groups, measured by examining the within-subjects IQR of the number of MEP phases across the 20 trials (Kruskal–Wallis p 5 0.033). Patients with epilepsy had a significantly increased IQR of the number of MEP phases compared with controls (Mann– Whitney p 5 0.009; patients 25th centile 0, 75th centile 1.5; controls 25th centile 0, 75th centile 0). Relatives and controls were not significantly different. There was a significant difference in the proportion of MEPs from each subject with more than 2 phases (polyphasic activity) across the groups (Kruskal–Wallis p 5 0.030) (see figure 2). The proportion of MEPs with more than 2 phases was greater in patients compared with controls (Mann–Whitney p 5 0.012; median for patients 0.118, median for controls 0.013). The proportion of MEPs with more than 2 phases was also greater in relatives compared with controls (Mann–Whitney p 5 0.044; median 0.088). Note that there were no significant differences between patients and relatives on any measures. These findings are summarized in figure 3, which shows the proportion of MEPs within the 20 trials for each subject that had between 1 and 6 phases (no subject had any MEP with .6 phases). Grouplevel minimum, 25th centile, median, 75th centile, and maximum are illustrated for each number of MEP phases, providing a summary overview of the entire dataset. Finally, we examined an established measure of cortical excitability (resting motor threshold) as a separate intergroup comparison. Leftand righthemisphere resting motor threshold was averaged and intergroup differences were assessed. There were no significant differences between any of the groups. Table 2 Summary of data obtained for each group Within-subjects measure Minimum 25th centile Median 75th centile Maximum