Interictal regional polyspikes in noninvasive EEG suggest cortical dysplasia as etiology of focal epilepsies

Authors


Address correspondence to Prof. Dr. Soheyl Noachtar, Department of Neurology, University of Munich, Marchioninistr. 15, 81337 Munich, Germany. E-mail: noa@med.uni-muenchen.de

Summary

Purpose: To evaluate the clinical significance of interictal regional polyspikes in focal epilepsies secondary to cortical dysplasia.

Methods: We performed a data search for the term “regional polyspikes” in the database of our epilepsy-monitoring unit. Patients with generalized epilepsies including Lennox-Gastaut syndrome were excluded. Regional interictal epileptiform discharges were recorded in 513 patients with noninvasive EEG.

Results: We identified 29 patients with interictal regional polyspikes and focal epilepsies. Another 484 patients showed regional epileptiform discharges other than polyspikes. The etiology of the epilepsy was significantly more frequently cortical dysplasia in the group of patients with regional polyspikes (35%, 10 of 29 patients) than in the patients with other regional epileptiform discharges (5%, 24 of 484 patients) (p < 0.01). The polyspikes were significantly more frequently localized to the extratemporal (72%; n = 21) than temporal (28%; n = 8) regions (p < 0.01). In contrast, regional epileptiform discharges other than polyspikes were significantly more frequently localized to the temporal lobe (75%; n = 362) than extratemporal regions (25%; n = 122) (p < 0.01). Eight of the 10 patients with focal cortical dysplasia had extratemporal polyspikes.

Discussion: Noninvasively recorded regional polyspikes suggest cortical dysplasias as etiology of predominantly extratemporal epilepsies.

Malformations of cortical development are disorders of cortical formation (proliferation, migration, and differentiation) and are frequently associated with medically refractory epilepsy (Brodtkorb et al., 1998; Hashizume et al., 2000). In selected patients, particularly with focal cortical dysplasia (FCD), resective epilepsy surgery is an option. Results of epilepsy depend on the complete resection of dysplastic cortex (Edwards et al., 2000). Preoperative evaluation includes EEG-video recording, MRI, positron emission tomography (PET) and single photon emission computerized tomography (SPECT) to identify the epileptogenic zone (Rosenow & Luders, 2001). MRI typically underestimates the extent of the pathology, which tends to be larger in histological investigations (Yagishita et al., 1997; Tassi et al., 2001, 2002). Several authors have indicated that dysplastic cortex has intrinsic epileptogenicity and they have reported this especially with intracranial studies (Palmini et al., 1995; Avoli et al., 1999; Kuruvilla & Flink, 2002). Selected patients, in whom electrocorticography (ECoG) showed polyspikes had also polyspikes in noninvasive EEG recordings (Gambardella et al., 1996).

In the present study, we investigated the frequency of regional interictal polyspikes in noninvasive EEG recordings and identified the relation to FCD in an unselected consecutive sample of patients with different focal epilepsy syndromes who underwent EEG-video monitoring for differential diagnosis of epilepsy and planning of epilepsy surgery.

Methods

We performed a data search for the term “regional polyspikes” in the database of our epilepsy-monitoring unit at the University of Munich between 1994 and 2003. Patients with polyspikes associated with generalized epilepsies including Lennox-Gastaut syndrome were excluded. Regional interictal epileptiform discharges (IEDs) were recorded in 513 patients with noninvasive EEG. The term regional is defined as EEG activity that is limited to a region of the scalp (Noachtar et al., 1999). All patients underwent EEG video monitoring for differential diagnosis or difficult to treat focal epilepsy for planning of epilepsy surgery.

Noninvasive EEG monitoring

All 513 patients underwent between 3 and 14 days of continuous noninvasive EEG-video monitoring with closely spaced surface electrodes using the international 10–10 electrode system with 32–64 channel EEG machines (Vanguard, Cleveland, OH, U.S.A.; XLTEK, Oakville, Ontario, Canada). IEDs were counted in randomly selected EEG periods of 2–10 min samples per hour during wakefulness and sleep. The localizations of all IED were defined and the relative frequency of each focus was calculated for the entire duration of recording. The EEGs were evaluated in daily monitoring conferences and at least two observers agreed on the classification and localization of the EEG findings.

Polyspikes were defined as at least three consecutive spikes with a frequency of at least 10 Hz lasting at least 300 ms. Ictal EEG seizure pattern consisting of polyspikes, which typically lasted more than 4 s were excluded. Thus, we only included regional polyspikes, which were not associated with any ictal clinical change of behavior or sensation.

Imaging studies

All patients underwent cranial MRI evaluation. Each MRI includes axial, coronal, and sagittal planes T1-weighted, T2-weighted, proton-weighted and fluid-attenuated inversion recovery (FLAIR) images with a slice thickness of not more than 5 mm. (1.0/1.5 Tesla Impact/Vision/Symphony/Siemens). Additional coronal 3-mm T1, T2, and FLAIR images perpendicular to the long axis of the hippocampus were also performed. The acquisition of high-resolution T1-weighted gradient echo sequence with an in-plane resolution and slides thickness of 1 mm was performed for detection of subtle FCD. FLAIR with 3-mm slice thickness was also performed. Contrast medium was used only if inflammation or tumors was suspected (Vollmar & Noachtar, 2004). Ictal brain perfusion SPECT with a technetium-99m-labeled ethylcysteinate dimer (99mTc-ECD, Neurolite; BMS Pharma, Brussels, Belgium) and interictal PET with fluorodeoxyglucose (FDG-PET) were performed mainly in selected extratemporal patients. The diagnosis of FCD in this study was based on the MRI results with the exception of one patient (Patient 23, Table 2), in whom histology of the resected specimen revealed FCD while MRI was normal.

Table 2.  Data of the 29 patients with FCDa
Pat.Age (y), SexAge of onset (y)Localization of the epileptogenic zoneEtiologyMRIInterictal polyspikesOther IEDIctal EEGEpilepsy surgery outcome class (Engel et al., 1993)b
Localization%Localization%
  1. aValues which are smaller than one have been rounded to one. Lt., left; Rt., right; focal, focal but not further localized; ND, not done; SUDEP, sudden unexpected death in epilepsy.

  2. bNumbers in this column refer to the Epilepsy Surgery Outcome Classification as proposed by Engel et al., 1993.

 138 (m)29Lt. hemisphereFCD Lt. hemisphereFCD Lt. hemisphereLt. posterior temporal201. Lt. temporal22 Rt. frontalND
2. Rt. temporal58 
 222 (f)14Rt. temporoparietalFCD Rt. temporal and temporoparietalFCD Rt. temporal and temporoparietalRt. post. temp.341. Rt. post. temp.151. Rt. post. temp.ND
2. Rt. temporal512. Rt. central 
3. Rt. centroparietal 
 329 (f)24Lt. hemisphereUnknownNormalLt. frontocentral100  NoneLt. frontocentralND
 433 (m)19Lt. frontalUnknownNormalLt. frontal131. Frontal nonlateralized57Frontal, nonlateralizedND
2. Lt. frontopolar30 
 542 (m)34Rt. frontalDiffuse gliosis Rt. frontalNormalRt. frontal 31. Rt. temporal811. Rt. frontocentral1a
2. Rt. frontal162. Rt. frontal 
 636 (f)13Lt. temporalUnknownNormalLt. temporooccipital671. Lt. temporooccipital271. Lt. temporalND
2. Lt. mesial temporal 62. Lt. temporooccipital 
 722 (f)12Left paracentralUnknownNormalLt. central791. Lt. central201. Lt. centralND
2. Rt. central 12. Rt. central 
3. Nonlateralized 
 831 (f) 6Lt. frontalFCD lt. frontalFCD lt. frontalLt. frontal100  NoneLt. frontal1a
 951 (m) 9FocalHypothalamic hamartomaHypothalamic hamartoma1. Lt. temporal391. Lt. temporal38Nonlateralized3
2. Rt. temporal142. Rt. temporal 8 
3. Rt. frontal 1 
109 (f) 6Rt. parietalModerate gliosis Rt. parietalNormalRt. parietal121. Rt. temporal67Rt. parietal3
2. Rt. frontal21 
1122 (m) 7FocalUnknownNormalLt. temporal 8Lt. temporal92Lt. frontalND
1219 (f) 9Rt. frontalFCD Rt. frontalFCD Rt. frontalMid central80Mid central20Mid central1c
1322 (m) 1Bilateral frontalCalcified lesion Lt. frontocentralCalcified lesion Lt. frontocentralLt. frontocentral161. Lt. frontocentral451. Lt. frontocentralND
2. Rt. frontocentral292. Rt. frontocentral 
3. Lt. temporal11 
1430 (m)11FocalUnknownNormalLt. temporoparietal75Lt. temporal25Lt. temporalND
1539 (f) 9Lt. paracentralUnknownNormalCentral100  None1. Lt. centralND
2. Nonlateralized 
1639 (f)11FocalHamartoma Rt. parietalHamartoma Rt. parietal1. Lt. frontal401. Lt. frontal131. Lt. frontal 2
2. Rt. frontocentral222. Rt. frontocentral252. Rt. frontal 
3. Nonlateralized 
1734 (f) 8Rt. frontalUnknownNormalRt. frontocentral341. Rt. frontocentral61Rt. frontalND
2. Rt. temporoparietal 2 
3. Lt. temporal 1 
4. Lt. frontal 1 
1833 (f)16Lt. parietooccipitalFCD Lt.FCD Lt.Rt. temporooccipital291. Rt. temporooccipital31Rt. temporooccipitalND
 parietooccipital > parietooccipital >  2. Lt. temporal-mesial35 
 Rt. parietooccipital Rt. parietooccipital  3. Rt. temporomesial 5 
1953 (f)13FocalFCD Lt. frontalFCD Lt. frontal & Lt. hippocampal sclerosisLt. frontal131. Rt. temporal mesial491. Rt. frontopolarND
2. Lt. frontal222. Lt. frontopolar 
3. Lt. temporal16 
2017 (m) 2Rt. frontalFCD Rt. frontalFCD Rt. frontal1. Rt. frontal 21. Rt. frontal96Rt. frontalND
2. Rt. frontocentral 2 
2125 (f)25FocalUnknownNormal1. Rt. occipital131. Rt. occipital70Lt. temporalND
2. Lt. occipital 2. Lt. occipital 3 
3. Lt. frontal 2 
4. Rt. frontal 3 
5. Lt. temporal 7 
6. Lt. parietal 2 
2220 (m)13FocalUnknownNormalRt. mesial temporal121. Rt. mesial temporal591. Lt. temporalND
2. Lt. mesial temporal292. Rt. temp.-occ. 
2332 (m)17Rt. frontalFCD Rt. frontalNormalRt. frontal72Rt. frontal281. Rt. frontal2
2. Rt. temporal 
3. Nonlateralized 
2436 (m) 5Rt. frontalFCD Rt. mesial frontalFCD Rt. mesial frontalRt. frontal63Rt. frontal37Rt. frontal2
2529 (m) 2Focal EFebrile seizures (amygdalo-hippocampectomy) 1983)Status post amygdalo-hippo-campectomyRt. parietal471. Rt. parietal491. Rt. frontalSUDEP
2. Rt. temporal 32. Rt. parietal 
3. Lt. temporal 1 
2633 (m) 7Rt. FLEFCD Rt. frontalFCD Rt. frontalRt. frontal64Rt. frontal36Rt. frontal1a
2743 (f) 9Focal ECavernoma Lt. frontal and Rt. occipitalCavernoma Lt. frontal and Rt. occipital1. Lt. temporal281. Lt. temporal391. Lt. frontocentralND
2. Rt. frontal 2. Rt. frontal 72. Lt. frontal 
3. Lt. frontal153. frontocentral nonlateralized 
4. Frontocentral nonlateralized 44. Rt. temporal 
5. Generalized 7 
2824 (f)21Focal EUnknownNormalRt. frontocentral401. Rt. posterior temporal471. Rt. frontalND
2. Rt. frontocentral132. Rt. temporal 
2927 (m)12Focal EUnknownNormalLt. anterior temporal191. Lt. temp.-ant.771. Lt. temporalND
2. Lt. posterior temporal 22. Rt. parietooccipital 
3. Lt. frontopolar 13. Lt. parietooccipital 
4. Rt. posterior temporal 1 

Statistical analysis

Chi-square analysis or Fisher's exact test were used to evaluate the significance of relationship of regional polyspike localization and etiology of epilepsy, assuming significance at p < 0.05.

Results

We identified 29 patients with regional polyspikes and focal epilepsies out of 513 patients who underwent noninvasive EEG video monitoring. This comprises 5.7% of the study population (n = 513). Another 484 patients showed regional IED other than polyspikes (94.3%) such as spikes, sharp waves, spike-wave complexes (Noachtar et al., 1999). Three of the 29 patients with regional polyspikes showed only polyspikes and did not have any other IEDs. The etiologies of epilepsy of all patients are summarized in Table 1. Table 2 provides all data on the 29 patients with regional polyspikes. The duration of interictal regional polyspikes lasted between 0.5 s and 3 s. Sleep and wake periods had no effect on localization and frequency of the regional polyspikes (Table 2).

Table 1.  Etiology of epilepsy in patients with regional polyspikes and other regional interictal epileptiform discharges (IEDs)
EtiologyRegional polyspikes n = 29 (5.7%)Other IEDs n = 484 (94.3%)p
n(%)n(%)
  1. The last column shows the statistical significance, with n.s. denoting a not significant result.

  2. aDual pathology in one patient (mesial temporal sclerosis and ipsilateral frontal FCD); not included in statistical analysis.

  3. –, not included in statistical analysis.

Unknown12(41)167 (35)n.s.
Tumor 3(10)79(16)0.03
Mesial temporal sclerosis  1a(3) 75(15)
Trauma39(8) 
Focal cortical dysplasia (FCD)10(34)24(5) 0.01
Infection19(4) 
Perinatal lesion23(5) 
Congenital malformation22(5) 
Other 4(14)36(7) 
Total29 (100)484  (100) 

Patients with regional polyspikes had significantly more frequently cortical dysplasia (34%, 10 of 29 patients) than the patients with other regional nonpolyspike IEDs (5%, 24 of 484 patients; p < 0.01) (Fig. 2). Tumors were more commonly the etiology of epilepsy in patients with nonpolyspike IEDs than in the polyspike group (n = 3 of 29 vs. n = 79 of 484) (Table 1) (p < 0.03). Pure mesial temporal sclerosis only occurred in the nonpolyspike IED (Table 1). One patient with frontal polyspikes had a dual pathology with a frontal FCD and an ipsilateral mesial temporal sclerosis (Table 1).

Figure 2.


Right frontal polyspikes during sleep EEG (longitudinal bipolar montage) in a 31-year-old patient with a right FCD.

The polyspikes were significantly more frequently localized to extratemporal (72%; n = 21) than temporal (28%, n = 8) regions (p < 0.01) (Table 3). In contrast, regional IEDs other than polyspikes were significantly more frequently localized to the temporal lobes (75%, n = 362) than extratemporally (25%, n = 122) (p < 0.01) (Table 3). Eight of the 10 patients with FCD had extratemporal polyspikes. The localizations of the regional polyspikes and the FCDs were consistent in 9 of 10 patients. In one patient with right frontal FCD the polyspikes were midcentral.

Table 3.  Frequency of patients with regional polyspikes and other regional interictal epileptiform discharges (IEDs) (n = 513) and localization of the IEDs
LocalizationTotal subjects n = 513Significance
Regional polyspikes n = 29 (5.7%)Other regional IEDs n = 484 (94.3%)
Temporal 8 (28%)362 (75%)p < 0.01
Extratemporal21 (72%)122 (25%)p < 0.01
Significancep < 0.01p < 0.01 

The regional polyspikes had a repetition rate of 10–22 Hz and occurred during wakefulness and sleep in patients with and without FCD. For the purpose of this study, we did not quantify the occurrence of regional polyspikes during sleep or wakefulness. There was no significant difference in the frequency and duration of the regional polyspikes in patients with and without FCD.

Discussion

This study shows that scalp-recorded interictal regional polyspikes are more commonly associated with FCD than other epileptiform discharges in epilepsy surgery candidates with poor antiepileptic drug (AED) control. To avoid the selection bias of former studies who primarily look at children with cortical dysplasia (Quirk et al., 1993) or patients who underwent invasive ECoG (Gambardella et al., 1996), we evaluated a series of unselected consecutive patients who all underwent noninvasive EEG-video monitoring. Our patient population was heterogeneous and reflects all patients referred to an epilepsy-monitoring unit for evaluation of possible epilepsy surgery and differential diagnosis of focal epilepsy. Thus, different etiologies of epilepsy are represented.

In invasive recordings (ECoG), FCD was associated with high-frequency spiking (polyspiking), and the prolonged epileptic activity in dysplastic tissue was considered a consequence of impairment of local inhibitory circuits (Palmini et al., 1995). Most common findings were recruiting/derecruiting spikes (48%), high-frequency rhythmic polyspikes (bursting pattern, 30%), and continuous/quasicontinuous rhythmic spiking pattern on intraoperative ECoG recordings (35%). In a retrospective analysis of the surface EEG of these patients, the occurrence of rhythmic epileptiform discharges on the noninvasive EEG and continuous epileptiform discharges on ECoG recordings were compared in patients who underwent resective epilepsy surgery (Gambardella et al., 1996). It was concluded that repetitive spiking/polyspiking was highly specific and a sensitive indicator for focal cortical dysplastic lesions. Autoradiography of surgical specimen of FCD revealed reduced density of GABA-A receptors as visualized preoperatively by flumazenil PET (Arnold et al., 2000). Although continuous spiking was also described in patients with gliosis after traumatic brain injury or brain tumors, it has been suggested that continuous spiking on preresection ECoG can predict the presence of coexisting cortical dysplasia in a high proportion of patients (91%) with a specificity of 96% (Ferrier et al., 2006). These results and our findings support that continuous spiking and regional polyspikes are seen significantly frequent in FCD. However, the specificity of these invasive EEG findings for cortical dysplasia has been questioned by others who found polyspiking in invasive recordings also in other etiologies such as tumors (Rosenow et al., 1998). In electrocorticographic recordings, continuous spiking has been seen in 55% versus 12% of patients with FCD and glioneural tumors (GNT), respectively, and the FCDs were more frequently localized extratemporally when compared to GNTs (Ferrier et al., 2006). In concordance with this invasive study, we found that regional extratemporal polyspikes in noninvasive EEG are highly associated with cortical dysplasia (80%).

Cortical dysplasias used to be recognized only in the resected tissue during surgical treatment of patients with intractable epilepsy until the development of modern imaging techniques. CT has a low sensitivity for FCD but MRI enabled the recognition and classification of the different types of lesions (Andermann, 2000). High-resolution MRI using special techniques may reveal dysplastic cortex, which was not detected by standard MRI (Hakamada et al., 1979; Quirk et al., 1993; Palmini et al., 1995; Raymond et al., 1995; Raymond & Fish, 1996). However there are medically refractory epilepsy patients with normal MRI (Sisodiya, 2000; Tassi et al., 2002). In some of these patients, postsurgical histological examination helps detecting cortical dysplasia, which was not identified by MRI (Raymond & Fish, 1996; Yagishita et al., 1997; Tassi et al., 2001; Tassi et al., 2002).

Our study shows the diagnostic value of interictal regional polyspikes as a correlate of FCD, which was more significant in extratemporal localizations. We conclude that regional polyspikes, especially in extratemporal location, should lead the clinician to perform advanced MRI studies to detect cortical dysplasia.

Acknowledgments

The authors thank E. Sincini, R. Grossmann, E. Scherbaum, R. Tschackert, O. Klein for technical assistance in the EEG-video monitoring unit of the Epilepsy Center, Department of Neurology, University of Munich.

Conflict of interest: 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. The authors report no conflicts of interest.

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