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Preliminary neurocognitive outcomes in Jeavons syndrome
Epilepsy & Behavior 52 (2015) 260–263
Contents lists available at ScienceDirect
Epilepsy & Behavior journal homepage: www.elsevier.com/locate/yebeh
Brief Communication
Preliminary neurocognitive outcomes in Jeavons syndrome Ashley S. Fournier-Goodnight a,⁎, Marsha Gabriel b, M. Scott Perry b a b
Department of Psychology, Neuropsychology Section, St. Jude Children's Research Hospital, Memphis, TN, USA Jane and John Justin Neurosciences Center, Cook Children's Medical Center, Fort Worth, TX, USA
a r t i c l e
i n f o
Article history: Received 29 June 2015 Revised 24 August 2015 Accepted 14 September 2015 Available online 6 November 2015 Keywords: Jeavons syndrome Eyelid myoclonia with absences Neurocognitive outcomes Neuropsychological profile
a b s t r a c t Jeavons syndrome (JS, eyelid myoclonia with absences [EMA]) consists of a triad of symptoms including eyelid myoclonia that may be accompanied by absence seizures, eye closure-induced EEG paroxysms or seizures, and photosensitivity. The age of onset ranges between 2 and 14 years with symptoms peaking between 6 and 8 years of age. Though investigation of the clinical, EEG, and neurological features of JS has occurred, neurocognitive functioning has not been well-delineated despite suggestion that a subtype of the syndrome is characterized in part by cognitive impairment. The purpose of this study was to define neurocognitive functioning in a more detailed manner by examining global IQ and relevant neurocognitive domains (i.e., verbal and nonverbal reasoning, attention, executive functioning, memory) in pediatric patients. The sample (N = 6, 4 females) ranged in age from 8 to 15 years (M = 11, SD = 2.82). All participants completed neuropsychological evaluations. Statistical analyses revealed performance that was below average on measures of global IQ, processing speed and rote, verbal learning coupled with average nonverbal reasoning, and sustained attention. There was also evidence of impaired higher-level verbal reasoning. While global IQ ranged from low average to borderline impaired, no participant could be accurately described as impaired or having intellectual disability (ID) given the consistently average performance noted on some higher-order tasks including nonverbal reasoning. © 2015 Elsevier Inc. All rights reserved.
1. Introduction Jeavons syndrome (JS, eyelid myoclonia with absences [EMA]) consists of a triad of symptoms including eyelid myoclonia that may be accompanied by absence seizures, eye closure-induced electroencephalogram (EEG) paroxysms or seizures, and photosensitivity [1,2]. Jeavons syndrome is a reflexive idiopathic generalized epilepsy (IGE) with well-defined features on EEG [3–5]. Specifically, multiple high amplitude spike-and-wave discharges are exhibited upon eye closure. Eyelid myoclonia is the defining feature of the syndrome, which can be associated with upward deviation of the eyes and head as well as alteration in consciousness [3,4,6]. When absence seizures occur, they are brief (i.e., 3 to 6 s); however, generalized tonic–clonic (GTC) seizures occasionally occur. Absence seizures are triggered by eye closure, flickering light, or continuous light. The clinico-EEG features of JS have been associated with disruption of the alpha generator in the occipital cortex, which impacts the brainstem, transcortical pathway, and thalamocortical network resulting in epileptiform as well as spikeand-wave discharges and eyelid myoclonia; however, other pathways are likely contributory [7,8]. Jeavons syndrome has not been formally recognized as a seizure syndrome by the International League Against ⁎ Corresponding author at: Department of Psychology, Neuropsychology Section, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Mail Stop 740, Memphis, TN 38105-3678, USA. Tel.: +1 901 595 4799. E-mail address: [email protected] (A.S. Fournier-Goodnight).
http://dx.doi.org/10.1016/j.yebeh.2015.09.022 1525-5050/© 2015 Elsevier Inc. All rights reserved.
Epilepsy (ILAE) given that eyelid myoclonia can occur in many epileptic conditions [7]. Therefore, the organization considers eyelid myoclonia a seizure type and places JS within the category of other visual sensitive epilepsies. With regard to prevalence, about 3% of adults with epilepsy meet criteria for JS [9,10]. This accounts for about 13% of IGEs that include absence seizures. The age of onset ranges between 2 and 14 years of age with symptoms peaking between 6 and 8 years of age. Jeavons syndrome is twice as common in females. The course of the disorder has been described as chronic and pervasive in that eyelid myoclonia is treatment-resistant, occurring multiple times daily; however, absence seizures and photosensitivity may subside over the lifespan. In addition to the avoidance of triggers, JS is treated with antiepileptic drugs (AEDs) such as levetiracetam, valproate, and ethosuximide as well as phenobarbital and benzodiazepines [11,12]. Despite extensive investigation of the clinical, EEG, and neurological features of JS, neurocognitive functioning in this population has not been well-delineated. Though a number of studies with larger sample sizes have referred to global intelligence quotient (IQ), this has been described broadly using somewhat ambiguous terminology (i.e., cognitive impairment, borderline mental level, developmental delay) [3,4,13–16]. The majority of studies using more definitive phraseology (i.e., mild mental retardation [MR], moderate MR) have reported neither specific cognitive measures utilized nor associated scores. This type of detailed data may be useful given that some authors have suggested the presence of a variant of JS based in part upon cognitive functioning
A.S. Fournier-Goodnight et al. / Epilepsy & Behavior 52 (2015) 260–263
[3,4]. Caraballo et al. described a subgroup of nine patients with earlyonset and intractable JS that was occasionally associated with GTC seizures and MR. Aspects of neurocognition have been more precisely discussed in case studies wherein patients had full scale IQs that were low average (i.e., standard score of 88) and well below average (i.e., standard score of 46) as measured by the Wechsler Intelligence Scale for Children (WISC) [17,18]. Though these case studies provide valuable information related to global functioning at seizure onset, there is currently a dearth of data related to the neurocognitive profile associated with JS. More specifically, performance across neurocognitive domains that contribute to global IQ has not been previously described among a group of children meeting diagnostic criteria for JS. The purpose of this study was to define neurocognitive functioning associated with JS in a more detailed manner. Thus, we sought to examine global IQ as well as relevant neurocognitive domains including verbal and nonverbal reasoning, attention and executive functioning, as well as memory in pediatric patients who met diagnostic criteria for JS. This goal is particularly relevant given the proposal by some researchers that a subgroup or variant of JS may exist that is characterized by the presence of cognitive impairment or Intellectual Disability (ID) [3,4].
Table 1 Subtests and indexes from the WISC-IV, CPT-II V.5, and WRAML2 with means, SDs, and effect sizes (i.e., Cohen's d). Measure
Index/subtest
M (±SD)
d
WISC-IV
FSIQ VCI Similarities Vocabulary Comprehension PRI Block design Picture concepts Matrix reasoning WMI Digit span Letter–number sequencing PSI Coding Symbol search Omissions Commissions Hit RT Verbal memory Story memory Story memory delay recall Verbal learning Verbal learning delay recall Visual memory Design memory Picture memory Verbal recognition Story memory recognition Verbal learning recognition Visual recognition Design memory recognition Picture memory recognition
80.16 (7.65)a,b 84.00 (10.48)a,b 7.33 (2.50)c 7.33 (2.33)c 6.83 (1.94)a,c 90.66 (7.65)b 7.66 (2.16)c 9.50 (1.37)c 8.16 (1.83)c 90.33 (14.33)b 8.33 (2.33)c 8.50 (3.14)c 72.66 (9.04)a,b 4.33 (2.50)a,c 5.66 (1.86)a,c 56.55 (16.23)d 57.21 (5.89)d 48.505 (14.70)d 81.66 (9.39)a,b 7.16 (3.86)c 8.33 (2.42)c 6.50 (0.54)a,c 5.83 (3.60)a,c 90.50 (6.68)b 7.16 (2.04)c 9.66 (2.42)c 88.83 (15.87)b 11.00 (2.00)c 5.33 (4.13)CE 89.50 (14.47)b 7.00 (3.09)c 9.83 (2.78)c
1.32 1.06
CPT-II V.5
WRAML2
2. Material and methods Data utilized in the current study were archival and culled from clinical neuropsychological evaluations conducted in the outpatient setting within a children's hospital; thus, this study was retrospective in nature. Participants (N = 6) were referred for neuropsychological evaluation by pediatric epileptologists following diagnosis with JS. Diagnoses were made through careful review of clinical history and correlation with EEG data. All patients between the ages of 4 and 18 years who were diagnosed with JS and referred for neuropsychological evaluation between 2012 and 2013 were included in this study. Patients who were non-English speaking or those with a history of head injury, neurosurgical intervention, or neurodevelopmental disorders (i.e., ID, autism spectrum disorder) were excluded from this study. The sample was predominantly girls (i.e., four girls) ranging in age from 8 to 15 years (M = 11, SD = 2.82). Age at seizure onset ranged from 2 to 6 years of age. All participants demonstrated and reported a right-hand preference and were taking AEDs at the time of assessment. Each participant was treated with monopharmacy consisting of levetiracetam (three participants), divalproex sodium (two participants), and ethosuximide. Retrospective approval from the facility's Institutional Review Board (IRB) was obtained. Assessment data were comprised of scores from subtests on the WISC, fourth edition (i.e., WISC-IV), the Connors' Continuous Performance Test, second edition, version 5 (CPT-II V.5), and the Wide Range Assessment of Memory and Learning, second edition (WRAML2, Table 1). The WISC-IV is a comprehensive measure of intellectual functioning while the CPT-II V.5 is a comprehensive measure of sustained attention. The WRAML2 provides an estimate of verbal as well as visual learning and recall. Each of these measures has demonstrated acceptable validity and reliability [19–21]. 2.1. EEG findings All participants demonstrated eyelid myoclonia and EEG findings consistent with JS. More specifically, each participant's EEG was remarkable for interictal and generalized polyspike-and-wave abnormalities reactive to eyelid closure. Two participants demonstrated occipital polyspike-andwave abnormalities elicited via interphotic stimulation, and one participant showed bifrontal polyspike-and-wave abnormalities. 2.2. Statistical analyses A post hoc power analysis was first conducted followed by calculation of means and SDs associated with relevant subtests, indexes, and
261
1.05
1.82 1.89 1.44
1.22
1.16 1.39
1.55
WISC-IV: Wechsler Intelligence Scale for Children, fourth edition; FSIQ: Full Scale IQ; VCI: Verbal Comprehension Index; PRI: Perceptual Reasoning Index; WMI: Working Memory Index; PSI: Processing Speed Index; CPT-II V.5: Conners' Continuous Performance Test, second edition, version 5; RT: response time; WRAML2: Wide Range Assessment of Memory and Learning, second edition. a M outside the average range. b Standard score (M = 100, SD = 15). c Scaled score (M = 10, SD = 3). d T-score (M = 50, SD = 10).
global scores for each measure to investigate collective neurocognitive performance. One-sample t-tests were conducted and effect sizes (i.e., Cohen's d) calculated for subtests and indexes where performance was outside the average range. For the current study, average was defined as the mean ± one SD based on age-standardized scores such that standard scores between 85 and 115, scaled scores between 7 and 13, and T-scores between 40 and 50 were considered average [22,23]. 3. Results Power analysis with power (1-β) set at 0.80 and α = 0.05, twotailed, revealed a sample size of two indicating the current study was adequately powered. Calculation of means and SDs revealed overall performance outside the average range for a number of subtests and indexes including the Full Scale IQ (i.e., FSIQ), Verbal Comprehension Index (VCI), and Processing Speed Index (PSI) from the WISC-IV (Table 1). Below average subtests from this measure included comprehension, coding, and symbol search. The verbal learning, verbal learning delay recall, and verbal learning recognition subtests as well as the verbal memory index from the WRAML2 were also below average. Performance was within the average range for all other subtests and indexes; however, large SDs were found for CPT-II V.5 omissions (M = 56.55, SD = 16.23) and hit response time (RT; M = 48.50, SD = 14.70). One-sample t-tests were significant and effect sizes large for all indexes and subtests from the WISC-IV (FSIQ: t(5) = 6.35, p = 0.00;
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VCI: t(5) = 3.73, p = 0.01; PSI: t(5) = 7.40, p = 0.00; comprehension: t(5) = 4.00, p = 0.01; coding: t(5) = 5.55, p = 0.00; symbol search: t(5) = 5.71, p = 0.00) and WRAML2 (verbal memory: t(5) = 4.78, p = 0.00; verbal learning: t(5) = 15.87, p = 0.00; verbal learning delay recall: t(5) = 2.83, p 0.03; and verbal learning recognition: t(5) = 2.76, p = 0.03; Table 1) for which performance was outside the average range. 4. Discussion Previous studies of JS that have included information related to global cognitive functioning have done so in a cursory manner [3,4,13–18]. The majority of these studies have not detailed global scores or the specific measures utilized to arrive at those scores and instead have relied upon broad descriptors of their samples' global intellectual functioning. Most typically, overall cognitive ability is noted to be impaired; however, precise neurocognitive deficits contributing to overall ability have not been described. The current study is the first to take preliminary steps in clearly defining global as well as specific neurocognitive functioning in a pediatric sample with JS. An understanding of specific neurocognitive sequelae rather than overall functioning informs individualized treatment decisions [24]. However, it warrants mention that the current findings may be impacted by time of seizure onset, socioeconomic status (SES), comorbid diagnoses, and treatment with AEDs [25–28]. 4.1. Global intellectual ability Global IQ was below average; however, this was primarily related to difficulty with speeded information processing. The PSI was borderline impaired with tightly clustered subtest scores across participants; thus, processing speed was limited for all participants. Though verbal comprehension was slightly below average, this was related to specific difficulty verbalizing appropriate social rules and norms. Other aspects of verbal reasoning were low average. Additional facets of global intellectual functioning were within the average range. In fact, nonverbal or perceptual reasoning was generally strong, ranging from average to slightly below average (i.e., 104 to 82). While working memory ability was average, individual capacity ranged broadly from average to borderline impaired (i.e., 110 to 71). There was no discernible relationship between processing speed and working memory such that a number of participants demonstrated limited processing speed coupled with strong working memory. While there is no single seizure profile, neurocognitive sequelae are more consistent across seizure syndromes than seizure types or EEG characteristics [29,30]. The current findings are generally consistent with neurocognitive outcomes associated with various seizure types and syndromes in that global IQ is often found to be low average or slightly below average; however, ID is variable across syndromes (i.e., Lennox–Gastaut syndrome, Landau–Kleffner syndrome). Processing speed deficits are common as well and have been associated with the use of AEDs [25–28]. While global verbal ability was just below average, higher-level verbal reasoning was problematic across participants, which is suggestive of specific deficits in this area. Additionally, the comparatively intact nonverbal reasoning noted across participants in the current sample is not often reported in epileptic syndromes or seizure types [29,30]. This strong nonverbal reasoning coupled with below average verbal reasoning may be related to decreased socialization secondary to medical treatment/chronic illness given that dysfunction in verbal reasoning was largely observed on a task requiring descriptions and explanations of appropriate social rules and norms. 4.2. Attention The sample demonstrated strong performance on a task of sustained attention, which was average and suggestive of the ability to maintain
attention to a lengthy, mundane activity. It is notable that performance was more variable than what would be expected with regard to the omission of target stimuli and the ability to respond to stimuli in a timely manner. However, participants did not omit or ignore target stimuli to a significant degree, and this variability was the result of well above average performance by one participant (i.e., scores ranged from 88 to 43). When this score was excluded from analyses, both the mean and SD for this measure were within normal limits (i.e., CPT-II V.5 omissions M = 50.24, SD = 5.49). Therefore, there were no concerns related to the omission or ignoring of relevant stimuli, which can be viewed as an indicator of inattention or distractibility. In contrast, the variability associated with response time encompassed performance that was below average (i.e., scores ranged from 69 to 30). Though slow response times may be suggestive of inattention, decreased processing speed likely also impacted performance. These findings are not entirely consistent with those associated with other seizure syndromes and types [26,31]. About 29% of individuals with epilepsy have comorbid psychiatric diagnoses with the majority meeting the diagnostic criteria for attention-deficit/hyperactivity disorder (ADHD), inattentive type [32,33]. This comorbidity is notably common in childhood absence epilepsy (CAE). 4.3. Learning and memory Verbal memory was below average; however, this was predominantly the result of difficulty with rote learning. More specifically, participants struggled to freely recall rote, verbal material (i.e., lists of unrelated words) even after frequent repetition. Thus, they demonstrated a depressed learning curve in comparison with same-age peers. Long-term memory for this material was also below average; however, there was greater variability in performance. This suggests that some participants benefitted from time for the consolidation and organization of verbal material such that they recalled more information while others did not. Recognition of rote, verbal material was below average indicating limited initial encoding of this material. Of note, performance was increasingly variable here, which would suggest that some participants experienced retrieval rather than encoding deficits. Other aspects of verbal memory (i.e., memory for lengthy, detailed information or information presented in context) and overall visual memory were intact. These findings are generally consistent with the neurocognitive sequelae associated with other pediatric seizure syndromes. Deficits in memory are often found in Rolandic epilepsy, CAE, and temporal lobe epilepsy [30,34,35]. However, the specific and consistent difficulty with rote learning and rote, verbal memory in comparison with other types of memory was notable in the current study. Difficulty with rote learning is often associated with inattention; however, attention was intact on measures tapping this function within the current sample. While it is possible that processing speed may have impacted the ability to quickly take in verbal material, average performance on other tasks of verbal memory that would be equally taxing for processing speed is curious. Specific difficulty with rote learning may have been related to aspects of executive dysfunction (i.e., difficulty organizing unrelated information in a strategic manner to facilitate memory) that were not directly assessed in this study. Though working memory, which is a facet of executive functioning, was average, suggesting intact ability to mentally manipulate incoming information, organization and planning were not formally assessed. These aspects of executive functioning would be more consistent with the ability to strategically organize verbal material. 5. Conclusions The most notable aspects of the neurocognitive profile associated with the current sample include significantly decreased processing speed as well as difficulty with higher-level verbal reasoning and rote learning coupled with average nonverbal reasoning and generally intact
A.S. Fournier-Goodnight et al. / Epilepsy & Behavior 52 (2015) 260–263
attention. Though processing speed is often limited in other seizure types and syndromes and may be related to the use of AEDs, the specific difficulty with aspects of verbal reasoning, rote learning, and memory as well as intact nonverbal reasoning and attention may be distinctive of JS. While overall cognitive ability ranged from low average to borderline impaired, no participant could be accurately described as impaired or ID given the consistently average performance noted on higher-order tasks including nonverbal reasoning. These findings underscore the importance of examining domains of neurocognitive functioning when attempting to characterize the cognitive ability of a clinical group. An understanding of specific deficits as opposed to global functioning is paramount in driving treatment including implementation of tailored cognitive and academic interventions. There are a number of methodological concerns that limit the generalizability of these findings. Given the rarity of the diagnosis, the sample size was very small; however, this study was adequately powered. The study was retrospective in nature and relied upon flexible clinical evaluations; therefore, it cannot be ruled out that patients with the most significant signs of cognitive and academic dysfunction were referred for evaluation. Related to the use of clinical batteries, limited clinical, demographic, and assessment data were collected. Future studies will benefit from a larger sample size allowing for the use of inferential statistics. These studies should employ a prospective research design with a focus on the collection of relevant clinical (i.e., time of seizure onset, number of GTC seizures, comorbid diagnoses), demographic (i.e., SES), and assessment (i.e., divided/alternating attention, executive functions, achievement) data. Acknowledgments The authors thank Dr. Heather Conklin and Dr. Lisa Jacola for their invaluable feedback and proofreading. Conflict of interest These authors have no disclosures or conflicts of interest. References [1] Jeavons PM. Nosological problems of myoclonic epilepsies in childhood and adolescence. Dev Med Child Neurol 1977;19:3–8. [2] Panayiotopoulos CP. A clinical guide to epileptic syndromes and their treatment. New York, NY: Springer Publishing; 2007. [3] Capovilla G, Striano P, Gambardella A, Beccaria F, Hirsch E, Casellato S, et al. Eyelid fluttering, typical EEG pattern, and impaired intellectual functioning: a homogeneous epileptic condition among the patients presenting with eyelid myoclonia. Epilepsia 2009;50(6):1536–41. [4] Caraballo RH, Fontana E, Darra F, Chacon S, Ross N, Fiorini E, et al. A study of 63 cases with eyelid myoclonia with or without absences: type of seizure or an epileptic syndrome? Seizure 2009;18:440–5. [5] Liu Y, Yang T, Liao W, Yang X, Liu I, Yan B, et al. EEG–fMRI study of the ictal and interictal epileptic activity in patients with eyelid myoclonia with absences. Epilepsia 2008;49(12):2078–86. [6] Panayiotopoulos CP. Elementary visual hallucinations, blindness, and headache in idiopathic occipital lobe epilepsy: differentiation from migraine. J Neurol Neurosurg Psychiatry 1999;66:536–40. [7] Vaudano EA, Ruggieri A, Tondelli M, Avanzini P, Benuzzi F, Gessaroli G, et al. The visual system in eyelid myoclonia with absences. Ann Neurol 2014;76:412–27. [8] Viravan S, Go C, Ochi A, Akiyama T, Snead III OC, Otsubo H. Jeavons syndrome existing as occipital cortex initiating generalized epilepsy. Epilepsia 2011;52(7): 1273–9.
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Contents lists available at ScienceDirect
Epilepsy & Behavior journal homepage: www.elsevier.com/locate/yebeh
Brief Communication
Preliminary neurocognitive outcomes in Jeavons syndrome Ashley S. Fournier-Goodnight a,⁎, Marsha Gabriel b, M. Scott Perry b a b
Department of Psychology, Neuropsychology Section, St. Jude Children's Research Hospital, Memphis, TN, USA Jane and John Justin Neurosciences Center, Cook Children's Medical Center, Fort Worth, TX, USA
a r t i c l e
i n f o
Article history: Received 29 June 2015 Revised 24 August 2015 Accepted 14 September 2015 Available online 6 November 2015 Keywords: Jeavons syndrome Eyelid myoclonia with absences Neurocognitive outcomes Neuropsychological profile
a b s t r a c t Jeavons syndrome (JS, eyelid myoclonia with absences [EMA]) consists of a triad of symptoms including eyelid myoclonia that may be accompanied by absence seizures, eye closure-induced EEG paroxysms or seizures, and photosensitivity. The age of onset ranges between 2 and 14 years with symptoms peaking between 6 and 8 years of age. Though investigation of the clinical, EEG, and neurological features of JS has occurred, neurocognitive functioning has not been well-delineated despite suggestion that a subtype of the syndrome is characterized in part by cognitive impairment. The purpose of this study was to define neurocognitive functioning in a more detailed manner by examining global IQ and relevant neurocognitive domains (i.e., verbal and nonverbal reasoning, attention, executive functioning, memory) in pediatric patients. The sample (N = 6, 4 females) ranged in age from 8 to 15 years (M = 11, SD = 2.82). All participants completed neuropsychological evaluations. Statistical analyses revealed performance that was below average on measures of global IQ, processing speed and rote, verbal learning coupled with average nonverbal reasoning, and sustained attention. There was also evidence of impaired higher-level verbal reasoning. While global IQ ranged from low average to borderline impaired, no participant could be accurately described as impaired or having intellectual disability (ID) given the consistently average performance noted on some higher-order tasks including nonverbal reasoning. © 2015 Elsevier Inc. All rights reserved.
1. Introduction Jeavons syndrome (JS, eyelid myoclonia with absences [EMA]) consists of a triad of symptoms including eyelid myoclonia that may be accompanied by absence seizures, eye closure-induced electroencephalogram (EEG) paroxysms or seizures, and photosensitivity [1,2]. Jeavons syndrome is a reflexive idiopathic generalized epilepsy (IGE) with well-defined features on EEG [3–5]. Specifically, multiple high amplitude spike-and-wave discharges are exhibited upon eye closure. Eyelid myoclonia is the defining feature of the syndrome, which can be associated with upward deviation of the eyes and head as well as alteration in consciousness [3,4,6]. When absence seizures occur, they are brief (i.e., 3 to 6 s); however, generalized tonic–clonic (GTC) seizures occasionally occur. Absence seizures are triggered by eye closure, flickering light, or continuous light. The clinico-EEG features of JS have been associated with disruption of the alpha generator in the occipital cortex, which impacts the brainstem, transcortical pathway, and thalamocortical network resulting in epileptiform as well as spikeand-wave discharges and eyelid myoclonia; however, other pathways are likely contributory [7,8]. Jeavons syndrome has not been formally recognized as a seizure syndrome by the International League Against ⁎ Corresponding author at: Department of Psychology, Neuropsychology Section, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Mail Stop 740, Memphis, TN 38105-3678, USA. Tel.: +1 901 595 4799. E-mail address: [email protected] (A.S. Fournier-Goodnight).
http://dx.doi.org/10.1016/j.yebeh.2015.09.022 1525-5050/© 2015 Elsevier Inc. All rights reserved.
Epilepsy (ILAE) given that eyelid myoclonia can occur in many epileptic conditions [7]. Therefore, the organization considers eyelid myoclonia a seizure type and places JS within the category of other visual sensitive epilepsies. With regard to prevalence, about 3% of adults with epilepsy meet criteria for JS [9,10]. This accounts for about 13% of IGEs that include absence seizures. The age of onset ranges between 2 and 14 years of age with symptoms peaking between 6 and 8 years of age. Jeavons syndrome is twice as common in females. The course of the disorder has been described as chronic and pervasive in that eyelid myoclonia is treatment-resistant, occurring multiple times daily; however, absence seizures and photosensitivity may subside over the lifespan. In addition to the avoidance of triggers, JS is treated with antiepileptic drugs (AEDs) such as levetiracetam, valproate, and ethosuximide as well as phenobarbital and benzodiazepines [11,12]. Despite extensive investigation of the clinical, EEG, and neurological features of JS, neurocognitive functioning in this population has not been well-delineated. Though a number of studies with larger sample sizes have referred to global intelligence quotient (IQ), this has been described broadly using somewhat ambiguous terminology (i.e., cognitive impairment, borderline mental level, developmental delay) [3,4,13–16]. The majority of studies using more definitive phraseology (i.e., mild mental retardation [MR], moderate MR) have reported neither specific cognitive measures utilized nor associated scores. This type of detailed data may be useful given that some authors have suggested the presence of a variant of JS based in part upon cognitive functioning
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[3,4]. Caraballo et al. described a subgroup of nine patients with earlyonset and intractable JS that was occasionally associated with GTC seizures and MR. Aspects of neurocognition have been more precisely discussed in case studies wherein patients had full scale IQs that were low average (i.e., standard score of 88) and well below average (i.e., standard score of 46) as measured by the Wechsler Intelligence Scale for Children (WISC) [17,18]. Though these case studies provide valuable information related to global functioning at seizure onset, there is currently a dearth of data related to the neurocognitive profile associated with JS. More specifically, performance across neurocognitive domains that contribute to global IQ has not been previously described among a group of children meeting diagnostic criteria for JS. The purpose of this study was to define neurocognitive functioning associated with JS in a more detailed manner. Thus, we sought to examine global IQ as well as relevant neurocognitive domains including verbal and nonverbal reasoning, attention and executive functioning, as well as memory in pediatric patients who met diagnostic criteria for JS. This goal is particularly relevant given the proposal by some researchers that a subgroup or variant of JS may exist that is characterized by the presence of cognitive impairment or Intellectual Disability (ID) [3,4].
Table 1 Subtests and indexes from the WISC-IV, CPT-II V.5, and WRAML2 with means, SDs, and effect sizes (i.e., Cohen's d). Measure
Index/subtest
M (±SD)
d
WISC-IV
FSIQ VCI Similarities Vocabulary Comprehension PRI Block design Picture concepts Matrix reasoning WMI Digit span Letter–number sequencing PSI Coding Symbol search Omissions Commissions Hit RT Verbal memory Story memory Story memory delay recall Verbal learning Verbal learning delay recall Visual memory Design memory Picture memory Verbal recognition Story memory recognition Verbal learning recognition Visual recognition Design memory recognition Picture memory recognition
80.16 (7.65)a,b 84.00 (10.48)a,b 7.33 (2.50)c 7.33 (2.33)c 6.83 (1.94)a,c 90.66 (7.65)b 7.66 (2.16)c 9.50 (1.37)c 8.16 (1.83)c 90.33 (14.33)b 8.33 (2.33)c 8.50 (3.14)c 72.66 (9.04)a,b 4.33 (2.50)a,c 5.66 (1.86)a,c 56.55 (16.23)d 57.21 (5.89)d 48.505 (14.70)d 81.66 (9.39)a,b 7.16 (3.86)c 8.33 (2.42)c 6.50 (0.54)a,c 5.83 (3.60)a,c 90.50 (6.68)b 7.16 (2.04)c 9.66 (2.42)c 88.83 (15.87)b 11.00 (2.00)c 5.33 (4.13)CE 89.50 (14.47)b 7.00 (3.09)c 9.83 (2.78)c
1.32 1.06
CPT-II V.5
WRAML2
2. Material and methods Data utilized in the current study were archival and culled from clinical neuropsychological evaluations conducted in the outpatient setting within a children's hospital; thus, this study was retrospective in nature. Participants (N = 6) were referred for neuropsychological evaluation by pediatric epileptologists following diagnosis with JS. Diagnoses were made through careful review of clinical history and correlation with EEG data. All patients between the ages of 4 and 18 years who were diagnosed with JS and referred for neuropsychological evaluation between 2012 and 2013 were included in this study. Patients who were non-English speaking or those with a history of head injury, neurosurgical intervention, or neurodevelopmental disorders (i.e., ID, autism spectrum disorder) were excluded from this study. The sample was predominantly girls (i.e., four girls) ranging in age from 8 to 15 years (M = 11, SD = 2.82). Age at seizure onset ranged from 2 to 6 years of age. All participants demonstrated and reported a right-hand preference and were taking AEDs at the time of assessment. Each participant was treated with monopharmacy consisting of levetiracetam (three participants), divalproex sodium (two participants), and ethosuximide. Retrospective approval from the facility's Institutional Review Board (IRB) was obtained. Assessment data were comprised of scores from subtests on the WISC, fourth edition (i.e., WISC-IV), the Connors' Continuous Performance Test, second edition, version 5 (CPT-II V.5), and the Wide Range Assessment of Memory and Learning, second edition (WRAML2, Table 1). The WISC-IV is a comprehensive measure of intellectual functioning while the CPT-II V.5 is a comprehensive measure of sustained attention. The WRAML2 provides an estimate of verbal as well as visual learning and recall. Each of these measures has demonstrated acceptable validity and reliability [19–21]. 2.1. EEG findings All participants demonstrated eyelid myoclonia and EEG findings consistent with JS. More specifically, each participant's EEG was remarkable for interictal and generalized polyspike-and-wave abnormalities reactive to eyelid closure. Two participants demonstrated occipital polyspike-andwave abnormalities elicited via interphotic stimulation, and one participant showed bifrontal polyspike-and-wave abnormalities. 2.2. Statistical analyses A post hoc power analysis was first conducted followed by calculation of means and SDs associated with relevant subtests, indexes, and
261
1.05
1.82 1.89 1.44
1.22
1.16 1.39
1.55
WISC-IV: Wechsler Intelligence Scale for Children, fourth edition; FSIQ: Full Scale IQ; VCI: Verbal Comprehension Index; PRI: Perceptual Reasoning Index; WMI: Working Memory Index; PSI: Processing Speed Index; CPT-II V.5: Conners' Continuous Performance Test, second edition, version 5; RT: response time; WRAML2: Wide Range Assessment of Memory and Learning, second edition. a M outside the average range. b Standard score (M = 100, SD = 15). c Scaled score (M = 10, SD = 3). d T-score (M = 50, SD = 10).
global scores for each measure to investigate collective neurocognitive performance. One-sample t-tests were conducted and effect sizes (i.e., Cohen's d) calculated for subtests and indexes where performance was outside the average range. For the current study, average was defined as the mean ± one SD based on age-standardized scores such that standard scores between 85 and 115, scaled scores between 7 and 13, and T-scores between 40 and 50 were considered average [22,23]. 3. Results Power analysis with power (1-β) set at 0.80 and α = 0.05, twotailed, revealed a sample size of two indicating the current study was adequately powered. Calculation of means and SDs revealed overall performance outside the average range for a number of subtests and indexes including the Full Scale IQ (i.e., FSIQ), Verbal Comprehension Index (VCI), and Processing Speed Index (PSI) from the WISC-IV (Table 1). Below average subtests from this measure included comprehension, coding, and symbol search. The verbal learning, verbal learning delay recall, and verbal learning recognition subtests as well as the verbal memory index from the WRAML2 were also below average. Performance was within the average range for all other subtests and indexes; however, large SDs were found for CPT-II V.5 omissions (M = 56.55, SD = 16.23) and hit response time (RT; M = 48.50, SD = 14.70). One-sample t-tests were significant and effect sizes large for all indexes and subtests from the WISC-IV (FSIQ: t(5) = 6.35, p = 0.00;
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VCI: t(5) = 3.73, p = 0.01; PSI: t(5) = 7.40, p = 0.00; comprehension: t(5) = 4.00, p = 0.01; coding: t(5) = 5.55, p = 0.00; symbol search: t(5) = 5.71, p = 0.00) and WRAML2 (verbal memory: t(5) = 4.78, p = 0.00; verbal learning: t(5) = 15.87, p = 0.00; verbal learning delay recall: t(5) = 2.83, p 0.03; and verbal learning recognition: t(5) = 2.76, p = 0.03; Table 1) for which performance was outside the average range. 4. Discussion Previous studies of JS that have included information related to global cognitive functioning have done so in a cursory manner [3,4,13–18]. The majority of these studies have not detailed global scores or the specific measures utilized to arrive at those scores and instead have relied upon broad descriptors of their samples' global intellectual functioning. Most typically, overall cognitive ability is noted to be impaired; however, precise neurocognitive deficits contributing to overall ability have not been described. The current study is the first to take preliminary steps in clearly defining global as well as specific neurocognitive functioning in a pediatric sample with JS. An understanding of specific neurocognitive sequelae rather than overall functioning informs individualized treatment decisions [24]. However, it warrants mention that the current findings may be impacted by time of seizure onset, socioeconomic status (SES), comorbid diagnoses, and treatment with AEDs [25–28]. 4.1. Global intellectual ability Global IQ was below average; however, this was primarily related to difficulty with speeded information processing. The PSI was borderline impaired with tightly clustered subtest scores across participants; thus, processing speed was limited for all participants. Though verbal comprehension was slightly below average, this was related to specific difficulty verbalizing appropriate social rules and norms. Other aspects of verbal reasoning were low average. Additional facets of global intellectual functioning were within the average range. In fact, nonverbal or perceptual reasoning was generally strong, ranging from average to slightly below average (i.e., 104 to 82). While working memory ability was average, individual capacity ranged broadly from average to borderline impaired (i.e., 110 to 71). There was no discernible relationship between processing speed and working memory such that a number of participants demonstrated limited processing speed coupled with strong working memory. While there is no single seizure profile, neurocognitive sequelae are more consistent across seizure syndromes than seizure types or EEG characteristics [29,30]. The current findings are generally consistent with neurocognitive outcomes associated with various seizure types and syndromes in that global IQ is often found to be low average or slightly below average; however, ID is variable across syndromes (i.e., Lennox–Gastaut syndrome, Landau–Kleffner syndrome). Processing speed deficits are common as well and have been associated with the use of AEDs [25–28]. While global verbal ability was just below average, higher-level verbal reasoning was problematic across participants, which is suggestive of specific deficits in this area. Additionally, the comparatively intact nonverbal reasoning noted across participants in the current sample is not often reported in epileptic syndromes or seizure types [29,30]. This strong nonverbal reasoning coupled with below average verbal reasoning may be related to decreased socialization secondary to medical treatment/chronic illness given that dysfunction in verbal reasoning was largely observed on a task requiring descriptions and explanations of appropriate social rules and norms. 4.2. Attention The sample demonstrated strong performance on a task of sustained attention, which was average and suggestive of the ability to maintain
attention to a lengthy, mundane activity. It is notable that performance was more variable than what would be expected with regard to the omission of target stimuli and the ability to respond to stimuli in a timely manner. However, participants did not omit or ignore target stimuli to a significant degree, and this variability was the result of well above average performance by one participant (i.e., scores ranged from 88 to 43). When this score was excluded from analyses, both the mean and SD for this measure were within normal limits (i.e., CPT-II V.5 omissions M = 50.24, SD = 5.49). Therefore, there were no concerns related to the omission or ignoring of relevant stimuli, which can be viewed as an indicator of inattention or distractibility. In contrast, the variability associated with response time encompassed performance that was below average (i.e., scores ranged from 69 to 30). Though slow response times may be suggestive of inattention, decreased processing speed likely also impacted performance. These findings are not entirely consistent with those associated with other seizure syndromes and types [26,31]. About 29% of individuals with epilepsy have comorbid psychiatric diagnoses with the majority meeting the diagnostic criteria for attention-deficit/hyperactivity disorder (ADHD), inattentive type [32,33]. This comorbidity is notably common in childhood absence epilepsy (CAE). 4.3. Learning and memory Verbal memory was below average; however, this was predominantly the result of difficulty with rote learning. More specifically, participants struggled to freely recall rote, verbal material (i.e., lists of unrelated words) even after frequent repetition. Thus, they demonstrated a depressed learning curve in comparison with same-age peers. Long-term memory for this material was also below average; however, there was greater variability in performance. This suggests that some participants benefitted from time for the consolidation and organization of verbal material such that they recalled more information while others did not. Recognition of rote, verbal material was below average indicating limited initial encoding of this material. Of note, performance was increasingly variable here, which would suggest that some participants experienced retrieval rather than encoding deficits. Other aspects of verbal memory (i.e., memory for lengthy, detailed information or information presented in context) and overall visual memory were intact. These findings are generally consistent with the neurocognitive sequelae associated with other pediatric seizure syndromes. Deficits in memory are often found in Rolandic epilepsy, CAE, and temporal lobe epilepsy [30,34,35]. However, the specific and consistent difficulty with rote learning and rote, verbal memory in comparison with other types of memory was notable in the current study. Difficulty with rote learning is often associated with inattention; however, attention was intact on measures tapping this function within the current sample. While it is possible that processing speed may have impacted the ability to quickly take in verbal material, average performance on other tasks of verbal memory that would be equally taxing for processing speed is curious. Specific difficulty with rote learning may have been related to aspects of executive dysfunction (i.e., difficulty organizing unrelated information in a strategic manner to facilitate memory) that were not directly assessed in this study. Though working memory, which is a facet of executive functioning, was average, suggesting intact ability to mentally manipulate incoming information, organization and planning were not formally assessed. These aspects of executive functioning would be more consistent with the ability to strategically organize verbal material. 5. Conclusions The most notable aspects of the neurocognitive profile associated with the current sample include significantly decreased processing speed as well as difficulty with higher-level verbal reasoning and rote learning coupled with average nonverbal reasoning and generally intact
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attention. Though processing speed is often limited in other seizure types and syndromes and may be related to the use of AEDs, the specific difficulty with aspects of verbal reasoning, rote learning, and memory as well as intact nonverbal reasoning and attention may be distinctive of JS. While overall cognitive ability ranged from low average to borderline impaired, no participant could be accurately described as impaired or ID given the consistently average performance noted on higher-order tasks including nonverbal reasoning. These findings underscore the importance of examining domains of neurocognitive functioning when attempting to characterize the cognitive ability of a clinical group. An understanding of specific deficits as opposed to global functioning is paramount in driving treatment including implementation of tailored cognitive and academic interventions. There are a number of methodological concerns that limit the generalizability of these findings. Given the rarity of the diagnosis, the sample size was very small; however, this study was adequately powered. The study was retrospective in nature and relied upon flexible clinical evaluations; therefore, it cannot be ruled out that patients with the most significant signs of cognitive and academic dysfunction were referred for evaluation. Related to the use of clinical batteries, limited clinical, demographic, and assessment data were collected. Future studies will benefit from a larger sample size allowing for the use of inferential statistics. These studies should employ a prospective research design with a focus on the collection of relevant clinical (i.e., time of seizure onset, number of GTC seizures, comorbid diagnoses), demographic (i.e., SES), and assessment (i.e., divided/alternating attention, executive functions, achievement) data. Acknowledgments The authors thank Dr. Heather Conklin and Dr. Lisa Jacola for their invaluable feedback and proofreading. Conflict of interest These authors have no disclosures or conflicts of interest. References [1] Jeavons PM. Nosological problems of myoclonic epilepsies in childhood and adolescence. Dev Med Child Neurol 1977;19:3–8. [2] Panayiotopoulos CP. A clinical guide to epileptic syndromes and their treatment. New York, NY: Springer Publishing; 2007. [3] Capovilla G, Striano P, Gambardella A, Beccaria F, Hirsch E, Casellato S, et al. Eyelid fluttering, typical EEG pattern, and impaired intellectual functioning: a homogeneous epileptic condition among the patients presenting with eyelid myoclonia. Epilepsia 2009;50(6):1536–41. [4] Caraballo RH, Fontana E, Darra F, Chacon S, Ross N, Fiorini E, et al. A study of 63 cases with eyelid myoclonia with or without absences: type of seizure or an epileptic syndrome? Seizure 2009;18:440–5. [5] Liu Y, Yang T, Liao W, Yang X, Liu I, Yan B, et al. EEG–fMRI study of the ictal and interictal epileptic activity in patients with eyelid myoclonia with absences. Epilepsia 2008;49(12):2078–86. [6] Panayiotopoulos CP. Elementary visual hallucinations, blindness, and headache in idiopathic occipital lobe epilepsy: differentiation from migraine. J Neurol Neurosurg Psychiatry 1999;66:536–40. [7] Vaudano EA, Ruggieri A, Tondelli M, Avanzini P, Benuzzi F, Gessaroli G, et al. The visual system in eyelid myoclonia with absences. Ann Neurol 2014;76:412–27. [8] Viravan S, Go C, Ochi A, Akiyama T, Snead III OC, Otsubo H. Jeavons syndrome existing as occipital cortex initiating generalized epilepsy. Epilepsia 2011;52(7): 1273–9.
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