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Prevalence of epileptic and nonepileptic events after pediatric traumatic brain injury
Epilepsy & Behavior 27 (2013) 233–237
Contents lists available at SciVerse ScienceDirect
Epilepsy & Behavior journal homepage: www.elsevier.com/locate/yebeh
Prevalence of epileptic and nonepileptic events after pediatric traumatic brain injury Joyce H. Matsumoto a, e,⁎, Rochelle Caplan b, d, David L. McArthur c, e, Marcy J. Forgey b, d, Sue Yudovin a, e, Christopher C. Giza a, c, e a
Department of Pediatrics, Division of Pediatric Neurology, David Geffen School of Medicine at UCLA, USA Department of Psychiatry, Division of Child and Adolescent Psychiatry, David Geffen School of Medicine at UCLA, USA Department of Neurosurgery, David Geffen School of Medicine at UCLA, USA d Semel Institute for Neuroscience and Human Behavior, USA e UCLA Brain Injury Research Center, USA b c
a r t i c l e
i n f o
Article history: Received 6 September 2012 Revised 23 January 2013 Accepted 29 January 2013 Available online 6 March 2013 Keywords: Traumatic brain injury Pediatric Nonepileptic Epilepsy
a b s t r a c t Though posttraumatic epilepsy (PTE) is a prominent sequela of traumatic brain injury (TBI), other nonepileptic phenomena also warrant consideration. Within two UCLA pediatric TBI cohorts, we categorized five spell types: 1) PTE; 2) Epilepsy with other potential etiologies (cortical dysplasia, primary generalized); 3) Psychopathology; 4) Behavior misinterpreted as seizures; and 5) Other neurologic events. The two cohort subsets differed slightly in injury severity, but they were otherwise similar. Overall, PTE occurred in 40%, other epilepsy etiologies in 14%, and nonepileptic spells collectively in 46%. Among children with spells, PTE was associated with severe TBI (p= 0.001), whereas psychopathology (p=0.014) and epilepsy with other etiologies (p=0.006) were associated with milder TBI severity. Posttraumatic epilepsy (p=0.002) and misinterpreted behavior (p=0.049) occurred with younger injury age. Psychopathology (p=0.020) and other neurologic events (p=0.002) occurred with older injury age. In evaluating possible PTE, clinicians should maintain a broad differential diagnosis to prevent misdiagnosis and inappropriate treatment. © 2013 Elsevier Inc. All rights reserved.
1. Introduction Traumatic brain injury (TBI) affects more than 475,000 children under 15 years of age annually, with the highest rates observed in children aged 0–4 and a second peak in adolescence [1,2]. Traumatic brain injury is a well-known risk factor for epilepsy, with the incidence of seizures increased seventeen-fold after severe TBI and by a factor of 1.5 even after mild TBI without skull fracture or prolonged loss of consciousness [3]. The risk for epilepsy remains elevated even ten years after injury [4]. Given these epidemiologic findings, clinicians often approach the evaluation of paroxysmal events in a child with a history of TBI with a heightened index of suspicion for epilepsy. In addition to posttraumatic epilepsy (PTE), other neurologic symptomatologies, such as postconcussive migraines and cognitive deficits, are often emphasized in the differential diagnosis of post-TBI “spells” [3,5–8]. However, a number of neuropsychiatric sequelae may also complicate recovery from pediatric TBI, including various episodic nonepileptic phenomena characterized by paroxysmal movements, unusual sensations, and staring. Pediatric TBI is associated with an increased risk of psychiatric diagnoses, including depression, posttraumatic stress ⁎ Corresponding author at: Division of Pediatric Neurology, Mattel Children's Hospital at UCLA, 22-474 MDCC, Box 951752, Los Angeles, CA 90095-1752, USA. Fax: +1 310 825 5834. E-mail address: [email protected] (J.H. Matsumoto). 1525-5050/$ – see front matter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.yebeh.2013.01.024
disorder, panic disorder, obsessive–compulsive disorder, and attention deficit hyperactivity disorder (ADHD) [9–11]. In one analysis, 46% of children suffering from TBI developed new-onset mood or anxiety disorders within 6 months of TBI, in comparison to 14% of controls with solely orthopedic injuries [12]. The occurrence of nonepileptic posttraumatic events is wellestablished in the adult TBI literature. A total of 33% of adults with a history of moderate to severe TBI admitted for video-EEG characterization of paroxysmal “spells” were diagnosed with nonepileptic events [13]. Conversely, 24–32% of adults with video-EEG-confirmed nonepileptic events attributed their “seizures” to a head injury, which had usually occurred less than 1 year prior to the onset of their spells [14,15]. Similar analyses have not been conducted in the pediatric TBI population. Therefore, we sought to explore if paroxysmal “spells” presenting in children with a history of TBI would similarly reflect a high frequency of nonepileptic symptomatology. The goal of this study was to compare the nature of paroxysmal events in two cohorts of pediatric TBI patients evaluated at the University of California Los Angeles (UCLA) Pediatric TBI center. Both early and late posttraumatic seizures have been associated with higher injury severity and younger age, particularly under the age of 2 years [16–19]. In contrast, prior video-EEG monitoring series have demonstrated nonepileptic events in 15–43% of children in non-TBI populations, most frequently diagnosed in adolescence [20–26]. We hypothesized that our cohort would demonstrate a high rate of nonepileptic events, and that, furthermore, the “spells”
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J.H. Matsumoto et al. / Epilepsy & Behavior 27 (2013) 233–237
Table 1 Cohort demographics.
Children with spells, n (%) % Female Injury severity, Mild n (%) Moderate Severe Age at injury Average (yrs) SD
Cohort 1 (n = 116) (2002–2005)
Cohort 2 (n = 178) (2005–2010)
38 (33%) 37% 23 (60%) 3 (8%) 12 (32%) 7.0 5.8
34 (19%) 38% 11 (32%) 8 (24%) 15 (44%) 8.8 6.4
p-Value
0.90 (chi-square) 0.04 (Fisher's exact)
0.22 (t-test)
would follow similar patterns to non-TBI populations, with epileptic seizures associated with higher injury severity and younger age of injury, and behavioral and other nonepileptic events associated with milder severity and older injury age. 2. Methods Seizure-like phenomena were assessed through a single center analysis of paroxysmal events evaluated in children with a history of TBI. Subjects were drawn from two previously established databases of children evaluated at the UCLA Pediatric TBI center, all of whom were either acutely treated for their head injury at our hospital or evaluated in the outpatient Pediatric TBI clinic for the sequelae of prior TBI. The first of the preexisting pediatric TBI databases was retrospectively collected and includes 116 children evaluated from 2002 to 2005. Because recruitment efforts occurred primarily in the outpatient setting, milder injuries were prominently represented, with 55% mild, 23% moderate, and 23% severe TBI cases. Injury severity was determined primarily by Glasgow Coma Scale (GCS) rating, with mild TBI generally associated with GCS of 13–15, moderate TBI with GCS between 8 and 13, and severe TBI with GCS b 8. Per convention at our institution, children with GCS ≥ 13 with intracranial hemorrhage or skull fracture found on neuroimaging were classified as having suffered moderate TBI. The second database consisted of 178 children who were prospectively enrolled between 2005 and 2010. This cohort was recruited both in the pediatric TBI clinic setting and during hospital admission for the treatment of head trauma, resulting in a larger proportion of children with more severe injuries: namely 36% mild, 39% moderate, and 25% severe TBI cases. Four children who had been enrolled in both databases were excluded from the earlier cohort and considered only with the 2005–2010 patients. Both database studies were approved by the UCLA Institutional Review Board. Informed consent was obtained from the families of all patients prior to inclusion in the 2005–2010 TBI database.
suffering solely from impact seizures or other early posttraumatic seizures confined to the first week following TBI, as well as children whose spells lacked any clinical concern for epileptic seizures, such as syncope or postconcussive migraines, for which the diagnosis was clearly identified from the outset. Spell semiology, neuroimaging and electroencephalography (EEG) results, clinical diagnosis, and supplementary demographic information were obtained from the TBI databases and medical record review. 3.2. Classification of spell types For each cohort subset, the spells were classified into five different categories based on the evaluation and assessment documented in the medical record: 1) PTE; 2) Epilepsy with other potential etiologies than TBI (e.g., clinical and/or EEG features suggestive of primary generalized or benign rolandic epilepsy, malformations of cortical development detected on neuroimaging); 3) Psychopathology (e.g., panic attacks); 4) Behavioral episodes (e.g., temper tantrums, attentional lapses) misinterpreted as seizures; and 5) Other neurologic events (e.g., sleep myoclonus, posturing, dysautonomia, postconcussive symptoms). 3.3. Statistical analysis All analyses were performed using R version 2.12.1 (R Development Core Team, 2011, Vienna, Austria). Categorical demographic data, such as spell classification, injury severity, and gender, were analyzed using chi-square analyses or Fisher's exact tests when some fields had values ≤5. Differences in age at the time of injury were compared using two-tailed t-tests. p-Values b 0.05 were considered statistically significant. 4. Results 4.1. Cohort subset comparison The 2002–2005 database (Cohort 1) included 38 children with spells (Table 1). Four children had spells of two types: two with psychopathology and other neurologic events and two with misinterpreted behavior and PTE. The 2005–2010 database (Cohort 2) contained 34 children with spells. Seven children had more than one spell type: four with a combination of PTE and other neurologic events, one with misinterpreted behavior and other neurologic events, one with PTE and misinterpreted behavior, and one with psychopathology and other neurologic events. Among children suffering from paroxysmal spells, Cohort 1 had a larger representation of mild TBI (60% vs. 32%), whereas Cohort 2 had more children with moderate TBI (8% vs. 24%). Gender distribution and average age at the time of injury were not significantly different (Table 1). The proportion of children was also similar between the two subsets for all spell classifications (Table 2).
3. Procedures 4.2. Combined cohort analyses 3.1. Cohort selection Within each of these databases, the subset of children reported to have events suspicious for epileptic seizures or spells of an uncertain nature was included for analysis. Exclusion criteria included children
Due to the similarities between Cohorts 1 and 2, the results were combined for further analyses (Fig. 1). This combined cohort consisted of 72 children with paroxysmal spells: 34 with history of mild TBI, 11 with moderate TBI, and 27 with severe TBI. Eighty-four
Table 2 Distribution of spell classification by cohort.
Cohort 1 (2002–2005) Cohort 2 (2005–2008) p-Value
Posttraumatic epilepsy
Epilepsy, other etiologies
Psychopathology
Misinterpreted behavior
Other neurologic events
18 14 0.77
8 3 0.20
7 7 0.95
3 5 0.46
7 12 0.18
Evaluated by chi-square or Fisher's exact test.
J.H. Matsumoto et al. / Epilepsy & Behavior 27 (2013) 233–237
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Fig. 1. Distribution of spell classification in the combined cohort.
total spells were classified: 32 PTE, 11 epilepsy with other etiologies, 18 other neurologic events, 14 related to psychopathology, and 6 misinterpreted behavior. Spell classification of the combined cohort was then compared with demographic variables, such as injury severity (Fig. 2), injury age, and gender (Table 3). Among children with spells, PTE was significantly more common in children with a history of severe TBI (Fisher's exact p = 0.001), whereas epilepsy with other etiologies (Fisher's exact p= 0.006) and events related to psychopathology (Fisher's exact p = 0.014) were more common after mild TBI (Fig. 2). Gender was not significantly associated with spell classification. Children with PTE (p= 0.002) and misinterpreted behavior (p= 0.049) were significantly younger than their counterparts. Injury age was older for episodes related to psychopathology (p= 0.021) and other neurologic events (p= 0.002) (Table 3). Electroencephalography data were available for 43 of 72 subjects (60%) in the combined cohort, including 33 outpatient EEG studies and 13 overnight inpatient video-EEG telemetry studies (3 subjects with both outpatient and overnight inpatient EEGs). Events were captured in 17 of 46 (37%) studies (6 outpatient EEGs and 11 inpatient video-EEG studies), only 7 (41%) of which demonstrated epileptic
seizures overall. Epileptiform discharges and background slowing (either focal or generalized) were seen in children with both epileptic and nonepileptic events (Table 4). Interestingly, normal background findings were seen in all 4 EEGs obtained from children diagnosed with events related to psychopathology.
5. Discussion To our knowledge, this is the first study to evaluate the nature of paroxysmal events in two large pediatric TBI cohorts, demonstrating that epilepsy occurred in over one-half and nonepileptic events in one-quarter of these children. Although children with a history of TBI are often regarded with a heightened index of suspicion for posttraumatic seizures, our findings indicate that paroxysmal events in this population cannot be presumed to be related to preceding TBI and, furthermore, are not always epileptic in nature. Posttraumatic spells presenting in children with a history of TBI during two separate time periods (2002–2005 vs. 2005–2010) were similar in most respects, with variations in injury severity mainly reflective of the composition of the parent cohorts. In both cohort Table 3 Gender and age differences between spell types in the combined cohort. n
Posttraumatic epilepsy All other spells Epilepsy, other etiologies All other spells Other neurologic events All other spells Psychopathology All other spells Behavior misinterpreted as seizures All other spells Fig. 2. Spell type vs. injury severity (evaluated by Fisher's exact test).
32 40 11 61 19 53 14 58 8 64
Gender
Age at injury (yrs)
% Female
p
Mean (SD)
p
34% 40% 36% 38% 37% 38% 50% 34% 25% 39%
0.806
5.3 9.8 7.0 8.0 11.4 6.5 11.2 7.0 3.8 8.3
0.002
1.000 0.836 0.442 0.701
(5.9) (5.5) (5.3) (6.2) (5.6) (5.8) (4.9) (6.1) (4.8) (6.1)
Gender difference compared by chi-square (df = 1) or Fisher's exact tests. Mean age at injury compared by two-tailed t-test.
0.626 0.002 0.020 0.049
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Table 4 Electroencephalography findings. Spell type (# EEG studies performed)
Typical events captured on EEG
Normal background
Presence of epileptiform discharges
Presence of focal or generalized slowing
Posttraumatic epilepsy (n = 20) Epilepsy, other etiologies (n = 9) Psychopathology (n = 4) Behavior misinterpreted as seizures (n = 5) Other neurologic events (n = 14) Total (n = 46)
45% 33% 0 60%
20% 11% 100% 40%
55% 89% 0 60%
65% 22% 0 60%
43% 37%
57% 37%
29% 50%
43% 46%
subsets, PTE comprised less than half of the cases. Nonneurologic events, either psychopathology or misinterpreted behavior, represented one-quarter of the spells presenting for evaluation. Interestingly, interictal EEG background is unlikely to be a good predictor of the epileptic or nonepileptic nature of these spells, as epileptiform discharges and other abnormal findings were often seen even when nonepileptic events were confirmed by EEG. The stability of these findings over time suggests that clinicians who manage children following traumatic brain injury must remain alert to the possibility of psychopathology and other diagnoses. Even in children whose posttraumatic events are confirmed to be epileptic in nature, one cannot assume that the epilepsy is related to the TBI. While 54% of the spells overall in our analysis were due to epilepsy, further evaluation revealed other likely etiologies for the epilepsy in 26% of these cases. Among children with spells, PTE was associated with severe TBI and younger age at the time of injury, whereas other potential epilepsy etiologies were most often found after mild injuries. It is unclear whether the TBI in these cases was coincidental, or if it somehow triggered the clinical manifestation of an underlying tendency towards epilepsy. One might argue that the prompt discovery of other epilepsy etiologies is not essential because the underlying epilepsy etiology may not significantly influence the initial treatment with broad spectrum seizure medication. However, diagnostic accuracy is critical in the discussion of prognosis and other future therapies. The potential for eventual remission is substantially different when comparing PTE with primary generalized or benign rolandic epilepsy. Furthermore, erroneous assumptions may delay detection of surgically amenable lesions, such as mesial temporal sclerosis or focal cortical dysplasia. In essence, failure to differentiate other potential diagnoses from PTE may lead to years of inappropriate and ineffective treatment, compounding the morbidity and disability which may result from brain injury. Therefore, to ensure that parents are appropriately counseled regarding the prognosis and therapeutic options for their children's epilepsy, diagnostic testing should not be curtailed due to the assumption of posttraumatic etiology. In our analysis of children with a history of TBI who later presented with paroxysmal spells, events related to psychopathology were more likely to occur in children with mild injury, or when the child was older at the time of injury (aged 11.2 vs. 7.0 years). Previously reported risk factors for post-TBI psychopathology include familial dysfunction, postinjury stress levels, and a premorbid history of psychiatric disturbance [12,27]. Our results suggest that the consideration of TBI as an epilepsy risk factor must also be balanced by an awareness of the psychiatric complications of TBI, so as to avoid delays in proper treatment, as well as the potential adverse effects of unneeded anticonvulsant medication (which may be progressively increased as the nonepileptic spells do not respond to treatment). The role of injury severity has been the subject of some controversy. While the potential for novel psychiatric disturbance is well-documented following severe TBI [12,27], early studies did not find a similar association with mild TBI [28,29]. Subsequent reports suggest that new-onset mood and anxiety
disorders also occur following mild TBI and may persist for more than two years following the injury [12,27,30,31]. The primary limitation of this study is its reliance on medical record review. Due to the sporadic, infrequent nature of many spells, diagnoses were often made without video-EEG confirmation. Spell classification was based on the clinical judgment of the pediatric TBI team, composed of a board-certified pediatric neurologist and a pediatric neurology nurse practitioner, both with significant expertise in the evaluation and treatment of children with TBI. Because our institution is also a tertiary care center for the comprehensive medical and surgical treatment of pediatric epilepsy, both of these individuals also have extensive experience in the diagnosis and management of epilepsy. However, our TBI specialists have not received specific training in the evaluation of psychiatric disorders; therefore, the prevalence of psychopathology in our cohorts may have been underestimated because not all children were referred to child psychiatry for expert evaluation. Lastly, findings from our tertiary care TBI center may not be applicable to all TBI patients evaluated in the community setting. Although more rigorous studies are needed to confirm these findings, our analysis suggests that clinicians should not allow the increased risk of epilepsy associated with TBI to prevent consideration and investigation of a thorough differential diagnosis. The prompt and accurate diagnosis of nonepileptic events is critical to avoid unnecessary anticonvulsant treatment, ineffective health care utilization, and secondary consequences, such as social stigma and missed work or school days. This is especially true because nonepileptic events may be rendered increasingly refractory with inappropriate treatment. A recent study found that 58% of US veterans with nonepileptic events diagnosed by video-EEG monitoring had been presumed to have seizures secondary to TBI [32]. A small study of 16 children with nonepileptic events reported 44% with a history of prior head injury [33]. Although shorter diagnostic delay has been associated with increased rates of remission [34], the mean interval between the onset and correct diagnosis of nonepileptic events in adults is as long as 7.2 years [35]. Similar pediatric data are sparse, though more optimistic; there is an approximate 1-year delay prior to correct diagnosis in children, with a range of approximately 1 month to 4–5 years [20,36,37]. Correspondingly, remission rates for nonepileptic events with proper treatment are reported between 72 and 82% in children compared with 40–52% in adults [38–40]. Therefore, given the possible negative medical, psychiatric, and psychosocial implications of misdiagnosing “spells” as epilepsy, clinicians should evaluate paroxysmal events in children with prior head injury with particular care.
Acknowledgments The authors thank Hannah Valino and Andrew Ng for their assistance with database entry and management. This study was supported by the Child Neurology Foundation/Winokur Family Foundation, the Today's and Tomorrow's Children Fund, the Thrasher Research Foundation and the UCLA Brain Injury Research Center.
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Contents lists available at SciVerse ScienceDirect
Epilepsy & Behavior journal homepage: www.elsevier.com/locate/yebeh
Prevalence of epileptic and nonepileptic events after pediatric traumatic brain injury Joyce H. Matsumoto a, e,⁎, Rochelle Caplan b, d, David L. McArthur c, e, Marcy J. Forgey b, d, Sue Yudovin a, e, Christopher C. Giza a, c, e a
Department of Pediatrics, Division of Pediatric Neurology, David Geffen School of Medicine at UCLA, USA Department of Psychiatry, Division of Child and Adolescent Psychiatry, David Geffen School of Medicine at UCLA, USA Department of Neurosurgery, David Geffen School of Medicine at UCLA, USA d Semel Institute for Neuroscience and Human Behavior, USA e UCLA Brain Injury Research Center, USA b c
a r t i c l e
i n f o
Article history: Received 6 September 2012 Revised 23 January 2013 Accepted 29 January 2013 Available online 6 March 2013 Keywords: Traumatic brain injury Pediatric Nonepileptic Epilepsy
a b s t r a c t Though posttraumatic epilepsy (PTE) is a prominent sequela of traumatic brain injury (TBI), other nonepileptic phenomena also warrant consideration. Within two UCLA pediatric TBI cohorts, we categorized five spell types: 1) PTE; 2) Epilepsy with other potential etiologies (cortical dysplasia, primary generalized); 3) Psychopathology; 4) Behavior misinterpreted as seizures; and 5) Other neurologic events. The two cohort subsets differed slightly in injury severity, but they were otherwise similar. Overall, PTE occurred in 40%, other epilepsy etiologies in 14%, and nonepileptic spells collectively in 46%. Among children with spells, PTE was associated with severe TBI (p= 0.001), whereas psychopathology (p=0.014) and epilepsy with other etiologies (p=0.006) were associated with milder TBI severity. Posttraumatic epilepsy (p=0.002) and misinterpreted behavior (p=0.049) occurred with younger injury age. Psychopathology (p=0.020) and other neurologic events (p=0.002) occurred with older injury age. In evaluating possible PTE, clinicians should maintain a broad differential diagnosis to prevent misdiagnosis and inappropriate treatment. © 2013 Elsevier Inc. All rights reserved.
1. Introduction Traumatic brain injury (TBI) affects more than 475,000 children under 15 years of age annually, with the highest rates observed in children aged 0–4 and a second peak in adolescence [1,2]. Traumatic brain injury is a well-known risk factor for epilepsy, with the incidence of seizures increased seventeen-fold after severe TBI and by a factor of 1.5 even after mild TBI without skull fracture or prolonged loss of consciousness [3]. The risk for epilepsy remains elevated even ten years after injury [4]. Given these epidemiologic findings, clinicians often approach the evaluation of paroxysmal events in a child with a history of TBI with a heightened index of suspicion for epilepsy. In addition to posttraumatic epilepsy (PTE), other neurologic symptomatologies, such as postconcussive migraines and cognitive deficits, are often emphasized in the differential diagnosis of post-TBI “spells” [3,5–8]. However, a number of neuropsychiatric sequelae may also complicate recovery from pediatric TBI, including various episodic nonepileptic phenomena characterized by paroxysmal movements, unusual sensations, and staring. Pediatric TBI is associated with an increased risk of psychiatric diagnoses, including depression, posttraumatic stress ⁎ Corresponding author at: Division of Pediatric Neurology, Mattel Children's Hospital at UCLA, 22-474 MDCC, Box 951752, Los Angeles, CA 90095-1752, USA. Fax: +1 310 825 5834. E-mail address: [email protected] (J.H. Matsumoto). 1525-5050/$ – see front matter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.yebeh.2013.01.024
disorder, panic disorder, obsessive–compulsive disorder, and attention deficit hyperactivity disorder (ADHD) [9–11]. In one analysis, 46% of children suffering from TBI developed new-onset mood or anxiety disorders within 6 months of TBI, in comparison to 14% of controls with solely orthopedic injuries [12]. The occurrence of nonepileptic posttraumatic events is wellestablished in the adult TBI literature. A total of 33% of adults with a history of moderate to severe TBI admitted for video-EEG characterization of paroxysmal “spells” were diagnosed with nonepileptic events [13]. Conversely, 24–32% of adults with video-EEG-confirmed nonepileptic events attributed their “seizures” to a head injury, which had usually occurred less than 1 year prior to the onset of their spells [14,15]. Similar analyses have not been conducted in the pediatric TBI population. Therefore, we sought to explore if paroxysmal “spells” presenting in children with a history of TBI would similarly reflect a high frequency of nonepileptic symptomatology. The goal of this study was to compare the nature of paroxysmal events in two cohorts of pediatric TBI patients evaluated at the University of California Los Angeles (UCLA) Pediatric TBI center. Both early and late posttraumatic seizures have been associated with higher injury severity and younger age, particularly under the age of 2 years [16–19]. In contrast, prior video-EEG monitoring series have demonstrated nonepileptic events in 15–43% of children in non-TBI populations, most frequently diagnosed in adolescence [20–26]. We hypothesized that our cohort would demonstrate a high rate of nonepileptic events, and that, furthermore, the “spells”
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Table 1 Cohort demographics.
Children with spells, n (%) % Female Injury severity, Mild n (%) Moderate Severe Age at injury Average (yrs) SD
Cohort 1 (n = 116) (2002–2005)
Cohort 2 (n = 178) (2005–2010)
38 (33%) 37% 23 (60%) 3 (8%) 12 (32%) 7.0 5.8
34 (19%) 38% 11 (32%) 8 (24%) 15 (44%) 8.8 6.4
p-Value
0.90 (chi-square) 0.04 (Fisher's exact)
0.22 (t-test)
would follow similar patterns to non-TBI populations, with epileptic seizures associated with higher injury severity and younger age of injury, and behavioral and other nonepileptic events associated with milder severity and older injury age. 2. Methods Seizure-like phenomena were assessed through a single center analysis of paroxysmal events evaluated in children with a history of TBI. Subjects were drawn from two previously established databases of children evaluated at the UCLA Pediatric TBI center, all of whom were either acutely treated for their head injury at our hospital or evaluated in the outpatient Pediatric TBI clinic for the sequelae of prior TBI. The first of the preexisting pediatric TBI databases was retrospectively collected and includes 116 children evaluated from 2002 to 2005. Because recruitment efforts occurred primarily in the outpatient setting, milder injuries were prominently represented, with 55% mild, 23% moderate, and 23% severe TBI cases. Injury severity was determined primarily by Glasgow Coma Scale (GCS) rating, with mild TBI generally associated with GCS of 13–15, moderate TBI with GCS between 8 and 13, and severe TBI with GCS b 8. Per convention at our institution, children with GCS ≥ 13 with intracranial hemorrhage or skull fracture found on neuroimaging were classified as having suffered moderate TBI. The second database consisted of 178 children who were prospectively enrolled between 2005 and 2010. This cohort was recruited both in the pediatric TBI clinic setting and during hospital admission for the treatment of head trauma, resulting in a larger proportion of children with more severe injuries: namely 36% mild, 39% moderate, and 25% severe TBI cases. Four children who had been enrolled in both databases were excluded from the earlier cohort and considered only with the 2005–2010 patients. Both database studies were approved by the UCLA Institutional Review Board. Informed consent was obtained from the families of all patients prior to inclusion in the 2005–2010 TBI database.
suffering solely from impact seizures or other early posttraumatic seizures confined to the first week following TBI, as well as children whose spells lacked any clinical concern for epileptic seizures, such as syncope or postconcussive migraines, for which the diagnosis was clearly identified from the outset. Spell semiology, neuroimaging and electroencephalography (EEG) results, clinical diagnosis, and supplementary demographic information were obtained from the TBI databases and medical record review. 3.2. Classification of spell types For each cohort subset, the spells were classified into five different categories based on the evaluation and assessment documented in the medical record: 1) PTE; 2) Epilepsy with other potential etiologies than TBI (e.g., clinical and/or EEG features suggestive of primary generalized or benign rolandic epilepsy, malformations of cortical development detected on neuroimaging); 3) Psychopathology (e.g., panic attacks); 4) Behavioral episodes (e.g., temper tantrums, attentional lapses) misinterpreted as seizures; and 5) Other neurologic events (e.g., sleep myoclonus, posturing, dysautonomia, postconcussive symptoms). 3.3. Statistical analysis All analyses were performed using R version 2.12.1 (R Development Core Team, 2011, Vienna, Austria). Categorical demographic data, such as spell classification, injury severity, and gender, were analyzed using chi-square analyses or Fisher's exact tests when some fields had values ≤5. Differences in age at the time of injury were compared using two-tailed t-tests. p-Values b 0.05 were considered statistically significant. 4. Results 4.1. Cohort subset comparison The 2002–2005 database (Cohort 1) included 38 children with spells (Table 1). Four children had spells of two types: two with psychopathology and other neurologic events and two with misinterpreted behavior and PTE. The 2005–2010 database (Cohort 2) contained 34 children with spells. Seven children had more than one spell type: four with a combination of PTE and other neurologic events, one with misinterpreted behavior and other neurologic events, one with PTE and misinterpreted behavior, and one with psychopathology and other neurologic events. Among children suffering from paroxysmal spells, Cohort 1 had a larger representation of mild TBI (60% vs. 32%), whereas Cohort 2 had more children with moderate TBI (8% vs. 24%). Gender distribution and average age at the time of injury were not significantly different (Table 1). The proportion of children was also similar between the two subsets for all spell classifications (Table 2).
3. Procedures 4.2. Combined cohort analyses 3.1. Cohort selection Within each of these databases, the subset of children reported to have events suspicious for epileptic seizures or spells of an uncertain nature was included for analysis. Exclusion criteria included children
Due to the similarities between Cohorts 1 and 2, the results were combined for further analyses (Fig. 1). This combined cohort consisted of 72 children with paroxysmal spells: 34 with history of mild TBI, 11 with moderate TBI, and 27 with severe TBI. Eighty-four
Table 2 Distribution of spell classification by cohort.
Cohort 1 (2002–2005) Cohort 2 (2005–2008) p-Value
Posttraumatic epilepsy
Epilepsy, other etiologies
Psychopathology
Misinterpreted behavior
Other neurologic events
18 14 0.77
8 3 0.20
7 7 0.95
3 5 0.46
7 12 0.18
Evaluated by chi-square or Fisher's exact test.
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Fig. 1. Distribution of spell classification in the combined cohort.
total spells were classified: 32 PTE, 11 epilepsy with other etiologies, 18 other neurologic events, 14 related to psychopathology, and 6 misinterpreted behavior. Spell classification of the combined cohort was then compared with demographic variables, such as injury severity (Fig. 2), injury age, and gender (Table 3). Among children with spells, PTE was significantly more common in children with a history of severe TBI (Fisher's exact p = 0.001), whereas epilepsy with other etiologies (Fisher's exact p= 0.006) and events related to psychopathology (Fisher's exact p = 0.014) were more common after mild TBI (Fig. 2). Gender was not significantly associated with spell classification. Children with PTE (p= 0.002) and misinterpreted behavior (p= 0.049) were significantly younger than their counterparts. Injury age was older for episodes related to psychopathology (p= 0.021) and other neurologic events (p= 0.002) (Table 3). Electroencephalography data were available for 43 of 72 subjects (60%) in the combined cohort, including 33 outpatient EEG studies and 13 overnight inpatient video-EEG telemetry studies (3 subjects with both outpatient and overnight inpatient EEGs). Events were captured in 17 of 46 (37%) studies (6 outpatient EEGs and 11 inpatient video-EEG studies), only 7 (41%) of which demonstrated epileptic
seizures overall. Epileptiform discharges and background slowing (either focal or generalized) were seen in children with both epileptic and nonepileptic events (Table 4). Interestingly, normal background findings were seen in all 4 EEGs obtained from children diagnosed with events related to psychopathology.
5. Discussion To our knowledge, this is the first study to evaluate the nature of paroxysmal events in two large pediatric TBI cohorts, demonstrating that epilepsy occurred in over one-half and nonepileptic events in one-quarter of these children. Although children with a history of TBI are often regarded with a heightened index of suspicion for posttraumatic seizures, our findings indicate that paroxysmal events in this population cannot be presumed to be related to preceding TBI and, furthermore, are not always epileptic in nature. Posttraumatic spells presenting in children with a history of TBI during two separate time periods (2002–2005 vs. 2005–2010) were similar in most respects, with variations in injury severity mainly reflective of the composition of the parent cohorts. In both cohort Table 3 Gender and age differences between spell types in the combined cohort. n
Posttraumatic epilepsy All other spells Epilepsy, other etiologies All other spells Other neurologic events All other spells Psychopathology All other spells Behavior misinterpreted as seizures All other spells Fig. 2. Spell type vs. injury severity (evaluated by Fisher's exact test).
32 40 11 61 19 53 14 58 8 64
Gender
Age at injury (yrs)
% Female
p
Mean (SD)
p
34% 40% 36% 38% 37% 38% 50% 34% 25% 39%
0.806
5.3 9.8 7.0 8.0 11.4 6.5 11.2 7.0 3.8 8.3
0.002
1.000 0.836 0.442 0.701
(5.9) (5.5) (5.3) (6.2) (5.6) (5.8) (4.9) (6.1) (4.8) (6.1)
Gender difference compared by chi-square (df = 1) or Fisher's exact tests. Mean age at injury compared by two-tailed t-test.
0.626 0.002 0.020 0.049
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Table 4 Electroencephalography findings. Spell type (# EEG studies performed)
Typical events captured on EEG
Normal background
Presence of epileptiform discharges
Presence of focal or generalized slowing
Posttraumatic epilepsy (n = 20) Epilepsy, other etiologies (n = 9) Psychopathology (n = 4) Behavior misinterpreted as seizures (n = 5) Other neurologic events (n = 14) Total (n = 46)
45% 33% 0 60%
20% 11% 100% 40%
55% 89% 0 60%
65% 22% 0 60%
43% 37%
57% 37%
29% 50%
43% 46%
subsets, PTE comprised less than half of the cases. Nonneurologic events, either psychopathology or misinterpreted behavior, represented one-quarter of the spells presenting for evaluation. Interestingly, interictal EEG background is unlikely to be a good predictor of the epileptic or nonepileptic nature of these spells, as epileptiform discharges and other abnormal findings were often seen even when nonepileptic events were confirmed by EEG. The stability of these findings over time suggests that clinicians who manage children following traumatic brain injury must remain alert to the possibility of psychopathology and other diagnoses. Even in children whose posttraumatic events are confirmed to be epileptic in nature, one cannot assume that the epilepsy is related to the TBI. While 54% of the spells overall in our analysis were due to epilepsy, further evaluation revealed other likely etiologies for the epilepsy in 26% of these cases. Among children with spells, PTE was associated with severe TBI and younger age at the time of injury, whereas other potential epilepsy etiologies were most often found after mild injuries. It is unclear whether the TBI in these cases was coincidental, or if it somehow triggered the clinical manifestation of an underlying tendency towards epilepsy. One might argue that the prompt discovery of other epilepsy etiologies is not essential because the underlying epilepsy etiology may not significantly influence the initial treatment with broad spectrum seizure medication. However, diagnostic accuracy is critical in the discussion of prognosis and other future therapies. The potential for eventual remission is substantially different when comparing PTE with primary generalized or benign rolandic epilepsy. Furthermore, erroneous assumptions may delay detection of surgically amenable lesions, such as mesial temporal sclerosis or focal cortical dysplasia. In essence, failure to differentiate other potential diagnoses from PTE may lead to years of inappropriate and ineffective treatment, compounding the morbidity and disability which may result from brain injury. Therefore, to ensure that parents are appropriately counseled regarding the prognosis and therapeutic options for their children's epilepsy, diagnostic testing should not be curtailed due to the assumption of posttraumatic etiology. In our analysis of children with a history of TBI who later presented with paroxysmal spells, events related to psychopathology were more likely to occur in children with mild injury, or when the child was older at the time of injury (aged 11.2 vs. 7.0 years). Previously reported risk factors for post-TBI psychopathology include familial dysfunction, postinjury stress levels, and a premorbid history of psychiatric disturbance [12,27]. Our results suggest that the consideration of TBI as an epilepsy risk factor must also be balanced by an awareness of the psychiatric complications of TBI, so as to avoid delays in proper treatment, as well as the potential adverse effects of unneeded anticonvulsant medication (which may be progressively increased as the nonepileptic spells do not respond to treatment). The role of injury severity has been the subject of some controversy. While the potential for novel psychiatric disturbance is well-documented following severe TBI [12,27], early studies did not find a similar association with mild TBI [28,29]. Subsequent reports suggest that new-onset mood and anxiety
disorders also occur following mild TBI and may persist for more than two years following the injury [12,27,30,31]. The primary limitation of this study is its reliance on medical record review. Due to the sporadic, infrequent nature of many spells, diagnoses were often made without video-EEG confirmation. Spell classification was based on the clinical judgment of the pediatric TBI team, composed of a board-certified pediatric neurologist and a pediatric neurology nurse practitioner, both with significant expertise in the evaluation and treatment of children with TBI. Because our institution is also a tertiary care center for the comprehensive medical and surgical treatment of pediatric epilepsy, both of these individuals also have extensive experience in the diagnosis and management of epilepsy. However, our TBI specialists have not received specific training in the evaluation of psychiatric disorders; therefore, the prevalence of psychopathology in our cohorts may have been underestimated because not all children were referred to child psychiatry for expert evaluation. Lastly, findings from our tertiary care TBI center may not be applicable to all TBI patients evaluated in the community setting. Although more rigorous studies are needed to confirm these findings, our analysis suggests that clinicians should not allow the increased risk of epilepsy associated with TBI to prevent consideration and investigation of a thorough differential diagnosis. The prompt and accurate diagnosis of nonepileptic events is critical to avoid unnecessary anticonvulsant treatment, ineffective health care utilization, and secondary consequences, such as social stigma and missed work or school days. This is especially true because nonepileptic events may be rendered increasingly refractory with inappropriate treatment. A recent study found that 58% of US veterans with nonepileptic events diagnosed by video-EEG monitoring had been presumed to have seizures secondary to TBI [32]. A small study of 16 children with nonepileptic events reported 44% with a history of prior head injury [33]. Although shorter diagnostic delay has been associated with increased rates of remission [34], the mean interval between the onset and correct diagnosis of nonepileptic events in adults is as long as 7.2 years [35]. Similar pediatric data are sparse, though more optimistic; there is an approximate 1-year delay prior to correct diagnosis in children, with a range of approximately 1 month to 4–5 years [20,36,37]. Correspondingly, remission rates for nonepileptic events with proper treatment are reported between 72 and 82% in children compared with 40–52% in adults [38–40]. Therefore, given the possible negative medical, psychiatric, and psychosocial implications of misdiagnosing “spells” as epilepsy, clinicians should evaluate paroxysmal events in children with prior head injury with particular care.
Acknowledgments The authors thank Hannah Valino and Andrew Ng for their assistance with database entry and management. This study was supported by the Child Neurology Foundation/Winokur Family Foundation, the Today's and Tomorrow's Children Fund, the Thrasher Research Foundation and the UCLA Brain Injury Research Center.
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