Journal of Neurological Sciences [Turkish] 33:(2)# 48; , Clinical Neurophysiology

Transcription

1 Journal of Neurological Sciences [Turkish] 33:(2)# 48; , Clinical Neurophysiology Interictal Rhythmic Midline Theta Rhythm is Common in Frontal Lobe Epilepsy But Not Specific to Any Subcompartment Leyla BAYSAL KIRAC 2, Jan REMI 1, Elisabeth HARTL 1, Anna Mira LOESCH 1, Christian VOLLMAR 1, Soheyl NOACHTAR 1 1 University of Munich, Department of Neurology, Epilepsy Center, Munich, Almanya 2 Goztepe Research and Training Hospital, Department of Neurology, Istanbul, Turkey Summary Purpose: The objective was to investigate whether rhythmic midline theta (RMT) is more common in mesial frontal lobe epilepsy (FLE) than in other FLEs. Methods: We reviewed our data base and included 19 patients with medically refractory FLE who underwent invasive evaluation for epilepsy surgery in the study. In all patients noninvasive EEG-video recordings have been performed prior to the invasive studies. Interictal RMT due to drowsiness was excluded. Results: RMT was observed in surface EEGs of 13 of 19 (68 %) FLE patients. The rate of RMT was as common in mesial frontal (6 of 8 patients; 75 %), orbitofrontal (4 of 5 patients, 80 %) and dorsolateral frontal (2 of 3 patients; 67%) seizure onset (p=0.9). RMT was observed in surface EEGs of 4 of 5 (80 %) patients who showed majority of the interictal epileptiform discharges (IEDs) in the temporal lobe region. Conclusions: Interictal RMT is common in patients with FLE and does not seem to have an association with a subcompartment of the frontal lobe. RMT is particularly valuable as a marker for frontal lobe epileptic dysfunction in patients whose IEDs dominate outside the frontal lobe. Key words: Frontal lobe epilepsy, epilepsy surgery, epilepsy monitoring, rhythmic midline theta Özet İnteriktal Ritmik Orta Hat Teta Ritmi Frontal Lob Epilepsisinde Sıktır, Ancak Herhangi Bir Alt Kompartmana Spesifik Değildir Amaç: Çalışmanın amacı ritmik orta hat teta ritminin (ROT) meziyal frontal lob epilepsisinde (FLE) diğer FLE sendromlarına göre daha sık izlenip izlenmediğinin araştırılmasıdır. Yöntem: Bu çalışmada epilepsi veri tabanımızı gözden geçirdikten sonra medikal tedaviye dirençli, epilepsi cerrahisi için invasiv monitorizasyon yapılan 19 hasta saptadık. Bu hastaların hepsine invasiv değerlendirme öncesi non-invasiv video-eeg monitorizasyonu yapılmıştı. Hafif uykululuğa bağlı ortaya çıkan ROT dışlandı. Sonuçlar: ROT yüzeyel EEG kaydı yapılan 19 FLE hastasının 13'ünde (% 68) gözlendi. ROT oranı meziyal frontal lob (8 hastanın 6'sı % 75), orbitofrontal lob (5 hastanın 4'ü, % 80) ve dorsolateral frontal lob (3 hastanın 2'si, % 67) başlangıçlı nöbetlerde aynı sıklıktaydı. ROT interiktal epileptiform deşarjlarının (IED) çoğu temporal lobda ortaya çıkan 5 hastanın 4'ünün (% 80) yüzeyel EEG'lerinde izlendi. 207

2 Sonuçlar: İnteriktal ROT FLE hastalarında sıktır ve frontal lobun herhangi bir alt kompartmanıyla ilişkili gözükmemektedir. ROT özellikle IED'lerinin çoğu frontal lob dışında olan hastalarda frontal lob epileptik disfonksiyonunun anlaşılması için önemli bir belirteçtir. Anahtar Kelimeler: Frontal lob epilepsisi, epilepsi cerrahisi, epilepsi monitorizasyonu, ritmik orta hat teta ritmi INTRODUCTION Frontal lobe epilepsy (FLE) is the second most common type of refractory focal epilepsies, occurring in about 25 % of epilepsy surgery candidates referred to epilepsy surgery centers (11). In a previous report we showed that the interictal rhythmic midline theta (RMT) during wakefulness is a common feature in FLE and may help to differentiate FLE from temporal lobe epilepsy (TLE) (1). All mesial FLE patients, established by invasive EEG showed RMT in the scalp EEGs (1). Therefore, it was concluded that RMT may reflect mesial frontal lobe abnormality. In this study, we investigate the frequency of RMT in patients with epilepsies arising from different subcompartments of the frontal lobe in order to determine the localization of the generators of RMT. For the purpose of this study, we included only patients in whom invasive EEG defined the epileptogenic zone in the frontal lobe. MATERIAL AND METHODS Patient selection Nineteen patients (5 women, 14 men) with medically refractory FLE who were admitted for presurgical evaluation between 2006 and 2014 recruited from the database of epilepsy monitoring unit of the University of Munich from a total of 223 invasively explored patients. We included only patients in whom the intracranial studies localized the epileptogenic zone within the frontal lobe. We excluded the patients whose surface EEG recordings could not be assessed (n=6). Mean age at video-eeg monitoring was 35 ± 12.2 years (range years), mean duration of epilepsy was 19.8 ± 12.8 years (range 3 to 43 years). No patient had any medical condition other than epilepsy. Prior to selection for invasive monitoring all patients underwent a detailed evaluation with clinical examination, seizure history and prolonged non-invasive video EEG monitoring with scalp EEG. Non-invasive EEG video monitoring was performed with selected closely spaced surface electrodes (10 10 system, 40-channel) and sphenoidal electrodes in all patients. High resolution magnetic resonance imaging (MRI) according to a standard epilepsy protocol, and ictal and interictal single-photon emission computed tomography (SPECT) (n=13) or fluoro-deoxyglucose positron emission tomography (FDG-PET) (n=7) were performed in selected patients. All patients were discussed in a multidisciplinary case management conference based on the results of EEGvideo monitoring, MRI, PET and SPECT findings. Out of 17 lesional patients, 14 of them showed a MRI abnormality restricted to the frontal lobe. Functional imaging (PET and SPECT) studies showed metabolic abnormalities restricted to the frontal lobe in 13 of the patients (Table 1). 208

3 Table 1: Clinical characteristics, invasive EEG data, and imaging findings of FLE patients Epileptogenic zone Patient Nr/Sex/Age 1/M/31 MRI lesion Lt. middle F gyrus gliosis (ganglioglioma resected) Functional imaging (hypometabolism on interictal PET or hyperperfusion on ictal SPECT) Lt. F (PET) Lt. F (SPECT) Ictal onset zone and evolution Lt. F polar Lt. mesial F Lt. Seizure types Subclinical Localization of IED on invasive/surface EEG Lt. sup and middle F gyrus/ Lt frontocentral RMT Outcome Engel (9 years) Mesial frontal lobe Patients (n=8) 2/M/17 3/M/48 4/M/48 5/M/30 6/M/54 7/F/48 8/M/19 Rt. sup F gyrus high signal Rt. sup F gyrus porencephalic cyst (ganglioglioma) Rt. sup mesial F and precentral gyrus high signal Rt. F gliosis (sequela of SAH ) Lt. sup F gyrus high signal Rt. sup and middle F gyrus lesion Lt. sup and middle F gyrus gliosis (posttraumatic) Rt. F polar (SPECT) Rt. mesial F Complex motor Rt. sup F gyrus/ Rt F (10 months) Rt. sup and middle F gyrus Rt. mesial F Rt. 1) Dialeptic Rt. sup and middle F gyrus/ (SPECT) 2) Lt. versive Rt F (20 months) 3) Lt. clonic 4) Lt. arm negative motor Rt. mesial F (PET) Rt. mesial F Rt. Bilat tonic Rt. sup F gyrus/ Yes Class 4 Rt. mesial F (SPECT) Rt FT (3 years) Not done Rt. F polar Rt. 1) Lt. clonic Rt. F polar and sup F gyrus/ Lt. F (PET) Lt. OF and TP (SPECT) Rt. middle and precentral F gyrus (SPECT) Lt. F (SPECT) mesial F Lt. mesial F Lt. ant T Rt. mesial F Rt. Lt. mesial F Lt. 2) Bilat tonic 1) Automotor Bilat tonic 2) Complex motor 1) Automotor 2) Dialeptic Bilat tonic 3) Lt. tonic Lt. versive Rt. versive Rt. Clonic Rt F Lt. sup F gyrus > Lt. sup T gyrus/ Lt T Rt. sup F gyrus and Rt. precentral gyrus/ Rt frontocentral Lt. sup and middle F gyrus/ Lt F (2 years) (6 months) No Class 1 (4 years) No Class 1 (4 years) Orbito frontal lobe Patients (n=5) 9/F/33 10/M/27 11/F/51 Rt. F gliosis Lt. FT gliosis (posttraumatic) Lt. F basal lesion, L sup F gyrus high signal (glioneuronal hamartoma) Rt. F basal (SPECT) Lt. OF (SPECT) Rt. OF Rt. Rt. OF Rt. mesial T Lt. OF Lt. T Lt. OF Lt. Hypermotor Automotor 1) Aphasic 2)Dialeptic Rt. clonic Rt. versive Not done Lt. OF Automotor Complex motor 12/F/40 Normal Rt. F (PET) Rt. OF Rt. mesial F Lt. mesial F 13/M/37 Rt. sup F gyrus gliosis (frontopolar abcess resected) 1) Complex motor Lt. clonic 2) Automotor Lt. clonic Rt. F polar, F basal, P (SPECT) Rt. OF Dialeptic Lt. versive 14/M/46 Bi, T and Lt. O gliosis Lt. F and T (PET) Lt. Lt. Automotor Rt. tonic Dorsolateral (posttraumatic) mesial T frontal lobe 15/M/26 Rt. sup F gyral abnormality Rt. F (PET) Rt. 1) Lt. tonic Lt. versive 2) Bilat tonic Patients (n=3) 16/M/42 Lt. middle F gyrus and Lt. uncal Lt. F and T (SPECT) Lt. Lt. OF Automotor Bilat tonic lesion (NF-1) Lt.versive 17/M/31 Rt. middle F gyrus high signal Lt. mesial F (PET) Bi 1) Bilat tonic 2) Bilat tonic Lt. clonic Frontal lobe not localised Patients (n=3) Rt. middle T gyrus> Rt. orbital gyrus/ Rt>Lt T Lt. middle F gyrus> Lt. lat orbital gyrus/ Lt F Lt. orbital gyrus/ Lt>Rt mesiotemporal Rt. orbital gyrus/ Lt>Rt F Rt. lat and medial orbital gyrus/ Rt mesiotemporal>f Lt. middle T and F gyrus / Lt T Rt. sup and middle F gyrus/ R F (9 years) (2 years) (5 years) Yes Surgery planned No Class 1 (16 months) Yes Surgery planned (7 years) Lt. T > Lt. orbital gyrus/ Lt T No Class 3 (6 years) Lt. F> Rt. F / Bi F and Bi T Yes Not done 18/F/24 Normal Not conclusive (SPECT) Bi Automotor Lt. sup F gyrus> Rt. sup F gyrus/ R F slow waves 19/M/13 Lt. F operculum high signal Rt. middle and inferior F gyrus (SPECT) Bi 1) Complex motor 2) Complex motor GTC 3) Complex motor Hypermotor Lt. middle F gyrus>rt. sup F gyrus / Lt F M: Male, F: Female, Rt: Right; Lt: Left, Sup: superior, Bilat: Bilateral, Lat: Lateral, IED: Interictal epileptic discharge, RMT: Rhythmic midline theta, F: Frontal, T: Temporal, P: Parietal, O: Occipital, OF: Orbitofrontal, FT: Frontotemporal, FCD: Focal Cortical Dysplasia, SAH: subarachnoid hemorrhage, NF: Neurofibromatosis, GTC: Generalised tonic clonic, MRI: Magnetic resonance imaging, PET: Positron emission tomography, SPECT: Single-photon emission computed tomography. Seizure classification follows the semiological seizure classification (8). No No Not done Not done 209

4 The decision about the electrode placement in invasive EEG monitoring was established based on hypothesis about epileptogenic zone localization derived from non-invasive EEG evaluation, seizure semiology and imaging findings. Invasive EEG included stereotactically implanted depth electrodes (n=12) and subdural strip and grid electrodes (n=7). At the time of the study fourteen patients underwent resective epilepsy surgery. Outcome of surgery was defined by the Engel's classifications (3). The post-operative mean follow up was between 6 months and 9 years with Engel class 1 outcome in 12 of the patients, Engel class 3 in 1, and Engel class 4 in 1 patient. Three patients whose invasive EEG evaluation showed bilateral frontal seizure onset zone, were not considered as suitable candidates for resection. For the purpose of this study FLE was further subclassified as dorsolateral frontal, mesial frontal and orbitofrontal based on the results of invasive EEG monitoring and imaging studies. EEG Analysis After patient selection a review of the continuous surface EEG recordings of all patients were performed by one epileptologist (L.B.K) for the occurrence and characterization of interictal RMT. RMT was defined as theta rhythms of 4-7 Hz frequency most prominently appeared in the Fz or Cz lead. RMT was included only if it lasted at least 3 s and occurred during definite awake states characterized by predominance of occipital alpha background activity, eye blinking and lack of any drowsy pattern (16). The EEGs of the patients were included for further analysis only if another senior epileptologist (S.N.) reviewed solely the most representative EEG periods considered by the first epileptologist and agreed upon the result of RMT. We excluded rhythmic slowing associated with drowsiness and mental activation as in the previous study (1). However, not all interictal video sequences of the invasive evaluations were stored and in some RMT phases, videos of the invasive recordings were not available for review. Although we cannot exclude mental activation associated with the invasive recordings in selected patients, none of these patients included in the current study showed RMT associated with mental activation during the prior non-invasive evaluations (1). Statistical analysis Fisher's exact test was used to evaluate the significance of association of RMT between the different groups. RESULTS Clinical characteristics, invasive EEG data and imaging findings of the patients are presented in table 1. Epileptogenic zone was localized to the mesial frontal lobe in 8 (42 %), orbitofrontal lobe in 5 (26 %), dorsolateral frontal lobe in 3 (16 %) of the patients. In 3 patients (16 %) seizures were arising in the bilateral frontal lobes. RMT was observed in surface EEGs of 13 of 19 FLE patients (68 %). A typical example of RMT in a FLE patient is given in Figure 1. When comparing the subcompartmental localization, 6 of the 8 mesial frontal (75 %), 4 of the 5 orbitofrontal (80 %), and 2 of the 3 dorsolateral frontal (67 %) patients showed RMT (p=0.9). The average frequency seen was 5 Hz (range 4-7 Hz). Average RMT bursts lasted 6 s (range 3-12 s). In individual patients RMT occurred daily 4-10 times/day. In surface EEGs majority of the interictal epileptiform discharges (IEDs) were found in the temporal region of 5 of 19 patients (26 %) (Table 1). RMT was present in the surface EEGs of 4 of 5 patients (80 %) who showed majority of the IEDs in the temporal lobe region. None of our patients lacked IED in surface EEG. The presence of RMT was neither related to any underlying pathology nor had any prognostic significance. We could not 210

5 show the invasive correlate of RMT in three patients who had simultaneous scalp and invasive EEG recordings. Figure 1: Interictal EEG in bipolar montage of a 48-year-old male with a right mesial FLE due to a porencephalic cyst in the right superior frontal gyrus. This EEG shows interictal rhythmic midline theta (RMT) localized to the frontocentral region (maximum at electrodes Fz and Cz). Muscle artifacts and eye blinks indicate the awake state of the patient. DISCUSSION This study shows that RMT is common in frontal lobe epilepsies and occurs equally commonly in FLE originating from different subcompartments. Our evaluation of patients in whom invasive studies documented seizure onset in orbitofrontal, mesial frontal and lateral frontal region failed to show any significant differences in the frequency of RMT in these patients. A former study in which few selected patients with invasive EEG gave the impression that RMT may be more common in mesial FLE could not be supported by this larger series (1). However, this finding does not exclude mesial structures as RMT generators, since functionally interconnected frontal lobe areas and various epileptic propagation patterns might contribute towards its generation from mesial structures. Furthermore the number of invasively evaluated patients may be too small to discern small differences in the frequency of RMT between subcompartments of the frontal lobe. However, the number of invasive evaluations dropped dramatically over the last years in most centers worldwide due to improvement of imaging studies in epilepsy surgery. There is certainly a bias since we specifically evaluated invasively FLE patients which is the target group for our study. Diagnosis of epilepsies originating from frontal lobe is challenging because of some misleading semiological and electrical features of frontal lobe. Although the scalp EEG often has a limited 211

6 diagnostic value, presence of RMT provides supporting diagnostic information for FLE after normal variants ruled out (1). However according to our study confirmed with intracranial EEG, RMT do not provide any further localizing information for the epilepsies originating from different subcompartments of the frontal lobe. RMT during wakefulness is a common finding in patients with refractory FLE who are considered for resective epilepsy surgery (1). This finding is particularly important because in contrast to TLE, there is a considerable discrepancy between MRI-documented lesions and localization of IEDs in FLE (4,12). Despite long-term EEG video monitoring, almost half of the patients with lesions restricted to the frontal lobe had the majority of the IEDs outside of the frontal lobe or lacked IEDs (12). Our study corroborates the additional localizing value of RMT in FLE patients whose IEDs dominate outside of the frontal lobe. RMT had been described in association with TLE (2). This has been challenged since the pattern also occurs in two physiological conditions such as drowsiness and during cognitive tasks (5,10,13,14,16). A previous study showed RMT in approximately half of patients with FLE, but rarely in TLE and not in a control group of nonepileptic patients, if drowsiness and mental activation associated with RMT were excluded (1). RMT might be associated with inhibitory mechanism that blocks out information when going to sleep or when trying to retain something in working memory (9). Previous studies in healthy subjects using magnetoencephelography (MEG) and EEG demonstrated that frontal midline theta was generated by multiple bilateral sources within the frontal lobes and the midline maximum is due to vector summation (15). Other MEG studies identified involvement of bilateral medial prefrontal cortices including anterior cingulated cortex (ACC) in the generation of frontal midline theta (5,6). However, theta rhythms were also recorded over broad areas of cortex from subdural electrode contacts during virtual navigation and it was proposed to be generated by multiple subdural generators which combine to produce the superficial field (7). Since the presence of RMT did not have a prognostic significance we did not investigate RMT postoperatively. There are relevant limitations to our study. The number of invasively evaluated patients in each subcompartment of the frontal lobe is small which obscures the specificity of our findings. Furthermore we could not show the correlation of RMT on scalp recording with simultaneous invasive monitoring. Despite these limitations, in conclusion, RMT seems to be a marker of FLE but does not seem to further localize to a subcompartment of the frontal lobe. This supports the hypothesis that surface recorded RMT on EEG reflects a summation of multiple sources in the frontal lobe and provides additional localizing value for FLE patients whose IEDs dominate outside of the frontal lobe. Conflicts of interest The authors report no conflicts of interest. Acknowledgments Dr. Baysal-Kirac is funded by the Turkish Neurological Socitety Educational Grant' during her stay in University of Munich. Correspondence to: Soheyl Noachtar Soheyl.Noachtar@med.unimuenchen.de Received by: 21 February 2016 Revised by: 09 March 2016 Accepted: 10 March

7 The Online Journal of Neurological Sciences (Turkish) This e-journal is run by Ege University Faculty of Medicine, Dept. of Neurological Surgery, Bornova, Izmir-35100TR as part of the Ege Neurological Surgery World Wide Web service. Comments and feedback: URL: Journal of Neurological Sciences (Turkish) Abbr: J. Neurol. Sci.[Turk] ISSNe REFERENCES 11. Rasmussen T. Tailoring of cortical excisions for frontal lobe epilepsy. Can J Neurol Sci 1991; 18: Remi J, Vollmar C, de Marinis A, Heinlin J, Peraud A, Noachtar S. Congruence and discrepancy of interictal and ictal EEG with MRI lesions in focal epilepsies. Neurology 2011; 77: Takahashi N, Shinomiya S, Mori D, Tachibana S. Frontal midline theta rhythm in young healthy adults. Clin Electroencephalogr 1997; 28: Sasaki K, Tsujimoto T, Nambu A, Matsuzaki R, Kyuhou S. Dynamic activities of the frontal association cortex in calculating and thinking. Neurosci Res 1994; 19: Sasaki K, Tsujimoto T, Nishikawa S, Nishitani N, Ishihara T. Frontal mental theta wave recorded simultaneously with magnetoencephalography and electroencephalography. Neurosci Res 1996; 26: Westmoreland BF, Klass DW. Midline theta rhythm. Arch Neurol 1986; 43: Beleza P, Bilgin O, Noachtar S. Interictal rhythmical midline theta differentiates frontal from temporal lobe epilepsies. Epilepsia 2009; 50: Ciganek L. Theta-discharges in the middle-line- EEG symptom of temporal lobe epilepsy. Electreoencephaolgr Clin Neurophysiol 1961; 13: Engel Jr J, Van Ness P, Rasmussen T, Ojemann LM. Outcome with respect to epileptic seizures. In: Engel Jr J, editor. Surgical treatment of the epilepsies. 2nd ed. New York: Raven Pres; p Foldvary N, Klem G, Hammel J, Bingaman W, Najm I, Luders H. The localizing value of ictal EEG in focal epilepsy. Neurology 2001; 57: Gevins A, Smith ME, McEvoy L, Yu D. Highresolution EEG mapping of cortical activation related to working memory: effects of task difficulty, type of processing, and practice. Cereb Cortex 1997; 7: Ishii R, Shinosaki K, Ukai S, Inouye T, Ishihara T, Yoshimine T, et al. Medial prefrontal cortex generates frontal midline theta rhythm. Neuroreport 1999; 10: Kahana MJ, Sekuler R, Caplan JB, Kirschen M, Madsen JR. Human theta oscillations exhibit task dependence during virtual maze navigation. Nature 1999; 399: Lüders H, Acharya J, Baumgartner C, Benbadis S, Bleasel A, Burgess R, et al. Semiological Seizure Classification. Epilepsia 1998; 39: Mitchell DJ, McNaughton N, Flanagan D, Kirk IJ. Frontal-midline theta from the perspective of hippocampal theta. Prog Neurobiol 2008; 86: Mokran V, Ciganek L, Kabatnik Z. Electroencephalographic theta discharges in the midline. Eur Neurol 1971; 5: