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Purpose: To compare long-term outcome in a population-based group of children with cryptogenic versus symptomatic focal epilepsy diagnosed from 1980 to 2004 and to define the course of epilepsy in the cryptogenic group.
Methods: We identified all children residing in Olmsted County, MN, 1 month through 17 years, with newly diagnosed, nonidiopathic focal epilepsy from 1980 to 2004. Children with idiopathic partial epilepsy syndromes were excluded. Medical records were reviewed to determine etiology, results of imaging and EEG studies, treatments used, and long-term outcome. Children were defined as having symptomatic epilepsy if they had a known genetic or structural/metabolic etiology, and as cryptogenic if they did not.
Key Findings: Of 359 children with newly diagnosed epilepsy, 215 (60%) had nonidiopathic focal epilepsy. Of these, 206 (96%) were followed for >12 months. Ninety-five children (46%) were classified as symptomatic. Median follow-up from diagnosis was similar in both groups, being 157 months (25%, 75%: 89, 233) in the cryptogenic group versus 134 months (25%, 75%: 78, 220) in the symptomatic group (p = 0.26). Of 111 cryptogenic cases, 66% had normal cognition. Long-term outcome was significantly better in those with cryptogenic versus symptomatic etiology (intractable epilepsy at last follow-up, 7% vs. 40%, p < 0.001; seizure freedom at last follow-up, 81% vs. 55%, p < 0.001). Of those who achieved seizure freedom at final follow-up, 68% of the cryptogenic group versus only 46% of the symptomatic group were off antiepileptic medications (p = 0.01). One-third of the cryptogenic group had a remarkably benign disorder, with no seizures seen after initiation of medication, or in those who were untreated, after the second afebrile seizure. A further 5% had seizures within the first year but remained seizure-free thereafter. With the exception of perinatal complications, which predicted against seizure remission, no other factors were found to significantly predict outcome in the cryptogenic group.
Significance: More than half of childhood nonidiopathic localization-related epilepsy is cryptogenic. This group has a significantly better long-term outcome than those with a symptomatic etiology, and should be distinguished from it.
Focal epilepsies in children were previously subdivided by etiology into idiopathic and symptomatic forms. Several idiopathic focal epilepsy syndromes have been described, including benign epilepsy with centrotemporal spikes and Panayiotopolous syndrome. These syndromes have specific electroclinical characteristics, usually respond well to antiepileptic drugs (AEDs), when treated, and remit with age. In contrast, symptomatic focal epilepsies are often more malignant, with higher rates of medical intractability and lower remission rates. According to the International Classification of Epilepsies and Epileptic Syndromes proposed by the International League Against Epilepsy (ILAE) in 1989, cryptogenic epilepsies are presumed to be symptomatic, but with an etiology that is unknown (Commission on Classification and Terminology of the International League Against Epilepsy, 1989).
However, the more recent report of the Commission on Classification and Terminology reclassified epilepsy based on three aspects: (1) mode of seizure onset (generalized vs. focal), (2) specific syndrome, if present, and (3) etiology (genetic, structural/metabolic or unknown) (Berg et al., 2010). Although distinctive constellations have been identified correlating with specific etiologies (e.g., mesial temporal lobe epilepsy with hippocampal sclerosis, Rasmussen syndrome, and gelastic seizures with hypothalamic hamartoma), a large proportion of focal epilepsy in children still does not fit into a clear syndrome and is of unknown etiology. The prognosis in these cases remains poorly understood (Reijs et al., 2006).
Several studies have attempted to address outcome in this subgroup of children. Unfortunately, previous studies have been limited by lack of a consistent definition of cryptogenic, a relatively short follow-up period, or because they were performed prior to availability of adequate neuroimaging techniques, particularly magnetic resonance imaging (MRI) (Camfield et al., 1993; Hauser et al., 1996; Sillanpaa et al., 1998; Verrotti et al., 2000; Berg et al., 2001; Camfield & Camfield, 2002; Arts et al., 2004; Geelhoed et al., 2005). Those studies with longer follow-up predominantly utilized computerized tomography (CT) scans of the head, which have poor sensitivity for detecting etiologies such as focal cortical dysplasia or mesial temporal sclerosis.
The aim of this study was twofold. First, we compared long-term outcome in children with newly diagnosed, focal epilepsy of unknown etiology, who do not fit into a clear syndrome (cryptogenic) to newly diagnosed focal epilepsy of known genetic or structural/metabolic etiology (symptomatic). Second, we evaluate the course of epilepsy and potential predictors of outcome in the cryptogenic group. Based on the current Classification Report (Berg et al., 2010), syndromes previously classified as idiopathic focal epilepsy, including benign epilepsy with centrotemporal spikes, Panayiotopolous syndrome, and benign infantile epilepsy are classified as of unknown etiology, but present with a distinct electroclinical picture. These entities were excluded from our study as they are known to have an excellent long-term prognosis.
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We identified 359 children with newly diagnosed epilepsy from 1980 through 2004 and while residing in Olmsted County. All children except three were seen on at least one occasion by a child neurologist who confirmed the diagnosis of epilepsy and most were followed over the course of their epilepsy. Of the remaining three, two were diagnosed with epilepsy by a general neurologist and one by a pediatrician.
A total of 215 (60%) met our criteria for symptomatic or cryptogenic nonidiopathic focal epilepsy. Of these children, 206 (96%) were followed for at least 12 months after diagnosis and comprise the study group (111 cryptogenic, 95 symptomatic). Median follow-up from diagnosis for these children was 157 months (25th percentile = 89 months, 75th percentile = 233 months) for the cryptogenic group versus 134 months (25th percentile = 78 months, 75th percentile = 220 months) for the symptomatic group (p = 0.26).
Symptomatic etiologies included prior brain insults (N = 48: 20 perinatal hypoxic–ischemic brain injury, 4 stroke, 4 hydrocephalus with shunt, 3 prematurity with periventricular leukomalacia, 3 meningitis/encephalitis, 2 hypoglycemia or hyponatremia, 2 head injury, 3 postnatal hypoxic ischemic brain injury, 3 remote ischemic lesion on MRI of presumed prenatal onset, 1 prior brain tumor, 1 kernicterus, 1 calcified granuloma, and 1 congenital cytomegalovirus infection), malformations of cortical development or tuberous sclerosis (N = 21), mesial temporal sclerosis (N = 7), vascular malformation (N = 6), chromosomal abnormalities (N = 5), tumor (N = 3), hypothalamic hamartoma (N = 1), and dual pathology of mesial temporal sclerosis with cortical dysplasia (N = 4).
Descriptive information for the cryptogenic and symptomatic cohorts is given in Table 1. The median age at onset of epilepsy was younger for symptomatic cases versus cryptogenic cases (p = 0.02). In addition, children with symptomatic epilepsy had higher rates of cognitive impairment (p < 0.001), more frequent abnormalities on neurologic examination (p < 0.001), were more commonly born prematurely (p = 0.012), had a higher frequency of neonatal seizures (p < 0.001), had a lower likelihood of secondarily generalized seizures at the time of presentation (p = 0.009), had higher numbers of seizures at treatment onset (p = 0.002), exhibited higher rates of status epilepticus both at presentation (p = 0.008) and ever (p < 0.001), had higher rates of epileptiform abnormalities on initial EEG (p = 0.02), and had a greater likelihood of background slowing on their initial EEG (p < 0.001) as compared to the cryptogenic group. However, the cryptogenic group had a higher rate of febrile seizures in general (p = 0.05), whereas the children in the symptomatic group were more likely to have complicated febrile seizures, if febrile seizures were present (p = 0.004).
Table 1. Cryptogenic and symptomatic focal epilepsy cohorts
|Characteristic||Cryptogenic (N = 111)a||Symptomatic (N = 95)a||p-Value|
|N (%)||N (%)|
|Sex, male||59 (53)||59 (62)||0.20|
|Age at onset (months)b||65.8 (30.9, 130.9)||52.8 (10.5, 105.0)||0.02|
|Length of follow-up (months)b||157.1 (88.7, 157.1)||134.3 (78.4, 219.8)||0.26 |
|Cognition at onset|
| Normal||73 (66)||40 (42)||<0.001|
| Mild delay||27 (24)||25 (26)|
| Severe delay||9 (8)||27 (28)|
| Unknown||1 (1)||3 (3)|
|Cognition at follow-up|
| Normal||73 (66)||31 (33)||<0.001|
| Mild delay||27 (24)||29 (31)|
| Severe delay||11 (10)||35 (37)|
|Neurologic exam, abnormal||13 (12)c||61 (64)||<0.001|
|Prenatal hospitalization||8/110 (7)||8/92 (9)||0.76|
|Gestational age <38 weeks||14/110 (13)||25/94 (27)||0.012|
|Perinatal NICU ≥7 days||9/110 (8)||43/94 (46)||<0.001|
|Neonatal seizures||3/110 (3)||19/93 (20)||<0.001|
|Head injury with LOC||4/110 (4)||2/94 (2)||0.53|
|Meningitis or encephalitis||0/110 (0)||6/93 (7)||0.007|
| Any||21/110 (19)||9 (9)||0.05|
| Complicated||9/21 (43)||9/9 (100)||0.004|
|2° GTCS at presentation||55 (50)||30 (32)||0.009|
|Partial seizures at presentation||82 (74)||68 (72)||0.71|
|No. of seizures at onset of AEDsb||3 (2, 4)||5 (2, 10)||0.002|
| At presentation||15 (14)||27 (28)||0.008|
| Ever||18 (16)||41 (43)||<0.001|
|First-degree family history of epilepsy||13/109 (12)||11/90 (12)||0.95|
|MRI completed||78 (70)||76 (80)|| |
| Mild, nonspecific changes||7/78 (9)d||1/76 (1)||0.032|
| Abnormal||0/78 (0)||72/76 (95)||<0.001|
|CT only||28 (25)||17 (18)|| |
| Abnormal||0/28 (0)||12/17 (71)||<0.001|
|No imaging||5 (5)||2 (2)|| |
| Epileptiform abnormality||69 (62)||71/92 (77)||0.02|
| Background slowing|
| Generalized||22 (20)||51/92 (55)||<0.001|
| Focal||18 (16)||35/92 (38)||<0.001|
Seizure freedom and intractability in cryptogenic versus symptomatic focal epilepsy
The proportion of children in the cryptogenic and symptomatic focal epilepsy groups who attained seizure freedom or developed intractable epilepsy is shown in Fig. 1. During the last year of follow-up, a significantly greater proportion of children in the cryptogenic group achieved seizure freedom than in the symptomatic group [90/111 (81%) vs. 52/95 (55%), p < 0.001]. Of those who achieved seizure freedom, 61 of 90 (68%) of those in the cryptogenic group versus 24 of 52 (46%) in the symptomatic group were off antiepileptic medications (p = 0.011). Similarly, significantly more children in the symptomatic group had developed medically intractable epilepsy at final follow-up than in the cryptogenic group [38/95 (40%) vs. 8/111 (7%), p < 0.001].
Figure 1. Seizure freedom and development of intractable epilepsy over time in children with cryptogenic and symptomatic focal epilepsy.
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Looking specifically at the MRI-negative cryptogenic group (N = 78), seizure freedom was achieved during the last year of follow-up in 60 of 78 (77%), and of these, 36 of 60 (60%) were off antiepileptic medications. Seven (9%) had developed medically intractable epilepsy at final follow-up.
Thirty-three children in the cryptogenic group did not have MRI imaging. Of these, seizure freedom was achieved in the final year of follow-up in 30 (91%) and only 1 (3%) had developed intractable epilepsy.
Twenty children (21%) in the symptomatic group versus only 1 (1%) in the cryptogenic group underwent resective epilepsy surgery. Twelve of the 20 symptomatic patients (60%) were seizure-free postoperatively, but six continued to have intractable epilepsy at final follow-up. The only cryptogenic patient who underwent surgery had negative pathology and continued to have intractable epilepsy at final follow-up.
Course of epilepsy and predictors of outcome in cryptogenic focal epilepsy
The course of epilepsy for the cryptogenic group is shown in Table 2. In 36 (32%) of the cryptogenic group, epilepsy was “smooth-sailing” (Camfield & Camfield, 2002), meaning that no further seizures were seen after antiepileptic medications were commenced, or in those who were never treated, after the second afebrile seizure. A further 6 (5%) had one or more seizures within the first year after initiation of medications, but remained seizure-free thereafter. Only 13 (12%) met criteria for intractable epilepsy at any point since diagnosis.
Table 2. Epilepsy course in cryptogenic focal epilepsy
|Epilepsy Course at final follow-up||Cryptogenic N (%)|
|Seizure-freea never treated with AEDs||6 (5)|
|Seizure-free and off AEDs. Epilepsy never intractableb||53 (48)|
|Seizure-free and off AEDs. Epilepsy was intractable at some point during its course||2 (2)|
|Seizure-free but on AEDs at final follow-up. Epilepsy never intractable||28 (25)|
|Seizure-free but on AEDs at final follow-up. Epilepsy was intractable at some point during its course||2 (2)|
|Not seizure-free and on AEDs at final follow-up. Epilepsy is not intractable||11 (10)|
|Not seizure-free and on AEDs at final follow-up. Epilepsy previously was intractable but is not at last follow-up||1 (1)|
|On AEDs at final follow-up. Epilepsy is intractable||8 (7)|
|Off AEDs but not seizure-free at final follow-up||0 (0)|
Of the 90 subjects who were seizure-free at final follow-up, 61 (68%) were in their first remission, 20 (22%) in their second remission, and 9 (10%) in their third or higher remission. Of 29 subjects who remained on antiepileptic medication despite being seizure-free at final follow-up, 11 (38%) previously had medications weaned with seizure recurrence. Of the 21 patients who were not seizure-free at final follow-up, 11 (52%) had previously achieved a remission lasting 12 months or longer, but then had relapse of their seizures.
Potential predictors of both seizure freedom and intractable epilepsy in cryptogenic focal epilepsy are shown in Table 3. The presence of perinatal complications correlated with a lower chance of seizure freedom at follow-up (p = 0.04). However, no other factor correlated significantly with either seizure freedom or intractability at final follow-up.
Table 3. Predictors of remission of seizures or development of intractable epilepsy in children with cryptogenic focal epilepsy
| ||Remission of seizures||Intractability epilepsy|
|Yes (N = 90)||No (N = 21)||p value||Yes (N = 8)||No (N = 103)||p value|
|N (%)||N (%)||N (%)||N (%)|
|Sex, male||47 (52)||12 (57)||0.68||4 (50)||55 (53)||0.85|
|Age at onset (months)a||64.1 (28.9, 128.8)||74.7 (39.8, 161.4)||0.60||39.8 (8.5, 145.9)||71.9 (30.9, 130.9)||0.61|
|Perinatal NICU >7 daysb||5/89 (6)||4/21 (19)||0.04||1/8 (13)||8/102 (8)||0.64|
| Any||19/89 (21)||2/21 (10)||0.22||1/8 (13)||20/102 (20)||0.62|
| Complicated||7/89 (8)||2/21 (10)||0.80||1/8 (13)||8/102 (8)||0.64|
| Generalized||19 (21)||3 (14)||0.48||0 (0)||22 (21)||0.14|
| Focal||14 (16)||4 (19)||0.70||1 (13)||17 (17)||0.77|
|Epileptiform dischargec||54 (60)||15 (71)||0.33||6 (75)||63 (61)||0.44|
| At presentation||14 (16)||1 (5)||0.19||0 (0)||15 (15)||0.25|
| Abnormal||9 (10)||4 (19)||0.25||2 (25)||11 (11)||0.23|
|First degree family history of epilepsyb||11/89 (12)||2/20 (10)||0.77||1/8 (13)||12/101 (12)||0.96|
|Cognitive delay at diagnosisb||26/89 (29)||10/21 (48)||0.11||5/8 (63)||30/102 (30)||0.06|
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In our population-based study of children with new-onset epilepsy, cryptogenic focal epilepsy, as defined by (1) lack of an underlying genetic, structural, or metabolic etiology and (2) not meeting criteria for a recognized idiopathic partial epilepsy syndrome, accounted for a significant proportion of new-onset cases of epilepsy in children. Nearly 30% of all incident cases of epilepsy, and just over half of nonidiopathic, focal epilepsies were cryptogenic. Prior reports on the proportion of cases classified as cryptogenic focal epilepsy have varied widely, from 15—49% of all cases of epilepsy, and 40–73% of all cases of nonidiopathic focal epilepsy (Eriksson & Koivikko, 1997; Waaler et al., 2000; Berg et al., 2004; Akiyama et al., 2006), as definitions have not been consistent. Some series have included all children without a known etiology, whereas others have excluded children with abnormal neurologic examinations or cognitive delay, believing these findings are suggestive of a symptomatic cause, even though no identifiable etiology has been found.
We found that the prognosis for cryptogenic focal epilepsy was strikingly better than for those with a symptomatic etiology, emphasizing the importance of distinguishing these two entities. Cryptogenic patients had a significantly higher likelihood of achieving seizure freedom at final follow-up, of ultimately stopping antiepileptic medication, and a significantly lower likelihood of developing intractable epilepsy. Prior studies have also reported high remission rates in children with cryptogenic focal epilepsy. In a cohort of 132 children, all of whom had normal intelligence, a normal neurologic examination, and normal imaging by CT scanning, two thirds had remission of their epilepsy over a mean follow-up period of 88 months (Camfield & Camfield, 2002). In Sillanpaa’s study of 32 children followed with cryptogenic localization-related epilepsy, 20 (63%) were in remission at final follow-up. However, the majority of these patients were studied prior to widespread use of neuroimaging (Sillanpaa et al., 1998). Finally, Shinnar et al. (1999) reported that 82% of 34 children with cryptogenic partial epilepsy were in remission after a mean follow-up of 8.3 years, although this study did not comment on the cognitive status of patients. Although only 55% of children with cryptogenic partial epilepsy in our study had truly remitted at final follow-up (seizure-free and off antiepileptic drugs), an additional 9% had achieved seizure freedom but were never given a trial off medication.
Previous studies have suggested that despite a high remission rate, recurrent relapses of seizures can be problematic in a portion of children with cryptogenic localization-related epilepsy. Using a Markov process to model remission and relapse, Berg found that the cryptogenic partial group had only a slightly lower chance of being in remission at any given time compared to the idiopathic partial group. However, because of the higher relapse rate, the cryptogenic partial group was increasingly less likely over time to be in their first remission. Rather, many were subjected to a pattern of repeated remission and relapse (Berg et al., 2004). However, Camfield found that 45% of patients with cryptogenic focal epilepsy had a “remarkably” benign disorder, becoming instantly seizure-free after starting medication, discontinuing medication after a few years, and remaining seizure-free (Camfield & Camfield, 2002). Our results are similar—we found 32% became immediately seizure-free and an additional 5% had only rare seizures in the first year and then remained seizure-free thereafter. Only 12% met criteria for intractable seizures at some point in the course of their epilepsy and only 7% were medically intractable at final follow-up. A pattern of repeated remission and relapse was not seen in most of our patients. Of those who were seizure-free at final follow-up, the majority (68%) were in their first remission, and only 10% had experienced three or more remissions with relapses.
These results suggest that, although the cryptogenic partial group is comprised of a large number of children with a remarkably benign epilepsy, it is clinically heterogeneous, as not all patients do well. Many of those with more resistant seizures may well have an as yet undetected symptomatic cause, possibly genetic or structural, as supported by our finding that children with cognitive delays tended to have poorer outcome.
The ILAE report from 1989 classifies cryptogenic epilepsy as probably symptomatic, but without a defined etiology. In the most recent Classification Report, the term “unknown” is used to describe etiologies that are not genetic or structural metabolic. Most child neurologists consider the severity of cryptogenic localization-related epilepsy to be intermediate between the idiopathic and symptomatic syndromes (Dunn et al., 2004). Using the Epilepsy Syndrome Severity Scores—Child, Dunn et al. found that neurologists rated the severity of cryptogenic partial epilepsy at a 7 on a 10 point scale, significantly higher than benign epilepsy of childhood with centrotemporal spikes (rated as a 2), but lower than Landau-Kleffner syndrome (rated as an 8). Based on our results, we believe that these ratings are excessively bleak. Rather than considering cryptogenic focal epilepsy as probably symptomatic, it should be considered as a separate entity, with a relatively favorable long-term outcome, particularly in children with normal imaging, normal neurologic examination and normal cognition.
Our study has a number of strengths. The Rochester Epidemiology Project allowed for complete identification of a population-based incidence cohort of children with new-onset epilepsy, and allowed access to all inpatient and outpatient records in the community. Therefore, our study sample was not contaminated by selection bias, which may be the case in reports arising strictly from an epilepsy center. Secondly, our patients had ready access to high-quality health care specialists and technology. Most children were seen by a child neurologist either at the time of diagnosis or shortly thereafter, and underwent neuroimaging with MRI. Thirdly, many of our patients were followed long-term, often into their adult years, allowing a more complete understanding of their risk of remission and risk of relapse.
A potential weakness of our study was that not all children in the cryptogenic group had undergone MRI imaging. These children may have had a structural abnormality that was not detected. However, this group did not have a lower rate of seizure freedom or higher rate of intractability at final follow-up. We suspect that in most of these cases, further imaging was not pursued as these children were doing well.
In summary, recognition of cryptogenic focal epilepsy as distinct from symptomatic focal epilepsy is important, given its favorable long-term prognosis. However, its definition requires that underlying etiologies be excluded. Children should be neurologically and cognitively normal—the presence of mental handicap should be considered evidence for an underlying symptomatic cause. Furthermore, neuroimaging, preferably MRI, should be performed to rule out a structural etiology such as a malformation of cortical development, prior injury, vascular abnormality, tumor, or mesial temporal sclerosis. In young children, particularly those between 6 and 30 months of age, incomplete myelination may limit detection of a focal cortical dysplasia or appreciation of its true extent (Colombo et al., 2009). Therefore, an MRI should be repeated after 30 months of age if seizures remain problematic and the initial study was unrevealing. Further investigations of this cohort of children with cryptogenic focal epilepsy may identify specific genes responsible for some of these conditions, which confer either a better or poorer prognosis. In addition, careful clinical characterization may allow descriptions of less common epilepsy syndromes with benign outcomes.