- Email: [email protected]
Interictal regional paroxysmal fast activity on scalp EEG is common in patients with underlying gliosis
Accepted Manuscript Interictal regional paroxysmal fast activity on scalp EEG is common in patients with underlying gliosis Gopal Krishna Dash, Chaturbhuj Rathore, Malcolm K Jeyaraj, Pandurang Wattamwar, Sankara P Sarma, Kurupath Radhakrishnan PII: DOI: Reference:
S1388-2457(18)30107-X https://doi.org/10.1016/j.clinph.2018.02.007 CLINPH 2008439
To appear in:
Clinical Neurophysiology
Accepted Date:
2 February 2018
Please cite this article as: Krishna Dash, G., Rathore, C., Jeyaraj, M.K., Wattamwar, P., Sarma, S.P., Radhakrishnan, K., Interictal regional paroxysmal fast activity on scalp EEG is common in patients with underlying gliosis, Clinical Neurophysiology (2018), doi: https://doi.org/10.1016/j.clinph.2018.02.007
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Interictal regional paroxysmal fast activity on scalp EEG is common in patients with underlying gliosis *
Gopal Krishna Dasha,1, Chaturbhuj Rathorea,2, Malcolm K Jeyaraja,3, Pandurang Wattamwara,4, Sankara P Sarmab, Kurupath Radhakrishnana,5 a
R. Madhavan Nayar Center for Comprehensive Epilepsy Care, Department of Neurology, Sree Chitra Tirunal Institute for Medical Sciences & Technology, Trivandrum, Kerala, India b
Achutha Menon Center for Health Science Studies, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum, Kerala, India. Email: [email protected] *
Address for correspondence:
Dr. Chaturbhuj Rathore, MD, DM Professor, Department of Neurology, Smt B K Shah Medical Institute and Research Center, Sumandeep Vidyapeeth, Piparia, Waghodiya, Vadodara- 391760, Gujarat, India. Telephone: 91-9909342232 Fax: 91- 02668-245292 Email: [email protected] Present Addresses 1
Department of Neurology, Narayana Hrudayalaya Hospital, Bengaluru, Karnataka, India. Email: [email protected] 2
Department of Neurology, Smt B K Shah Medical Institute and Research Center, Sumandeep Vidyapeeth, Vadodara, Gujarat, India. 3
Department of Neurology, Stanley Medical College, Chennai, Tamilnadu, India. Email: [email protected] 4
Department of Neurology, United CIIGMA Hospital, Aurangabad, Maharashtra, India. Email: [email protected] 5
Amrita Advanced Epilepsy Centre, Department of Neurology, Amrita Institute of Medical Sciences, Kochi, Kerala, India. Email: [email protected] Abbreviations AEDs: antiepileptic drugs; EEG: electroencephalogram; FCD: focal cortical dysplasia; IED: interictal epileptiform discharges; MRI: magnetic resonance imaging; MTS: mesial temporal sclerosis; RVFA: regional paroxysmal fast activity.
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ABSTRACT Objective: Interictal regional paroxysmal fast activity (RPFA) on scalp EEG is common in patients with focal cortical dysplasia (FCD). Little data exists regarding the presence of RPFA in other etiologies. Methods: We studied the association between RPFA and etiology on MRI in patients with drug resistant focal epilepsy undergoing presurgical evaluation in 2011. RPFA was defined as ≥3 consecutive spikes with a frequency of ≥10Hz lasting ≥300 ms but <4 seconds. Results: 626 patients fulfilled the inclusion criteria. Of these, 138 (22%) patients had RPFA while rest had other interictal epileptiform discharges (IEDs). RPFA was located at posterior head region in 52.2% patients, frontal regions in 24.6% patients and over temporal regions in 17.4% patients. Focal gliosis (61, 44%) and FCD (27, 19%) were common etiologies in patients with RPFA. Compared to patients with other IEDs, patients with RPFA were more likely to have focal gliosis (61/138 vs. 39/488; p<0.0001) or FCD (27/138 vs 37/488; p<0.001) as the etiology of epilepsy. Conclusion: In developing countries, focal gliosis is more common than FCD as the underlying etiology in patients with RPFA on scalp EEG. Significance: Focal gliosis should be considered as one of the common substrate for RPFA on scalp EEG.
Keywords: Regional paroxysmal fast activity, drug resistant epilepsy, gliosis, focal cortical dysplasia.
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HIGHLIGHTS
Regional paroxysmal fast activity is present in 25% of patients with drug resistant focal epilepsy.
Regional paroxysmal fast activity is equally common in patients with gliosis and dysplasia.
Perinatal injury with gliosis is common cause for paroxysmal fast activity in developing countries.
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1.
Introduction
The morphology and the distribution of interictal epileptiform discharges (IEDs) on scalp EEG provide useful information about the syndromic diagnosis of epilepsy and its localization in cases of focal epilepsy (Niedermeyer, 1999). Traditionally, IEDs are considered to have a limited specificity with regard to the underlying etiology of epilepsy. However, certain EEG patterns in the form of continuous or semi-continuous rhythmic IEDs and interictal regional polyspikes on intraoperative electrocorticography and scalp EEG have been demonstrated more commonly in patients with focal cortical dysplasia (FCD) (Ferrier et al., 2006; Gambardella et al., 1996; Noachtar et al., 2008; Palmini et al., 1995; Rosenow et al., 1998). Based upon these findings, the presence of interictal regional polyspikes or regional paroxysmal fast activity (RPFA) on scalp EEG is considered to represent FCD as underlying etiology of epilepsy, which presumably results from the intrinsic epileptogenecity of FCDs (Avoli et al., 1999; Palmini et al., 1995). However, only few studies have examined the relationship between the RPFA on scalp EEG and different etiologies of epilepsies. It is not clear whether RPFA on scalp EEG occurs in patients with other etiologies, and if yes, then to what extent. Recently we observed RPFA in patients of drug resistant epilepsy associated with focal gliosis, a common etiology of extratemporal lobe epilepsies in developing countries (Dash et al., 2012). It is possible that the demonstration of RPFA in patients with FCD may be due to the selective inclusion of these patients in previous studies, mainly from developed countries. To clarify this issue, we undertook this study with the following objectives: (1) To study the prevalence of RPFA in consecutive patients with drug resistant focal
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epilepsy, and (2) To study the association between the RPFA on scalp EEG and the underlying etiology for epilepsy in these patients.
2.
Methods
2.1. Study setting and patient selection The study was conducted at the Sree Chitra Tirunal Institute for Medical Sciences and Technology, situated at Trivandrum, Kerala, India. From our long-term Video-EEG database, we reviewed the interictal EEG data of all the patients who had drug resistant focal epilepsy and who underwent Video-EEG from January 1st to December 31st, 2011. We excluded patients with generalized epilepsies, epileptic encephalopathies, presumed benign focal epilepsies and those with nonepileptic events from this study. All these patients were evaluated as per the systematic pre-surgical evaluation protocol which basically consisted of detailed clinical evaluation, neuropsychological testing, long-term Video-EEG monitoring, and high resolution 1.5 T MRI, as described previously (Lachhwani et al., 2008; Rathore et al., 2011; Sylaja et al., 2004). Additional tests were done whenever needed during the process of presurgical evaluation.
2.2. MRI evaluation All the patients underwent high resolution 1.5 T MRI (Sigma, GE Medical Systems, Milwaukee, MI, USA) as per the standard protocol which has been described by us previously (Sylaja et al., 2004). All the MRI images were reviewed by one of the radiologists involved in the epilepsy program and the findings were recorded in case
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records which were reviewed for this study. MRI images of all the patients with RPFA were again reviewed by the study epileptologists (GKD, CR) for the purpose of this study. Any discrepancy in findings was resolved by the mutual consensus.
2.3. Long-term Video-EEG monitoring We used standard 10-20 system of electrode placement with additional anterior temporal (T1 and T2) electrodes during long-term Video-EEG monitoring, as described by us previously (Chemmanam et al., 2009). We used sphenoidal electrodes in patients with temporal lobe epilepsy and discordant or nonlocalizing/nonlateralizing data. We tried to record minimum of two habitual seizures for each patient. For reviewing the EEG records, standard longitudinal bipolar and common average montages were used. During routine management of patients, the interictal and ictal data were reviewed by two of the epileptologists involved in the epilepsy program during the morning VideoEEG meetings. We again reviewed the stored interictal data for this study (GKD and CR). Any discrepancy in findings was resolved by the mutual discussion. The IEDs confined to anterior and midtemporal electrodes (F7, F8, T1, T2, T3, and T4) were defined as temporal IEDs while other were classified as extratemporal IEDs. We classified IEDs as unilateral if ≥90% of IEDs were confined to one side. Regional and multifocal spikes were defined as per the standard guidelines (Noachtar et al., 1999). We defined the regional paroxysmal fast activity (RPFA) as minimum of three successive spikes with a minimum frequency of 10 Hz and lasting for at least 300 ms (Noachtar et al., 2008). We excluded RPFA which lasted for more than four seconds from this analysis, to differentiate it from ictal patterns. In patients with documented MRI
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abnormality, we classified RPFA as concordant if it involved the electrodes over the same lobe as that of the MRI lesion or the two adjacent lobes.
2.4. Statistical analysis We used descriptive statistic to summarize the data. We used Fisher’s exact test and student’s t test to study the association between RPFA and underlying etiology on MRI. All analyses were performed by using IBM SPSS Statistics for Windows, Version 21.0. Armonk, NY: IBM Corp. and we considered a p value of 0.05 as significant.
3.
Results
A total of 1019 patients underwent Video-EEG monitoring during the study period, of which 626 patients with drug resistant focal epilepsy of presumed symptomatic etiology were eligible for the inclusion in this study. Rest of the 393 patients were excluded due to the various reasons: 143 had epileptic encephalopathy, 81 had idiopathic generalized epilepsy, 87 had nonepileptic events and 82 patients were admitted for confirming the syndromic diagnosis of epilepsy. Of the 626 patients included in this study, 138 (22%) patients had RPFA on scalp EEG while 488 (78%) patients had other IEDs.
3.1. Clinical characteristics of patients with RPFA The mean age of the patients with RPFA was 18.9 ± 9.5 years, the mean age at onset of epilepsy was 9.7 ± 8.2 years and the mean duration of the epilepsy was 11.2 ± 7.2 years. The history of antecedent event was present in 62 (45%) patients which consisted of perinatal injury, either hypoxia or hypoglycemia, in 32 (52%), meningoencephalitis in 13 (21%), febrile seizures in 8 (13%), neonatal seizures in 5 (8%) and
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head trauma in 4 (6%) patients. All except six patients had complex partial seizures while 60 patients had additional secondarily generalized seizures. Out of 138 patients with RPFA, 130 (94.2%) patients also had coexistent other IEDs. In these patients with RPFA, majority (115; 83.3%) had extratemporal IEDs. When compared with the final ictal onset and lesional zone as defined by the ictal recordings and MRI findings, 111 (80.4%) patients had ipsilateral RPFA. Of the rest, 13 (9.4%) had bilateral RPFA and 14 (10.1%) had contralateral RPFA, majority of them had bilateral posterior head region gliosis as the etiology. The most common location for RPFA was posterior head (posterior temporo-parieto-occipital) region which was noted in 72 (52.2%) patients while 34 (24.6%) patients had RPFA in the frontal regions and 24 (17.4%) patients had RPFA confined to the temporal regions. Rest of the patients had multiregional PFA.
3.2. RPFA and etiology of epilepsy The distribution of various etiological diagnoses in patients with RPFA and in patients with other IEDs is presented in Table 2. The most common etiology of epilepsy in patients with RPFA was focal gliosis which was present in 61 (44.2%) patients while 27 (19.5%) patients had FCD and 31 (22.5%) had normal MRI. Only six patients in this group had mesial temporal sclerosis (MTS), five of which had associated temporal neocortical changes in the form of poor grey-white matter differentiation. In patients with other IEDs, the most common etiology of epilepsy was hippocampal sclerosis which was present in 121 (24.8%) patients while 188 (38.5%) patients in this group had normal MRI. Overall, RPFA was present in 61% patients with focal gliosis and in 42% patients with FCD. As compared to the patients with other IEDs, patients with RPFA were more likely to have either focal gliosis (61/138 vs. 39/488; p<0.001) or FCD
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(27/138 vs 37/488; p<0.001) as the underlying etiology of epilepsy. MTS as pathology was more common in patients with other IEDS as compared to patients with RPFA (121/488 vs 6/138; p<0.001). Patients with other IEDs were also more likely to have normal MRI as compared to the patients with RPFA (188/488 vs 31/138; p=0.001). RPFA was also present in a small number of patients with low grade neoplasms, other malformations of cortical development and diffuse cerebral atrophy. Examples of RPFA with underlying gliosis at different regions and FCD are presented in Figures 1-5.
4.
Discussion
As per our results, RPFA on scalp EEG was present in approximately 22% of patients with drug resistant symptomatic focal epilepsy. RPFA was more common in patients with extratemporal epilepsy as compared to those with temporal lobe epilepsy. We also found that the most common etiologies of epilepsy in patients with RPFA were focal gliosis and FCD. The presence of RPFA has been well documented in patients with FCD, both on scalp EEG and intraoperative electrocorticography (Avoli et al., 1999; Ferrier et al., 2006; Gambardella et al., 1996; Noachtar et al., 2008; Palmini et al., 1995; Rosenow et al., 1998). In one of the earliest studies involving 34 patients with FCD, Palmini and colleagues reported ictal or continuous epileptiform discharges in 16 (47%) patients on scalp EEG and in 23 (67%) patients on intraoperative electrocorticography (Gambardella et al., 1996; Palmini et al., 1995). In another series of 512 consecutive patients with focal epilepsy, Noachtar and colleagues found RPFA in 29 (5.7%) patients (Noachtar et al., 2008). The most common etiology of RPFA in their series was FCD
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which was present in 35% of patients. The differences in the etiology, the baseline characteristics of patients and variations in the classification of different patterns constituting continuous epileptiform discharges in different series are the likely reason for the variable prevalence of RPFA in these studies. Based upon these studies, the presence of rhythmic spikes or repetitive bursts of polyspikes (RPFA) on electrocorticography and scalp EEG are considered to represent FCD as underlying etiology of epilepsy. However, this notion has been questioned by other studies which reported these patterns in other etiologies such as tumors and gliosis (Ferrier et al., 2006; Guerreiro et al, 2003; Rosenow et al., 1998). Still, the presence of RPFA on both invasive and noninvasive EEG is less well documented with other etiologies as compared to FCD. Our study shows that RPFA is equally common in patients with gliosis. In an intraoperative electrocorticogram study involving 30 patients, continuous epileptiform discharges in the form of either continuous or semi-continuous rhythmic spike discharges or repetitive bursts of rhythmic polyspike activity was found in 11 patients, seven with focal gliosis and four with FCD (Guerreiro et al., 2003). Our study further shows that RPFA is also common on scalp EEG of patients with focal gliosis in one of the largest series of patients with RPFA detected on scalp EEG. Gliosis, predominantly resulting from perinatal injury is the main cause of extratemporal lobe epilepsy in India (Dash et al., 2012). In our series of 71 patients who underwent focal extratemporal resections, the most common etiology was focal gliosis in 27 (38%) patients followed by FCD in 19 (27%) patients (Dash et al., 2012). Perinatal problems and the difficult labor, which are the usual antecedent events associated with gliosis, have been documented as significant risk factors for epilepsy in a population based
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study form our center (Kannoth et al. 2009). The major antecedents noted in our series were perinatal injury and meningo-encephalitis, which commonly lead to gliosis or encephalomalacia. This is in contrast to the studies from developed countries, where gliosis is uncommonly seen, mostly due to the well developed perinatal care (Bien et al., 2009; Elsharkawy et al., 2008; Lee et al., 2005). We feel that this is one of the most important reasons why gliosis is not well recognized as the common etiology in patients with RPFA. Continuous epileptiform discharges in patients with FCD are considered to result from the intrinsic epileptogenecity of these lesions (Palmini et al., 1995). Intrinsic epileptogenecity of FCD results from the loss of gabanergic interneurons within the dysplastic cortex leading to impairment of local inhibitory circuits and generation of continuous epileptiform discharges (Ferrer et al., 1992). It is possible that development of acquired dysplasia surrounding the gliosis may also be responsible for RPFA in patients with gliosis. The presence of dysplastic tissue has been well documented in the surrounding regions of gliosis, which has been classified as FCD IIId (Blümcke et al., 2011). Majority of patients with RPFA and gliosis have early perinatal injury which has been well documented as one of the important risk factors in patients with histopathologically proven Type I FCD (Krsek et al., 2010). In this study of 200 patients with proven FCD or mild malformations of cortical development, 23 patients had evidence of perinatal injury and majority had Type 1 FCD or mild malformations of cortical development. Of these, 12 (48%) patients had associated gliosis on MRI (Krsek et al., 2010). Thus perinatal injury is a risk factor for both gliosis and Type 1 FCD and these two pathologies may have common pathophysiological mechanisms. We can
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hypothesize that an early injury to the vulnerable neurons in the perinatal period may result in the formation of both acquired dysplasia and gliosis. The resultant intrinsic epileptogenecity of surrounding dysplastic neurons may be responsible for the generation of RPFA in patients with focal gliosis. On the other hand, gliotic tissue might itself have intrinsic epileptogenecity leading to generation of RPFA. However, these hypotheses require further examination by careful pathological studies in patients of gliosis with and without RVFA for the detection of associated dysplasia. Many different patterns have been described as continuous epileptiform activity in patients with FCD (Palmini et al., 1995). The study by Guerreiro et al. (2003) did not find any morphological difference in the continuous epileptiform activity generated by gliosis and FCD. In our study, we focused only on the detection of RPFA and did not evaluate other continuous epileptiform patterns like recruiting rhythms or rhythmic spikes discharges, an area which requires further study. The usual pattern and morphology of IEDs in patients with focal epilepsy largely depends upon the location of the epileptogenic source and the propagation of the electrical activity through the brain tissue. RPFA was uncommon in patients with MTS and those with normal MRI. The IEDs generated within hippocampus in patients with MTS are propagated through neocortex and the RPFA with restricted spatial distribution is unlikely to be detected on scalp EEG (Tao et al., 2005). In fact majority of our patients with MTS and RFA had associated temporal neocortical changes, probably suggesting the neocortical generation of RVFA in these patients. Thus the presence of RPFA in patients with temporal lobe epilepsy and MTS might suggest associated temporal neocortical epileptogenecity. Similarly, the patients with normal MRI are likely to have
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small deeply seated lesions and microspcopic dysplasias, mostly at the bottom of sulci, which are unlikely to produce RPFA on scalp EEG (Besson et al., 2008). We acknowledge certain limitations of our study. Our diagnosis of etiology was based upon the MRI findings and no pathological data were available. As discussed above, it may be useful to study the pathological substrates in patients with gliosis who show RPFA on scalp EEG and compare it with those without RPFA to further elucidate the mechanisms of epileptogenecity of gliosis and generation of RPFA. We also focused only on RPFA and did not study the other specific patterns associated with FCD. Though, we detected RPFA more commonly on sleep EEG, we did not systematically studied the differential effects of wakefulness and sleep in the location and the distribution of RPFA.
Conclusions RPFA was present in 22% of patients with drug resistant symptomatic focal epilepsy. In developing countries, focal gliosis is one of the commonest underlying etiologies in patients with RPFA. Development of acquired dysplasia and subsequent intrinsic epileptogenecity surrounding the chronic gliosis may be responsible for RPFA.
Conflict of interest None of the authors have potential conflicts of interest to be disclosed.
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Ferrer I, Pineda M, Tallada M, Oliver B, Russi A, Oller L, et al. Abnormal local-circuit neurons in epilepsia partialis continua associated with focal cortical dysplasia. Acta Neuropathol 1992;83:647-52. Ferrier C, Aronica E, Leijten FSS, Spliet WGM, van Huffelen AC, van Rijen PC, et al. Electrocorticographic discharge patterns in glioneuronal tumors and focal cortical dysplasia. Epilepsia 2006;47:1477-86. Gambardella A, Palmini A, Andermann F, Dubeau F, Da Costa JC, Quesney LF, et al. Usefulnes of focal rhythmic discharges on scalp EEG of patients with focal cortical dysplasia and intractable epilepsy. Electroencephalogr Clin Neurophysiol 1996;98:243-9. Guerreiro MM, Quesney LF, Salanova V, Snipes GJ. Continuous electrocorticogram epileptiform discharges due to brain gliosis. J Clin Neurophysiol 2003;20:239-42. Kannoth S, Unnikrishnan JP, Santhosh Kumar T, Sankara Sarma P, Radhakrishnan K. Risk factors for epilepsy: a population-based case-control study in Kerala, southern India. Epilepsy Behav 2009;16:58-63. Krsek P, Jahodova A, Maton B, Jayakar P, Dean P, Korman B, et al. Low-grade focal cortical dysplasia is associated with prenatal and perinatal brain injury. Epilepsia 2010;51:2440-8. Lachhwani DK, Radhakrishnan K. Epilepsy surgery in India. In: Lüders HO, ed. Textbook of Epilepsy Surgery. Boca Raton, FL: Taylor & Francis; 2008:134 –44.
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Lee SK, Lee SY, Kim KK, Hong KS, Lee DS, Chung CK. Surgical outcome and prognostic factors of cryptogenic neocortical epilepsy. Ann Neurol 2005;58:525-32. Niedermeyer E. Abnormal EEG patterns: epileptic and paroxysmal. In: Niedermeyer E, Lopes da Silva FH, eds. Electroencephalography: Basic Principles, Clinical Applications, and Related Fields. Baltimore: Lippincott Williams & Wilkins; 1999:23560. Noachtar S, Bilgin O, Rémi J, Chang N, Midi I, Vollmar C, et al. Interictal regional polyspikes in noninvasive EEG suggest cortical dysplasia as etiology of focal epilepsies. Epilepsia 2008;49:1011-7. Noachtar S, Binnie C, Ebersole J, Mauguière F, Sakamoto A, Westmoreland B. A glossary of terms most commonly used by clinical electroencephalographers and proposal for the report form for the EEG findings. The International Federation of Clinical Neurophysiology. Electroencephalogr Clin Neurophysiol Suppl. 1999;52:2141. Palmini A, Gambardella A, Andermann F, Dubeau F, da Costa JC, Olivier A, et al. Intrinsic epileptogenicity of human dysplastic cortex as suggested by corticography and surgical results. Ann Neurol 1995; 37:476–87. Rathore C, Kesavadas C, Ajith J, Sasikala AC, Sarma PS, Radhakrishanan K. Costeffective utilization of single photon emission computed tomography (SPECT) in decision making for epilepsy surgery. Seizure 2011;20:107–14.
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LEGEND TO FIGURES Figure 1: Interictal EEG showing regional paroxysmal fast activity over the right occipital region (A) in a patient with right parieto-occipital gliosis, related to perinatal injury, as noted on axial Fluid Attenuated Inversion Recovery (FLAIR) MRI sequence (B)
Figure 2: Interictal EEG common average referential montage showing regional paroxysmal fast activity over the left parietal region (P3; A, B) in a patient with left parieto-occipital gliosis with ulegyria, related to perinatal injury, as noted on axial Fluid Attenuated Inversion Recovery (FLAIR) sequence (C) Figure 3: Interictal EEG in longitudinal bipolar montage showing regional paroxysmal fast activity predominantly over the left frontal region (A, B) in a patient with posttraumatic bifrontal gliosis as noted on axial T2W MRI sequence (C) Figure 4: Interictal EEG showing regional paroxysmal fast activity over the right posterior head region (T6, O2; A) in a patient with right occipital gliosis, related to perinatal injury, as seen on coronal Fluid Attenuated Inversion Recovery (FLAIR) MRI sequence (B) Figure 5: Interictal EEG showing regional paroxysmal fast activity over the right fronto-central region (A; arrows) in a patient with right frontal focal cortical dysplasia as noted on coronal Fluid Attenuated Inversion Recovery (FLAIR) MRI sequence (B)
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Table 1: Characteristics of patients with RPFA (n=138). Characteristics
Years ± SD
Mean age at evaluation
18.9 ± 9.5
Mean age of onset of epilepsy
9.7 ± 8.2
Mean epilepsy duration
11.2 ± 7.2 N (%)
Presence of antecedents
62 (45)
Types of seizures CPS SGTCS
132 (96.6) 60 (43.4)
Location of RPFA Posterior head region
72 (52.2%)
Frontal
34 (24.6%)
Temporal
24 (17.4%)
Distribution of RPFA Ipsilateral
111 (80.4)
Contralateral
14 (10.1)
Bilateral
13 (9.4)
Presence of other IEDs
130 (94.2)
CPS-complex partial seizure; IEDs: interictal epileptiform discharges; SGTCS secondarily generalized seizure; RPFA- regional paroxysmal fast activity
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Etiology
Table 2: Etiology of epilepsy in patients with RPFA and other regional IEDs. RPFA (N=138) Other IEDs (N=488) Significance (p value) N (%) N (%)
Gliosis 61 (44.2) 39 (8.0) <0.001 FCD 27 (19.5) 37 (7.6) 0.001 Normal MRI 31 (22.5) 188 (38.5) 0.001 MTS 6 (4.3) 121 (24.8) <0.001 Low Grade tumor 4 (2.9) 28 (5.7) 0.271 MCD 3 (2.1) 3 (0.6) 0.124 Atrophy 4 (2.9) 16 (3.2) 1.000 Nonspecific white matter changes 1 (0.7) 13 (2.7) 0.320 Othera 1 (0.7) 36 (7.4) 0.220 FCD- focal cortical dysplasia; IEDs: interictal epileptiform discharges; MCDmalformations of cortical development other than FCD; MTS- mesial temporal sclerosis; RPFA- regional paroxysmal fast activity a Other included patients with vascular malformations, focal encephalitis, calcified granuloma and struge-weber syndrome
S1388-2457(18)30107-X https://doi.org/10.1016/j.clinph.2018.02.007 CLINPH 2008439
To appear in:
Clinical Neurophysiology
Accepted Date:
2 February 2018
Please cite this article as: Krishna Dash, G., Rathore, C., Jeyaraj, M.K., Wattamwar, P., Sarma, S.P., Radhakrishnan, K., Interictal regional paroxysmal fast activity on scalp EEG is common in patients with underlying gliosis, Clinical Neurophysiology (2018), doi: https://doi.org/10.1016/j.clinph.2018.02.007
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
1
Interictal regional paroxysmal fast activity on scalp EEG is common in patients with underlying gliosis *
Gopal Krishna Dasha,1, Chaturbhuj Rathorea,2, Malcolm K Jeyaraja,3, Pandurang Wattamwara,4, Sankara P Sarmab, Kurupath Radhakrishnana,5 a
R. Madhavan Nayar Center for Comprehensive Epilepsy Care, Department of Neurology, Sree Chitra Tirunal Institute for Medical Sciences & Technology, Trivandrum, Kerala, India b
Achutha Menon Center for Health Science Studies, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum, Kerala, India. Email: [email protected] *
Address for correspondence:
Dr. Chaturbhuj Rathore, MD, DM Professor, Department of Neurology, Smt B K Shah Medical Institute and Research Center, Sumandeep Vidyapeeth, Piparia, Waghodiya, Vadodara- 391760, Gujarat, India. Telephone: 91-9909342232 Fax: 91- 02668-245292 Email: [email protected] Present Addresses 1
Department of Neurology, Narayana Hrudayalaya Hospital, Bengaluru, Karnataka, India. Email: [email protected] 2
Department of Neurology, Smt B K Shah Medical Institute and Research Center, Sumandeep Vidyapeeth, Vadodara, Gujarat, India. 3
Department of Neurology, Stanley Medical College, Chennai, Tamilnadu, India. Email: [email protected] 4
Department of Neurology, United CIIGMA Hospital, Aurangabad, Maharashtra, India. Email: [email protected] 5
Amrita Advanced Epilepsy Centre, Department of Neurology, Amrita Institute of Medical Sciences, Kochi, Kerala, India. Email: [email protected] Abbreviations AEDs: antiepileptic drugs; EEG: electroencephalogram; FCD: focal cortical dysplasia; IED: interictal epileptiform discharges; MRI: magnetic resonance imaging; MTS: mesial temporal sclerosis; RVFA: regional paroxysmal fast activity.
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ABSTRACT Objective: Interictal regional paroxysmal fast activity (RPFA) on scalp EEG is common in patients with focal cortical dysplasia (FCD). Little data exists regarding the presence of RPFA in other etiologies. Methods: We studied the association between RPFA and etiology on MRI in patients with drug resistant focal epilepsy undergoing presurgical evaluation in 2011. RPFA was defined as ≥3 consecutive spikes with a frequency of ≥10Hz lasting ≥300 ms but <4 seconds. Results: 626 patients fulfilled the inclusion criteria. Of these, 138 (22%) patients had RPFA while rest had other interictal epileptiform discharges (IEDs). RPFA was located at posterior head region in 52.2% patients, frontal regions in 24.6% patients and over temporal regions in 17.4% patients. Focal gliosis (61, 44%) and FCD (27, 19%) were common etiologies in patients with RPFA. Compared to patients with other IEDs, patients with RPFA were more likely to have focal gliosis (61/138 vs. 39/488; p<0.0001) or FCD (27/138 vs 37/488; p<0.001) as the etiology of epilepsy. Conclusion: In developing countries, focal gliosis is more common than FCD as the underlying etiology in patients with RPFA on scalp EEG. Significance: Focal gliosis should be considered as one of the common substrate for RPFA on scalp EEG.
Keywords: Regional paroxysmal fast activity, drug resistant epilepsy, gliosis, focal cortical dysplasia.
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HIGHLIGHTS
Regional paroxysmal fast activity is present in 25% of patients with drug resistant focal epilepsy.
Regional paroxysmal fast activity is equally common in patients with gliosis and dysplasia.
Perinatal injury with gliosis is common cause for paroxysmal fast activity in developing countries.
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1.
Introduction
The morphology and the distribution of interictal epileptiform discharges (IEDs) on scalp EEG provide useful information about the syndromic diagnosis of epilepsy and its localization in cases of focal epilepsy (Niedermeyer, 1999). Traditionally, IEDs are considered to have a limited specificity with regard to the underlying etiology of epilepsy. However, certain EEG patterns in the form of continuous or semi-continuous rhythmic IEDs and interictal regional polyspikes on intraoperative electrocorticography and scalp EEG have been demonstrated more commonly in patients with focal cortical dysplasia (FCD) (Ferrier et al., 2006; Gambardella et al., 1996; Noachtar et al., 2008; Palmini et al., 1995; Rosenow et al., 1998). Based upon these findings, the presence of interictal regional polyspikes or regional paroxysmal fast activity (RPFA) on scalp EEG is considered to represent FCD as underlying etiology of epilepsy, which presumably results from the intrinsic epileptogenecity of FCDs (Avoli et al., 1999; Palmini et al., 1995). However, only few studies have examined the relationship between the RPFA on scalp EEG and different etiologies of epilepsies. It is not clear whether RPFA on scalp EEG occurs in patients with other etiologies, and if yes, then to what extent. Recently we observed RPFA in patients of drug resistant epilepsy associated with focal gliosis, a common etiology of extratemporal lobe epilepsies in developing countries (Dash et al., 2012). It is possible that the demonstration of RPFA in patients with FCD may be due to the selective inclusion of these patients in previous studies, mainly from developed countries. To clarify this issue, we undertook this study with the following objectives: (1) To study the prevalence of RPFA in consecutive patients with drug resistant focal
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epilepsy, and (2) To study the association between the RPFA on scalp EEG and the underlying etiology for epilepsy in these patients.
2.
Methods
2.1. Study setting and patient selection The study was conducted at the Sree Chitra Tirunal Institute for Medical Sciences and Technology, situated at Trivandrum, Kerala, India. From our long-term Video-EEG database, we reviewed the interictal EEG data of all the patients who had drug resistant focal epilepsy and who underwent Video-EEG from January 1st to December 31st, 2011. We excluded patients with generalized epilepsies, epileptic encephalopathies, presumed benign focal epilepsies and those with nonepileptic events from this study. All these patients were evaluated as per the systematic pre-surgical evaluation protocol which basically consisted of detailed clinical evaluation, neuropsychological testing, long-term Video-EEG monitoring, and high resolution 1.5 T MRI, as described previously (Lachhwani et al., 2008; Rathore et al., 2011; Sylaja et al., 2004). Additional tests were done whenever needed during the process of presurgical evaluation.
2.2. MRI evaluation All the patients underwent high resolution 1.5 T MRI (Sigma, GE Medical Systems, Milwaukee, MI, USA) as per the standard protocol which has been described by us previously (Sylaja et al., 2004). All the MRI images were reviewed by one of the radiologists involved in the epilepsy program and the findings were recorded in case
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records which were reviewed for this study. MRI images of all the patients with RPFA were again reviewed by the study epileptologists (GKD, CR) for the purpose of this study. Any discrepancy in findings was resolved by the mutual consensus.
2.3. Long-term Video-EEG monitoring We used standard 10-20 system of electrode placement with additional anterior temporal (T1 and T2) electrodes during long-term Video-EEG monitoring, as described by us previously (Chemmanam et al., 2009). We used sphenoidal electrodes in patients with temporal lobe epilepsy and discordant or nonlocalizing/nonlateralizing data. We tried to record minimum of two habitual seizures for each patient. For reviewing the EEG records, standard longitudinal bipolar and common average montages were used. During routine management of patients, the interictal and ictal data were reviewed by two of the epileptologists involved in the epilepsy program during the morning VideoEEG meetings. We again reviewed the stored interictal data for this study (GKD and CR). Any discrepancy in findings was resolved by the mutual discussion. The IEDs confined to anterior and midtemporal electrodes (F7, F8, T1, T2, T3, and T4) were defined as temporal IEDs while other were classified as extratemporal IEDs. We classified IEDs as unilateral if ≥90% of IEDs were confined to one side. Regional and multifocal spikes were defined as per the standard guidelines (Noachtar et al., 1999). We defined the regional paroxysmal fast activity (RPFA) as minimum of three successive spikes with a minimum frequency of 10 Hz and lasting for at least 300 ms (Noachtar et al., 2008). We excluded RPFA which lasted for more than four seconds from this analysis, to differentiate it from ictal patterns. In patients with documented MRI
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abnormality, we classified RPFA as concordant if it involved the electrodes over the same lobe as that of the MRI lesion or the two adjacent lobes.
2.4. Statistical analysis We used descriptive statistic to summarize the data. We used Fisher’s exact test and student’s t test to study the association between RPFA and underlying etiology on MRI. All analyses were performed by using IBM SPSS Statistics for Windows, Version 21.0. Armonk, NY: IBM Corp. and we considered a p value of 0.05 as significant.
3.
Results
A total of 1019 patients underwent Video-EEG monitoring during the study period, of which 626 patients with drug resistant focal epilepsy of presumed symptomatic etiology were eligible for the inclusion in this study. Rest of the 393 patients were excluded due to the various reasons: 143 had epileptic encephalopathy, 81 had idiopathic generalized epilepsy, 87 had nonepileptic events and 82 patients were admitted for confirming the syndromic diagnosis of epilepsy. Of the 626 patients included in this study, 138 (22%) patients had RPFA on scalp EEG while 488 (78%) patients had other IEDs.
3.1. Clinical characteristics of patients with RPFA The mean age of the patients with RPFA was 18.9 ± 9.5 years, the mean age at onset of epilepsy was 9.7 ± 8.2 years and the mean duration of the epilepsy was 11.2 ± 7.2 years. The history of antecedent event was present in 62 (45%) patients which consisted of perinatal injury, either hypoxia or hypoglycemia, in 32 (52%), meningoencephalitis in 13 (21%), febrile seizures in 8 (13%), neonatal seizures in 5 (8%) and
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head trauma in 4 (6%) patients. All except six patients had complex partial seizures while 60 patients had additional secondarily generalized seizures. Out of 138 patients with RPFA, 130 (94.2%) patients also had coexistent other IEDs. In these patients with RPFA, majority (115; 83.3%) had extratemporal IEDs. When compared with the final ictal onset and lesional zone as defined by the ictal recordings and MRI findings, 111 (80.4%) patients had ipsilateral RPFA. Of the rest, 13 (9.4%) had bilateral RPFA and 14 (10.1%) had contralateral RPFA, majority of them had bilateral posterior head region gliosis as the etiology. The most common location for RPFA was posterior head (posterior temporo-parieto-occipital) region which was noted in 72 (52.2%) patients while 34 (24.6%) patients had RPFA in the frontal regions and 24 (17.4%) patients had RPFA confined to the temporal regions. Rest of the patients had multiregional PFA.
3.2. RPFA and etiology of epilepsy The distribution of various etiological diagnoses in patients with RPFA and in patients with other IEDs is presented in Table 2. The most common etiology of epilepsy in patients with RPFA was focal gliosis which was present in 61 (44.2%) patients while 27 (19.5%) patients had FCD and 31 (22.5%) had normal MRI. Only six patients in this group had mesial temporal sclerosis (MTS), five of which had associated temporal neocortical changes in the form of poor grey-white matter differentiation. In patients with other IEDs, the most common etiology of epilepsy was hippocampal sclerosis which was present in 121 (24.8%) patients while 188 (38.5%) patients in this group had normal MRI. Overall, RPFA was present in 61% patients with focal gliosis and in 42% patients with FCD. As compared to the patients with other IEDs, patients with RPFA were more likely to have either focal gliosis (61/138 vs. 39/488; p<0.001) or FCD
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(27/138 vs 37/488; p<0.001) as the underlying etiology of epilepsy. MTS as pathology was more common in patients with other IEDS as compared to patients with RPFA (121/488 vs 6/138; p<0.001). Patients with other IEDs were also more likely to have normal MRI as compared to the patients with RPFA (188/488 vs 31/138; p=0.001). RPFA was also present in a small number of patients with low grade neoplasms, other malformations of cortical development and diffuse cerebral atrophy. Examples of RPFA with underlying gliosis at different regions and FCD are presented in Figures 1-5.
4.
Discussion
As per our results, RPFA on scalp EEG was present in approximately 22% of patients with drug resistant symptomatic focal epilepsy. RPFA was more common in patients with extratemporal epilepsy as compared to those with temporal lobe epilepsy. We also found that the most common etiologies of epilepsy in patients with RPFA were focal gliosis and FCD. The presence of RPFA has been well documented in patients with FCD, both on scalp EEG and intraoperative electrocorticography (Avoli et al., 1999; Ferrier et al., 2006; Gambardella et al., 1996; Noachtar et al., 2008; Palmini et al., 1995; Rosenow et al., 1998). In one of the earliest studies involving 34 patients with FCD, Palmini and colleagues reported ictal or continuous epileptiform discharges in 16 (47%) patients on scalp EEG and in 23 (67%) patients on intraoperative electrocorticography (Gambardella et al., 1996; Palmini et al., 1995). In another series of 512 consecutive patients with focal epilepsy, Noachtar and colleagues found RPFA in 29 (5.7%) patients (Noachtar et al., 2008). The most common etiology of RPFA in their series was FCD
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which was present in 35% of patients. The differences in the etiology, the baseline characteristics of patients and variations in the classification of different patterns constituting continuous epileptiform discharges in different series are the likely reason for the variable prevalence of RPFA in these studies. Based upon these studies, the presence of rhythmic spikes or repetitive bursts of polyspikes (RPFA) on electrocorticography and scalp EEG are considered to represent FCD as underlying etiology of epilepsy. However, this notion has been questioned by other studies which reported these patterns in other etiologies such as tumors and gliosis (Ferrier et al., 2006; Guerreiro et al, 2003; Rosenow et al., 1998). Still, the presence of RPFA on both invasive and noninvasive EEG is less well documented with other etiologies as compared to FCD. Our study shows that RPFA is equally common in patients with gliosis. In an intraoperative electrocorticogram study involving 30 patients, continuous epileptiform discharges in the form of either continuous or semi-continuous rhythmic spike discharges or repetitive bursts of rhythmic polyspike activity was found in 11 patients, seven with focal gliosis and four with FCD (Guerreiro et al., 2003). Our study further shows that RPFA is also common on scalp EEG of patients with focal gliosis in one of the largest series of patients with RPFA detected on scalp EEG. Gliosis, predominantly resulting from perinatal injury is the main cause of extratemporal lobe epilepsy in India (Dash et al., 2012). In our series of 71 patients who underwent focal extratemporal resections, the most common etiology was focal gliosis in 27 (38%) patients followed by FCD in 19 (27%) patients (Dash et al., 2012). Perinatal problems and the difficult labor, which are the usual antecedent events associated with gliosis, have been documented as significant risk factors for epilepsy in a population based
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study form our center (Kannoth et al. 2009). The major antecedents noted in our series were perinatal injury and meningo-encephalitis, which commonly lead to gliosis or encephalomalacia. This is in contrast to the studies from developed countries, where gliosis is uncommonly seen, mostly due to the well developed perinatal care (Bien et al., 2009; Elsharkawy et al., 2008; Lee et al., 2005). We feel that this is one of the most important reasons why gliosis is not well recognized as the common etiology in patients with RPFA. Continuous epileptiform discharges in patients with FCD are considered to result from the intrinsic epileptogenecity of these lesions (Palmini et al., 1995). Intrinsic epileptogenecity of FCD results from the loss of gabanergic interneurons within the dysplastic cortex leading to impairment of local inhibitory circuits and generation of continuous epileptiform discharges (Ferrer et al., 1992). It is possible that development of acquired dysplasia surrounding the gliosis may also be responsible for RPFA in patients with gliosis. The presence of dysplastic tissue has been well documented in the surrounding regions of gliosis, which has been classified as FCD IIId (Blümcke et al., 2011). Majority of patients with RPFA and gliosis have early perinatal injury which has been well documented as one of the important risk factors in patients with histopathologically proven Type I FCD (Krsek et al., 2010). In this study of 200 patients with proven FCD or mild malformations of cortical development, 23 patients had evidence of perinatal injury and majority had Type 1 FCD or mild malformations of cortical development. Of these, 12 (48%) patients had associated gliosis on MRI (Krsek et al., 2010). Thus perinatal injury is a risk factor for both gliosis and Type 1 FCD and these two pathologies may have common pathophysiological mechanisms. We can
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hypothesize that an early injury to the vulnerable neurons in the perinatal period may result in the formation of both acquired dysplasia and gliosis. The resultant intrinsic epileptogenecity of surrounding dysplastic neurons may be responsible for the generation of RPFA in patients with focal gliosis. On the other hand, gliotic tissue might itself have intrinsic epileptogenecity leading to generation of RPFA. However, these hypotheses require further examination by careful pathological studies in patients of gliosis with and without RVFA for the detection of associated dysplasia. Many different patterns have been described as continuous epileptiform activity in patients with FCD (Palmini et al., 1995). The study by Guerreiro et al. (2003) did not find any morphological difference in the continuous epileptiform activity generated by gliosis and FCD. In our study, we focused only on the detection of RPFA and did not evaluate other continuous epileptiform patterns like recruiting rhythms or rhythmic spikes discharges, an area which requires further study. The usual pattern and morphology of IEDs in patients with focal epilepsy largely depends upon the location of the epileptogenic source and the propagation of the electrical activity through the brain tissue. RPFA was uncommon in patients with MTS and those with normal MRI. The IEDs generated within hippocampus in patients with MTS are propagated through neocortex and the RPFA with restricted spatial distribution is unlikely to be detected on scalp EEG (Tao et al., 2005). In fact majority of our patients with MTS and RFA had associated temporal neocortical changes, probably suggesting the neocortical generation of RVFA in these patients. Thus the presence of RPFA in patients with temporal lobe epilepsy and MTS might suggest associated temporal neocortical epileptogenecity. Similarly, the patients with normal MRI are likely to have
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small deeply seated lesions and microspcopic dysplasias, mostly at the bottom of sulci, which are unlikely to produce RPFA on scalp EEG (Besson et al., 2008). We acknowledge certain limitations of our study. Our diagnosis of etiology was based upon the MRI findings and no pathological data were available. As discussed above, it may be useful to study the pathological substrates in patients with gliosis who show RPFA on scalp EEG and compare it with those without RPFA to further elucidate the mechanisms of epileptogenecity of gliosis and generation of RPFA. We also focused only on RPFA and did not study the other specific patterns associated with FCD. Though, we detected RPFA more commonly on sleep EEG, we did not systematically studied the differential effects of wakefulness and sleep in the location and the distribution of RPFA.
Conclusions RPFA was present in 22% of patients with drug resistant symptomatic focal epilepsy. In developing countries, focal gliosis is one of the commonest underlying etiologies in patients with RPFA. Development of acquired dysplasia and subsequent intrinsic epileptogenecity surrounding the chronic gliosis may be responsible for RPFA.
Conflict of interest None of the authors have potential conflicts of interest to be disclosed.
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LEGEND TO FIGURES Figure 1: Interictal EEG showing regional paroxysmal fast activity over the right occipital region (A) in a patient with right parieto-occipital gliosis, related to perinatal injury, as noted on axial Fluid Attenuated Inversion Recovery (FLAIR) MRI sequence (B)
Figure 2: Interictal EEG common average referential montage showing regional paroxysmal fast activity over the left parietal region (P3; A, B) in a patient with left parieto-occipital gliosis with ulegyria, related to perinatal injury, as noted on axial Fluid Attenuated Inversion Recovery (FLAIR) sequence (C) Figure 3: Interictal EEG in longitudinal bipolar montage showing regional paroxysmal fast activity predominantly over the left frontal region (A, B) in a patient with posttraumatic bifrontal gliosis as noted on axial T2W MRI sequence (C) Figure 4: Interictal EEG showing regional paroxysmal fast activity over the right posterior head region (T6, O2; A) in a patient with right occipital gliosis, related to perinatal injury, as seen on coronal Fluid Attenuated Inversion Recovery (FLAIR) MRI sequence (B) Figure 5: Interictal EEG showing regional paroxysmal fast activity over the right fronto-central region (A; arrows) in a patient with right frontal focal cortical dysplasia as noted on coronal Fluid Attenuated Inversion Recovery (FLAIR) MRI sequence (B)
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Table 1: Characteristics of patients with RPFA (n=138). Characteristics
Years ± SD
Mean age at evaluation
18.9 ± 9.5
Mean age of onset of epilepsy
9.7 ± 8.2
Mean epilepsy duration
11.2 ± 7.2 N (%)
Presence of antecedents
62 (45)
Types of seizures CPS SGTCS
132 (96.6) 60 (43.4)
Location of RPFA Posterior head region
72 (52.2%)
Frontal
34 (24.6%)
Temporal
24 (17.4%)
Distribution of RPFA Ipsilateral
111 (80.4)
Contralateral
14 (10.1)
Bilateral
13 (9.4)
Presence of other IEDs
130 (94.2)
CPS-complex partial seizure; IEDs: interictal epileptiform discharges; SGTCS secondarily generalized seizure; RPFA- regional paroxysmal fast activity
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Etiology
Table 2: Etiology of epilepsy in patients with RPFA and other regional IEDs. RPFA (N=138) Other IEDs (N=488) Significance (p value) N (%) N (%)
Gliosis 61 (44.2) 39 (8.0) <0.001 FCD 27 (19.5) 37 (7.6) 0.001 Normal MRI 31 (22.5) 188 (38.5) 0.001 MTS 6 (4.3) 121 (24.8) <0.001 Low Grade tumor 4 (2.9) 28 (5.7) 0.271 MCD 3 (2.1) 3 (0.6) 0.124 Atrophy 4 (2.9) 16 (3.2) 1.000 Nonspecific white matter changes 1 (0.7) 13 (2.7) 0.320 Othera 1 (0.7) 36 (7.4) 0.220 FCD- focal cortical dysplasia; IEDs: interictal epileptiform discharges; MCDmalformations of cortical development other than FCD; MTS- mesial temporal sclerosis; RPFA- regional paroxysmal fast activity a Other included patients with vascular malformations, focal encephalitis, calcified granuloma and struge-weber syndrome