Epilepsy & Behavior 33 (2014) 122–125
Contents lists available at ScienceDirect
Epilepsy & Behavior journal homepage: www.elsevier.com/locate/yebeh
Are seizures in the setting of sleep deprivation provoked?☆ Nicholas Lawn ⁎,1, Sam Lieblich 1, Judy Lee 1, John Dunne 1 Department of Neurology, Royal Perth Hospital, Perth, Western Australia, Australia
a r t i c l e
i n f o
Article history: Received 11 January 2014 Revised 4 February 2014 Accepted 5 February 2014 Available online 19 March 2014 Keywords: First seizure Sleep-deprived Provoked ILAE
a b s t r a c t It is generally accepted that sleep deprivation contributes to seizures. However, it is unclear whether a seizure occurring in the setting of sleep deprivation should be considered as provoked or not and whether this is influenced by seizure type and etiology. This information may have an important impact on epilepsy diagnosis and management. We prospectively analyzed the influence of sleep deprivation on the risk of seizure recurrence in patients with first-ever unprovoked seizures and compared the findings with patients with first-ever provoked seizures. Of 1026 patients with first-ever unprovoked seizures, 204 (20%) were associated with sleep deprivation. While the overall likelihood of seizure recurrence was slightly lower in sleep-deprived patients with first-ever seizures (log-rank p = 0.03), sleep deprivation was not an independent predictor of seizure recurrence on multivariate analysis. Seizure recurrence following a first-ever unprovoked seizure associated with sleep deprivation was far more likely than for 174 patients with a provoked first-ever seizure (log-rank p b 0.0001). Our findings support the International League Against Epilepsy recommendation that seizures occurring in the setting of sleep deprivation should not be regarded as provoked. © 2014 Elsevier Inc. All rights reserved.
1. Introduction A common clinical presentation, often in a young adult, is with a first-ever seizure in the setting of significant sleep deprivation. While it is generally accepted that sleep deprivation contributes to seizures, it is unclear whether seizures occurring in this situation should be regarded as provoked. The International League Against Epilepsy (ILAE) guidelines for epidemiologic studies on epilepsy do not define seizures associated with sleep deprivation as provoked [1], but the rationale for this has not been systematically studied. This information may have an important impact on the diagnosis and management of epilepsy. To clarify this issue, we analyzed the likelihood of seizure recurrence in patients with first-ever unprovoked seizures occurring with and without sleep deprivation. The findings were compared with those of patients with first-ever seizures related to a clearly defined proximate cause.
factors for seizure recurrence. The methodology has previously been described [2,3]. All patients underwent a standardized assessment with specific questions on potential seizure precipitants including the presence of sleep deprivation prior to the seizures. Sleep deprivation was defined as an exceptional lack of sleep for that patient, requiring 50% or less of their usual sleep, typically less than 4 h, over the 24 h prior to the seizures [4,5]. Seizure type, etiology, and electroclinical syndrome (focal-in-onset, generalized-in-onset, or unclassified) were categorized for the presenting seizures according to published guidelines [1]. Unprovoked seizures were defined as “remote symptomatic” if there was a history of or neuroimaging evidence for a prior CNS insult (including brain tumors) and “idiopathic” if there was no obvious cause (encompassing genetic epilepsy syndromes and “cryptogenic” seizures).
2.1. Follow-up 2. Methods The Western Australian first-seizure database, established in 2000, is an ongoing prospective study of adults with first-ever seizures seen by a hospital-based epilepsy service aiming to identify outcomes and risk ☆ We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. ⁎ Corresponding author at: Department of Neurology, Royal Perth Hospital, GPO Box X2213, Perth, Western Australia 6847, Australia. Tel.: +61 8 9224 2593; fax: + 61 8 9224 7020. E-mail address: [email protected] (N. Lawn). 1 All authors have read and approved the submitted manuscript.
http://dx.doi.org/10.1016/j.yebeh.2014.02.008 1525-5050/© 2014 Elsevier Inc. All rights reserved.
Patients were assessed in the clinic three to nine months after the index seizure and, if there had been no further seizures, were thereafter contacted by phone every one to two years until seizure recurrence occurred or death. For those who were not contactable by phone, the integrated hospital computer system was checked for attendance at other major hospitals in Western Australia, and if so, the related medical records were obtained. A second seizure occurring during follow-up, provoked or unprovoked, was considered a recurrence. The circumstances of any seizure recurrence were also documented including whether sleep deprivation was present. Patients who had a second seizure after being referred but prior to being seen at the clinic were included, with
N. Lawn et al. / Epilepsy & Behavior 33 (2014) 122–125
the initial seizure being analyzed as the first seizure and the second being defined as a recurrence.
123
The hypothesis was that sleep deprivation was not an independent predictor of recurrence after a first-ever unprovoked seizure and, unlike first seizures with a clearly defined proximate cause, was not associated with a lower risk of recurrence. We compared the clinical features and prognosis (occurrence of a second seizure) in patients with first-ever unprovoked seizures with sleep deprivation with those without sleep deprivation and according to seizure etiology. Comparisons between groups were conducted using t tests and analysis of variance for normally distributed data and the Mann–Whitney or the Kruskal–Wallis test for non-normal data. The chi-squared and Fisher exact tests were used to analyze categorical data. Holm's method was used to correct for multiple comparisons. Patients with missing data were excluded from univariate analyses. A comparison was also made in patients satisfying the ILAE criteria for a provoked first-ever seizure [1], excluding those with a CNS lesion known to predispose to further seizures and those patients who were also sleep-deprived. Seizure recurrence was analyzed using Kaplan–Meier curves and log-rank statistics. Sleep deprivation and other variables potentially predictive of seizure recurrence identified in prior first-seizure studies were examined using Cox proportional hazards models [2,3,6]. Variables significant at the 10% level in preliminary univariate analyses were included in the multivariate models. Hazard ratio (HR), odds ratio (OR), and 95% confidence interval (CIs) for multivariate analyses were calculated from the final models. Results were considered statistically significant at the 5% level. The study was approved by the Royal Perth Hospital Ethics Committee.
and, equally, in sleep-deprived and nonsleep-deprived patients. The clinical and investigation findings are summarized in Table 1. Stepwise logistic regression showed that sleep-deprived patients with unprovoked seizures were both younger (OR = 0.97, 95% CI = 0.96–0.98, p b 0.001) and more likely have generalized epileptiform abnormalities (OR = 2.1, 95% CI = 1.2–3.4, p = 0.005). Overall, a first seizure in association with sleep deprivation had a slightly lower likelihood of seizure recurrence when compared with nonsleep-deprived patients (log-rank p = 0.03; Fig. 1); but this difference was not evident when comparing the annual rate of seizure recurrence (Table 2). Patients with generalized-onset first-ever seizures were more likely to be sleep-deprived (21%) compared with patients with focal-onset seizures (6%) (p = 0.002), but recurrence rates were similar regardless of seizure type (Fig. 2). Cox proportional hazards modeling found that sleep deprivation was not predictive of seizure recurrence. The independent predictors of seizure recurrence were remote symptomatic etiology (HR = 1.36, 95% CI = 1.15–1.62, p b 0.001), epileptiform abnormalities on EEG (HR = 1.40, 95% CI = 1.15–1.71, p = 0.001), seizures from sleep (HR = 1.27, 95% CI = 1.05–1.52, p = 0.01), and a focal-onset seizure (HR = 1.65, 95% CI = 1.21–2.27, p = 0.001). Treatment did not alter seizure recurrence rate irrespective of etiological subgroup or seizure type. For patients with unprovoked first-ever seizures in whom no cause could be identified on imaging and EEG was normal (n = 565, 20% were sleepdeprived), the presence of sleep deprivation did not alter the risk of recurrence. Data on the presence of sleep deprivation with the second seizure were available in 96% of the patients who had an unprovoked recurrence. If the first unprovoked seizure was sleep deprived, a second unprovoked seizure was also sleep deprived in 29% compared with 5% of recurrences when sleep deprivation was not present with the first seizure (p b 0.0001).
3. Results
3.2. Provoked first seizures
3.1. Unprovoked seizures
One hundred seventy-four patients with first seizures in association with an accepted provoking factor by the ILAE criteria were identified, excluding 100 patients with a CNS lesion and 122 with sleep deprivation (Table 1). The causes were as follows: alcohol-related — 34 (19%), drug withdrawal or overdose — 28 (16%), metabolic — 17 (10%), prescribed drug — 76 (44%), illicit drug — 15 (9%), and other — 4 (2%). The
2.2. Study aims and statistical analysis
One thousand twenty-six of 1032 patients with first-ever unprovoked seizures were studied; six patients were excluded because of an absence of information on sleep deprivation status. EEG and neuroimaging (CT, MRI, or both) were performed in 99% and 98% of patients, respectively,
Table 1 Clinical and EEG findings in sleep-deprived and nonsleep-deprived patients with first-ever unprovoked seizures. Unprovoked N = 1026 Sleep-deprived (n = 204) Gender male n (%) Median age, years (range) First-degree relative with epilepsy n (%) Seizure type Tonic–clonic n (%) Other n (%) Electroclinical diagnosis Focal n (%) Generalized n (%) Unclassified n (%) Seizure from sleep n (%) Cluster n (%) Status n (%) Epileptiform n (%) Focal n (%) Generalized n (%) Epileptogenic lesion on CT or MRI n (%) Treated after first seizure n (%) Mean duration of follow-up, days (range)
p valuea
Provoked N = 174
Nonsleep-deprived (n = 822)
122 (60) 33 (14–87) 20 (10)
527 (64) 43 (14–91) 85 (11)
ns b0.0001 ns
90 (52) 34 (15–85) 14 (8)
200 (98) 4 (2)
755 (92) 67 (8)
0.001
175 (100) 0
b0.0001 ns 0.02 ns 0.007 ns b0.0001 0.001 b0.0001 0.03
15 (9) 13 (7) 146 (84) 10 (6) 38 (22) 4 (2) 14 (8) 2 (1) 12 (7) 0 21 (12) 1372 (30–4202)
73 (36) 37 (18) 94 (46) 38 (19) 24 (12) 4 (2) 49 (24) 17 (8) 32 (16) 40 (20) 27 (13) 1635 (7–4389)
431 (52) 54 (7) 337 (41) 200 (24) 156 (19) 15 (2) 124 (16) 77 (10) 47 (6) 254 (31) 238 (29) 1458 (4–4341)
Those remaining significant after the correction for multiple comparisons are indicated in bold. a p values are for univariate, comparisons between unprovoked sleep-deprived and nonsleep-deprived patients.
124
N. Lawn et al. / Epilepsy & Behavior 33 (2014) 122–125 100 Cumulative probability seizure recurrence at 1 year
90
.9
Percentage (±95%CI)
Cumulative probability of second seizure
1
.8 .7
unprovoked (not sleep deprived)
.6 unprovoked (sleep deprived)
.5 .4
provoked
.3
Sleep Deprived
80
Not sleep deprived
70 60 50 40 30 20 10
.2
0 ALL SEIZURE TYPES
Partial Seizure
Generalised Seizure
Unclassified Seizure
Seizure type
.1 0 0
365
730
1095
1460
1825
2190
2555
Days since first seizure presentation Fig. 1. Cumulative probability of unprovoked seizure recurrence in sleep-deprived and nonsleep-deprived patients with first-ever unprovoked seizures and in patients with provoked seizures non-sleep deprivation.
likelihood of any seizure recurrence following a provoked seizure was markedly lower than that following an unprovoked seizure (Fig. 1), including those unprovoked seizures associated with sleep deprivation, overall (log-rank p b 0.0001) and for etiological subgroups. Exclusion of patients with second seizures that were provoked did not alter these findings. 4. Discussion Sleep deprivation had little or no influence on the likelihood of seizure recurrence after a first unprovoked seizure, and it is not an independent predictor of seizure recurrence. Unprovoked seizures associated with sleep deprivation have a markedly higher likelihood of recurrence when compared with seizures provoked by a clearly defined proximate cause. Therefore, our findings support the ILAE recommendation that seizures occurring in the setting of sleep deprivation should not be regarded as provoked. The definition and classification of provoked seizures are evolving [7,8]. Our data are consistent with sleep deprivation being a nonspecific “trigger” rather than a specific provoker of a seizure. Incorrectly defining a sleep-deprived seizure as provoked may have significant ramifications, most importantly underestimating the likelihood of seizure recurrence. The strength of our data is the prospective and systematic ascertainment of sleep deprivation in all patients with first-ever seizures prior to knowing the subsequent outcome, thereby minimizing any recall bias. Furthermore, most recurrences in patients in whom the first seizure was associated with sleep deprivation were not sleep deprived. Studies which have attempted to differentiate between total and partial sleep deprivation (24 or more hours of sleep loss versus shorter
Fig. 2. Cumulative probability of seizure recurrence in sleep-deprived and nonsleepdeprived patients with first-ever unprovoked seizures according to seizure type.
periods of sleep loss) have not shown definite clinical differences or effects on EEG [9]. We have used a pragmatic definition of sleep deprivation as a significant and unusual lack of sleep for that patient rather than total sleep deprivation for the 24 hours prior to the seizure, so we are unable to determine whether sleep deprivation has a dose–response effect or not. Other definitions are unlikely to adequately encompass the uniquely variable effects of sleep deprivation [10].
5. Conclusion Seizures occurring in the setting of sleep deprivation should be considered unprovoked. Counseling and management decisions for patients with first-ever seizures should be directed by established risk factors for recurrence rather than an association with sleep deprivation. Driving restrictions should not be altered on the assumption that a sleep deprived seizure is provoked. Conflict of Interest The authors declare no conflict of interest.
Author contributions Dr. Lawn — study concept and design, acquisition of data, analysis and interpretation, drafted and revised manuscript, study supervision. Dr. Lieblich — acquisition of data, analysis and interpretation, critical revision of the manuscript for important intellectual content. Judy Lee — acquisition of data, analysis and interpretation. Dr. Dunne — study concept and design, acquisition of data, analysis and interpretation, critical revision of the manuscript for important intellectual content, statistical analyses.
Table 2 Seizure recurrence. p valuea
Unprovoked N = 1026
Cumulative probability of seizure recurrence % (95% CI) One year Two years Five years Mean time to seizure recurrence, days (range) Second seizure unprovoked and sleep-deprived n (%) a
Sleep-deprived (n = 204)
Nonsleep-deprived (n = 822)
43 (36–50) 50 (43–57) 58 (50–66) 298 (1–2750) 21 of 72 (29)
49 (46–53) 56 (53–60) 64 (60–68) 279 (1–3291) 19 of 357 (5)
p values are for univariate comparisons between unprovoked sleep-deprived and nonsleep-deprived patients.
ns b0.0001
Provoked N = 174
27 (21–34) 31 (24–38) 34 (26–41) 246 (1–3302)
N. Lawn et al. / Epilepsy & Behavior 33 (2014) 122–125
Acknowledgments Funding for the establishment and maintenance of the first-seizure database in the form of a grant to cover the costs of a research assistant was received from the Medical Research Foundation of Royal Perth Hospital and UCB Pharma. References [1] Commission on Epidemiology and Prognosis, International League Against Epilepsy. Guidelines for epidemiologic studies on epilepsy. Epilepsia 1993;34:592–6. [2] Kho LK, Lawn ND, Dunne JW, Linto J. First seizure presentation: do multiple seizures within 24 hours predict recurrence? Neurology 2006;67:1047–9. [3] Lawn ND, Kelly A, Dunne J, Lee J, Wesseldine A. First seizure in the older patient: clinical features and prognosis. Epilepsy Res 2013;107:109–14.
125
[4] Gunderson CH, Dunne PB, Feyer TL. Sleep deprived seizures. Neurology 1973;23: 678–86. [5] Tan J, Wilder-Smith E, Lim ECH, Ong BKC. Frequency of provocative factors in epileptic patients admitted for seizures: a prospective study in Singapore. Seizure 2005;14: 464–9. [6] Berg AT. Risk of recurrence after a first unprovoked seizure. Epilepsia 2008;49(Suppl. 1): 13–8. [7] Beghi E, Carpio A, Forsgren L, Hesdorffer DC, Malmgren K, Sander JW, et al. Recommendation for a definition of acute symptomatic seizure. Epilepsia 2010;51:671–5. [8] Shorvon S. The etiologic classification of epilepsy. Epilepsia 2011;56:1052–7. [9] Foldvary-Schaefer N, Grigg-Damberger M. Sleep and epilepsy: what we know, don’t know, and need to know. J Clin Neurophysiol 2006;23:4–20. [10] Goel N, Banks S, Mignot E, Dinges DF. DQB1*0602 predicts interindividual differences in physiologic sleep, sleepiness, and fatigue. Neurology 2010;75:1509–19.
Contents lists available at ScienceDirect
Epilepsy & Behavior journal homepage: www.elsevier.com/locate/yebeh
Are seizures in the setting of sleep deprivation provoked?☆ Nicholas Lawn ⁎,1, Sam Lieblich 1, Judy Lee 1, John Dunne 1 Department of Neurology, Royal Perth Hospital, Perth, Western Australia, Australia
a r t i c l e
i n f o
Article history: Received 11 January 2014 Revised 4 February 2014 Accepted 5 February 2014 Available online 19 March 2014 Keywords: First seizure Sleep-deprived Provoked ILAE
a b s t r a c t It is generally accepted that sleep deprivation contributes to seizures. However, it is unclear whether a seizure occurring in the setting of sleep deprivation should be considered as provoked or not and whether this is influenced by seizure type and etiology. This information may have an important impact on epilepsy diagnosis and management. We prospectively analyzed the influence of sleep deprivation on the risk of seizure recurrence in patients with first-ever unprovoked seizures and compared the findings with patients with first-ever provoked seizures. Of 1026 patients with first-ever unprovoked seizures, 204 (20%) were associated with sleep deprivation. While the overall likelihood of seizure recurrence was slightly lower in sleep-deprived patients with first-ever seizures (log-rank p = 0.03), sleep deprivation was not an independent predictor of seizure recurrence on multivariate analysis. Seizure recurrence following a first-ever unprovoked seizure associated with sleep deprivation was far more likely than for 174 patients with a provoked first-ever seizure (log-rank p b 0.0001). Our findings support the International League Against Epilepsy recommendation that seizures occurring in the setting of sleep deprivation should not be regarded as provoked. © 2014 Elsevier Inc. All rights reserved.
1. Introduction A common clinical presentation, often in a young adult, is with a first-ever seizure in the setting of significant sleep deprivation. While it is generally accepted that sleep deprivation contributes to seizures, it is unclear whether seizures occurring in this situation should be regarded as provoked. The International League Against Epilepsy (ILAE) guidelines for epidemiologic studies on epilepsy do not define seizures associated with sleep deprivation as provoked [1], but the rationale for this has not been systematically studied. This information may have an important impact on the diagnosis and management of epilepsy. To clarify this issue, we analyzed the likelihood of seizure recurrence in patients with first-ever unprovoked seizures occurring with and without sleep deprivation. The findings were compared with those of patients with first-ever seizures related to a clearly defined proximate cause.
factors for seizure recurrence. The methodology has previously been described [2,3]. All patients underwent a standardized assessment with specific questions on potential seizure precipitants including the presence of sleep deprivation prior to the seizures. Sleep deprivation was defined as an exceptional lack of sleep for that patient, requiring 50% or less of their usual sleep, typically less than 4 h, over the 24 h prior to the seizures [4,5]. Seizure type, etiology, and electroclinical syndrome (focal-in-onset, generalized-in-onset, or unclassified) were categorized for the presenting seizures according to published guidelines [1]. Unprovoked seizures were defined as “remote symptomatic” if there was a history of or neuroimaging evidence for a prior CNS insult (including brain tumors) and “idiopathic” if there was no obvious cause (encompassing genetic epilepsy syndromes and “cryptogenic” seizures).
2.1. Follow-up 2. Methods The Western Australian first-seizure database, established in 2000, is an ongoing prospective study of adults with first-ever seizures seen by a hospital-based epilepsy service aiming to identify outcomes and risk ☆ We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. ⁎ Corresponding author at: Department of Neurology, Royal Perth Hospital, GPO Box X2213, Perth, Western Australia 6847, Australia. Tel.: +61 8 9224 2593; fax: + 61 8 9224 7020. E-mail address: [email protected] (N. Lawn). 1 All authors have read and approved the submitted manuscript.
http://dx.doi.org/10.1016/j.yebeh.2014.02.008 1525-5050/© 2014 Elsevier Inc. All rights reserved.
Patients were assessed in the clinic three to nine months after the index seizure and, if there had been no further seizures, were thereafter contacted by phone every one to two years until seizure recurrence occurred or death. For those who were not contactable by phone, the integrated hospital computer system was checked for attendance at other major hospitals in Western Australia, and if so, the related medical records were obtained. A second seizure occurring during follow-up, provoked or unprovoked, was considered a recurrence. The circumstances of any seizure recurrence were also documented including whether sleep deprivation was present. Patients who had a second seizure after being referred but prior to being seen at the clinic were included, with
N. Lawn et al. / Epilepsy & Behavior 33 (2014) 122–125
the initial seizure being analyzed as the first seizure and the second being defined as a recurrence.
123
The hypothesis was that sleep deprivation was not an independent predictor of recurrence after a first-ever unprovoked seizure and, unlike first seizures with a clearly defined proximate cause, was not associated with a lower risk of recurrence. We compared the clinical features and prognosis (occurrence of a second seizure) in patients with first-ever unprovoked seizures with sleep deprivation with those without sleep deprivation and according to seizure etiology. Comparisons between groups were conducted using t tests and analysis of variance for normally distributed data and the Mann–Whitney or the Kruskal–Wallis test for non-normal data. The chi-squared and Fisher exact tests were used to analyze categorical data. Holm's method was used to correct for multiple comparisons. Patients with missing data were excluded from univariate analyses. A comparison was also made in patients satisfying the ILAE criteria for a provoked first-ever seizure [1], excluding those with a CNS lesion known to predispose to further seizures and those patients who were also sleep-deprived. Seizure recurrence was analyzed using Kaplan–Meier curves and log-rank statistics. Sleep deprivation and other variables potentially predictive of seizure recurrence identified in prior first-seizure studies were examined using Cox proportional hazards models [2,3,6]. Variables significant at the 10% level in preliminary univariate analyses were included in the multivariate models. Hazard ratio (HR), odds ratio (OR), and 95% confidence interval (CIs) for multivariate analyses were calculated from the final models. Results were considered statistically significant at the 5% level. The study was approved by the Royal Perth Hospital Ethics Committee.
and, equally, in sleep-deprived and nonsleep-deprived patients. The clinical and investigation findings are summarized in Table 1. Stepwise logistic regression showed that sleep-deprived patients with unprovoked seizures were both younger (OR = 0.97, 95% CI = 0.96–0.98, p b 0.001) and more likely have generalized epileptiform abnormalities (OR = 2.1, 95% CI = 1.2–3.4, p = 0.005). Overall, a first seizure in association with sleep deprivation had a slightly lower likelihood of seizure recurrence when compared with nonsleep-deprived patients (log-rank p = 0.03; Fig. 1); but this difference was not evident when comparing the annual rate of seizure recurrence (Table 2). Patients with generalized-onset first-ever seizures were more likely to be sleep-deprived (21%) compared with patients with focal-onset seizures (6%) (p = 0.002), but recurrence rates were similar regardless of seizure type (Fig. 2). Cox proportional hazards modeling found that sleep deprivation was not predictive of seizure recurrence. The independent predictors of seizure recurrence were remote symptomatic etiology (HR = 1.36, 95% CI = 1.15–1.62, p b 0.001), epileptiform abnormalities on EEG (HR = 1.40, 95% CI = 1.15–1.71, p = 0.001), seizures from sleep (HR = 1.27, 95% CI = 1.05–1.52, p = 0.01), and a focal-onset seizure (HR = 1.65, 95% CI = 1.21–2.27, p = 0.001). Treatment did not alter seizure recurrence rate irrespective of etiological subgroup or seizure type. For patients with unprovoked first-ever seizures in whom no cause could be identified on imaging and EEG was normal (n = 565, 20% were sleepdeprived), the presence of sleep deprivation did not alter the risk of recurrence. Data on the presence of sleep deprivation with the second seizure were available in 96% of the patients who had an unprovoked recurrence. If the first unprovoked seizure was sleep deprived, a second unprovoked seizure was also sleep deprived in 29% compared with 5% of recurrences when sleep deprivation was not present with the first seizure (p b 0.0001).
3. Results
3.2. Provoked first seizures
3.1. Unprovoked seizures
One hundred seventy-four patients with first seizures in association with an accepted provoking factor by the ILAE criteria were identified, excluding 100 patients with a CNS lesion and 122 with sleep deprivation (Table 1). The causes were as follows: alcohol-related — 34 (19%), drug withdrawal or overdose — 28 (16%), metabolic — 17 (10%), prescribed drug — 76 (44%), illicit drug — 15 (9%), and other — 4 (2%). The
2.2. Study aims and statistical analysis
One thousand twenty-six of 1032 patients with first-ever unprovoked seizures were studied; six patients were excluded because of an absence of information on sleep deprivation status. EEG and neuroimaging (CT, MRI, or both) were performed in 99% and 98% of patients, respectively,
Table 1 Clinical and EEG findings in sleep-deprived and nonsleep-deprived patients with first-ever unprovoked seizures. Unprovoked N = 1026 Sleep-deprived (n = 204) Gender male n (%) Median age, years (range) First-degree relative with epilepsy n (%) Seizure type Tonic–clonic n (%) Other n (%) Electroclinical diagnosis Focal n (%) Generalized n (%) Unclassified n (%) Seizure from sleep n (%) Cluster n (%) Status n (%) Epileptiform n (%) Focal n (%) Generalized n (%) Epileptogenic lesion on CT or MRI n (%) Treated after first seizure n (%) Mean duration of follow-up, days (range)
p valuea
Provoked N = 174
Nonsleep-deprived (n = 822)
122 (60) 33 (14–87) 20 (10)
527 (64) 43 (14–91) 85 (11)
ns b0.0001 ns
90 (52) 34 (15–85) 14 (8)
200 (98) 4 (2)
755 (92) 67 (8)
0.001
175 (100) 0
b0.0001 ns 0.02 ns 0.007 ns b0.0001 0.001 b0.0001 0.03
15 (9) 13 (7) 146 (84) 10 (6) 38 (22) 4 (2) 14 (8) 2 (1) 12 (7) 0 21 (12) 1372 (30–4202)
73 (36) 37 (18) 94 (46) 38 (19) 24 (12) 4 (2) 49 (24) 17 (8) 32 (16) 40 (20) 27 (13) 1635 (7–4389)
431 (52) 54 (7) 337 (41) 200 (24) 156 (19) 15 (2) 124 (16) 77 (10) 47 (6) 254 (31) 238 (29) 1458 (4–4341)
Those remaining significant after the correction for multiple comparisons are indicated in bold. a p values are for univariate, comparisons between unprovoked sleep-deprived and nonsleep-deprived patients.
124
N. Lawn et al. / Epilepsy & Behavior 33 (2014) 122–125 100 Cumulative probability seizure recurrence at 1 year
90
.9
Percentage (±95%CI)
Cumulative probability of second seizure
1
.8 .7
unprovoked (not sleep deprived)
.6 unprovoked (sleep deprived)
.5 .4
provoked
.3
Sleep Deprived
80
Not sleep deprived
70 60 50 40 30 20 10
.2
0 ALL SEIZURE TYPES
Partial Seizure
Generalised Seizure
Unclassified Seizure
Seizure type
.1 0 0
365
730
1095
1460
1825
2190
2555
Days since first seizure presentation Fig. 1. Cumulative probability of unprovoked seizure recurrence in sleep-deprived and nonsleep-deprived patients with first-ever unprovoked seizures and in patients with provoked seizures non-sleep deprivation.
likelihood of any seizure recurrence following a provoked seizure was markedly lower than that following an unprovoked seizure (Fig. 1), including those unprovoked seizures associated with sleep deprivation, overall (log-rank p b 0.0001) and for etiological subgroups. Exclusion of patients with second seizures that were provoked did not alter these findings. 4. Discussion Sleep deprivation had little or no influence on the likelihood of seizure recurrence after a first unprovoked seizure, and it is not an independent predictor of seizure recurrence. Unprovoked seizures associated with sleep deprivation have a markedly higher likelihood of recurrence when compared with seizures provoked by a clearly defined proximate cause. Therefore, our findings support the ILAE recommendation that seizures occurring in the setting of sleep deprivation should not be regarded as provoked. The definition and classification of provoked seizures are evolving [7,8]. Our data are consistent with sleep deprivation being a nonspecific “trigger” rather than a specific provoker of a seizure. Incorrectly defining a sleep-deprived seizure as provoked may have significant ramifications, most importantly underestimating the likelihood of seizure recurrence. The strength of our data is the prospective and systematic ascertainment of sleep deprivation in all patients with first-ever seizures prior to knowing the subsequent outcome, thereby minimizing any recall bias. Furthermore, most recurrences in patients in whom the first seizure was associated with sleep deprivation were not sleep deprived. Studies which have attempted to differentiate between total and partial sleep deprivation (24 or more hours of sleep loss versus shorter
Fig. 2. Cumulative probability of seizure recurrence in sleep-deprived and nonsleepdeprived patients with first-ever unprovoked seizures according to seizure type.
periods of sleep loss) have not shown definite clinical differences or effects on EEG [9]. We have used a pragmatic definition of sleep deprivation as a significant and unusual lack of sleep for that patient rather than total sleep deprivation for the 24 hours prior to the seizure, so we are unable to determine whether sleep deprivation has a dose–response effect or not. Other definitions are unlikely to adequately encompass the uniquely variable effects of sleep deprivation [10].
5. Conclusion Seizures occurring in the setting of sleep deprivation should be considered unprovoked. Counseling and management decisions for patients with first-ever seizures should be directed by established risk factors for recurrence rather than an association with sleep deprivation. Driving restrictions should not be altered on the assumption that a sleep deprived seizure is provoked. Conflict of Interest The authors declare no conflict of interest.
Author contributions Dr. Lawn — study concept and design, acquisition of data, analysis and interpretation, drafted and revised manuscript, study supervision. Dr. Lieblich — acquisition of data, analysis and interpretation, critical revision of the manuscript for important intellectual content. Judy Lee — acquisition of data, analysis and interpretation. Dr. Dunne — study concept and design, acquisition of data, analysis and interpretation, critical revision of the manuscript for important intellectual content, statistical analyses.
Table 2 Seizure recurrence. p valuea
Unprovoked N = 1026
Cumulative probability of seizure recurrence % (95% CI) One year Two years Five years Mean time to seizure recurrence, days (range) Second seizure unprovoked and sleep-deprived n (%) a
Sleep-deprived (n = 204)
Nonsleep-deprived (n = 822)
43 (36–50) 50 (43–57) 58 (50–66) 298 (1–2750) 21 of 72 (29)
49 (46–53) 56 (53–60) 64 (60–68) 279 (1–3291) 19 of 357 (5)
p values are for univariate comparisons between unprovoked sleep-deprived and nonsleep-deprived patients.
ns b0.0001
Provoked N = 174
27 (21–34) 31 (24–38) 34 (26–41) 246 (1–3302)
N. Lawn et al. / Epilepsy & Behavior 33 (2014) 122–125
Acknowledgments Funding for the establishment and maintenance of the first-seizure database in the form of a grant to cover the costs of a research assistant was received from the Medical Research Foundation of Royal Perth Hospital and UCB Pharma. References [1] Commission on Epidemiology and Prognosis, International League Against Epilepsy. Guidelines for epidemiologic studies on epilepsy. Epilepsia 1993;34:592–6. [2] Kho LK, Lawn ND, Dunne JW, Linto J. First seizure presentation: do multiple seizures within 24 hours predict recurrence? Neurology 2006;67:1047–9. [3] Lawn ND, Kelly A, Dunne J, Lee J, Wesseldine A. First seizure in the older patient: clinical features and prognosis. Epilepsy Res 2013;107:109–14.
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