BAYESIAN NON-HOMOGENEOUS HIDDEN MARKOV MODEL WITH VARIABLE SELECTION FOR INVESTIGATING DRIVERS OF SEIZURE RISK CYCLING.

A major issue in the clinical management of epilepsy is the unpredictability of seizures. Yet, traditional approaches to seizure forecasting and risk assessment in epilepsy rely heavily on raw seizure frequencies, which are a stochastic measurement of seizure risk. We consider a Bayesian non-homogeneous hidden Markov model for unsupervised clustering of zero-inflated seizure count data. The proposed model allows for a probabilistic estimate of the sequence of seizure risk states at the individual level. It also offers significant improvement over prior approaches by incorporating a variable selection prior for the identification of clinical covariates that drive seizure risk changes and accommodating highly granular data. For inference, we implement an efficient sampler that employs stochastic search and data augmentation techniques. We evaluate model performance on simulated seizure count data. We then demonstrate the clinical utility of the proposed model by analyzing daily seizure count data from 133 patients with Dravet syndrome collected through the Seizure Tracker™ system, a patient-reported electronic seizure diary. We report on the dynamics of seizure risk cycling, including validation of several known pharmacologic relationships. We also uncover novel findings characterizing the presence and volatility of risk states in Dravet syndrome, which may directly inform counseling to reduce the unpredictability of seizures for patients with this devastating cause of epilepsy.

A Bayesian switching linear dynamical system for estimating seizure chronotypes.

Epilepsy is a disorder characterized by paroxysmal transitions between multistable states. Dynamical systems have been useful for modeling the paroxysmal nature of seizures. At the same time, intracranial electroencephalography (EEG) recordings have recently discovered that an electrographic measure of epileptogenicity, interictal epileptiform activity, exhibits cycling patterns ranging from ultradian to multidien rhythmicity, with seizures phase-locked to specific phases of these latent cycles. However, many mechanistic questions about seizure cycles remain unanswered. Here, we provide a principled approach to recast the modeling of seizure chronotypes within a statistical dynamical systems framework by developing a Bayesian switching linear dynamical system (SLDS) with variable selection to estimate latent seizure cycles. We propose a Markov chain Monte Carlo algorithm that employs particle Gibbs with ancestral sampling to estimate latent cycles in epilepsy and apply unsupervised learning on spectral features of latent cycles to uncover clusters in cycling tendency. We analyze the largest database of patient-reported seizures in the world to comprehensively characterize multidien cycling patterns among 1,012 people with epilepsy, spanning from infancy to older adulthood. Our work advances knowledge of cycling in epilepsy by investigating how multidien seizure cycles vary in people with epilepsy, while demonstrating an application of an SLDS to frame seizure cycling within a nonlinear dynamical systems framework. It also lays the groundwork for future studies to pursue data-driven hypothesis generation regarding the mechanistic drivers of seizure cycles.

Seizure count forecasting to aid diagnostic testing in epilepsy.

OBJECTIVE: Epilepsy monitoring unit (EMU) admissions are critical for presurgical evaluation of drug-resistant epilepsy but may be nondiagnostic if an insufficient number of seizures are recorded. Seizure forecasting algorithms have shown promise for estimating the likelihood of seizures as a binary event in individual patients, but methods to predict how many seizures will occur remain elusive. Such methods could increase the diagnostic yield of EMU admissions and help patients mitigate seizure-related morbidity. Here, we evaluated the performance of a state-space method that uses prior seizure count data to predict future counts. METHODS: A Bayesian negative-binomial dynamic linear model (DLM) was developed to forecast daily electrographic seizure counts in 19 patients implanted with a responsive neurostimulation (RNS) device. Holdout validation was used to evaluate performance in predicting the number of electrographic seizures for forecast horizons ranging 1-7 days ahead. RESULTS: One-day-ahead prediction of the number of electrographic seizures using a negative-binomial DLM resulted in improvement over chance in 73.1% of time segments compared to a random chance forecaster and remained >50% for forecast horizons of up to 7 days. Superior performance (mean error = .99) was obtained in predicting the number of electrographic seizures in the next day compared to three traditional methods for count forecasting (integer-valued generalized autoregressive conditional heteroskedasticity model or INGARCH, 1.10; Croston, 1.06; generalized linear autoregressive moving average model or GLARMA, 2.00). Number of electrographic seizures in the preceding day and laterality of electrographic pattern detections had highest predictive value, with greater number of electrographic seizures and RNS magnet swipes in the preceding day associated with a higher number of electrographic seizures the next day. SIGNIFICANCE: This study demonstrates that DLMs can predict the number of electrographic seizures a patient will experience days in advance with above chance accuracy. This study represents an important step toward the translation of seizure forecasting methods into the optimization of EMU admissions.

Evidence of state-dependence in the effectiveness of responsive neurostimulation for seizure modulation.

BACKGROUND: An implanted device for brain-responsive neurostimulation (RNS® System) is approved as an effective treatment to reduce seizures in adults with medically-refractory focal epilepsy. Clinical trials of the RNS System demonstrate population-level reduction in average seizure frequency, but therapeutic response is highly variable. HYPOTHESIS: Recent evidence links seizures to cyclical fluctuations in underlying risk. We tested the hypothesis that effectiveness of responsive neurostimulation varies based on current state within cyclical risk fluctuations. METHODS: We analyzed retrospective data from 25 adults with medically-refractory focal epilepsy implanted with the RNS System. Chronic electrocorticography was used to record electrographic seizures, and hidden Markov models decoded seizures into fluctuations in underlying risk. State-dependent associations of RNS System stimulation parameters with changes in risk were estimated. RESULTS: Higher charge density was associated with improved outcomes, both for remaining in a low seizure risk state and for transitioning from a high to a low seizure risk state. The effect of stimulation frequency depended on initial seizure risk state: when starting in a low risk state, higher stimulation frequencies were associated with remaining in a low risk state, but when starting in a high risk state, lower stimulation frequencies were associated with transition to a low risk state. Findings were consistent across bipolar and monopolar stimulation configurations. CONCLUSION: The impact of RNS on seizure frequency exhibits state-dependence, such that stimulation parameters which are effective in one seizure risk state may not be effective in another. These findings represent conceptual advances in understanding the therapeutic mechanism of RNS, and directly inform current practices of RNS tuning and the development of next-generation neurostimulation systems.

Identification of nasal eosinophils using two-photon excited fluorescence.

BACKGROUND: Eosinophils trigger symptoms in allergic rhinitis. New diagnostic methods for identifying nasal eosinophils based on autofluorescence of flavin adenine dinucleotide in eosinophil granules could offer rapid monitoring without fixation or staining. Two-photon excitation is a powerful method for detecting this intrinsic fluorescence. OBJECTIVES: To demonstrate the use of 2-photon excited fluorescence (TPEF) to detect eosinophils from nasal mucosa in a proof-of-concept study for a future miniature in vivo imaging instrument. METHODS: Thirty subjects with rhinitis were recruited. Results of our standard environmental panel were recorded. Fluorescence images were collected from nasal cytology smears with a 2-photon microscope. Cells were evaluated for intensity and size, and compared with Hansel stains. Correlation of cell count was made by linear regression, diagnostic performance was evaluated at various intensity thresholds, and correlation of nasal eosinophil count to allergic status was done through the Wilcoxon rank-sum test. RESULTS: The fluorescence intensity of eosinophils compared with epithelial cells was 13.8 ± 4.3 versus 3.7 ± 1.8 (P < .01), and the size was 27.0 ± 10.2 versus 392.0 ± 214.6 µm2 (P < .01), respectively. Using both fluorescence intensity and size, a total accuracy of 100% is achieved. Eosinophil count on TPEF correlates with Hansel stain, R(2) = 0.91. Nasal eosinophil count correlates with allergic status on both TPEF (P = .008) and Hansel stain images (P = .027). CONCLUSIONS: TPEF is a promising novel technique for identifying and quantifying nasal eosinophils on nasal cytology specimens without the need for fixation or staining. Future development of a rhinoscope-compatible 2-photon microscope could be used as a clinical adjunct for the diagnosis and management of rhinitis patients in vivo.