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Keywords:

  • Seizure clustering;
  • Status epilepticus;
  • Intractable epilepsy;
  • Extratemporal epilepsy;
  • Head trauma

Abstract

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgments
  7. REFERENCES

Summary: Purpose: Patients with epilepsy often experience seizures in clusters. In this preliminary study, we examined the prevalence of self-reported clustering and identified potential risk factors and outcomes associated with reported clustering for further analysis in an ongoing prospective diary study.

Methods: Detailed intake questionnaires were administered. Subjects reporting their typical seizure pattern to be three or more seizures within a 24-h period were classified as clusterers. Magnetic resonance imaging (MRI) and EEG data were obtained, and epilepsy was classified by International League Against Epilepsy (ILAE) criteria. All subjects completed Beck Anxiety and Depression Inventories, and Quality of Life in Epilepsy testing.

Results: Overall, 29% of subjects reported typical seizure clustering. Extratemporal lobe epilepsy [p = 0.02; OR, 3.0 (1.1–7.8)] was significantly associated with reported seizure clustering. Remote symptomatic epilepsy was associated with clustering [p = 0.03; OR, 2.3 (1.1–4.3)], particularly in association with a history of head trauma with loss of consciousness before epilepsy onset [p = 0.003; OR, 4.2 (1.6–11.1)], although this analysis was limited. Reported clustering was significantly associated with a history of convulsive status epilepticus (SE) [p = 0.029; OR, 3.0 (1.1–8.3)], other seizure-related hospitalization [p = 0.006; OR, 5.3 (1.5–17.6)], and worse seizure control (p = 0.004). Quality-of-life measures were not significantly associated with reported clustering.

Conclusions: These preliminary results identify extratemporal epilepsy and possibly head trauma as potential risk factors for reported seizure clustering and indicate a significant association between reported clustering and convulsive SE. Additionally, seizure clustering appears to be a marker for more intractable epilepsy. The ongoing diary study will refine the definition of seizure clustering and further evaluate specific predictors of poor and favorable outcomes of clustering.

A clear subset of patients with epilepsy experience their seizures in clusters or flurries (1–3). The prevalence of seizure clustering in an epilepsy population has been reported to be >20% (1), and as high as 47% in patients with intractable partial epilepsy (4). Although it is clear that overall increased seizure frequency has a negative impact on epilepsy, the impact of the temporal occurrence of seizures is less well studied.

As part of an ongoing prospective seizure-diary cohort study, we examined seizure patterns as reported by subjects before maintaining the year-long seizure diary. The aim of this preliminary study was to identify the prevalence of reported seizure clustering and to explore potential risk factors and outcomes associated with clustering for further evaluation by the prospective study.

METHODS

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgments
  7. REFERENCES

Subject recruitment

Subjects were recruited from the Epilepsy Management Center at Montefiore Medical Center (MMC) and from the general neurology clinic. The MMC IRB approved the study, and all subjects signed an informed consent. Inclusion criteria: age 18 years or older; documented diagnosis of epilepsy; ≥1 seizure during the prior year; ability to maintain a detailed seizure diary; and English or Spanish speaking. Subjects with primary generalized epilepsy were excluded, to account for potentially different mechanisms and outcomes of clustering in localization-related and primary generalized epilepsies. Subjects who reported a typical seizure pattern of three or more seizures every day were excluded as inherent in the definition of clustering, in the assumption that the cluster represents an increase over the mean daily seizure frequency. Of 163 eligible subjects approached for recruitment between November 2002 and September 2004, 147 (90%) were enrolled, for whom adequate data are available for 141, who are the subject of this report (Table 1).

Table 1. Demographic and epilepsy characteristics
 No. of subjects (%)
Gender
 Male 52 (37)
 Female 89 (63)
Mean age (yr)40.2 ± 18.5 
Mean age at epilepsy onset (yr)20.7 ± 15.8 
Mean epilepsy duration (yr)17.6 ± 13.8 
Mean maximal time seizure-free (mo)15.5 ± 26.4 
Range of maximal seizure-free months0–135 (25)
 2–536 (25)
 6–1232 (23)
 13–2412 (8) 
 >2426 (19)
Number of seizures reported during prior month027 (19)
 1–586 (61)
 6–1010 (7) 
 11–207 (5)
 >2011 (8) 
History of febrile seizures 7 (5)
History of childhood remission 9 (6)
Localization-related epilepsyTemporal lobe55 (39)
 Frontal lobe13 (9) 
 Extratemporal, other18 (13)
 Multifocal  2 (1.5)
 Unknown localization53 (38)

Data collection

A full medical and epilepsy history; detailed description of seizure type, frequency, and temporal pattern; and psychosocial history were obtained. The Beck Anxiety Inventory (BAI), Beck Depression Inventory (BDI), and Quality of Life in Epilepsy-89 (QOLIE-89) questionnaires were administered. Magnetic resonance imaging (MRI), electroencephalographic (EEG), epilepsy classification, and seizure-localization data were obtained by chart review. Subjects received detailed seizure diaries to be maintained. The seizure diary data are ongoing and not reported here.

Variable definitions

Seizure clustering by history

A seizure cluster was considered to be the occurrence of three or more seizures within a 24-h period, as previously defined (5). Subjects who reported their typical seizure pattern as three or more seizures on a day in which they were having seizures were characterized as subjects with seizure clustering.

Seizure type

Seizure types were classified in accordance with International League Against Epilepsy (ILAE) criteria (6).

Epilepsy syndrome classification and localization

Epilepsy classification was assigned in accordance with ILAE criteria (7). Etiology was classified in accordance with ILAE guidelines for epidemiologic studies (8). Localization was defined as: temporal lobe epilepsy, frontal lobe epilepsy, or other extratemporal lobe epilepsy; multifocal epilepsy; localization-related epilepsy with unknown localization; and generalized epilepsy. Localization was considered unknown in subjects with a history of partial seizures, normal or nonlocalizable EEG and MRI data, and no inpatient epilepsy-monitoring information.

Degree of seizure control

Degree of epilepsy control was assessed by maximal seizure-free months and the number of reported seizures during the month before recruitment.

Head trauma

History of head trauma was defined as a head trauma associated with any loss of consciousness (LOC) before the onset of epilepsy. This definition is not sufficient to define posttraumatic epilepsy (8). Therefore these subjects were not classified as remote symptomatic or posttraumatic unless they also met the ILAE criteria for posttraumatic epilepsy (8).

Statistical analysis

Seizure clustering was classified as a dichotomous outcome. Associations between seizure clustering and categoric variables were tested for significance by using Fisher's exact test. Associations between seizure clustering and continuous variables were tested for significance by using either Student's t test, if assumptions were met, or the Wilcoxon rank sum test. Variables for which the associations with seizure clustering yielded p values <0.10 were entered into an initial multiple logistic regression model. A backward stepwise elimination procedure was used with attention to the proportion of missing values for each variable. Variables with significance levels <0.05 were retained in the final model (9).

RESULTS

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgments
  7. REFERENCES

Prevalence of seizure clustering

Of the 141 subjects, 41 (29%) reported clustering as their typical seizure pattern, and 100 (71%) subjects were classified as nonclusterers. Twenty-two subjects reported that they had at some point experienced one or more seizure clusters but did not typically experience clustering; therefore these subjects were assigned to the nonclustering group.

Risk factors for seizure clustering

Etiology of epilepsy

Remote symptomatic epilepsy was significantly associated with reported seizure clustering, as was head trauma with any LOC (Table 2). Unfortunately, the true prevalence of posttraumatic epilepsy in these subjects is not known, because of lack of access to remote medical records related to the head trauma.

Table 2. Risk factors for seizure clustering
 Seizure clustering no. (%)Nonclustering no. (%)Significance
  1. LOC, loss of consciousness; OR, odds ratio.

  2. aCorrected in regression analysis.

Remote symptomatic epilepsy28/41 (68)  46/99 (46) p = 0.03; OR, 2.3 (1.1–4.3)
History of head trauma with LOC15/41 (36.5)18/100 (18)  p = 0.003; OR, 4.2 (1.6–11) correcteda
Extratemporal localization 14/26      19/62     p = 0.02; OR, 3.0 (1.1–7.8) correcteda
EEG: Extratemporal spikes/slowing12/34 (35)  15/81 (18.5)p = 0.05; OR, 2.4 (1.1–5.9)
Mean age at epilepsy onset20.720.6p = 0.9
Duration of epilepsy16.118.2p = 0.4
Epilepsy localization

In patients with known localization (n = 88), extratemporal epilepsy was significantly associated with seizure clustering (Table 3). Frontal lobe epilepsy was not independently associated with a seizure-clustering pattern; however, the total number of subjects with frontal lobe epilepsy was small. Similarly, the presence of extratemporal spikes and/or slow-wave abnormalities on EEG was significantly associated with reported seizure clustering (p = 0.04).

Table 3. Outcomes and associations related to seizure clustering
 Seizure clustering no. (%)Nonclustering no. (%)Significance
  1. OR, odds ratio; BAI, Beck Anxiety Inventory; BDI, Beck Depression Inventory; QOLIE, quality of life in epilepsy.

  2. aCorrected in regression analysis.

Mean no. of seizures in past month 7.0 2.5p = 0.004
History of convulsive status epilepticus (SE)16/41 (39)12/100 (12)p = 0.03; OR, 3.0 (1.1–8.3) correcteda
Seizure-related hospitalization (non-SE)30/41 (73)59/100 (59)p = 0.006; OR, 5.3 (1.5–17.6) correcteda
Mean score: BAI16.113.1p = 0.27
Mean score: BDI-II16.114.2p = 0.46
Mean score: QOLIE-8956.260.1p = 0.37
MRI findings

An abnormal MRI was not associated with clustering, nor were any specific imaging abnormalities.

Other clinical variables

Clinical variables not significantly associated with seizure clustering include age, gender, history of febrile seizures, seizure type, mean age at epilepsy onset, and mean duration of epilepsy (Table 2).

Regression model

Head trauma (p = 0.003; OR, 4.2; 95% CI, 1.6–11.1) and extratemporal epilepsy (p = 0.02; OR, 3.0; 95% CI, 1.1–7.8) remained significant in the model.

Seizure clustering and status epilepticus

Reported typical seizure clustering was strongly associated with a reported history of convulsive status epilepticus (SE) (Table 3). Subject reporting of nonconvulsive SE was not thought to be reliable and was not included in the analysis.

Seizure clustering and injury/hospitalization

Seizure-related injury was not significantly associated with reported seizure clustering. Emergency seizure-related hospitalization did demonstrate a significant association with reported clustering (Table 3).

Seizure clustering and seizure control

Mean number of seizures in the prior month was significantly higher for subjects with seizure clustering than for nonclusterers, although the absolute maximal number of seizure-free months was not significantly different among groups (Table 3).

Seizure clustering and psychosocial measures

Mean psychological test scores were not statistically different for clusterers versus nonclusterers (Table 3). Seizure clustering was not significantly associated with marital status, number of children, employment status, or driving status.

Regression model

SE (p = 0.029; OR, 3.01; 95% CI, 1.1–8.3) and hospitalizations (p = 0.006; OR, 5.3; 95% CI, 1.5–17.6) remained significant in the model.

DISCUSSION

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgments
  7. REFERENCES

Our findings confirm that many subjects with epilepsy report seizure clustering. Prior studies examining seizure clustering reported rates of clustering ranging from 47% (4,10,11) to 61% (12). These high percentages may reflect the impact of medication discontinuation during epilepsy monitoring and a selection bias toward subjects with more intractable epilepsy. In our more heterogeneous epilepsy population with a wider range of seizure control, nearly 30% of subjects reported clustering as their typical seizure pattern.

A primary aim of this preliminary study was to identify potential risk factors and outcomes associated with seizure clustering, for further evaluation prospectively. Extratemporal epilepsy, which has not been documented to be associated with clustering in prior studies (12,13), was significantly associated with reported seizure clustering in this study. Remote symptomatic epilepsy was identified as another potential risk factor for seizure clustering. Although head trauma with loss of consciousness appears to be a particular risk, this analysis is limited by the lack of remote medical records required to confirm the duration of LOC.

Perhaps the most significant association identified in this preliminary study is a potential relation between reported seizure clustering and a history of convulsive SE, a finding that has previously contradictory results (4,12). Similarly, seizure-related hospitalization independent of convulsive SE was significantly increased for reported clusterers, and clustering appears to be a marker for worse seizure control, as has been previously suggested (2,4).

The findings in this study are preliminary, with seizure patterns based on subject reporting, and a definition of seizure clustering that is empirical and may be imperfect. The ongoing prospective diary study will refine the definition of seizure clustering and the accuracy of patient reporting to documented seizure occurrence. However, the current results already indicate potentially significant findings to be further explored. Seizure clustering is common, and a thorough epilepsy history should include inquiry about seizure pattern as well as frequency. A history of extratemporal epilepsy and/or remote symptomatic epilepsy, particularly with a history of head trauma with LOC, should alert caregivers to the potential for clustering. Patients reporting clustering may be at potentially higher risk of convulsive SE and seizure-related hospitalization and may be experiencing poorer epilepsy control than do patients without clustering. These findings may mandate a more aggressive approach to therapy for these patients, as well as consideration of abortive therapy for seizure episodes.

Acknowledgments

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgments
  7. REFERENCES

Acknowledgment:  Funding for this study was supported by NIH grant K23 NS02192 (PI: Dr. Haut).

REFERENCES

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgments
  7. REFERENCES
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