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Specificity of electroclinical features in the diagnosis of ring chromosome 20
Epilepsy & Behavior 80 (2018) 215–220
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Epilepsy & Behavior journal homepage: www.elsevier.com/locate/yebeh
Specificity of electroclinical features in the diagnosis of ring chromosome 20 A.B. Gago-Veiga a, R. Toledano b, I. García-Morales b, M.A. Pérez-Jiménez c, J. Bernar d, A. Gil-Nagel b,⁎ a
Epilepsy Unit, Department of Neurology, Hospital Universitario de La Princesa, Diego de León 62, 28006 Madrid, Spain Epilepsy Program, Department of Neurology, Hospital Ruber International, La Masó 38, 28034 Madrid, Spain Epilepsy Monitoring Unit, Clinical Neurophysiology Department, Niño Jesús Pediatric University Hospital, Menendez Pelayo 65, 28009 Madrid, Spain d Department of Genetics, Hospital Ruber International, La Masó 38, 28034 Madrid, Spain b c
a r t i c l e
i n f o
Article history: Received 11 July 2017 Revised 1 December 2017 Accepted 1 December 2017 Available online xxxx Keywords: Nonconvulsive status epilepticus Drug-resistant epilepsy EEG Frontal lobe seizures Ring chromosome 20
a b s t r a c t Background: Ring chromosome 20 (R20) syndrome is a chromosomal disorder characterized mainly by drugresistant frontal lobe seizures, recurrent nonconvulsive status epilepticus (NCSE), and typical EEG features. The aim of this study was to investigate if this triad is common and specific to all patients with R20. Methods: In this cross-sectional study (from 2000 to 2011), we selected patients who fulfilled at least two out of three criteria: drug-resistant frontal lobe seizures, recurrent NCSE, and characteristic electroencephalography (EEG) features. In all patients, diagnosis was based on karyotype analysis of at least 100 metaphases. Results: We identified 36 patients who met at least two of the selected criteria: six patients (16.7%) with R20 and 30 (83.3%) without R20 (non-R20). All patients with R20 met all three criteria. Eleven (36.7%) patients without R20, however, also displayed the full triad. In 19 patients without R20 (63.3%), one of the three clinical features was missing: frontal lobe seizures were not resistant to antiepileptic drugs (AED) in four (13.3%), recurrent NCSE was missing in six (20%), and nine (30%) patients did not have typical EEG features. Based on this data, specificity was 63.3%, positive predictive value was 35.3%, and sensitivity and negative predictive values were 100%. Additionally, a review of all publications describing the R20 phenotype revealed that 81.98% of patients with R20 display the full electroclinical triad. Conclusions: In our study, all patients with R20 displayed the three electroclinical characteristics. This is in line with previous reports (presenting high sensitivity and negative predictive value). However, these features can also be observed in other epilepsies and are not specific to R20. Our findings suggest that in the presence of the full triad of symptoms, karyotype analysis focused on chromosome 20 should be conducted. © 2017 Elsevier Inc. All rights reserved.
1. Introduction Ring chromosome 20 (R20) syndrome is a rare chromosomal disease. Its diagnosis depends heavily on the detection of its clinical manifestations. The presence of a ring-shaped chromosome 20, however, is the only requisite condition for an “R20 syndrome” diagnosis. It is usually assumed that this disorder has a distinct electroclinical phenotype [1–5], with the most salient features being refractory seizures with frontal lobe semiology, recurrent nonconvulsive status epilepticus (NCSE), and characteristic EEG alterations. These three electroclinical characteristics have been found repeatedly in patients with this chromosomal disorder and are, therefore, thought to be highly suggestive of R20 syndrome. Their specificity with respect to a differential
⁎ Corresponding author. E-mail address: [email protected] (A. Gil-Nagel).
https://doi.org/10.1016/j.yebeh.2017.12.001 1525-5050/© 2017 Elsevier Inc. All rights reserved.
diagnosis of R20 syndrome with other epilepsies still remains to be determined, however. Our main objective in this cross-sectional study was to evaluate whether the presence of either two or three main features of this electroclinical triad distinguishes patients with R20 syndrome from patients with other types of epilepsy, which may share a similar phenotype. We have also reviewed all R20 cases described in the literature with an emphasis on the degree of compliance with the electroclinical triad. 2. Methods 2.1. Patient selection Between the years 2000 and 2011, we identified six patients in Hospital Ruber Internacional and Hospital Niño Jesus with R20 syndrome. In the same time period, 30 consecutive patients fulfilling
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either two or three features of the electroclinical triad described, prior to the assessment in our clinic, but without a chromosomal disorder were recruited as controls. All patients underwent 24-hour video-EEG or longer, always including at least one night of spontaneous sleep and wakefulness. Only patients with seizure onset before the age of 21 years were included; this age range was selected because it is the latest epilepsy onset in R20 described in the existing literature [2]. The main features that characterize the electroclinical triad are detailed as follows: a) Refractory frontal lobe seizures: Based on previous reports [2–4, 6], three types of frontal lobe seizure were included. Nocturnal seizures (hyperkinetic or hypermotor seizures) are characterized by waking up, staring, mild tonic stiffening evolving to clonic movements of the face and extremities, followed by agitation and confusion. Subtle nocturnal seizures are expressed as minimal motor activity, such as subtle stretching, turning, or rubbing movements. Unresponsiveness (complex partial or automotor seizures) consists of blank staring and confusion, with or without oral or motor automatisms, frightened expression, and focal motor symptoms including head turning. b) Recurrent NCSE: For operational purposes, patients with at least three episodes of NCSE were included. Clinical semiology during NCSE consisted of altered state of vigilance, staring, loss of emotional facial expression, reduced spontaneous motor activity, and speech production, with a slow response to questions. Associated motor symptoms, such as myoclonus, head turning were also common, as well as oral automatisms and frightened facial expression [2,4,6]. There is controversy as to whether clusters of seizures with mild impairment of consciousness and NCSE can be considered the same phenomena in R20, as very often it is difficult to distinguish them on clinical grounds. This is due to the slow onset and finalization of some frontal lobe seizures or atypical absence seizures, and the persistence of subtle manifestations between more prominent episodes in this group of patients. Because of this, and in line with other studies, we included both patients with clear-cut NCSE and seizure clusters with this type of phenomenology. c) Typical EEG findings: According to previous reports [1,3,7–9], we selected patients who had the following patterns: brief frontal epileptic discharges and long-lasting high-voltage slow waves with occasional uni- or bilateral frontal spikes. Frequent trains of theta waves in frontotemporal areas that are not influenced by eye-opening, a pattern that has been considered very specific in the diagnosis of R20 [10], were present in all patients with R20, but not required to be present in patients without R20 in our study (Fig. 1).
2.2. Cytogenetic studies Karyotype analysis was performed on lymphocytes. Blood was drawn into lithium heparin tubes, cultured in Lymphochrome (BioWhittaker™) medium for 72 h, and processed under standard conditions for T-G banding. For each patient, at least 100 metaphases were analyzed for the presence of ring chromosome 20.
2.3. Neuroimaging All patients underwent a 1.5 T brain MRI. For the purpose of this study, we excluded patients with structural abnormalities depicted by the MRI that were considered to be the cause of their epilepsy. No structural abnormalities were observed in patients with R20.
2.4. Evaluation of cognitive status To evaluate cognitive status, we used the Wechsler Adult Intelligent Scale (WAIS). 2.5. Literature search methods To check the presence of the triad in the R20 cases published, a systematic search of the medical literature between 1978 and January 2015 was performed using the PubMed and MEDLINE databases. Search terms included ring chromosome 20, ring 20 epilepsy, and ring-20 syndrome. 2.6. Statistical analysis Descriptive statistics were provided on demographic and clinical characteristics for both patients with R20 and patients without R20. Patients without R20 without the triad were considered True negative (TN); patients without R20 with the triad were False positive (FP); patients with R20 with the triad were True positive (TP); and patients with R20 without triad were False negative (FN). Descriptive statistics were calculated for the triad and the validation of instruments based on our series: Specificity [TP / TP + FP], sensitivity [TP / TP + FN], positive predictive value [TP / FP + TP], and negative predictive value [TN / TN + FN]. To expand on this data, we reviewed all the literature to identify the true positive (R20 with triad) and false negative rate (R20 without triad). 3. Results 3.1. Our sample of patients Thirty-six patients who fulfilled at least two of the three electroclinical characteristics were recruited from the epilepsy clinic of Hospital Ruber Internacional. These included six patients with confirmed cytogenetic diagnoses of R20 syndrome. Clinical features of patients with R20 are shown in Table 1. Comparing both groups, we observed some differences, although not statistically significant, which are detailed as follows: patients with R20 had a later age of epilepsy onset, and lower rate of convulsive status epilepticus and dysmorphic craniofacial features. Febrile seizures were not present in any of the six patients with R20, but were present in 16.7% of patients in the group without R20. Cognitive impairment, behavioral disturbances, and family history of epilepsy were similar in both groups (Table 2). 3.1.1. Specificity of the electroclinical triad Seventeen out of 36 (47.2%) fulfilled the three criteria, 6/6 patients with R20 syndrome and 11/30 patients without R20 (36.7%) (p b 0,05). In 19 patients without R20 (63.3%), one feature was missing, nine (30%) did not have the typical EEG features, four of them (13.3%) had frontal seizures controlled with medication, and six (20%) did not have recurrent NCSE. Based on our results and according to the statistical methods previously described, the specificity of this triad for the diagnosis of R20 is 63.3%, its positive predictive value is 35.3%, while the sensitivity and negative predictive values are 100%. 3.1.2. Epilepsy syndromes in patients without R20 The group without R20 included eleven patients (36.7%) with cryptogenic frontal lobe epilepsy (3/11 with the full triad) and 19 (63.3%) with other epilepsy syndromes (8/19 with the full triad). Epilepsy syndromes in the eleven patients who had the full triad (3 + 8) are specified in Table 3.
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A.
B.
Fig. 1. A. Characteristic video-EEG in a patient with R20. Trains of 5 Hz generalized rhythmic theta activity (longitudinal montage). B. Train of rhythmic theta activity and acute waves in both anterior temporal regions (average reference montage).
Because of our inclusion criteria, patients with continuous spike and wave during slow sleep (CSWS) were only included in the group without R20 when recurrent NCSE was present during wakefulness, a
clinical feature that was only observed when incorrect treatment with sodium channel blockers had been prescribed. In these cases, long runs of theta waves during sleep were also observed.
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Table 1 Description of our 6 patients with R20 confirmed by karyotype. NCSE: Nonconvulsive status epilepticus; CSE: Convulsive status epilepticus; VNS: Vagal nerve stimulation; CBZ: Carbamazepine; TPM: Topiramate; CLB: Clobazam; OXC: Oxacarbazepine; RTG: Retigabine; LEV: Levetiracetam; VPA: Valproic acid; LTG: Lamotrigine. Patient 1
Patient 2
Patient 3
Patient 4
Patient 5
Patient 6
Sex
Female
Female
Female
Female
Female
Male
Family history
Cousin with language disturbance
Not relevant
2 brothers with parasomnia Great uncle with epilepsy
Uncle with epilepsy
Not relevant
Not relevant
6 6 12 Yes Yes No In the evening Yes
2 2 11 Yes Yes No Yes Yes
12 12 30 Yes Yes Yes Late evening Yes
13 13 27 Yes Yes No Yes Yes
9 13 14 Yes No No In the evening Yes
4 15 17 Yes No No In the evening Yes
CBZ, TPM, CLB, OXC, RTG VPA + LTG Ketogenic diet (slight improvement) Aggression and apathy After Yes Yes, minor Since the age of 4 years Worse after NCSE onset 84% mosaicism
LEV, VPA, CLB –
VPA LTG + CBZ VNS
LTG, LEV, OXC CBZ
CBZ, LEV VPA, ZNS
No – Yes No
No – No –
Apathy After Yes No
TPM VPA, LEV, LTG Ketogenic diet (Slight improvement) No – Yes No
No – No –
Yes 70% mosaicism
– 22% mosaicism (20% ring and 2% chromosome 20 monosomy)
Yes 30% mosaicism
Yes 46% mosaicism
– 44% mosaicism
Epileptic feature Epilepsy onset (years) NCSE onset (years) Age of diagnosis Subtle nocturnal seizures Tonic–clonic seizures CSE Daily seizures Nocturnal seizures Treatment No improvement Improvement in Seizures
Behavioral problems Before/after epilepsy onset Intellectual disability Before epilepsy onset After epilepsy onset Genetics
3.2. Literature review
4. Discussion
In the literature, we found 170 cases of R20 syndrome. We excluded 54 out of 170 because either they had not been studied with prolonged video-EEG monitoring or not enough information was provided. Additionally, five more patients were also excluded because they were younger than 3 years, age at which the electroclinical expression of the syndrome is rarely fully developed [7,11–14]. Complete information was gathered in 111 patients and, according to the descriptions of those cases, 91 (81.98%) of them had the full triad [1–11,15–39], eleven (9.91%) had two features (one lacked the typical EEG, four did not have drug-resistant frontal seizures, and six did not have NCSE) [2,3,5, 7,8,10,31], and, finally, nine patients (8.11%) had none or only one feature [2,10,11,15,32,39] (Supplementary Material 1).
In our study, we have observed that all the patients with a confirmed cytogenetic diagnosis of R20 syndrome had the full triad of signs and symptoms (drug-resistant frontal lobe seizures, recurrent NCSE, and typical EEG), providing the electroclinical triad a great sensitivity and negative predictive value (100%). This finding is in line with previously published cases, in which 81.98% patients also meet the three electroclinical features, when the clinical description is complete enough to perform the analysis. Therefore, this combination of signs and symptoms could be relevant when it comes to selecting candidates for genetic analysis. The difference in sensitivity found in our group of patients compared with the literature might be related to our small sample series and our systematic use of prolonged video-EEG monitoring, which included wakefulness and at least one night of spontaneous sleep. However, while the use of prolonged video-EEG improves the diagnosis of R20 electroclinical features, it might detect similar characteristics in other epilepsies. In order to evaluate this, we looked for the same electroclinical features in a population of patients with other epilepsy syndromes. In our analysis, we found the full triad in eleven out of 30 patients without R20 that had been selected based on the presence of at least two electroclinical features (refractory frontal lobe seizures, recurrent NCSE, or similar EEG). Epilepsy syndromes in patients without
Table 2 Comparative table between patients who met at least two criteria of the triad, with confirmed R20 and non-R20. Demographic characteristic and clinical features
R20 (6 patients)
Non-R20 (30 patients)
Statistical values
Sex (females) Age of epilepsy onset Age of NCSE onset
5 (83.3%) 7.67 (2–13) 10.2 (2–15)
19 (63.3%) 4.65 (0.1–20) 8.51 (0.1–27)
p N 0,05 p N 0,05 p N 0,05
Selection criteria 1 and 2 2 and 3 1 and 3 1, 2, and 3
0 0 0 6 (100%)
9 (30%) 4 (13.3%) 6 (20%) 11 (36.7%)
p b 0,05
Other clinical features Convulsive status Dysmorphic features Cognitive decline Behavioral disturbance Febrile seizures Family history of epilepsy
2 (33%) 0 4 (66.6%) 2 (33.3%) 0 2 (33.3%)
16 (53%) 3 (10%) 18 (60%) 10 (33.3%) 5 (16.7%) 11 (36.7%)
p N 0,05 p N 0,05 p N 0,05 p N 0,05 p N 0,05 p N 0,05
Criteria 1. Frontal lobe seizures (drug-resistant). Criteria 2. Recurrent NCSE. Criteria 3. Typical EEG.
Table 3 Epilepsy syndromes of patients without R20 with full triad. Epilepsy syndromes
Number of cases
Partial epilepsy continuous spike and wave during slow wave sleep (CSWS or EPOCS ESES), including Rolandic Epilepsy with inadequate treatment Dravet syndrome Cryptogenic frontal lobe epilepsy Right frontal cortical dysplasia (3 T MRI) Ring chromosome 10 Lennox–Gastaut syndrome
2
2 3 1 1 2
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R20 showing the full triad at the time of their evaluation in our center included four patients with cryptogenic frontal epilepsy (although one turned to be a frontal lobe dysplasia when a 3 T MRI was performed), two with Lennox–Gastaut syndrome, two with Dravet syndrome, two with CSWS inadequately treated with sodium channel blockers, and one with ring chromosome 10 (R10). Beyond the complete presence of the triad, it is important to acknowledge that other clinical features are also important for a correct diagnosis. In patients with Dravet syndrome, for example, onset of seizures in the first year, seizure type, and hyperthermia-induced seizures are distinct features; atonic seizures are often present in Lennox– Gastaut syndrome; and patients with R10 present delayed growth or genital alteration. In contrast, patients with R20 have additional clinical features, all of them present in our patients, including a more variable age of onset (up to 21 years) [2], ictal fear and terrifying hallucinations [40] during frontal lobe seizure, and a rhythmic theta activity pattern not responsive to eye opening in EEG recordings [10] (Fig. 1). We also analyzed other features that have been previously described in patients with R20. Febrile seizures were absent in the six patients with R20 from our series, in contrast with some studies [5,15,26], but consistent with what has been published in the majority of previous descriptions. Abnormal behavior in our series was milder than usually reported in the literature [1,3,6,10,12,14,15,17,28,31,32], and consisted mainly in apathy and lack of initiative in two patients. This behavior correlates with frontal lobe involvement, probably secondary to abundant epileptiform activity, and has been linked to dopaminergic deficit by previous authors [24]. As mentioned above, no dysmorphic signs were present in any of our patients, and therefore, we did not found that it could assist in the diagnosis. Diagnosis of the syndrome was relatively straightforward once patients were evaluated with prolonged video-EEG monitoring, which allows a complete electroclinical phenotypic categorization. It is not just clinical suspicion that is important, however in one patient (number 3) of our series, the diagnosis was missed in a first karyotype because only 20 metaphases were analyzed, while a second test on 150 lymphocyte metaphases showed 20% R20 cells. This highlights the importance of analyzing a sufficient number of cells in order to identify patients with low rates of abnormal chromosomes. In our patients, the age of epilepsy onset was over 2 years; we cannot, therefore, extrapolate these findings to all ages, and we cannot correlate the presence of the triad and patient's age, as recently reported by Vignoli et al. [40]. Therefore, our findings might not be applicable in the assessment of younger patients with R20, particularly in the first year of life. While all patients with R20 in our series had refractory epilepsy, each patient continued with the treatment that had provided best seizure control and fewer side effects. This included a variety of antiepileptic drug combinations, which does not allow us to ascertain whether there is a better response to a specific treatment. One patient did, however, improve with a combination of valproic acid and zonisamide, and another improved with valproic acid and lamotrigine. The second combination is supported in the literature as one of the most effective [2,3,6,8,31]. One patient also improved with vagus nerve stimulation, in line with previous reports [6,31]. Two patients were treated with a ketogenic diet, resulting in no significant improvement, similar to one case described in the literature [37]. One patient was treated with retigabine/ezogabine without any improvement, in contrast to a previous report [37].
5. Conclusion Having shown the high sensitivity of the triad (drug-resistant frontal lobe seizures, recurrent NCSE, and typical EEG features), we believe that the triad allows for a high suspicion of R20, and when present should prompt physicians to look into this chromosomopathy. It could also
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act as a guide for geneticists in order to focus on chromosome 20, analyze sufficient metaphases, and consider other techniques. Despite the small sample size of our group, we think that our findings have clinical relevance, given that in the absence of dysmorphism or intellectual impairment, chromosomal abnormalities such as R20 are easily overlooked, and a delay in the diagnosis could lead to unnecessary tests, incorrect therapies, and a deterioration in the patient's quality of life. Supplementary data to this article can be found online at https://doi. org/10.1016/j.yebeh.2017.12.001. Ethical publication statement We confirm that we have read the Journal's position on issues involved in ethical publication and confirm that this report is consistent with those guidelines. Disclosure Antonio Gil-Nagel has served on advisory boards and received financial support from Bial, Eisai, GSK, GW Pharma, Nutricia, and UCB Pharma. Irene García-Morales has served on advisory boards and received financial support from Bial, Eisai, GSK, UCB Pharma, and ViroPharma. The remaining authors have no conflicts of interest. Acknowledgments This work was supported by “Fundación Gmp” and “Fundación Iniciativa para las Neurociencias (INCE)”. We'd like to express our sincere thanks to all the patients involved in this study and their families. References [1] Inoue Y, Fujiwara T, Matsuda K, Kubota H, Tanaka M, Yagi K, et al. Ring chromosome 20 and nonconvulsive status. Brain 1997;120:939-935. [2] Canevini MP, Sgro V, Zuffardi O, Canger R, Carrozzo R, Rossi E, et al. Chromosome 20 ring: a chromosomal disorder associated with a particular electroclinical pattern. Epilepsia 1998;39:942–51. [3] Elens I, Varykel K, De Waele L, Jansen K, Segeren M, Van Paesschen M, et al. Ring chromosome 20 syndrome: electroclinical description of six patients and review of the literature. Epilepsy Behav 2012;23:409–14. [4] Kamoun FF, Ellouz EJ, Hsairi IG, Triki CC. Frontal motor seizure following nonconvulsive status epilepticus in ring chromosome 20 syndrome. Neurosciences (Riyadh) 2012;17:74–7. [5] Radhakrishnan A, Menon RN, Hariharan S, Radhakrishnan K. The evolving electroclinical syndrome of “epilepsy with ring chromosome 20”. Seizure 2012;21: 92–7. [6] Augustijn PB, Parra J, Wouters CH, Joosten P, Lindhout D, van Emde Boas W. Ring chromosome 20 epilepsy syndrome in children: electroclinical features. Neurology 2001;57:1108–11. [7] Ville D, Kaminska A, Bahi-Buisson N, Biraben A, Plouin P, Telvi L, et al. Early pattern of epilepsy in the ring chromosome 20 syndrome. Epilepsia 2006;47:543–9. [8] Vignoli A, Canevini MP, Darra F, La Selva L, Fiorini E, Piazzini A, et al. Ring chromosome 20 syndrome: a link between epilepsy onset and neuropsychological impairment in three children. Epilepsia 2009;50:f20–7. [9] Vega-Zelaya L, Alonso-Cerezo C, Quesada JF, Sola RG, Pastor J. Electroclinical characteristics of patient with ring chrosomosome 20 syndrome. Rev Neurol 2014;58: 450–4. [10] Avanzini P, Vaudano AE, Vignoli A, Ruggieri A, Benuzzi F, Darra F, et al. Low frequency mu-like activity characterizes cortical rhythms in epilepsy due to ring chromosome 20. Clin Neurophysiol 2014;125:239–49. [11] Zambrelli E, Vignoli A, Nobili L, Didato G, Mastrangelo M, Turner K, et al. Sleep in ring chromosome 20 syndrome: a peculiar electroencephalographic pattern. Funct Neurol 2013;28:47–53. [12] Porfirio B, Valorani MG, Giannotti A, Sabetta G, Dallapiccola B. Ring 20 chromosome phenotype. J Med Genet 1987;24:375–7. [13] Cignini P, Dugo N, Giorlandino C, Gauci R, Spata A, Capriglione S, et al. Prenatal diagnosis of a fetus with a ring chromosome 20 characterized by array-CGH. J Prenatal Med 2012;6:72–3. [14] Steward JM, Cavanagh N, Hughes DT. Ring 20 chromosome in a child with seizures, minor anomalies, and retardation. Arch Dis Child 1979;54:477–9. [15] Back E, Voiculescu I, Brünger M, Wolff G. Familiar ring (20) chromosomal mosaicism. Hum Genet 1989;83:148–54. [16] Holopainen I, Penttinen M, Lakkala T, Aarimaa T. Ring chromosome 20 mosaicism in a girl with complex partial seizures. Dev Med Child Neurol 1994;36:70–3.
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Specificity of electroclinical features in the diagnosis of ring chromosome 20 A.B. Gago-Veiga a, R. Toledano b, I. García-Morales b, M.A. Pérez-Jiménez c, J. Bernar d, A. Gil-Nagel b,⁎ a
Epilepsy Unit, Department of Neurology, Hospital Universitario de La Princesa, Diego de León 62, 28006 Madrid, Spain Epilepsy Program, Department of Neurology, Hospital Ruber International, La Masó 38, 28034 Madrid, Spain Epilepsy Monitoring Unit, Clinical Neurophysiology Department, Niño Jesús Pediatric University Hospital, Menendez Pelayo 65, 28009 Madrid, Spain d Department of Genetics, Hospital Ruber International, La Masó 38, 28034 Madrid, Spain b c
a r t i c l e
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Article history: Received 11 July 2017 Revised 1 December 2017 Accepted 1 December 2017 Available online xxxx Keywords: Nonconvulsive status epilepticus Drug-resistant epilepsy EEG Frontal lobe seizures Ring chromosome 20
a b s t r a c t Background: Ring chromosome 20 (R20) syndrome is a chromosomal disorder characterized mainly by drugresistant frontal lobe seizures, recurrent nonconvulsive status epilepticus (NCSE), and typical EEG features. The aim of this study was to investigate if this triad is common and specific to all patients with R20. Methods: In this cross-sectional study (from 2000 to 2011), we selected patients who fulfilled at least two out of three criteria: drug-resistant frontal lobe seizures, recurrent NCSE, and characteristic electroencephalography (EEG) features. In all patients, diagnosis was based on karyotype analysis of at least 100 metaphases. Results: We identified 36 patients who met at least two of the selected criteria: six patients (16.7%) with R20 and 30 (83.3%) without R20 (non-R20). All patients with R20 met all three criteria. Eleven (36.7%) patients without R20, however, also displayed the full triad. In 19 patients without R20 (63.3%), one of the three clinical features was missing: frontal lobe seizures were not resistant to antiepileptic drugs (AED) in four (13.3%), recurrent NCSE was missing in six (20%), and nine (30%) patients did not have typical EEG features. Based on this data, specificity was 63.3%, positive predictive value was 35.3%, and sensitivity and negative predictive values were 100%. Additionally, a review of all publications describing the R20 phenotype revealed that 81.98% of patients with R20 display the full electroclinical triad. Conclusions: In our study, all patients with R20 displayed the three electroclinical characteristics. This is in line with previous reports (presenting high sensitivity and negative predictive value). However, these features can also be observed in other epilepsies and are not specific to R20. Our findings suggest that in the presence of the full triad of symptoms, karyotype analysis focused on chromosome 20 should be conducted. © 2017 Elsevier Inc. All rights reserved.
1. Introduction Ring chromosome 20 (R20) syndrome is a rare chromosomal disease. Its diagnosis depends heavily on the detection of its clinical manifestations. The presence of a ring-shaped chromosome 20, however, is the only requisite condition for an “R20 syndrome” diagnosis. It is usually assumed that this disorder has a distinct electroclinical phenotype [1–5], with the most salient features being refractory seizures with frontal lobe semiology, recurrent nonconvulsive status epilepticus (NCSE), and characteristic EEG alterations. These three electroclinical characteristics have been found repeatedly in patients with this chromosomal disorder and are, therefore, thought to be highly suggestive of R20 syndrome. Their specificity with respect to a differential
⁎ Corresponding author. E-mail address: [email protected] (A. Gil-Nagel).
https://doi.org/10.1016/j.yebeh.2017.12.001 1525-5050/© 2017 Elsevier Inc. All rights reserved.
diagnosis of R20 syndrome with other epilepsies still remains to be determined, however. Our main objective in this cross-sectional study was to evaluate whether the presence of either two or three main features of this electroclinical triad distinguishes patients with R20 syndrome from patients with other types of epilepsy, which may share a similar phenotype. We have also reviewed all R20 cases described in the literature with an emphasis on the degree of compliance with the electroclinical triad. 2. Methods 2.1. Patient selection Between the years 2000 and 2011, we identified six patients in Hospital Ruber Internacional and Hospital Niño Jesus with R20 syndrome. In the same time period, 30 consecutive patients fulfilling
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either two or three features of the electroclinical triad described, prior to the assessment in our clinic, but without a chromosomal disorder were recruited as controls. All patients underwent 24-hour video-EEG or longer, always including at least one night of spontaneous sleep and wakefulness. Only patients with seizure onset before the age of 21 years were included; this age range was selected because it is the latest epilepsy onset in R20 described in the existing literature [2]. The main features that characterize the electroclinical triad are detailed as follows: a) Refractory frontal lobe seizures: Based on previous reports [2–4, 6], three types of frontal lobe seizure were included. Nocturnal seizures (hyperkinetic or hypermotor seizures) are characterized by waking up, staring, mild tonic stiffening evolving to clonic movements of the face and extremities, followed by agitation and confusion. Subtle nocturnal seizures are expressed as minimal motor activity, such as subtle stretching, turning, or rubbing movements. Unresponsiveness (complex partial or automotor seizures) consists of blank staring and confusion, with or without oral or motor automatisms, frightened expression, and focal motor symptoms including head turning. b) Recurrent NCSE: For operational purposes, patients with at least three episodes of NCSE were included. Clinical semiology during NCSE consisted of altered state of vigilance, staring, loss of emotional facial expression, reduced spontaneous motor activity, and speech production, with a slow response to questions. Associated motor symptoms, such as myoclonus, head turning were also common, as well as oral automatisms and frightened facial expression [2,4,6]. There is controversy as to whether clusters of seizures with mild impairment of consciousness and NCSE can be considered the same phenomena in R20, as very often it is difficult to distinguish them on clinical grounds. This is due to the slow onset and finalization of some frontal lobe seizures or atypical absence seizures, and the persistence of subtle manifestations between more prominent episodes in this group of patients. Because of this, and in line with other studies, we included both patients with clear-cut NCSE and seizure clusters with this type of phenomenology. c) Typical EEG findings: According to previous reports [1,3,7–9], we selected patients who had the following patterns: brief frontal epileptic discharges and long-lasting high-voltage slow waves with occasional uni- or bilateral frontal spikes. Frequent trains of theta waves in frontotemporal areas that are not influenced by eye-opening, a pattern that has been considered very specific in the diagnosis of R20 [10], were present in all patients with R20, but not required to be present in patients without R20 in our study (Fig. 1).
2.2. Cytogenetic studies Karyotype analysis was performed on lymphocytes. Blood was drawn into lithium heparin tubes, cultured in Lymphochrome (BioWhittaker™) medium for 72 h, and processed under standard conditions for T-G banding. For each patient, at least 100 metaphases were analyzed for the presence of ring chromosome 20.
2.3. Neuroimaging All patients underwent a 1.5 T brain MRI. For the purpose of this study, we excluded patients with structural abnormalities depicted by the MRI that were considered to be the cause of their epilepsy. No structural abnormalities were observed in patients with R20.
2.4. Evaluation of cognitive status To evaluate cognitive status, we used the Wechsler Adult Intelligent Scale (WAIS). 2.5. Literature search methods To check the presence of the triad in the R20 cases published, a systematic search of the medical literature between 1978 and January 2015 was performed using the PubMed and MEDLINE databases. Search terms included ring chromosome 20, ring 20 epilepsy, and ring-20 syndrome. 2.6. Statistical analysis Descriptive statistics were provided on demographic and clinical characteristics for both patients with R20 and patients without R20. Patients without R20 without the triad were considered True negative (TN); patients without R20 with the triad were False positive (FP); patients with R20 with the triad were True positive (TP); and patients with R20 without triad were False negative (FN). Descriptive statistics were calculated for the triad and the validation of instruments based on our series: Specificity [TP / TP + FP], sensitivity [TP / TP + FN], positive predictive value [TP / FP + TP], and negative predictive value [TN / TN + FN]. To expand on this data, we reviewed all the literature to identify the true positive (R20 with triad) and false negative rate (R20 without triad). 3. Results 3.1. Our sample of patients Thirty-six patients who fulfilled at least two of the three electroclinical characteristics were recruited from the epilepsy clinic of Hospital Ruber Internacional. These included six patients with confirmed cytogenetic diagnoses of R20 syndrome. Clinical features of patients with R20 are shown in Table 1. Comparing both groups, we observed some differences, although not statistically significant, which are detailed as follows: patients with R20 had a later age of epilepsy onset, and lower rate of convulsive status epilepticus and dysmorphic craniofacial features. Febrile seizures were not present in any of the six patients with R20, but were present in 16.7% of patients in the group without R20. Cognitive impairment, behavioral disturbances, and family history of epilepsy were similar in both groups (Table 2). 3.1.1. Specificity of the electroclinical triad Seventeen out of 36 (47.2%) fulfilled the three criteria, 6/6 patients with R20 syndrome and 11/30 patients without R20 (36.7%) (p b 0,05). In 19 patients without R20 (63.3%), one feature was missing, nine (30%) did not have the typical EEG features, four of them (13.3%) had frontal seizures controlled with medication, and six (20%) did not have recurrent NCSE. Based on our results and according to the statistical methods previously described, the specificity of this triad for the diagnosis of R20 is 63.3%, its positive predictive value is 35.3%, while the sensitivity and negative predictive values are 100%. 3.1.2. Epilepsy syndromes in patients without R20 The group without R20 included eleven patients (36.7%) with cryptogenic frontal lobe epilepsy (3/11 with the full triad) and 19 (63.3%) with other epilepsy syndromes (8/19 with the full triad). Epilepsy syndromes in the eleven patients who had the full triad (3 + 8) are specified in Table 3.
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A.
B.
Fig. 1. A. Characteristic video-EEG in a patient with R20. Trains of 5 Hz generalized rhythmic theta activity (longitudinal montage). B. Train of rhythmic theta activity and acute waves in both anterior temporal regions (average reference montage).
Because of our inclusion criteria, patients with continuous spike and wave during slow sleep (CSWS) were only included in the group without R20 when recurrent NCSE was present during wakefulness, a
clinical feature that was only observed when incorrect treatment with sodium channel blockers had been prescribed. In these cases, long runs of theta waves during sleep were also observed.
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Table 1 Description of our 6 patients with R20 confirmed by karyotype. NCSE: Nonconvulsive status epilepticus; CSE: Convulsive status epilepticus; VNS: Vagal nerve stimulation; CBZ: Carbamazepine; TPM: Topiramate; CLB: Clobazam; OXC: Oxacarbazepine; RTG: Retigabine; LEV: Levetiracetam; VPA: Valproic acid; LTG: Lamotrigine. Patient 1
Patient 2
Patient 3
Patient 4
Patient 5
Patient 6
Sex
Female
Female
Female
Female
Female
Male
Family history
Cousin with language disturbance
Not relevant
2 brothers with parasomnia Great uncle with epilepsy
Uncle with epilepsy
Not relevant
Not relevant
6 6 12 Yes Yes No In the evening Yes
2 2 11 Yes Yes No Yes Yes
12 12 30 Yes Yes Yes Late evening Yes
13 13 27 Yes Yes No Yes Yes
9 13 14 Yes No No In the evening Yes
4 15 17 Yes No No In the evening Yes
CBZ, TPM, CLB, OXC, RTG VPA + LTG Ketogenic diet (slight improvement) Aggression and apathy After Yes Yes, minor Since the age of 4 years Worse after NCSE onset 84% mosaicism
LEV, VPA, CLB –
VPA LTG + CBZ VNS
LTG, LEV, OXC CBZ
CBZ, LEV VPA, ZNS
No – Yes No
No – No –
Apathy After Yes No
TPM VPA, LEV, LTG Ketogenic diet (Slight improvement) No – Yes No
No – No –
Yes 70% mosaicism
– 22% mosaicism (20% ring and 2% chromosome 20 monosomy)
Yes 30% mosaicism
Yes 46% mosaicism
– 44% mosaicism
Epileptic feature Epilepsy onset (years) NCSE onset (years) Age of diagnosis Subtle nocturnal seizures Tonic–clonic seizures CSE Daily seizures Nocturnal seizures Treatment No improvement Improvement in Seizures
Behavioral problems Before/after epilepsy onset Intellectual disability Before epilepsy onset After epilepsy onset Genetics
3.2. Literature review
4. Discussion
In the literature, we found 170 cases of R20 syndrome. We excluded 54 out of 170 because either they had not been studied with prolonged video-EEG monitoring or not enough information was provided. Additionally, five more patients were also excluded because they were younger than 3 years, age at which the electroclinical expression of the syndrome is rarely fully developed [7,11–14]. Complete information was gathered in 111 patients and, according to the descriptions of those cases, 91 (81.98%) of them had the full triad [1–11,15–39], eleven (9.91%) had two features (one lacked the typical EEG, four did not have drug-resistant frontal seizures, and six did not have NCSE) [2,3,5, 7,8,10,31], and, finally, nine patients (8.11%) had none or only one feature [2,10,11,15,32,39] (Supplementary Material 1).
In our study, we have observed that all the patients with a confirmed cytogenetic diagnosis of R20 syndrome had the full triad of signs and symptoms (drug-resistant frontal lobe seizures, recurrent NCSE, and typical EEG), providing the electroclinical triad a great sensitivity and negative predictive value (100%). This finding is in line with previously published cases, in which 81.98% patients also meet the three electroclinical features, when the clinical description is complete enough to perform the analysis. Therefore, this combination of signs and symptoms could be relevant when it comes to selecting candidates for genetic analysis. The difference in sensitivity found in our group of patients compared with the literature might be related to our small sample series and our systematic use of prolonged video-EEG monitoring, which included wakefulness and at least one night of spontaneous sleep. However, while the use of prolonged video-EEG improves the diagnosis of R20 electroclinical features, it might detect similar characteristics in other epilepsies. In order to evaluate this, we looked for the same electroclinical features in a population of patients with other epilepsy syndromes. In our analysis, we found the full triad in eleven out of 30 patients without R20 that had been selected based on the presence of at least two electroclinical features (refractory frontal lobe seizures, recurrent NCSE, or similar EEG). Epilepsy syndromes in patients without
Table 2 Comparative table between patients who met at least two criteria of the triad, with confirmed R20 and non-R20. Demographic characteristic and clinical features
R20 (6 patients)
Non-R20 (30 patients)
Statistical values
Sex (females) Age of epilepsy onset Age of NCSE onset
5 (83.3%) 7.67 (2–13) 10.2 (2–15)
19 (63.3%) 4.65 (0.1–20) 8.51 (0.1–27)
p N 0,05 p N 0,05 p N 0,05
Selection criteria 1 and 2 2 and 3 1 and 3 1, 2, and 3
0 0 0 6 (100%)
9 (30%) 4 (13.3%) 6 (20%) 11 (36.7%)
p b 0,05
Other clinical features Convulsive status Dysmorphic features Cognitive decline Behavioral disturbance Febrile seizures Family history of epilepsy
2 (33%) 0 4 (66.6%) 2 (33.3%) 0 2 (33.3%)
16 (53%) 3 (10%) 18 (60%) 10 (33.3%) 5 (16.7%) 11 (36.7%)
p N 0,05 p N 0,05 p N 0,05 p N 0,05 p N 0,05 p N 0,05
Criteria 1. Frontal lobe seizures (drug-resistant). Criteria 2. Recurrent NCSE. Criteria 3. Typical EEG.
Table 3 Epilepsy syndromes of patients without R20 with full triad. Epilepsy syndromes
Number of cases
Partial epilepsy continuous spike and wave during slow wave sleep (CSWS or EPOCS ESES), including Rolandic Epilepsy with inadequate treatment Dravet syndrome Cryptogenic frontal lobe epilepsy Right frontal cortical dysplasia (3 T MRI) Ring chromosome 10 Lennox–Gastaut syndrome
2
2 3 1 1 2
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R20 showing the full triad at the time of their evaluation in our center included four patients with cryptogenic frontal epilepsy (although one turned to be a frontal lobe dysplasia when a 3 T MRI was performed), two with Lennox–Gastaut syndrome, two with Dravet syndrome, two with CSWS inadequately treated with sodium channel blockers, and one with ring chromosome 10 (R10). Beyond the complete presence of the triad, it is important to acknowledge that other clinical features are also important for a correct diagnosis. In patients with Dravet syndrome, for example, onset of seizures in the first year, seizure type, and hyperthermia-induced seizures are distinct features; atonic seizures are often present in Lennox– Gastaut syndrome; and patients with R10 present delayed growth or genital alteration. In contrast, patients with R20 have additional clinical features, all of them present in our patients, including a more variable age of onset (up to 21 years) [2], ictal fear and terrifying hallucinations [40] during frontal lobe seizure, and a rhythmic theta activity pattern not responsive to eye opening in EEG recordings [10] (Fig. 1). We also analyzed other features that have been previously described in patients with R20. Febrile seizures were absent in the six patients with R20 from our series, in contrast with some studies [5,15,26], but consistent with what has been published in the majority of previous descriptions. Abnormal behavior in our series was milder than usually reported in the literature [1,3,6,10,12,14,15,17,28,31,32], and consisted mainly in apathy and lack of initiative in two patients. This behavior correlates with frontal lobe involvement, probably secondary to abundant epileptiform activity, and has been linked to dopaminergic deficit by previous authors [24]. As mentioned above, no dysmorphic signs were present in any of our patients, and therefore, we did not found that it could assist in the diagnosis. Diagnosis of the syndrome was relatively straightforward once patients were evaluated with prolonged video-EEG monitoring, which allows a complete electroclinical phenotypic categorization. It is not just clinical suspicion that is important, however in one patient (number 3) of our series, the diagnosis was missed in a first karyotype because only 20 metaphases were analyzed, while a second test on 150 lymphocyte metaphases showed 20% R20 cells. This highlights the importance of analyzing a sufficient number of cells in order to identify patients with low rates of abnormal chromosomes. In our patients, the age of epilepsy onset was over 2 years; we cannot, therefore, extrapolate these findings to all ages, and we cannot correlate the presence of the triad and patient's age, as recently reported by Vignoli et al. [40]. Therefore, our findings might not be applicable in the assessment of younger patients with R20, particularly in the first year of life. While all patients with R20 in our series had refractory epilepsy, each patient continued with the treatment that had provided best seizure control and fewer side effects. This included a variety of antiepileptic drug combinations, which does not allow us to ascertain whether there is a better response to a specific treatment. One patient did, however, improve with a combination of valproic acid and zonisamide, and another improved with valproic acid and lamotrigine. The second combination is supported in the literature as one of the most effective [2,3,6,8,31]. One patient also improved with vagus nerve stimulation, in line with previous reports [6,31]. Two patients were treated with a ketogenic diet, resulting in no significant improvement, similar to one case described in the literature [37]. One patient was treated with retigabine/ezogabine without any improvement, in contrast to a previous report [37].
5. Conclusion Having shown the high sensitivity of the triad (drug-resistant frontal lobe seizures, recurrent NCSE, and typical EEG features), we believe that the triad allows for a high suspicion of R20, and when present should prompt physicians to look into this chromosomopathy. It could also
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act as a guide for geneticists in order to focus on chromosome 20, analyze sufficient metaphases, and consider other techniques. Despite the small sample size of our group, we think that our findings have clinical relevance, given that in the absence of dysmorphism or intellectual impairment, chromosomal abnormalities such as R20 are easily overlooked, and a delay in the diagnosis could lead to unnecessary tests, incorrect therapies, and a deterioration in the patient's quality of life. Supplementary data to this article can be found online at https://doi. org/10.1016/j.yebeh.2017.12.001. Ethical publication statement We confirm that we have read the Journal's position on issues involved in ethical publication and confirm that this report is consistent with those guidelines. Disclosure Antonio Gil-Nagel has served on advisory boards and received financial support from Bial, Eisai, GSK, GW Pharma, Nutricia, and UCB Pharma. Irene García-Morales has served on advisory boards and received financial support from Bial, Eisai, GSK, UCB Pharma, and ViroPharma. The remaining authors have no conflicts of interest. Acknowledgments This work was supported by “Fundación Gmp” and “Fundación Iniciativa para las Neurociencias (INCE)”. We'd like to express our sincere thanks to all the patients involved in this study and their families. References [1] Inoue Y, Fujiwara T, Matsuda K, Kubota H, Tanaka M, Yagi K, et al. Ring chromosome 20 and nonconvulsive status. Brain 1997;120:939-935. [2] Canevini MP, Sgro V, Zuffardi O, Canger R, Carrozzo R, Rossi E, et al. Chromosome 20 ring: a chromosomal disorder associated with a particular electroclinical pattern. Epilepsia 1998;39:942–51. [3] Elens I, Varykel K, De Waele L, Jansen K, Segeren M, Van Paesschen M, et al. Ring chromosome 20 syndrome: electroclinical description of six patients and review of the literature. Epilepsy Behav 2012;23:409–14. [4] Kamoun FF, Ellouz EJ, Hsairi IG, Triki CC. Frontal motor seizure following nonconvulsive status epilepticus in ring chromosome 20 syndrome. Neurosciences (Riyadh) 2012;17:74–7. [5] Radhakrishnan A, Menon RN, Hariharan S, Radhakrishnan K. The evolving electroclinical syndrome of “epilepsy with ring chromosome 20”. Seizure 2012;21: 92–7. [6] Augustijn PB, Parra J, Wouters CH, Joosten P, Lindhout D, van Emde Boas W. Ring chromosome 20 epilepsy syndrome in children: electroclinical features. Neurology 2001;57:1108–11. [7] Ville D, Kaminska A, Bahi-Buisson N, Biraben A, Plouin P, Telvi L, et al. Early pattern of epilepsy in the ring chromosome 20 syndrome. Epilepsia 2006;47:543–9. [8] Vignoli A, Canevini MP, Darra F, La Selva L, Fiorini E, Piazzini A, et al. Ring chromosome 20 syndrome: a link between epilepsy onset and neuropsychological impairment in three children. Epilepsia 2009;50:f20–7. [9] Vega-Zelaya L, Alonso-Cerezo C, Quesada JF, Sola RG, Pastor J. Electroclinical characteristics of patient with ring chrosomosome 20 syndrome. Rev Neurol 2014;58: 450–4. [10] Avanzini P, Vaudano AE, Vignoli A, Ruggieri A, Benuzzi F, Darra F, et al. Low frequency mu-like activity characterizes cortical rhythms in epilepsy due to ring chromosome 20. Clin Neurophysiol 2014;125:239–49. [11] Zambrelli E, Vignoli A, Nobili L, Didato G, Mastrangelo M, Turner K, et al. Sleep in ring chromosome 20 syndrome: a peculiar electroencephalographic pattern. Funct Neurol 2013;28:47–53. [12] Porfirio B, Valorani MG, Giannotti A, Sabetta G, Dallapiccola B. Ring 20 chromosome phenotype. J Med Genet 1987;24:375–7. [13] Cignini P, Dugo N, Giorlandino C, Gauci R, Spata A, Capriglione S, et al. Prenatal diagnosis of a fetus with a ring chromosome 20 characterized by array-CGH. J Prenatal Med 2012;6:72–3. [14] Steward JM, Cavanagh N, Hughes DT. Ring 20 chromosome in a child with seizures, minor anomalies, and retardation. Arch Dis Child 1979;54:477–9. [15] Back E, Voiculescu I, Brünger M, Wolff G. Familiar ring (20) chromosomal mosaicism. Hum Genet 1989;83:148–54. [16] Holopainen I, Penttinen M, Lakkala T, Aarimaa T. Ring chromosome 20 mosaicism in a girl with complex partial seizures. Dev Med Child Neurol 1994;36:70–3.
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