The respiratory control of carbon dioxide in children and adolescents referred for treatment of psychogenic non-epileptic seizures

Psychogenic non-epileptic seizures (PNES) is a nonspecific, umbrella category referring to non-epileptic seizures that are of presumed emotional or psychological origin, are not explained by neurological disease, and are thought to reflect abnormal central nervous system functioning [1, 2]. PNES are diagnosed following a comprehensive evaluation involving a detailed history and negative finding of ictal electrical activity on electroencephalogram [either video EEG (vEEG) or EEG telemetry] [3]. A limitation of the diagnosis is that the neurophysiological mechanisms underlying the seizures remain unexplained, whereas the current move within neurology and psychiatry is to identify the biological mechanisms that underpin different subtypes of PNES [4‐7].

A growing number of studies have examined the neurophysiological characteristics of patients with PNES. Key findings include: (1) increased baseline arousal indexed by elevated cortisol, elevated heart rate (HR), decreased heart rate variability (HRV) [8‐10]¹; (2) exaggerated neurophysiological responses—lower HRV recovery, increased cortisol release, and increased amplitudes of event-related potentials (ERPs)—to psychological or physiological stress stimuli [8, 14, 15]; (3) increased vigilance, and motor readiness to respond, to emotional signals [8, 11]; (4) changes in connectivity in resting-state brain networks, with alterations in brain circuits mediating emotion regulation and arousal, cognitive control, self-referential processing, and motor planning and coordination [5]; (5) changes in EEG synchrony, both within cortical brain systems and between cortical and subcortical brain systems [16‐19]; (6) arousal-related impairments in prefrontal cortex function [12, 14]; and (7) increased avoidance tendencies to social-threat cues [20]. Taken together, these findings suggest that PNES may emerge in the context of an upregulated stress system and extreme reactivity to psychological or physiological threat stimuli.

Threat stimuli prepare the body for action by mediating increases in arousal, respiration, and motor readiness. Increases in ventilation—indexed by breathing rate and tidal volume—occur alongside a multitude of other changes. When the breathing exceeds metabolic demands—termed hyperventilation (HV)—there is a depletion of CO₂ stores, a respiratory alkalosis (high pH), and biphasic brain response [see Supplemental Text Box 1 (online) for a summary of the neurophysiology of hyperventilation]. An initial excitatory phase is marked by an increase in cortical excitability in widely distributed networks [21, 22]. A subsequent hypoxic phase, mediated by cerebral artery constriction, involves a decrease in cortical function [23‐25]. This hypoxic phase is marked by central symptoms, including: impaired mental performance/gaps in memory; dizziness and lightheadedness; visual phenomena (blurred, clouded, or tunnel vision; flashing lights; or complete blackout); and changes in level of consciousness ranging from disorientation/staring to a complete loss of consciousness (syncope) [23, 26, 27]. The degree of hypoxia is determined by, and proportional to, individual variations in cerebral artery constriction [28, 29]. Because the developing brain is more sensitive to the central effects of HV than the adult brain [25, 30], children/adolescents are likely to be more vulnerable than adults to HV-induced changes in brain function.

In the paediatric literature, PNES secondary to HV have been described in case reports since the 1960s [31‐45], but data from larger cohort studies are sparse. In two Indian studies examining the clinical characteristics of youth referred to psychological services for functional neurological symptom disorder, a quarter of the youth presenting with PNES experienced HV [6/21 (29%) in one study; 6/25 (24%) in the other], with or without fainting spells [40, 41]. A Hungarian study of PNES during vEEG documented HV in 14/75 (18.7%) of child/adolescent patients [46]. In adult studies, approximately 70–83% of patients report multiple panic-like symptoms—presumably accompanied by increased respiratory rate—during PNES [47, 48]. Taken together, the above-described studies suggest that panic-like symptoms or hyperventilation occur in association with some PNES, with some indication that hyperventilation may play a causal role.

The current study used respiratory measures to assess the motor readiness of the respiratory system and the respiratory regulation of CO₂ in children/adolescents referred for treatment of PNES and in controls. We hypothesized that, compared to controls, patients with PNES would show elevated baseline respiratory rates at clinical assessment and aberrant patterns of PCO₂ regulation during the hyperventilation component of the vEEG, including (1) lower baseline resting PCO₂ levels, (2) faster drops in PCO₂, (3) lower PCO₂ levels following 5 min of routine hyperventilation during the vEEG procedure, and (4) less efficient recoveries back to a homeostatic norm (≥36 mmHg) following hyperventilation. We also expected that compared to healthy controls, patients with PNES would show elevated baseline HR, in line with previous findings [10].

The PNES Hyperventilation Study used respiratory measures—baseline respiratory rate at clinical assessment and percutaneous CO₂ monitoring during the hyperventilation component of routine vEEG—to assess motor readiness and CO₂ regulation in children/adolescents with PNES and in controls. Baseline HR was also documented. As a group, patients with PNES had elevated baseline respiratory rates, elevated baseline HR, and skewed HV-challenge profiles, with significantly lower levels of arterial CO₂ at all timepoints of the HV challenge. Symptoms of cerebral hypoxia were also almost five times more frequent in patients with PNES than in controls during the HV challenge. The study findings suggest patients presented in a state of readiness-for-action characterized by high arousal coupled with activation of the respiratory motor system and increases in ventilation. Their CO₂ profiles during the HV challenge were shifted downward away from the homeostatic range, suggesting that excessive activation of the respiratory motor system, coupled with difficulties in regulating CO₂, may contribute to the functional neural mechanisms that underpin PNES.

Although motor activity (mediated by the skeletomotor system) and sympathetic arousal (mediated by the visceromotor system) involve separate neural systems, they are interrelated and activated in a coordinated manner. Activation of the motor system (including its ventilatory component) is always coupled with sympathetic arousal, and sympathetic arousal is always coupled with activation of the motor system (at least an increase in muscle tone) [54‐56]. This close interconnection between motor activation, including ventilation, and sympathetic arousal is a product of brain structure and function; the cortical areas involved in preparing and generating motor (skeletomotor) outputs overlap with those from which sympathetic (visceromotor) outputs originate [56]. Motor activity, including states of motor readiness and motor preparation, are accompanied by concurrent changes in ventilation and sympathetic output that match the metabolic demands of the movement. In the face of perceived threat, increased ventilation and a correlative increase in sympathetic arousal are part of the body’s preparation for action [54, 55]. In our study, however, we found that children/adolescents with PNES had low baseline PCO₂ and failure of PCO₂ recovery back to homeostasis following the HV challenge. These findings indicate overreactivity and dysregulation of the finely tuned interconnections between motor activity and sympathetic arousal. This result matches, in part, the results of our previous studies, in which all children/adolescents with functional neurological symptoms—including the PNES subgroup—showed increased arousal and motor readiness to emotion stimuli. A striking difference in the PNES subgroup, however, is their excessive activation of the respiratory motor system and the associated dysregulation of CO₂ control, which may well contribute to their propensity for PNES.

As noted in the introduction, neurophysiological studies show that patients with PNES demonstrate altered properties in brain networks—changes (both decreases and increases) in the relationship between cortical brain regions that normally function together [5, 16‐19, 57‐59]—resulting in functional disruptions in both the brain’s horizontal integration (between cortical regions) and its vertical integration (between cortical and subcortical regions). These functional disruptions are likely to weaken executive control over motor areas and to prioritize reflexive control of behaviors, thereby enabling release or activation of prewired autonomous motor programs [4]—presumably those that are represented at the level of the basal ganglia, midbrain, and brainstem.

We suggest that in children/adolescents, HV may contribute to functional brain disruptions and, via two different mechanisms, to a propensity to PNES. First, because of the close coupling between respiration and sympathetic arousal, HV-induced increases in cortical arousal could trigger PNES by disrupting cortical executive control over the motor cortex and cortico–basal ganglia–thalamocortical loops. Since children/adolescents with PNES show increased baseline autonomic and cortical arousal [10, 13, 15], even minor elevations in arousal mediated by HV could disrupt cortical control and serve to disrupt cortical integration [60‐62] and trigger PNES. Second, if HV continues beyond the excitatory stage into the hypoxic stage, then hypoxia-related impairments in the cortex and basal ganglia [63] will likewise contribute to dysfunction in top–down control mechanisms within the motor system and to disruptions in the brain’s vertical integration. Because the basal ganglia and brain stem mediate changes in muscle tone and consciousness [64], a subset of PNES patients with HV-induced hypoxia will experience changes in consciousness and losses of muscle tone.

Contrary to our original hypothesis, we found no significant differences between patients with PNES and controls in time to lowest PCO₂ levels and in rates of PCO₂ drop, and the PNES group had a smaller, not greater, ∆PCO₂. These findings are consistent with a downwardly skewed HV-challenge profile, where the ∆PCO₂ was smaller because patients had decreased reserves and reached a floor effect, as evidenced by central symptoms of HV-induced hypoxia. Son et al. [65] likewise found that ∆PCO₂ was not useful in the assessment of EEG slowing (and of the associated cerebral dysfunction) in child/adolescent patients.

All the PNES patients in this study reported stressors prior to the onset of PNES—illness, injury, emotional distress secondary to adverse life events, or psychological trauma. Not all stressors involved psychological distress per se. These findings highlight that from the perspective of the body, the types of stressors that effect brain-body stress systems and that predispose children/adolescents to PNES go well beyond those that are subsumed under the umbrella of “psychogenic”. From the perspective of the body, various stressors—pain, inflammation, and disruptions of the circadian cycle, as well as psychological stress and psychological trauma—may function to activate a sensitized, highly reactive stress system and to change functional organization of the brain [43, 60, 61, 66‐70], with PNES being an unwanted by-product of the body’s response to threat.

This study was carried out as part of our busy routine clinical practice. It has a number of limitations. First, although transcutaneous measures of PCO₂ correlate well with arterial blood levels, the diffusion of CO₂ from the blood to the skin is slow; changes in arterial PCO₂ are registered with a delay of 1–2 min, and sharp changes are blunted [71]. Second, skewed HV-challenge profiles—and trough-PCO₂ levels, in particular—in combination with EEG slowing are an approximate measure of HV-induced neurophysiological changes. In future studies, more direct measures of vasoconstriction/cerebral artery blood flow (via Doppler ultrasound) would help to clarify underlying neurophysiological mechanisms, as would measuring changes in patterns of brain oxygenation (via functional magnetic resonance imaging). Third, no simple, direct measures of cortical arousal are currently available. Techniques to measure such changes on a second-to-second basis would help to clarify underlying neurophysiological mechanisms. Fourth, respiratory rates were measured at clinical assessment but not during the vEEG procedure. That said, arterial CO₂ is the gold standard for measuring HV. Elevated respiratory rates alone (without consideration of tidal volume) can flag the possibility of HV but do not measure it directly. Finally, it would have been useful to collect data about the contribution of disturbed sleep and the menstrual cycle (in 27/60 postpubertal girls) to the upregulation of the stress system [72, 73].

Despite limitations, this study contributes to current research efforts to identify the biological mechanisms that underpin PNES. The study has important implications for assessing and treating PNES in paediatric practice. Children/adolescents with PNES present in a state of increased baseline arousal. In a subset, increased arousal is coupled with excessive activation and reactivity of the motor respiratory system, and in these children/adolescents, PNES can be preceded and triggered by paroxysmal increases in arousal coupled with HV. Identifying patients in whom HV appears to trigger PNES is important because the majority of child/adolescent patients are able to utilize breathing interventions to slow their breathing, downregulate arousal, and avert PNES episodes. Once the PNES have come under control, the children, adolescents, and families are better placed to address the psychological or physiological threats that triggered their PNES in the first place.