State of the art and new directions of Quantitative Electroencephalography use in Differential Diagnosis of ADHD / Estado de la cuestión y uso de la electroencefalografía cuantitativa en el diagnóstico diferencial del TDAH

Advances in technology in recent years have made the use of quantitative electroencephalogram more accessible to clinicians. The incorporation ofnormative databases in QEEG studies and the possibility of detecting different electroencephalographic patterns in patients with a given pathology,despite showing an apparent symptomatology homogeneity, make it an interesting source of information. The relationship of these patterns with apossible response to treatment or with prognostic estimates would justify its inclusion as a routine test in the process of the differential diagnosisof ADHD. In this paper, we present the possible benefits of the use of QEEG in the differential diagnosis of ADHD, the different electroencephalographic patterns associated with ADHD most common in the literature, and a case showcasing the use of the technique in a patient with ADHD. (AU)

El avance de la tecnología en los últimos años ha hecho que el uso del electroencefalograma cuantitativo sea más accesible a los clínicos. La incorporación de bases de datos normativas enlos estudios de QEEG y la posibilidad de detectar diferentes patrones electroencefalográficos en pacientes con una patología determinada, a pesarde mostrar una aparente homogeneidad sintomatológica, hacen que sea una fuente de información interesante. La relación de estos patrones conuna posible respuesta a tratamientos o con estimaciones pronósticas justificarían su inclusión como prueba rutinaria en el proceso de diagnósticodiferencial del TDAH. En este trabajo se presentan los posibles beneficios del uso del QEEG en el diagnóstico diferencial del TDAH, los diferentespatrones electroencefalográficos asociados al TDAH más comunes en la literatura y un caso ilustrativo del uso de la técnica en un paciente con TDAH. (AU)

EEG patterns and their correlations with short- and long-term mortality in patients with hypoxic encephalopathy.

OBJECTIVE: To analyze the association between electroencephalographic (EEG) patterns and overall, short- and long-term mortality in patients with hypoxic encephalopathy (HE). METHODS: Retrospective, mono-center analysis of 199 patients using univariate log-rank tests (LR) and multivariate cox regression (MCR). RESULTS: Short-term mortality, defined as death within 30-days post-discharge was 54.8%. Long-term mortality rates were 69.8%, 71.9%, and 72.9%, at 12-, 24-, and 36-months post-HE, respectively. LR revealed a significant association between EEG suppression (SUP) and short-term mortality, and identified low voltage EEG (LV), burst suppression (BSP), periodic discharges (PD) and post-hypoxic status epilepticus (PSE) as well as missing (aBA) or non-reactive background activity (nrBA) as predictors for overall, short- and long-term mortality. MCR indicated SUP, LV, BSP, PD, aBA and nrBA as significantly associated with overall and short-term mortality to varying extents. LV and BSP were significant predictors for long-term mortality in short-term survivors. Rhythmic delta activity, stimulus induced rhythmic, periodic or ictal discharges and sharp waves were not significantly associated with a higher mortality. CONCLUSION: The presence of several specific EEG patterns can help to predict overall, short- and long-term mortality in HE patients. SIGNIFICANCE: The present findings may help to improve the challenging prognosis estimation in HE patients.

Diagnostic contribution and therapeutic perspectives of transcranial magnetic stimulation in dementia.

Transcranial magnetic stimulation (TMS) is a powerful tool to probe in vivo brain circuits, as it allows to assess several cortical properties such asexcitability, plasticity and connectivity in humans. In the last 20 years, TMS has been applied to patients with dementia, enabling the identification of potential markers of thepathophysiology and predictors of cognitive decline; moreover, applied repetitively, TMS holds promise as a potential therapeutic intervention. The objective of this paper is to present a comprehensive review of studies that have employed TMS in dementia and to discuss potential clinical applications, from the diagnosis to the treatment. To provide a technical and theoretical framework, we first present an overview of the basic physiological mechanisms of the application of TMS to assess cortical excitability, excitation and inhibition balance, mechanisms of plasticity and cortico-cortical connectivity in the human brain. We then review the insights gained by TMS techniques into the pathophysiology and predictors of progression and response to treatment in dementias, including Alzheimer's disease (AD)-related dementias and secondary dementias. We show that while a single TMS measure offers low specificity, the use of a panel of measures and/or neurophysiological index can support the clinical diagnosis and predict progression. In the last part of the article, we discuss the therapeutic uses of TMS. So far, only repetitive TMS (rTMS) over the left dorsolateral prefrontal cortex and multisite rTMS associated with cognitive training have been shown to be, respectively, possibly (Level C of evidence) and probably (Level B of evidence) effective to improve cognition, apathy, memory, and language in AD patients, especially at a mild/early stage of the disease. The clinical use of this type of treatment warrants the combination of brain imaging techniques and/or electrophysiological tools to elucidate neurobiological effects of neurostimulation and to optimally tailor rTMS treatment protocols in individual patients or specific patient subgroups with dementia or mild cognitive impairment.

Variation in perioperative cerebral and hemodynamic monitoring during carotid endarterectomy.

BACKGROUND: Hemodynamic disturbances cause half of the perioperative strokes following carotid endarterectomy (CEA). Guidelines strongly recommend strict pre- and postoperative blood pressure (BP) monitoring in CEA patients, but do not provide firm practical recommendations. Although in the Netherlands 50 centres perform CEA, no national protocol on perioperative hemodynamic, and cerebral monitoring exists. To assess current monitoring policies of all Dutch CEA-centres, a national survey was conducted. METHODS: Between May and July 2017 all 50 Dutch CEA-centres were invited to complete a 42-question survey addressing perioperative hemodynamic and cerebral monitoring during CEA. Nonresponders received a reminder after 1 and 2 months. By November 2017 the survey was completed by all centres. RESULTS: Preoperative baseline BP was based on a single bilateral BP-measurement at the outpatient-clinic in the majority of centres (n = 28). In 43 centres (86%) pre-operative monitoring (transcranial Doppler (TCD, n = 6), electroencephalography (EEG, n = 11), or TCD + EEG (n = 26)) was performed as a baseline reference. Intraoperatively, large diversity for type of anaesthesia (general: 45 vs. local [LA]:5) and target systolic BP (>100 mm hg - 160 mm hg [n = 12], based on preoperative outpatient-clinic or admission BP [n = 18], other [n = 20]) was reported. Intraoperative cerebral monitoring included EEG + TCD (n = 28), EEG alone (n = 13), clinical neurological examination with LA (n = 5), near-infrared spectroscopy with stump pressure (n = 1), and none due to standard shunting (n = 3). Postoperatively, significant variation was reported in standard duration of admission at a recovery or high-care unit (range 3-48 hr, mean:12 hr), maximum accepted systolic BP (range >100 mm hg - 180 mm Hg [n = 32]), postoperative cerebral monitoring (standard TCD [n = 16], TCD on indication [n = 5] or none [n = 24]) and in timing of postoperative cerebral monitoring (range directly postoperative - 24 hr postoperative; median 3 hr). CONCLUSIONS: In Dutch centres performing CEA the perioperative hemodynamic and cerebral monitoring policies are widely diverse. Diverse policies may theoretically lead to over- or under treatment. The results of this national audit may serve as the baseline dataset for development of a standardized and detailed (inter)national protocol on perioperative hemodynamic and cerebral monitoring during CEA.

Use of Stereoelectroencephalography Beyond Epilepsy: A Systematic Review.

BACKGROUND: Stereoelectroencephalography (sEEG) is an increasingly popular surgical technique used clinically to study neural circuits involved in medication-refractory epilepsy, and it is concomitantly used in the scientific investigation of neural circuitry underlying behavior. METHODS: Using PRISMA guidelines, the U.S. National Library of Medicine at the National Institutes of Health PubMed database was queried for investigational or therapeutic applications of sEEG in human subjects. Abstracts were analyzed independently by 2 authors for inclusion or exclusion. RESULTS: The study search identified 752 articles, and after exclusion criteria were applied, 8 studies were selected for in-depth review. Among those 8 studies, 122 patients were included, with indications ranging from schizophrenia to Parkinson disease. All the included studies were single-institution case series representing level IV scientific evidence. CONCLUSIONS: sEEG is an important method in epilepsy surgery that could be applied to other neurologic and psychiatric diseases. Information from these studies could provide additional pathophysiologic information and lead to further development and refinement of neuromodulation therapies for such conditions.

Age-dependent cross frequency coupling features from children to adults during general anesthesia.

BACKGROUND: The frequency coupling characteristics in electroencephalogram (EEG) induced by anesthetics have been well studied in adults, but the investigation of the age-dependent cross frequency coupling features from children to adults is still lacking. METHODS: We analyzed EEG signals recorded from pediatric to adult patients (n = 131), separated into six age groups: <1 year (n = 15), 1-3 years (n = 23), 3-6 years (n = 19), 6-12 years (n = 18), 12-18 years (n = 16), and 18-45 years (n = 40). Age related EEG power and cross frequency coupling analysis (phase amplitude coupling (PAC) and quadratic phase coupling) of data from maintenance of a surgical state of anesthesia (MOSSA) was conducted. Also, for patients of ages less than 6 years, we analyzed the performance of cross frequency coupling derived indices in distinguishing the states of wakefulness, MOSSA, and recovery of consciousness (ROC). RESULTS: (1) During MOSSA, EEG power substantially increased with age from infancy to 3-6 years then decreased with age in the theta-gamma frequency bands. The infant group (<1 year) had the highest slow oscillation (SO) power among all age groups. (2) The distinct PAC pattern is absent in patients less than 1 year of age both in SO-alpha and delta-alpha frequency band coupling during propofol induced unconsciousness. The modulation index between delta and alpha oscillations in MOSSA increased with age. (3) Wavelet bicoherence derived indices reach their peaks in the 3-6 years group and then decrease with age growth. (4) The Diag_En index (normalized entropy of the diagonal bicoherence entries of the bicoherence matrix) performed the best at distinguishing different states for ages less than 6 years (p<0.05). CONCLUSIONS: The combination of propofol induction and sevoflurane maintenance exhibited age-dependent EEG power spectra, PAC, and bicoherence, likely related to brain development. These observations suggest new rules for infant and child brain state monitoring during general anesthesia are needed.

Prognostic value of neonatal EEG following therapeutic hypothermia in survivors of hypoxic-ischemic encephalopathy.

OBJECTIVE: Early prediction of neurological deficits following neonatal hypoxic-ischemic encephalopathy (HIE) may help to target support. Neonatal animal models suggest that recovery following hypoxia-ischemia depends upon cortical bursting. To test whether this holds in human neonates, we correlated the magnitude of cortical bursting during recovery (≥postnatal day 3) with neurodevelopmental outcomes. METHODS: We identified 41 surviving infants who received therapeutic hypothermia for HIE (classification at hospital discharge: 19 mild, 18 moderate, 4 severe) and had 9-channel electroencephalography (EEG) recordings as part of their routine care. We correlated burst power with Bayley-III cognitive, motor and language scores at median 24 months. To examine whether EEG offered additional prognostic information, we controlled for structural MRI findings. RESULTS: Higher power of central and occipital cortical bursts predicted worse cognitive and language outcomes, and higher power of central cortical bursts predicted worse motor outcome, all independently of structural MRI findings. CONCLUSIONS: Clinical EEG after postnatal day 3 may provide additional prognostic information by indexing persistent active mechanisms that either support recovery or exacerbate brain damage, especially in infants with less severe encephalopathy. SIGNIFICANCE: These findings could allow for the effect of clinical interventions in the neonatal period to be studied instantaneously in the future.

Headache in people with epilepsy.

Epidemiological estimates indicate that individuals with epilepsy are more likely to experience headaches, including migraine, than individuals without epilepsy. Headaches can be temporally unrelated to seizures, or can occur before, during or after an episode; seizures and migraine attacks are mostly not temporally linked. The pathophysiological links between headaches (including migraine) and epilepsy are complex and have not yet been fully elucidated. Correct diagnoses and appropriate treatment of headaches in individuals with epilepsy is essential, as headaches can contribute substantially to disease burden. Here, we review the insights that have been made into the associations between headache and epilepsy over the past 5 years, including information on the pathophysiological mechanisms and genetic variants that link the two disorders. We also discuss the current best practice for the management of headaches co-occurring with epilepsy and highlight future challenges for this area of research.

Source imaging of seizure onset predicts surgical outcome in pediatric epilepsy.

OBJECTIVE: To assess whether ictal electric source imaging (ESI) on low-density scalp EEG can approximate the seizure onset zone (SOZ) location and predict surgical outcome in children with refractory epilepsy undergoing surgery. METHODS: We examined 35 children with refractory epilepsy. We dichotomized surgical outcome into seizure- and non-seizure-free. We identified ictal onsets recorded with scalp and intracranial EEG and localized them using equivalent current dipoles and standardized low-resolution magnetic tomography (sLORETA). We estimated the localization accuracy of scalp EEG as distance of scalp dipoles from intracranial dipoles. We also calculated the distances of scalp dipoles from resection, as well as their resection percentage and compared between seizure-free and non-seizure-free patients. We built receiver operating characteristic curves to test whether resection percentage predicted outcome. RESULTS: Resection distance was lower in seizure-free patients for both dipoles (p = 0.006) and sLORETA (p = 0.04). Resection percentage predicted outcome with a sensitivity of 57.1% (95% CI, 34-78.2%), a specificity of 85.7% (95% CI, 57.2-98.2%) and an accuracy of 68.6% (95% CI, 50.7-83.5%) (p = 0.01). CONCLUSION: Ictal ESI performed on low-density scalp EEG can delineate the SOZ and predict outcome. SIGNIFICANCE: Such an application may increase the number of children who are referred for epilepsy surgery and improve their outcome.

Recent Advances in Neuroimaging of Epilepsy.

Human neuroimaging has had a major impact on the biological understanding of epilepsy and the relationship between pathophysiology, seizure management, and outcomes. This review highlights notable recent advancements in hardware, sequences, methods, analyses, and applications of human neuroimaging techniques utilized to assess epilepsy. These structural, functional, and metabolic assessments include magnetic resonance imaging (MRI), positron emission tomography (PET), and magnetoencephalography (MEG). Advancements that highlight non-invasive neuroimaging techniques used to study the whole brain are emphasized due to the advantages these provide in clinical and research applications. Thus, topics range across presurgical evaluations, understanding of epilepsy as a network disorder, and the interactions between epilepsy and comorbidities. New techniques and approaches are discussed which are expected to emerge into the mainstream within the next decade and impact our understanding of epilepsies. Further, an increasing breadth of investigations includes the interplay between epilepsy, mental health comorbidities, and aberrant brain networks. In the final section of this review, we focus on neuroimaging studies that assess bidirectional relationships between mental health comorbidities and epilepsy as a model for better understanding of the commonalities between both conditions.

Hippocampal and Orbitofrontal Theta Band Coherence Diminishes During Conflict Resolution.

OBJECTIVE: Coherence between the hippocampus and other brain structures has been shown with the theta frequency (3-8 Hz). Cortical decreases in theta coherence are believed to reflect response accuracy efficiency. However, the role of theta coherence during conflict resolution is poorly understood in noncortical areas. In this study, coherence between the hippocampus and orbitofrontal cortex (OFC) was measured during a conflict resolution task. Although both brain areas have been previously implicated in the Stroop task, their interactions are not well understood. METHODS: Nine patients were implanted with stereotactic electroencephalography contacts in the hippocampus and OFC. Local field potential data were sampled throughout discrete phases of a Stroop task. Coherence was calculated for hippocampal and OFC contact pairs, and coherence spectrograms were constructed for congruent and incongruent conditions. Coherence changes during cue processing were identified using a nonparametric cluster-permutation t test. Group analysis was conducted to compare overall theta coherence changes among conditions. RESULTS: In 6 of 9 patients, decreased theta coherence was observed only during the incongruent condition (P < 0.05). Congruent theta coherence did not change from baseline. Group analysis showed lower theta coherence for the incongruent condition compared with the congruent condition (P < 0.05). CONCLUSIONS: Theta coherence between the hippocampus and OFC decreased during conflict. This finding supports existing theories that theta coherence desynchronization contributes to improved response accuracy and processing efficiency during conflict resolution. The underlying theta coherence observed between the hippocampus and OFC during conflict may be distinct from its previously observed role in memory.

Ten year cumulative incidence of dementia after late onset epilepsy of unknown etiology.

Recent epidemiological studies suggest late life onset epilepsy of unknown etiology (LOEU) is a risk factor for future dementia. These studies rely on inclusion and exclusion of multiple diagnostic codes rather than structured data and neuroimaging findings, and thus challenging to interpret clinically. We assessed the cumulative incidence of dementia in patients with LOEU diagnosed through admission data and neuroimaging over a 10-year follow-up and compared baseline characteristics that distinguish group level incident dementia. We screened our hospital records for patients aged 55-69 with new epilepsy, admitted between 2000 and 2008, and excluded patients diagnosed with epilepsy from an underlying cause on medical records or neuroimaging. We used retrospective hospital data to follow patients for incident dementia or mortality at 10 years and compared baseline (demographics, depression or anxiety, vascular risk factors, results of electroencephalogram (EEG) studies, antidepressant use and type of ant seizure medication) and follow up (seizure recurrence, incident cerebrovascular disease) characteristics for patients with and without incident dementia. Fifty-four LOEU cases were screened, age at first seizure was 61 ± 5. The 10-year cumulative incidence of dementia was 22.20% (95% Confidence Interval 22.08-23.10%) and time to dementia diagnosis was 5.4 ± 3.9 years. Patients with incident dementia were more likely to be women (83% vs 38%, p = 0.002), have interictal epileptic form discharges (IED) on baseline EEG (70% vs 29%, p = 0.011) and depression or anxiety (50% vs 18%, p = 0.026). No differences were found in other baseline or follow up characteristics. Our results support recent findings of dementia incidence in LOEU. Prospective studies on LOEU should evaluate phenotypic determinants of individuals with late life epilepsy and the rate of progression to dementia.

Time course of cortical response complexity during extended wakefulness and its differential association with vigilance in young and older individuals.

Characterization of the complexity of electroencephalogram (EEG) responses has provided important insights in cognitive function as well as in the brain bases of consciousness and vigilance. Whether brain response complexity changes during prolonged wakefulness and sleep deprivation -when vigilance level considerably varies- is not fully elucidated yet. In the present study, we repeatedly assessed EEG responses to transcranial magnetic stimulation (TMS) over 34 h of sleep deprivation under constant routine conditions in healthy younger (N = 13; 5 women; 18-30 y) and older (N = 12; 6 women; 50-70 y) individuals, while they were performing a vigilance task. Response complexity was computed both at the global (all scalp sensors) and local (sensors surrounding TMS hotspot) levels using the Lempel-Ziv algorithm. Response complexity was significantly higher in the older compared to the young volunteers over the entire protocol. Global complexity response significantly changed with time spent awake, with an increasing trend from the beginning to the middle of the biological night, followed by a decreasing trend from the middle of the biological night to the following afternoon. An unexpected different link between vigilance performance and brain response complexity was detected across age groups: higher response complexity was associated with lower performance in the older group, particularly in the morning sessions. These findings show that cortical activity complexity changes with vigilance variation, as experienced during sleep deprivation and circadian misalignment, in two age groups, with no evident time course difference across age-groups. Aside from classical linear EEG analyses, computation of Lempel-Ziv complexity provides additional insights on the neurophysiology of the processes associated with vigilance and their modifications throughout ageing.

Long-term Home Video EEG for Recording Clinical Events.

SUMMARY: Around 50 years after the first EEG acquisition by Hans Berger, its use in ambulatory setting was demonstrated. Ever since, ambulatory EEG has been widely available and routinely used in the United States (and to a lesser extent in Europe) for diagnosis and management of patients with epilepsy. This technology alone cannot help with semiological characterization, and absence of video is one of its main drawbacks. Addition of video to ambulatory EEG potentially improves diagnostic yield and opens new aspects of utility for better characterization of patient's events, including differential diagnosis, classification, and quantification of seizure burden. Studies evaluating quality of ambulatory video EEG (aVEEG) suggest good quality recordings are feasible. In the utilization of aVEEG, to maximize yield, it is important to consider pretest probability. Having clear pretest questions and a strong index of suspicion for focal, generalized convulsive or non-epileptic seizures further increases the usefulness of aVEEG. In this article, which is part of the topical issue "Ambulatory EEG," the authors compare long-term home aVEEG to inpatient video EEG monitoring, discuss aVEEG's use in diagnosis and follow-up of patients, and present the authors' own experience of the utility of aVEEG in a teaching hospital setting.

Ambulatory EEG Usefulness in Epilepsy Management.

SUMMARY: Long-term video-EEG monitoring has been the gold standard for diagnosis of epileptic and nonepileptic events. Medication changes, safety, and a lack of recording EEG in one's habitual environment may interfere with diagnostic representation and subsequently affect management. Some spells defy standard EEG because of ultradian and circadian times of occurrence, manifest nocturnal expression of epileptiform activity, and require classification for clarifying diagnostic input to identify optimal treatment. Some patients may be unaware of seizures, have frequent events, or subclinical seizures that require quantification before optimal management. The influence on antiseizure drug management and clinical drug research can be enlightened by long-term outpatient ambulatory EEG monitoring. With recent governmental shifts to focus on mobile health, ambulatory EEG monitoring has grown beyond diagnostic capabilities to target the dynamic effects of medical and nonmedical treatment for patients with epilepsy in their natural environment. Furthermore, newer applications in ambulatory monitoring include additional physiologic parameters (e.g., sleep, detection of myogenic signals, etc.) and extend treatment relevance to patients beyond seizure reduction alone addressing comorbid conditions. It is with this focus in mind that we direct our discussion on the present and future aspects of using ambulatory EEG monitoring in the treatment of patients with epilepsy.

High-Density EEG in Current Clinical Practice and Opportunities for the Future.

SUMMARY: High-density EEG (HD-EEG) recordings use a higher spatial sampling of scalp electrodes than a standard 10-20 low-density EEG montage. Although several studies have demonstrated improved localization of the epileptogenic cortex using HD-EEG, widespread implementation is impeded by cost, setup and interpretation time, and lack of specific or sufficient procedural billing codes. Despite these barriers, HD-EEG has been in use at several institutions for years. These centers have noted utility in a variety of clinical scenarios where increased spatial resolution from HD-EEG has been required, justifying the extra time and cost. We share select scenarios from several centers, using different recording techniques and software, where HD-EEG provided information above and beyond the standard low-density EEG. We include seven cases where HD-EEG contributed directly to current clinical care of epilepsy patients and highlight two novel techniques which suggest potential opportunities to improve future clinical care. Cases illustrate how HD-EEG allows clinicians to: case 1-lateralize falsely generalized interictal epileptiform discharges; case 2-improve localization of falsely generalized epileptic spasms; cases 3 and 4-improve localization of interictal epileptiform discharges in anatomic regions below the circumferential limit of standard low-density EEG coverage; case 5-improve noninvasive localization of the seizure onset zone in lesional epilepsy; cases 6 and 7-improve localization of the seizure onset zone to guide invasive investigation near eloquent cortex; case 8-identify epileptic fast oscillations; and case 9-map language cortex. Together, these nine cases illustrate that using both visual analysis and advanced techniques, HD-EEG can play an important role in clinical management.

Electroencephalographic Abnormalities are Common in COVID-19 and are Associated with Outcomes.

OBJECTIVE: The aim was to determine the prevalence and risk factors for electrographic seizures and other electroencephalographic (EEG) patterns in patients with Coronavirus disease 2019 (COVID-19) undergoing clinically indicated continuous electroencephalogram (cEEG) monitoring and to assess whether EEG findings are associated with outcomes. METHODS: We identified 197 patients with COVID-19 referred for cEEG at 9 participating centers. Medical records and EEG reports were reviewed retrospectively to determine the incidence of and clinical risk factors for seizures and other epileptiform patterns. Multivariate Cox proportional hazards analysis assessed the relationship between EEG patterns and clinical outcomes. RESULTS: Electrographic seizures were detected in 19 (9.6%) patients, including nonconvulsive status epilepticus (NCSE) in 11 (5.6%). Epileptiform abnormalities (either ictal or interictal) were present in 96 (48.7%). Preceding clinical seizures during hospitalization were associated with both electrographic seizures (36.4% in those with vs 8.1% in those without prior clinical seizures, odds ratio [OR] 6.51, p = 0.01) and NCSE (27.3% vs 4.3%, OR 8.34, p = 0.01). A pre-existing intracranial lesion on neuroimaging was associated with NCSE (14.3% vs 3.7%; OR 4.33, p = 0.02). In multivariate analysis of outcomes, electrographic seizures were an independent predictor of in-hospital mortality (hazard ratio [HR] 4.07 [1.44-11.51], p < 0.01). In competing risks analysis, hospital length of stay increased in the presence of NCSE (30 day proportion discharged with vs without NCSE: HR 0.21 [0.03-0.33] vs 0.43 [0.36-0.49]). INTERPRETATION: This multicenter retrospective cohort study demonstrates that seizures and other epileptiform abnormalities are common in patients with COVID-19 undergoing clinically indicated cEEG and are associated with adverse clinical outcomes. ANN NEUROL 2021;89:872-883.

Cycles in epilepsy.

Epilepsy is among the most dynamic disorders in neurology. A canonical view holds that seizures, the characteristic sign of epilepsy, occur at random, but, for centuries, humans have looked for patterns of temporal organization in seizure occurrence. Observations that seizures are cyclical date back to antiquity, but recent technological advances have, for the first time, enabled cycles of seizure occurrence to be quantitatively characterized with direct brain recordings. Chronic recordings of brain activity in humans and in animals have yielded converging evidence for the existence of cycles of epileptic brain activity that operate over diverse timescales: daily (circadian), multi-day (multidien) and yearly (circannual). Here, we review this evidence, synthesizing data from historical observational studies, modern implanted devices, electronic seizure diaries and laboratory-based animal neurophysiology. We discuss advances in our understanding of the mechanistic underpinnings of these cycles and highlight the knowledge gaps that remain. The potential clinical applications of a knowledge of cycles in epilepsy, including seizure forecasting and chronotherapy, are discussed in the context of the emerging concept of seizure risk. In essence, this Review addresses the broad question of why seizures occur when they occur.

Long-term seizure dynamics are determined by the nature of seizures and the mutual interactions between them.

The seemingly random and unpredictable nature of seizures is a major debilitating factor for people with epilepsy. An increasing body of evidence demonstrates that the epileptic brain exhibits long-term fluctuations in seizure susceptibility, and seizure emergence seems to be a consequence of processes operating over multiple temporal scales. A deeper insight into the mechanisms responsible for long-term seizure fluctuations may provide important information for understanding the complex nature of seizure genesis. In this study, we explored the long-term dynamics of seizures in the tetanus toxin model of temporal lobe epilepsy. The results demonstrate the existence of long-term fluctuations in seizure probability, where seizures form clusters in time and are then followed by seizure-free periods. Within each cluster, seizure distribution is non-Poissonian, as demonstrated by the progressively increasing inter-seizure interval (ISI), which marks the approaching cluster termination. The lengthening of ISIs is paralleled by: increasing behavioral seizure severity, the occurrence of convulsive seizures, recruitment of extra-hippocampal structures and the spread of electrographic epileptiform activity outside of the limbic system. The results suggest that repeated non-convulsive seizures obey the 'seizures-beget-seizures' principle, leading to the occurrence of convulsive seizures, which decrease the probability of a subsequent seizure and, thus, increase the following ISI. The cumulative effect of repeated convulsive seizures leads to cluster termination, followed by a long inter-cluster period. We propose that seizures themselves are an endogenous factor that contributes to long-term fluctuations in seizure susceptibility and their mutual interaction determines the future evolution of disease activity.

Twenty-four-hour patterns in electrodermal activity recordings of patients with and without epileptic seizures.

OBJECTIVE: Daytime and nighttime patterns affect the dynamic modulation of brain and body functions and influence the autonomic nervous system response to seizures. Therefore, we aimed to evaluate 24-hour patterns of electrodermal activity (EDA) in patients with and without seizures. METHODS: We included pediatric patients with (a) seizures (SZ), including focal impaired awareness seizures (FIAS) or generalized tonic-clonic seizures (GTCS), (b) no seizures and normal electroencephalography (NEEG), or (c) no seizures but epileptiform activity in the EEG (EA) during vEEG monitoring. Patients wore a device that continuously recorded EDA and temperature (TEMP). EDA levels, EDA spectral power, and TEMP levels were analyzed. To investigate 24-hour patterns, we performed a nonlinear mixed-effects model analysis. Relative mean pre-ictal (-30 min to seizure onset) and post-ictal (I: 30 min after seizure offset; II: 30 to 60 min after seizure offset) values were compared for SZ subgroups. RESULTS: We included 119 patients (40 SZ, 17 NEEG, 62 EA). EDA level and power group-specific models (SZ, NEEG, EA) (h = 1; P < .01) were superior to the all-patient cohort model. Fifty-nine seizures were analyzed. Pre-ictal EDA values were lower than respective 24-hour modulated SZ group values. Post hoc comparisons following the period-by-seizure type interaction (EDA level: χ2  = 18.50; P < .001, and power: χ2  = 6.73; P = .035) revealed that EDA levels were higher in the post-ictal period I for FIAS and GTCS and in post-ictal period II for GTCS only compared to the pre-ictal period. SIGNIFICANCE: Continuously monitored EDA shows a pattern of change over 24 hours. Curve amplitudes in patients with recorded seizures were lower as compared to patients who did not exhibit seizures during the recording period. Sympathetic skin responses were greater and more prolonged in GTCS compared to FIAS. EDA recordings from wearable devices offer a noninvasive tool to continuously monitor sympathetic activity with potential applications for seizure detection, prediction, and potentially sudden unexpected death in epilepsy (SUDEP) risk estimation.