Multimodal nocturnal seizure detection: Do we need to adapt algorithms for children?

OBJECTIVE: To assess the performance of a multimodal seizure detection device, first tested in adults (sensitivity 86%, PPV 49%), in a pediatric cohort living at home or residential care. METHODS: In this multicenter, prospective, video-controlled cohort-study, nocturnal seizures were detected by heartrate and movement changes in children with epilepsy and intellectual disability. Participants with a history of >1 monthly major motor seizure wore Nightwatch bracelet at night for 3 months. Major seizures were defined as tonic-clonic, generalized tonic >30 s, hyperkinetic, or clusters (>30 min) of short myoclonic or tonic seizures. The video of all events (alarms and nurse diaries) and about 10% of whole nights were reviewed to classify major seizures, and minor or no seizures. RESULTS: Twenty-three participants with focal or generalized epilepsy and nightly motor seizures were evaluated during 1511 nights, with 1710 major seizures. First 1014 nights, 4189 alarms occurred with average of 1.44/h, showing average sensitivity of 79.9% (median 75.4%) with mean PPV of 26.7% (median 11.1%) and false alarm rate of 0.2/hour. Over 90% of false alarms in children was due to heart rate (HR) part of the detection algorithm. To improve this rate, an adaptation was made such that the alarm was only triggered when the wearer was in horizontal position. For the remaining 497 nights, this was tested prospectively, 384 major seizures occurred. This resulted in mean PPV of 55.5% (median 58.1%) and a false alarm rate 0.08/h while maintaining a comparable mean sensitivity of 79.4% (median 93.2%). SIGNIFICANCE: Seizure detection devices that are used in bed which depend on heartrate and movement show similar sensitivity in children and adults. However, children do show general higher false alarm rate, mostly triggered while awake. By correcting for body position, the false alarms can be limited to a level that comes close to that in adults.

Multimodal nocturnal seizure detection in a residential care setting: A long-term prospective trial.

OBJECTIVE: To develop and prospectively evaluate a method of epileptic seizure detection combining heart rate and movement. METHODS: In this multicenter, in-home, prospective, video-controlled cohort study, nocturnal seizures were detected by heart rate (photoplethysmography) or movement (3-D accelerometry) in persons with epilepsy and intellectual disability. Participants with >1 monthly major seizure wore a bracelet (Nightwatch) on the upper arm at night for 2 to 3 months. Major seizures were tonic-clonic, generalized tonic >30 seconds, hyperkinetic, or others, including clusters (>30 minutes) of short myoclonic/tonic seizures. The video of all events (alarms, nurse diaries) and 10% completely screened nights were reviewed to classify major (needing an alarm), minor (needing no alarm), or no seizure. Reliability was tested by interobserver agreement. We determined device performance, compared it to a bed sensor (Emfit), and evaluated the caregivers' user experience. RESULTS: Twenty-eight of 34 admitted participants (1,826 nights, 809 major seizures) completed the study. Interobserver agreement (major/no major seizures) was 0.77 (95% confidence interval [CI] 0.65-0.89). Median sensitivity per participant amounted to 86% (95% CI 77%-93%); the false-negative alarm rate was 0.03 per night (95% CI 0.01-0.05); and the positive predictive value was 49% (95% CI 33%-64%). The multimodal sensor showed a better sensitivity than the bed sensor (n = 14, median difference 58%, 95% CI 39%-80%, p < 0.001). The caregivers' questionnaire (n = 33) indicated good sensor acceptance and usability according to 28 and 27 participants, respectively. CONCLUSION: Combining heart rate and movement resulted in reliable detection of a broad range of nocturnal seizures.

Safety and efficiency of medication withdrawal at home prior to long-term EEG video-monitoring.

PURPOSE: Long-term video-EEG monitoring (LTM) is frequently used for diagnostic purposes and in the workup of epilepsy surgery to determine the seizure onset zone. Different strategies are applied to provoke seizures during LTM, of which withdrawal of anti-epileptic drugs (AED) is most effective. Remarkably, there is no standardized manner of AED withdrawal. For instance, the majority of clinics taper medication during clinical admission, whereas we prefer to taper medication at home prior to admission. Our aim was to study the advantages (efficiency and diagnostic yield) and disadvantages (safety and complication rates) of predominantly tapering of medication at home. METHOD: We report a retrospective observational cohort of 273 patients who had a LTM at our tertiary epilepsy center from 2005 until 2011. Provocation methods to induce seizures were determined on individual basis. Success rate (duration of admittance, time to first seizure, efficiency and diagnostic yield) and complications and serious adverse events were assessed. RESULTS: AED were tapered in 180 (66%) patients, in 93 (24%) of these patients with additional (partial) sleep deprivation. In all of these patients tapering started at home one to four weeks prior to admission. In the other patients, only (partial) sleep deprivation or none provocation method at all was applied. Seizure recordings were successful in 79,9% of patients. Complications occurred in 19 patients (10.9%) of which 3 had (1.7%) serious adverse events (status epilepticus (SE)) with AED withdrawal. These complications only occurred during admittance, not at home. CONCLUSIONS: AED withdrawal at home prior to LTM is an efficient and convenient method to increase the diagnostic yield of LTM and appears relatively safe.

Morningness and eveningness: when do patients take their antiepileptic drugs?

Almost one-third of epilepsy patients continue to have seizures despite adequate drug treatment. Chronotherapy (based on dynamic changes in drug pharmacology and disease-related processes) could be a promising treatment option. We aimed to explore whether different circadian types adjust administration times of anti-epileptic drugs (AEDs) as a step in exploring chronotherapeutic possibilities. We performed a questionnaire-based study to compare behavior of different circadian types in relation to times of taking drugs. Circadian type was determined by the Morningness-Eveningness Questionnaire. Results clearly show that morning types are taking their AEDs significantly earlier than do evening types on free days. Times of taking AEDs in the morning on work days also differ significantly between morning and evening types. Regardless of circadian type, drugs on free days are taken later than on working days. In conclusion, our study shows that patients adapt times of taking medication to their circadian type.

Timing of temporal and frontal seizures in relation to the circadian phase: a prospective pilot study.

There is strong evidence that epileptic seizures occur in diurnal or 24-h patterns. A study in rat models of partial epilepsy showed circadian seizure patterns, and in humans circadian rhythmicity in interictal discharges has been found, suggesting that circadian rhythm may play a role in epilepsy. Circadian influences on human seizure patterns have not been investigated. We performed a pilot study to ascertain influences of the circadian rhythm on seizure occurrence. We prospectively outlined circadian rhythms of patients admitted for long term EEG and video monitoring, using measurement of the dim light melatonin onset (DLMO). Seizures during admission were recorded with continuous EEG and video monitoring. The DLMO ranged from 18:46h to 23:13h (mean 21:22h). One hundred and twenty-four seizures of 21 patients were analysed. Seizures of temporal lobe origin occurred mainly between 11:00 and 17:00h and frontal seizures were seen mostly between 23:00 and 05:00h. When correlating seizure timing to the individual's circadian phase as measured by the DLMO, the following was seen: temporal seizures occurred most frequently in the 6h before DLMO and frontal seizures mainly in 6-12h after the DLMO. The results of this pilot study suggest that temporal and frontal seizures occur in a non-random fashion synchronized to a hormonal marker of the circadian timing system.

Chronotypes and subjective sleep parameters in epilepsy patients: a large questionnaire study.

Accumulating evidence suggests epilepsy and seizures may influence circadian rhythms and that circadian rhythms may influence epilepsy. It is also conceivable that seizure timing influences the timing of daily activities, sleeping, and wakefulness (i.e., chronotype). Only one group has studied the distribution of chronotypes of epileptics, showing significant differences between the diurnal activity patterns in two groups of patients with different epilepsy syndromes. The authors performed a questionnaire-based study of 200 epilepsy patients to compare the distribution of chronotypes and subjective sleep parameters of sleep duration and time of mid-sleep on free days to the distribution in the general population (n = 4042). Within this large group of epilepsy patients, we also compared the chronotypes of subsamples with well-defined epilepsy syndromes, i.e., temporal lobe epilepsy [TLE; n = 46], frontal lobe epilepsy [FLE; n = 30], and juvenile myoclonic epilepsy [JME; n = 38]. In addition, 27 patients who had had surgery for TLE were compared with those with TLE who had not had surgery. Both the Morningness-Eveningness Questionnaire and Munich Chronotype Questionnaire were used to determine chronotypes and subjective sleep parameters. Significant differences in morningness/eveningness distribution, timing of mid-sleep (corrected for sleep duration), and total sleep time on free days were found between epileptics and healthy controls. Those with epilepsy were more morning oriented, had earlier mid-sleep on free days, and longer sleep duration on free days (p < .001). However, distributions of chronotypes and sleep parameters between the groups of people with TLE, FLE, and JME did not differ. Persons who had surgery for TLE had similar morningness-eveningness parameters and similar sleep durations compared to those without surgery, but mid-sleep on free days was earlier in operated patients (p = .039). In conclusion, this is the first large study focusing on chronotypes in people with epilepsy. We show that the distribution of chronotypes and subjective sleep parameters of epileptics, in general, is different from that of healthy controls. Nevertheless, no differences are observed between patients with specified epilepsy syndromes, although they exhibit seizures with different diurnal patterns. Our results suggest that epilepsy, itself, rather than seizure timing, has a significant influence on chronotype behavior and subjective sleep parameters.

Wnt2 regulates progenitor proliferation in the developing ventral midbrain.

Wnts are secreted, lipidated proteins that regulate multiple aspects of brain development, including dopaminergic neuron development. In this study, we perform the first purification and signaling analysis of Wnt2 and define the function of Wnt2 in ventral midbrain precursor cultures, as well as in Wnt2-null mice in vivo. We found that purified Wnt2 induces the phosphorylation of both Lrp5/6 and Dvl-2/3, and activates beta-catenin in SN4741 dopaminergic cells. Moreover, purified Wnt2 increases progenitor proliferation, and the number of dopaminergic neurons in ventral midbrain precursor cultures. In agreement with these findings, analysis of the ventral midbrain of developing Wnt2-null mice revealed a decrease in progenitor proliferation and neurogenesis that lead to a decrease in the number of postmitotic precursors and dopaminergic neurons. Collectively, our observations identify Wnt2 as a novel regulator of dopaminergic progenitors and dopaminergic neuron development.

Diurnal rhythms in seizures detected by intracranial electrocorticographic monitoring: an observational study.

Few studies have evaluated human seizure occurrence over the 24-hour day, and only one group has employed intracranial electrocorticography monitoring to record seizures. Circadian patterns in seizures may have important implications in diagnosis and therapy and provide opportunities in research. We have analyzed spontaneous seizures in 33 consecutive patients with long-term intracranial EEG and video monitoring. Several aspects of seizures were noted, including time of day, origin, type, and behavioral state (sleeping/awake). We recorded 450 seizures that showed an uneven distribution over the day, depending on lobe of origin: temporal lobe seizures occurred preferentially between 1100 and 1700 hours, frontal seizures between 2300 and 0500 hours, and parietal seizures between 1700 and 2300 hours. In the awake state, larger proportions of clinical seizures were seen from 0500 to 1100 hours and from 1700 to 2300 hours. During sleep, larger proportions occurred from 1100 to 1700 hours and from 2300 to 0500 hours. Our results suggest that seizures from different brain regions have a strong tendency to occur in different diurnal patterns.

The circadian rhythm and its interaction with human epilepsy: a review of literature.

Knowledge on the interaction between circadian rhythm and human epilepsy is relatively poor, although if it exists, this interaction may be of value for better knowledge of pathophysiology and for timing of diagnostic procedures and therapy. It appears that human seizure occurrence may have 24-h rhythmicity, depending on the origin. These findings are endorsed by animal studies. Rats placed in constant darkness showed spontaneous limbic seizures occurring in an endogenously mediated circadian pattern. More studies are available on the influence of epilepsy on circadian rhythms. Significant differences in chronotypes between patients with different epilepsy syndromes have been found and numerous studies have described influences of epilepsy and seizures on sleep. In contrast, knowledge on (core) body temperature and clock genes in patients is minimal. Reduced heart rate variability and changed hormone levels, which are under the influence of the biological clock, have been observed in people with epilepsy. In short, large gaps in the knowledge about the interaction of circadian rhythm and human epilepsy still remain. Proposals for studies in this borderline area between the biological clock and epilepsy will be discussed.

Temporal distribution of clinical seizures over the 24-h day: a retrospective observational study in a tertiary epilepsy clinic.

PURPOSE: Very few studies have evaluated seizure occurrence in humans over the 24-h day; data from children are particularly scarce. Circadian patterns in seizure occurrence may be of importance in epilepsy research and may have important implications in diagnosis and therapy. METHODS: We have analyzed clinical seizures of 176 consecutive patients (76 children, 100 adults) who had continuous electroencephalography (EEG) and video monitoring lasting more than 22 h. Several aspects of seizures were noted, including classification, time of day, origin, and sleep stage. RESULTS: More than 800 seizures were recorded. Significantly more seizures were observed from 11:00 to 17:00 h, and from 23:00 to 05:00 h significantly fewer seizures were seen. The daytime peak incidences were observed in seizures overall, complex partial seizures (in children and adults), seizures of extratemporal origin (in children), and seizures of temporal origin (in adults). Incidences significantly lower than expected were seen in the period 23:00 to 05:00 h in seizures overall, complex partial seizures (in children and adults), and in tonic seizures (in children). In addition, significantly fewer seizures of temporal (in children and adults) and extratemporal origin (in children) were observed in this period. DISCUSSION: The results suggest that certain types of seizures have a strong tendency to occur in true diurnal patterns. These patterns are characterized by a peak during midday and a low in the early night.

How to assess circadian rhythm in humans: a review of literature.

It is well known that seizures of some types of epilepsy tend to occur in patterns. The circadian rhythm may play a significant role in this phenomenon. In animal studies it has been found that seizures in experimental partial epilepsy are probably under the influence of the biological clock. In this review an introduction to the influence of the human circadian rhythm in epilepsy is given. Furthermore, the methodology of measuring the circadian rhythm in humans is explored. An overview of widely used methods includes protocols used to desynchronize circadian rhythm, and sleep-wake and biological markers such as the dim light melatonin onset, core body temperature, and cortisol that are employed to determine the phase of the circadian rhythm. Finally, the use of sleep parameters, actigraphy, and questionnaires is discussed. These are also important in assessment of the circadian rhythm.