Analysis of seizure-cluster circadian periodicity from a long-term, open-label safety study of diazepam nasal spray.

OBJECTIVE: Seizure clusters require prompt medical treatment to minimize possible progression to status epilepticus, increased health care use, and disruptions to daily life. Isolated seizures may exhibit cyclical patterns, including circadian and longer rhythms. However, little is known about the cyclical patterns in seizure clusters. This post hoc analysis of data from a long-term, phase 3, open-label, repeat-dose safety study of diazepam nasal spray modeled the periodicity of treated seizure clusters. METHODS: Mixed-effects cosinor analysis evaluated circadian rhythmicity, and single component cosinors using 12 and 24 h were used to calculate cosinor parameters (e.g., midline statistic of rhythm, wave ampitude, and acrophase [peak]). Analysis was completed for the full cohort and a consistent cohort of participants with two or more seizure clusters in each of four, 3-month periods. The influence of epilepsy type on cosinor parameters was also analyzed. RESULTS: Seizure-cluster events plotted across 24 h showed a bimodal distribution with acrophases (peaks) at ~06:30 and ~18:30. A 12-h plot showed a single peak at ~06:30. Cosinor analyses of the full and consistent cohort aligned, with acrophases for both models predicting peak seizure activity at ~23:30 on a 24-h scale and ~07:30 on a 12-h scale. The consistent cohort was associated with increases in baseline and peak seizure-cluster activity. Analysis by epilepsy type identified distinct trends. Seizure clusters in the focal epilepsy group peaked in the evening (acrophase 19:19), whereas events in the generalized epilepsy group peaked in the morning (acrophase 04:46). Together they compose the bimodal clustering observed over 24 h. SIGNIFICANCE: This analysis of seizure clusters treated with diazepam nasal spray demonstrated that seizure clusters occur cyclically in 12- and 24-h time frames similar to that reported with isolated seizures. Further elucidation of these patterns may provide important information for patient care, ranging from improved patient-centered outcomes to seizure-cluster prediction.

Multifocal hypometabolic correlates to deficits of verbal memory in mesial temporal lobe epilepsy.

BACKGROUND AND OBJECTIVES: Neuropsychological research on mesial temporal lobe epilepsy (MTLE) often highlights material-specific memory deficits, but a lesion-focused model may not accurately reflect the underlying networks that support episodic memory in these patients. Our study evaluated the pathophysiology behind verbal learning/memory deficits as revealed by hypometabolism quantified through 18-fluorodeoxyglucose positron emission tomography (FDG-PET). METHODS: This retrospective study included thirty presurgical patients with intractable unilateral MTLE who underwent interictal FDG-PET and verbal memory assessment (12 females, mean age: 38.73 years). Fluorodeoxyglucose-positron emission tomography mapping was performed with voxel-based mapping of glucose utilization to a database of age-matched controls to derive regional Z-scores. Neuropsychological outcome variables included scores on learning and recall trials of two distinct verbal memory measures validated for use in epilepsy research. Pearson's correlations evaluated relationships between clinical variables and verbal memory. Linear regression was used to relate regional hypometabolism and verbal memory assessment. Post hoc analyses assessed areas of FDG-PET hypometabolism (threshold Z ≤ -1.645 below mean) where verbal memory was impaired. RESULTS: Verbal memory deficits correlated with hypometabolism in limbic structures ipsilateral to language dominance but also correlated with hypometabolism in networks involving the ipsilateral perisylvian cortex and contralateral limbic and nonlimbic structures. DISCUSSION: We conclude that traditional models of verbal memory may not adequately capture cognitive deficits in a broader sample of patients with MTLE. This study has important implications for epilepsy surgery protocols that use neuropsychological data and FDG-PET to draw conclusions about surgical risks.

Mapping epileptic directional brain networks using intracranial EEG data.

The human brain is a directional network system, in which brain regions are network nodes and the influence exerted by one region on another is a network edge. We refer to this directional information flow from one region to another as directional connectivity. Seizures arise from an epileptic directional network; abnormal neuronal activities start from a seizure onset zone and propagate via a network to otherwise healthy brain regions. As such, effective epilepsy diagnosis and treatment require accurate identification of directional connections among regions, i.e., mapping of epileptic patients' brain networks. This article aims to understand the epileptic brain network using intracranial electroencephalographic data-recordings of epileptic patients' brain activities in many regions. The most popular models for directional connectivity use ordinary differential equations (ODE). However, ODE models are sensitive to data noise and computationally costly. To address these issues, we propose a high-dimensional state-space multivariate autoregression (SSMAR) model for the brain's directional connectivity. Different from standard multivariate autoregression and SSMAR models, the proposed SSMAR features a cluster structure, where the brain network consists of several clusters of densely connected brain regions. We develop an expectation-maximization algorithm to estimate the proposed model and use it to map the interregional networks of epileptic patients in different seizure stages. Our method reveals the evolution of brain networks during seizure development.

Synergistic effect of sleep depth and seizures correlates with postictal heart rate.

Our objective was to determine the effect of sleep on heart rate following a recorded seizure. We prospectively acquired heart rate data in hospitalized epilepsy monitoring unit patients. We analyzed heart rate trends for multiple seizures (n = 101) in patients (n = 42) with electroencephalographically confirmed events. The patient's sleep state was scored for the 5 min preceding each seizure and correlated with the postictal nadir heart rate (PINHR). The depth of sleep during the 5 min before a seizure correlated (correlation coefficient [CC] = -.229, p < .05) with PINHR. This result was more significant and strengthened (CC = -.272, 95% confidence interval = -.392 to -.152, p < .001) when adjusted for covariates of age, generalized tonic-clonic seizures, and baseline heart rate. Sleep depth is an independent predictor of the change in heart rate following a seizure. Diminished heart rate following a seizure in the setting of sleep is likely secondary to non-rapid eye movement sleep's synergistic effect on parasympathetic tone.

Dynamic FDG-PET in localization of focal epilepsy: A pilot study.

Epilepsy surgery remains underutilized, in part because non-invasive methods of potential seizure foci localization are inadequate. We used high-resolution, parametric quantification from dynamic 2-[18F] fluoro-2-deoxy-d-glucose positron emission tomography (dFDG-PET) imaging to locate hypometabolic foci in patients whose standard clinical static PET images were normal. We obtained dFDG-PET brain images with simultaneous EEG in a one-hour acquisition on seven patients with no MRI evidence of focal epilepsy to record uptake and focal radiation decay. Images were attenuation- and motion-corrected and co-registered with high-resolution T1-weighted patient MRI and segmented into 18 regions of interest (ROI) per hemisphere. Tracer uptake was calibrated with a model corrected blood input function with partial volume (PV) corrections to generate tracer parametric maps compared between mean radiation values between hemispheres with z-scores. We identified ROI with the lowest negative z scores (<-1.65 SD) as hypometabolic. Dynamic 2-[18F] fluoro-2-deoxy-d-glucose positron emission tomography ( found focal regions of altered metabolism in all cases in which standard clinical FDG-PET found no abnormalities. This pilot study of dynamic FDG-PET suggests that further research is merited to evaluate whether glucose dynamics offer improved clinical utility for localization of epileptic foci over standard static techniques.

Direct and indirect costs associated with stereotactic radiosurgery or open surgery for medial temporal lobe epilepsy: Results from the ROSE trial.

OBJECTIVE: To determine whether a less-invasive approach to surgery for medically refractory temporal lobe epilepsy is associated with lower health care costs and costs of lost productivity over time, compared to open surgery. METHODS: We compared direct medical costs and indirect productivity costs associated with treatment with stereotactic radiosurgery (SRS) or anterior temporal lobectomy (ATL) in the ROSE (Radiosurgery or Open Surgery for Epilepsy) trial. Health care use was abstracted from hospital bills, the study database, and diaries in which participants recorded health care use and time lost from work while seeking care. Costs of use were calculated using a Medicare costing approach used in a prior study of the costs of ATL. The power of many analyses was limited by the sample size and data skewing. RESULTS: Combined treatment and follow-up costs (in thousands of US dollars) did not differ between SRS (n = 20, mean = $76.6, 95% confidence interval [CI] = 50.7-115.6) and ATL (n = 18, mean = $79.0, 95% CI = 60.09-103.8). Indirect costs also did not differ. More ATL than SRS participants were free of consciousness-impairing seizures in each year of follow-up (all P < 0.05). Costs declined following ATL (P = 0.005). Costs tended to increase over the first 18 months following SRS (P = 0.17) and declined thereafter (P = 0.06). This mostly reflected hospitalizations for SRS-related adverse events in the second year of follow-up. SIGNIFICANCE: Lower initial costs of SRS for medial temporal lobe epilepsy were largely offset by hospitalization costs related to adverse events later in the course of follow-up. Future studies of less-invasive alternatives to ATL will need to assess adverse events and major costs systematically and prospectively to understand the economic implications of adopting these technologies.

Radiosurgery versus open surgery for mesial temporal lobe epilepsy: The randomized, controlled ROSE trial.

OBJECTIVE: To compare stereotactic radiosurgery (SRS) versus anterior temporal lobectomy (ATL) for patients with pharmacoresistant unilateral mesial temporal lobe epilepsy (MTLE). METHODS: This randomized, single-blinded, controlled trial recruited adults eligible for open surgery among 14 centers in the USA, UK, and India. Treatment was either SRS at 24 Gy to the 50% isodose targeting mesial structures, or standardized ATL. Outcomes were seizure remission (absence of disabling seizures between 25 and 36 months), verbal memory (VM), and quality of life (QOL) at 36-month follow-up. RESULTS: A total of 58 patients (31 in SRS, 27 in ATL) were treated. Sixteen (52%) SRS and 21 (78%) ATL patients achieved seizure remission (difference between ATL and SRS = 26%, upper 1-sided 95% confidence interval = 46%, P value at the 15% noninferiority margin = .82). Mean VM changes from baseline for 21 English-speaking, dominant-hemisphere patients did not differ between groups; consistent worsening occurred in 36% of SRS and 57% of ATL patients. QOL improved with seizure remission. Adverse events were anticipated cerebral edema and related symptoms for some SRS patients, and cerebritis, subdural hematoma, and others for ATL patients. SIGNIFICANCE: These data suggest that ATL has an advantage over SRS in terms of proportion of seizure remission, and both SRS and ATL appear to have effectiveness and reasonable safety as treatments for MTLE. SRS is an alternative to ATL for patients with contraindications for or with reluctance to undergo open surgery.

Quality of life in adults with epilepsy is associated with anticonvulsant polypharmacy independent of seizure status.

RATIONALE: Polypharmacy, sometimes necessary to control epilepsy, can result in adverse effects that may affect quality of life (QOL). Our purpose was to determine the association of polypharmacy with QOL. METHODS: Two hundred seven patients with epilepsy were surveyed on characteristics within the last 4weeks: QOL Quality of Life in Epilepsy-Patient-Weighted (QOLIE-10-P) and seizure status (seizure-free or not), demographics, epilepsy characteristics, insomnia, sleepiness, mood, sleep-wake timing, healthcare use, and employment. Those on polypharmacy (antiepileptic drug (AED)>1) were compared with controls (AED=1) with univariate comparisons and subsequent multivariate regression. RESULTS: Patients on polypharmacy had worse QOL scores (mean 33.3±6.9 versus 36.7±5.7), were less likely to be seizure-free (39 (44%) versus 82 (68%)), had more evening-weighted wakefulness, and were more likely unemployed (74% versus 49%). Polypharmacy was associated with worse QOL (odds ratio 1.068 and 95th CI 1.018-1.121) even after controlling for seizure status. Covariates offered no improvement to the model. CONCLUSION: Polypharmacy was associated with worse QOL in patients with epilepsy despite seizure control. Further investigation into specific etiology of polypharmacy's influence on QOL is warranted in order to develop paradigms for optimal treatment.

Circadian and ultradian patterns of epileptiform discharges differ by seizure-onset location during long-term ambulatory intracranial monitoring.

OBJECTIVE: Previous studies reporting circadian patterns of epileptiform activity and seizures are limited by (1) short-term recording in an epilepsy monitoring unit (EMU) with altered antiepileptic drugs (AEDs) and sleep, or (2) subjective seizure diary reports. We studied circadian patterns using long-term ambulatory intracranial recordings captured by the NeuroPace RNS System. METHODS: Retrospective study of RNS System trial participants with stable detection parameters over a continuous 84-day period. We analyzed all detections and long device-detected epileptiform events (long episodes) and defined a subset of subjects in whom long episodes represented electrographic seizures (LE-SZ). Spectrum resampling determined the dominant frequency periodicity and cosinor analysis identified significant circadian peaks in detected activity. Chi-square analysis was used to compare subjects grouped by region of seizure onset. RESULTS: In the 134 subjects, detections showed a strongly circadian and uniform pattern irrespective of region of onset that peaked during normal sleep hours. In contrast, long episodes and LE-SZ patterns varied by region. Neocortical regions had a monophasic, nocturnally dominant rhythm, whereas limbic regions showed a more complex pattern and diurnal peak. Rhythms in some individual limbic subjects were best fit by a dual oscillator (circadian + ultradian) model. SIGNIFICANCE: Epileptiform activity has a strong 24 h periodicity with peak nocturnal occurrence. Limbic and neocortical epilepsy show divergent circadian influences. These findings confirm that circadian patterns of epileptiform activity vary by seizure-onset zone, with implications for treatment and safety, including SUDEP.

Interrater reliability in interpretation of electrocorticographic seizure detections of the responsive neurostimulator.

OBJECTIVE: Electrocorticographic (ECoG) recordings from patients with medically intractable partial-onset seizures treated with a responsive neurostimulator system (the RNS System) that detects and stores physician-specified ECoG events provide a new data resource. Interpretation of these recordings has not yet been validated. The purpose was to evaluate the interrater interpretation of chronic ambulatory ECoG recordings obtained by the RNS System. METHODS: Five pairs of five experts independently classified 7,221 ECoG recordings obtained from 128 patients with medically intractable partial seizures who participated in a randomized controlled trial of the safety and efficacy of the RNS System. ECoG detections--"long episodes" or "saturations"--were classified as "seizures" or "not seizures" based on a reference definition. Interrater agreement rates and kappa score reliabilities were calculated between rater pairs from the ECoG sample as a whole and within individual patients who had more than the median number of individual ECoG recordings. RESULTS: The overall interrater agreement was 79%, with a reliability κ = 0.57 (moderate agreement). Agreement between pairs of reviewers ranged from 0.69 to 0.85. Agreement rates were 94% or better for 50% of patients. Only 25% of patients had ECoG recordings agreement rates worse than 75%. ECoGs with mixed interpretations (one reviewer "seizure"/the other--"not seizure") consisted of periods of low amplitude activity that evolved in amplitude or periodic discharges near 2 Hz. SIGNIFICANCE: Although reliability as a whole was moderate, for the majority of patients, detections yielded highly reliably interpreted events of either electrographic seizures or nonictal epileptiform activity.

Improvement in non-24-h sleep-wake rhythm disorder in a sighted individual treated with a melatonin receptor agonist.

Non-24-hour sleep-wake rhythm disorder (N24SWD) typically presents in patients with visual impairments that disrupt the ability to entrain to the 24 hour solar cycle. We discuss a 43 year old sighted man who presented with periodic daytime hypersomnia and nighttime insomnia, occasionally leading to <3 hours of sleep per day. Previous polysomnography showed an apnea hypopnea index of 6.2 events per hour. A sleep log of 3 months showed irregular time of sleep onset, and an average of 3 hours of sleep per day. Wrist actigraphy confirmed N24SWD. A trial of tasimelteon 20 mg/day resulting in improved daytime hypersomnia (pre-Epworth Sleepiness Scale (ESS) = 21/24, post-ESS = 5/24; a score of > 10/24 is considered sleepy). Follow-up actigraphy showed marked resolution of phase delay with an average of five hours of sleep. The case demonstrates that tasimelteon is a possible treatment for N24SWD in sighted individuals.

Interrelationship of Sleep Disturbances and Cognitive Status on Mortality.

Sleep disturbances may promote the development and advancement of Alzheimer's disease. Our purpose was to determine if sleep disturbances were associated with earlier mortality while accounting for cognition. The National Alzheimer's Coordinating Center database was used to evaluate mortality risk conferred by sleep, and the Montreal Cognitive Assessment score determined cognitive status. Demographics, sleep disturbances, cognitive status, and comorbid/other neuropsychiatric conditions were examined as predictors of survival time via Cox regression. The sample (N = 31,110) had a median age [interquartile range] of 72 [66, 79] years, MoCA score of 23 [16, 26], and survival time of 106.0 months [104.0,108.0]; 10,278 (33%) died during follow-up; 21% (n = 6461) experienced sleep disturbances. Sleep disturbances impacted survival time depending on cognition, with the greatest effect in transition from normal to cognitive impairment (P < .001). Findings support that sleep disturbances negatively impact survival time, and the impact of sleep disturbances on survival time is interrelated with cognition.

A medico-legal perspective on postictal violence: A case study and systematic review of postictal delirium.

Detailed descriptions of violent postictal episodes are rare. We provide evidence from an index case and from a systematic review of violent postictal episodes that demonstrates the encephalopathic features of some violent postictal behaviors. We discuss how these cases may fit in the legal framework of culpability. The data support the view that some episodes of violent postictal behavior are more accurately classified as a neurological delirium or encephalopathy rather than as a postictal psychosis. Current medical terminology may present unwarranted (and presumably unintended) barriers to exculpation for patients who exhibit post-ictal violence during an episode of delirium during which the patient was unaware of his or her violent conduct.

Visual field defects after radiosurgery for mesial temporal lobe epilepsy.

PURPOSE: Gamma knife radiosurgery (RS) may be an alternative to open surgery for mesial temporal lobe epilepsy (MTLE), but morbidities and the anticonvulsant mechanisms of RS are unclear. Examination of visual field defects (VFDs) after RS may provide evidence of the extent of a postoperative fixed lesion. VFDs occur in 52-100% of patients following open surgery for MTLE. METHODS: This multicenter prospective trial of RS enrolled patients with unilateral hippocampal sclerosis and concordant video-electroencephalography (EEG) findings. Patients were randomized to low (20 Gy) or high (24 Gy) doses delivered to the amygdala, hippocampal head, and parahippocampal gyrus. Postoperative perimetry were obtained at 24 months after RS. Visual field defect ratios (VFDRs) were calculated to quantify the degree of VFDs. Results were contrasted with age, RS dose and 50% isodose volume, peak volume of radiation-induced change at the surgical target, quality of life measurements, and seizure remission. KEY FINDINGS: No patients reported visual changes and no patients had abnormal bedside visual field examinations. Fifteen (62.5%) of 24 patients had postoperative VFDs, all homonymous superior quadrantanopsias. None of the VFDs were consistent with injury to the optic nerve or chiasm. Clinical diagnosis of VFDs correlated significantly with VFDRs (p = 0.0005). Patients with seizure remission had smaller (more severe) VFDRs (p = 0.04). No other variables had significant correlations. SIGNIFICANCE: VFDs appeared after RS in proportions similar to historical comparisons from open surgery for MTLE. The nature of VFDs was consistent with lesions of the optic radiations. The findings support the hypothesis that the mechanism of RS involves some degree of tissue damage and is not confined entirely to functional changes in neuromodulation.

Sleep-EEG in comorbid pain and insomnia: implications for the treatment of pain disorders.

Introduction: Patients with chronic pain experience a high prevalence of comorbid insomnia, which is associated with functional impairment. Recent advances in sleep electroencephalography (sleep-EEG) may clarify the mechanisms that link sleep and chronic pain. In this clinical update, we outline current advancements in sleep-EEG assessments for pain and provide research recommendations. Results: Promising preliminary work suggests that sleep-EEG spectral bands, particularly beta, gamma, alpha, and delta power, may create candidate neurophysiological signatures of pain, and macro-architectural parameters (e.g., total sleep time, arousals, and sleep continuity) may facilitate EEG-derived sleep phenotyping and may enable future stratification in the treatment of pain. Conclusion: Integration of measures obtained through sleep-EEG represent feasible and scalable approaches that could be adopted in the future. We provide research recommendations to progress the field towards a deeper understanding of their utility and potential future applications in clinical practice.

Sleep Disturbances Predict Cognitive Decline in Cognitively Healthy Adults.

BACKGROUND: The effect of nighttime behaviors on cognition has not been studied independently from other neuropsychiatric symptoms. OBJECTIVE: We evaluate the following hypotheses that sleep disturbances bring increased risk of earlier cognitive impairment, and more importantly that the effect of sleep disturbances is independent from other neuropsychiatric symptoms that may herald dementia. METHODS: We used the National Alzheimer's Coordinating Center database to evaluate the relationship between Neuropsychiatric Inventory Questionnaire (NPI-Q) determined nighttime behaviors which served as surrogate for sleep disturbances and cognitive impairment. Montreal Cognitive Assessment scores defined two groups: conversion from 1) normal to mild cognitive impairment (MCI) and 2) MCI to dementia. The effect of nighttime behaviors at initial visit and covariates of age, sex, education, race, and other neuropsychiatric symptoms (NPI-Q), on conversion risk were analyzed using Cox regression. RESULTS: Nighttime behaviors predicted earlier conversion time from normal cognition to MCI (hazard ratio (HR): 1.09; 95% CI: [1.00, 1.48], p = 0.048) but were not associated with MCI to dementia conversion (HR: 1.01; [0.92, 1.10], p = 0.856). In both groups, older age, female sex, lower education, and neuropsychiatric burden increased conversion risk. CONCLUSION: Our findings suggest that sleep disturbances predict earlier cognitive decline independently from other neuropsychiatric symptoms that may herald dementia.

Circannual seizure provocation as the day lengthens in the northern and southern hemispheres.

Circannual status epilepticus (SE) patterns in communities near Earth's poles best test the hypothesis that SE susceptibility varies with light exposure because these communities are routinely subject to large changes in annual light exposure, which may result in changes to daily sleep time. We compared northern hemispheric circannual SE occurrence in Kivalliq, Canada (latitude-62.8° N) to southern hemispheric Auckland, New Zealand (latitude-36.9° S). Instead of peaking at a similar calendar time, SE peaked at a similar solar time during the increasing daylight phase after each region's respective winter solstice. This demonstrates that cumulative effects of increasing light exposure can mediate SE susceptibility.

Painful Cutaneous Laser Stimulation for Temporal Summation of Pain Assessment.

Variability in pain sensitivity arises not only from the differences in peripheral sensory receptors but also from the differences in central nervous system (CNS) pain inhibition and facilitation mechanisms. Temporal summation of pain (TSP) is an experimental protocol commonly used in human studies of pain facilitation but is susceptible to confounding when elicited with the skin-contact thermode, which adds the responses of touch-related Aß low-threshold mechanoreceptors to nociceptive receptors. In the present study, we evaluate an alternative method involving the use of a contactless cutaneous laser for TSP assessment. We show that repetitive laser stimulations with a one second inter-stimulus interval evoked reliable TSP responses in a significant proportion of healthy subjects (N = 36). Female subjects (N = 18) reported greater TSP responses than male subjects confirming earlier studies of sex differences in central nociceptive excitability. Furthermore, repetitive laser stimulations during TSP induction elicited increased time-frequency electroencephalography (EEG) responses. The present study demonstrates that repetitive laser stimulation may be an alternative to skin-contact methods for TSP assessment in patients and healthy controls. PERSPECTIVE: Temporal summation of pain (TSP) is an experimental protocol commonly used in human studies of pain facilitation. We show that contactless cutaneous laser stimulation is a reliable alternative to the skin contact approaches during TSP assessment.

Chronic Neurocognitive, Neuropsychological, and Pulmonary Symptoms in Outpatient and Inpatient Cohorts After COVID-19 Infection.

Neuropsychological symptoms associated with post-COVID-19 conditions may prevent patients from resuming normal activities at home or work. We report a retrospective, cross-sectional evaluation of neuropsychological and cardiopulmonary outcomes in 2 groups of patients: outpatients with mild enough infection to be spared from hospitalization and those who required inpatient admission. We hypothesized a dose-response model of post-COVID symptom severity in which persistent consequences would be more severe in those who experienced worse acute infections. In a dedicated COVID clinic, 321 patients were seen (33% outpatient, 67% inpatient). Outpatients skewed female, White, non-Hispanic, and younger. Outpatients had worse insomnia (measured with insomnia severity index) and were less able to resume their usual activities (EQ-5D-5L usual activities scale), despite inpatients experiencing worse cognition (Montreal Cognitive Assessment), having greater obesity (body mass index), decreased exercise tolerance (6-minute-walk distance), and more exertional oxygen desaturation. In both groups, insomnia worsened while cognition improved significantly with time from infection to testing while controlling for patient age; other variables did not. In logistic regression, female sex, higher MoCA score, EQ-5D-5L "usual activities" subscore, less oxygen desaturation with exertion, and longer time from infection remained as significant associations with outpatient status. Our study demonstrated that the functional sequelae of post-COVID-19 conditions in patients with mild acute disease have the potential to be as severe as that in patients who have recovered from severe illness.