Joshua B. Silverman

Laryngospasm, central and obstructive apnea during seizures: Defining pathophysiology for sudden death in a rat model

Seizure spread into the autonomic nervous system can result in life-threatening cardiovascular and respiratory dysfunction. Here we report on a less-studied consequence of such autonomic derangements-the possibility of laryngospasm and upper-airway occlusion. We used parenteral kainic acid to induce recurring seizures in urethane-anesthetized Sprague Dawley rats. EEG recordings and combinations of cardiopulmonary monitoring, including video laryngoscopy, were performed during multi-unit recordings of recurrent laryngeal nerve (RLN) activity or head-out plethysmography with or without endotracheal intubation. Controlled occlusions of a tracheal tube were used to study the kinetics of cardiac and respiratory changes after sudden obstruction. Seizure activity caused significant firing increases in the RLN that were associated with abnormal, high-frequency movements of the vocal folds. Partial airway obstruction from laryngospasm was evident in plethysmograms and was prevented by intubation. Complete glottic closure (confirmed by laryngoscopy) occurred in a subset of non-intubated animals in association with the largest increases in RLN activity, and cessation of airflow was followed in all obstructed animals within tens of seconds by ST-segment elevation, bradycardia, and death. Periods of central apnea occurred in both intubated and non-intubated rats during seizures for periods up to 33s and were associated with modestly increased RLN activity, minimal cardiac derangements, and an open airway on laryngoscopy. In controlled complete airway occlusions, respiratory effort to inspire progressively increased, then ceased, usually in less than 1min. Respiratory arrest was associated with left ventricular dilatation and eventual asystole, an elevation of systemic blood pressure, and complete glottic closure. Severe laryngospasm contributed to the seizure- and hypoxemia-induced conditions that resulted in sudden death in our rat model, and we suggest that this mechanism could contribute to sudden death in epilepsy.

Seizure-associated central apnea in a rat model: Evidence for resetting the respiratory rhythm and activation of the diving reflex

Respiratory derangements, including irregular, tachypnic breathing and central or obstructive apnea can be consequences of seizure activity in epilepsy patients and animal models. Periods of seizure-associated central apnea, defined as periods >1s with rapid onset and offset of no airflow during plethysmography, suggest that seizures spread to brainstem respiratory regions to disrupt breathing. We sought to characterize seizure-associated central apneic episodes as an indicator of seizure impact on the respiratory rhythm in rats anesthetized with urethane and given parenteral kainic acid to induce recurring seizures. We measured central apneic period onsets and offsets to determine if onset-offset relations were a consequence of 1) a reset of the respiratory rhythm, 2) a transient pausing of the respiratory rhythm, resuming from the pause point at the end of the apneic period, 3) a transient suppression of respiratory behavior with apnea offset predicted by a continuation of the breathing pattern preceding apnea, or 4) a random re-entry into the respiratory cycle. Animals were monitored with continuous ECG, EEG, and plethysmography. One hundred ninety central apnea episodes (1.04 to 36.18s, mean: 3.2±3.7s) were recorded during seizure activity from 7 rats with multiple apneic episodes. The majority of apneic period onsets occurred during expiration (125/161 apneic episodes, 78%). In either expiration or inspiration, apneic onsets tended to occur late in the cycle, i.e. between the time of the peak and end of expiration (82/125, 66%) or inspiration (34/36, 94%). Apneic period offsets were more uniformly distributed between early and late expiration (27%, 34%) and inspiration (16%, 23%). Differences between the respiratory phase at the onset of apnea and the corresponding offset phase varied widely, even within individual animals. Each central apneic episode was associated with a high frequency event in EEG or ECG records at onset. High frequency events that were not associated with flatline plethysmographs revealed a constant plethysmograph pattern within each animal, suggesting a clear reset of the respiratory rhythm. The respiratory rhythm became highly variable after about 1s, however, accounting for the unpredictability of the offset phase. The dissociation of respiratory rhythm reset from the cessation of airflow also suggested that central apneic periods involved activation of brainstem regions serving the diving reflex to eliminate the expression of respiratory movements. This conclusion was supported by the decreased heart rate as a function of apnea duration. We conclude that seizure-associated central apnea episodes are associated with 1) a reset of the respiratory rhythm, and 2) activation of brainstem regions serving the diving reflex to suppress respiratory behavior. The significance of these conclusions is that these details of seizure impact on brainstem circuitry represent metrics for assessing seizure spread and potentially subclassifying seizure patterns.

Obstructive apnea due to laryngospasm links ictal to postictal events in SUDEP cases and offers practical biomarkers for review of past cases and prevention of new ones

Seizure spread into autonomic and respiratory brainstem regions is thought to play an important role in sudden unexpected death in epilepsy (SUDEP). As the clinical dataset of cases of definite SUDEP available for study grows, evidence points to a sequence of events that includes postictal apnea, bradycardia, and asystole as critical events that can lead to death. One possible link between the precipitating seizure and the critical postictal sequence is seizure‐driven laryngospasm sufficient to completely obstruct the airway for an extended period, but ictal laryngospasm is difficult to fully assess. Herein, we demonstrate in a rat model how the electrical artifacts of attempts to inspire during airway obstruction and features of the cardiac rhythm establish this link between ictal and postictal activity and can be used as practical biomarkers of obstructive apnea due to laryngospasm or other causes of airway obstruction.

Quantitative video laryngoscopy to monitor recovery from recurrent laryngeal nerve injury in the rat.

Recovery from unilateral vocal-fold paralysis is lengthy, unpredictable, and often incomplete, highlighting the need for better treatments of the injured recurrent laryngeal nerve. To be able to monitor recovery of vocal-fold motion in studies with rats, we developed a procedure for quantitative video laryngoscopy. An asymmetry index was defined as a continuous and robust measure of unequal vocal-fold motion and calculated from spectral-density plots of vocal-fold displacements. In a cohort of 8 animals, unilateral vocal-fold paralysis was observed within seconds after clamping of the right recurrent laryngeal nerve and was accompanied by a markedly negative asymmetry index. Over the next month, the asymmetry index gradually returned to zero, concomitant with a visible recovery of vocal-fold motion. Our results suggest that quantitative video laryngoscopy is a sensitive and discriminating method for monitoring recovery from recurrent laryngeal nerve injury and set the stage for testing novel surgical and pharmacological treatments of unilateral vocal-fold paralysis.

Asthma outcomes after adenotonsillectomy: A systematic review

OUTCOME OBJECTIVE For over fifty years, otolaryngologists, allergists, and immunologists have debated the effect of adenoidectomy or adenotonsillectomy on asthma outcomes in children. Although some have suggested that adenotonsillectomy may contribute to the subsequent development of asthma in children, others have argued that a common mechanism may cause both upper and lower airway disease, and that children who have symptoms severe enough to warrant adenotonsillectomy are also at increased risk of asthma and atopic disease. The link between asthma and upper airway disease may involve upper airway inflammation. Our goal is to perform a systematic review of asthma outcomes following adenoidectomy or adenotonsillectomy in the pediatric population. Our goal is to assess the effect of adenoidectomy or adenotonsillectomy on markers of asthma severity in children with obstructive sleep apnea. METHODS We performed a systematic review using the PubMed, EMBASE, and CINAHL databases using search terms related to asthma, adenoidectomy, and adenotonsillectomy. Inclusion criteria were defined as pediatric subjects aged 18 years or younger with a history of asthma, undergoing adenoidectomy, or adenotonsillectomy for obstructive sleep apnea. Database studies and case studies with or without control groups were included in the study. Exclusion criteria were patients with follow-up greater than 1 year after surgery, craniofacial syndromes, or additional significant comorbidities. RESULTS A total of 567 abstracts were identified; 549 were excluded immediately. Eighteen full-text articles were assessed for eligibility and four articles were included in the qualitative synthesis. These data are consistent in correlating adenotonsillectomy in asthmatic children with decreased asthma severity. Markers of asthma severity including respiratory medication use, emergency room visits for asthma-related symptoms, overall asthma symptoms, and asthma-related exacerbations were all significantly reduced following adenotonsillectomy. CONCLUSION We present a systematic review of asthma outcomes following surgical intervention for sleep apnea in the pediatric population. All included studies found clinically significant reductions in markers of asthma severity after adenotonsillectomy. Though further prospective trials are needed to determine a causal relationship between adenotonsillectomy and modulation of asthma, the compilation of data suggest a definitive association.

Systematic review for surgical treatment of adult and adolescent laryngotracheal stenosis

To determine if open surgical treatment options for adult and adolescent laryngotracheal stenosis are more successful than endoscopic procedures.

An Extubation Protocol for Angioedema

Angioedema—nonpitting edema of the mucous membranes and skin—most commonly occurs as a complication from the use of angiotensin-converting enzyme inhibitors. At our institution, the otolaryngology department has incorporated the use of the endotracheal tube cuff-leak test and bedside direct laryngoscopy to aid in timing for extubation of angioedema patients. Prospective data collection of patients presenting to the emergency department with angioedema was performed. Of 76 patients with angioedema, 9 required fiberoptic intubation. Intubation was performed at a median of 73 hours (range, 44-118). An endotracheal tube cuff-leak test was performed in 7 patients prior to extubation, and bedside direct laryngoscopy was also performed in 3 of these 7 patients to document resolution of laryngeal edema. The use of the endotracheal tube cuff-leak test and bedside direct laryngoscopy is an easy and inexpensive method to help determine eligibility for extubation in patients intubated for angioedema.

Restoration of Recurrent-Laryngeal-Nerve Function after Injury in a Rat Model

Objectives: Recurrent laryngeal nerve (RLN) injury occurs in 4-10% of thyroid surgeries. Spontaneous RLN regeneration takes months and is often incomplete. Lithium promotes neuronal growth in vitro. We developed methods to objectively detect vocal-fold impairment in the rat and tested whether systemic lithium enhances recovery after RLN injury. Methods: The right RLN was crushed in eight adult rats, and osmotic pumps releasing either lithium or water were implanted. Eight sham-operated animals were also implanted with either lithium or water pumps. Vocal-fold motion was captured by microsuspension laryngoscopy and was measured quantitatively by image analysis at the time of surgery and at one and four weeks. Vocalizations, breathing patterns, and laryngeal electromyography were assessed at four weeks. Results: Cessation of unilateral vocal-fold motion was observed simultaneously with every RLN crush. One week after surgery, 50% of “Crush/Water” animals exhibited full vocal-fold motion, compared to 75% of “Crush/Lithium” and 100% of the sham-operated animals. In animals with unilateral vocal-fold immobility, the quantitative analysis also revealed a subtle decrease of vocal-fold movement on the non-operated side. At four weeks after surgery, vocalizations, breathing patterns, vocal-fold motion, and electromyograms were indistinguishable among all groups. Lithium-treated animals weighed 5% less than water-treated controls. Conclusions: Quantitative endoscopy is a sensitive and efficient tool for detecting vocal-fold impairment in rats. While our results might suggest enhanced recovery in lithium treated animals, all animals showed a rapid return of vocal-fold motion. Perhaps more severe nerve injury is necessary to uncover an effect of lithium on nerve regeneration.

The Rat as a Potential Animal Model for Dysphonia

Objectives: Dysphonia, or hoarseness, is the primary complaint of patients with unilateral vocal-fold paralysis due to damage to the recurrent laryngeal nerve (RLN). Animal models for RLN injury exist but are generally limited to histological, endoscopic, and electrophysiological approaches. As a step towards using the rat as a model system for dysphonia, we have characterized ultrasonic vocalizations in healthy adult animals. Methods: Ultrasonic vocalizations were evoked individually from adult male Sprague-Dawley rats by manual stroking on two different days one month apart. The vocalizations were visualized and recorded by using an ultrasound microphone attached to a computer. Parameters such as duration, amplitude, pitch, and entropy were measured for each vocalization as well as the preceding silent period with Sound Analysis Pro 2011 software. Results: For a total of 980 vocalizations from five rats, the following parameter values (mean ± standard deviation) were obtained: duration, 14 ± 10 msec; amplitude, 13 ± 6 relative units; pitch, 57 ± 7 kHz; and entropy, -3.9 ± 1.0. No differences were noticed among animals or days. However, the vocalizations were distinct from the background noise during the preceding silent period: amplitude, -1.4 ± 2.9 relative units; pitch, 42 ± 6 kHz; and entropy, -1.2 ± 0.9. Virtually none of the vocalizations were located in the 20-kHz band associated with distress. Conclusions: Ultrasound vocalizations can be recorded from adult rats easily and reliably. The features of the vocalizations are consistent among individuals and over time. Experiments with RLN-lesioned animals are now underway.