Traditional concepts of breath-holding spells invoked clearly distinct mechanisms for cyanotic and for pallid spells. Cyanotic breath-holding spells were thought to result from oxygen desaturation during a period of apnea. Pallid spells were thought to be mediated by vagally-mediated bradycardia or asystole. Loss of consciousness in either type was attributed to transient cerebral ischemia as a result of the Valsalva maneuver and hypocapnia (Emery 1990).
However, there appears to be evidence of parasympathetic reflex cardio-respiratory inhibition in both types, as well as subtle generalized autonomic dysregulation (DiMario and Burleson 1993; Anil et al 2005; Kolkiran et al 2005). Furthermore, mixed and cyanotic breath-holding spells have a complex pathogenesis involving interactions among hyperventilation, end-expiratory apnea, increased intrathoracic pressure, and intrinsic pulmonary mechanisms (Breningstall 1996). This “autonomic dysregulation” may be detected in some patients by a high resting heart rate and diastolic blood pressure, positive orthostatic signs, as well as hypersensitivity of pupils to pilocarpine instillation (Anil et al 2005).
“Excessive vagal tone” or “vagal overactivity” related to autonomic dysregulation (Lucet et al 2000; Kolkiran et al 2005) is currently believed to be the primary biological basis of breath-holding spells. Numerous investigators have proposed that there is dysfunction of the autonomic nervous system in infants and children who have breath-holding spells. Recent studies in a small group of children with pallid breath-holding spells showed a significant decrease in mean arterial blood pressure and increase in pulse rate during the change from lying to standing (DiMario et al 1990; DiMario and Burleson 1993). Findings further suggested greater sympathetic activity in children with cyanotic breath-holding spells.
DiMario and colleagues demonstrated a marked difference in respiratory sinus arrhythmia in children with pallid breath-holding spells when compared to controls or subjects with cyanotic breath-holding spells. This suggested that autonomic dysregulation in pallid breath-holding spells is “caused by a primary central parasympathetic disturbance distinct from the dysregulation found in cyanotic breath-holding spells” (DiMario et al 1997).
Some investigators maintain that children with breath-holding spells are more likely to have a positive ocular compression test (Stephenson 1978; Lucet et al 2000). Ocular compression (triggering the oculovagal or oculocardiac reflex) can provoke periods of asystole and clinical episodes in as many as one-half of these patients, a finding that suggests hyperreactivity of the vagal nucleus (DiMario et al 1990). An abnormal oculocardiac reflex, manifested by significant slowing of the heart rate and lengthening of the beat-to-beat interval, is present in most children with pallid breath-holding spells and in many with cyanotic spells (DiMario et al 1997).
Ocular compression also induced longer asystoles in infants with pallid breath-holding spells, compared to those with cyanotic breath-holding spells (Kahn et al 1991). Vagal mediation of pallid breath-holding spells is further suggested by the observation that atropine can sometimes mitigate this abnormal response to ocular compression (Maulsby and Kellaway 1964; Lombroso and Lerman 1967). It is unlikely, however, that autonomic dysregulation exerts its primary clinical effect on the heart. DiMario and colleagues has postulated that significant arteriovenous shunting at peripheral sites may precipitate breath-holding spells (DiMario et al 1997).
Stephenson has recently reviewed the use of ocular compression during EEG (Stephenson 2007). This procedure has been reported as useful in distinguishing breath-holding spells and syncope from epileptic seizures. However, Stephenson argues that use of this procedure is not an appropriate way to obtain a diagnosis of episodic loss of consciousness in children. Accurate and thorough clinical history remains the mainstays of diagnosis.
Disturbances of respiration during sleep have also been noted in infants with breath-holding spells. A polysomnographic study of infants with breath-holding spells, compared with age-matched controls, disclosed that the breath-holding infants (1) were more likely to be covered with sweat during sleep or wakefulness, (2) had significantly less NREM sleep, more indeterminate sleep, more arousals, and more sleep-stage changes, and (3) had more brief airway obstructions and snoring during sleep (Kahn et al 1990).
More recently, Guilleminault and colleagues demonstrated in 14 children with cyanotic breath-holding spells, that sleep-disordered breathing and abnormal respiratory disturbance index may be present during polysomnography, related to the presence of a narrow upper-airway. Surgical intervention with adenotonsillectomy eliminated sleep disordered breathing in this group of children (Guilleminault 2007).
Another study showed decreased average numbers of both REMs and bursts of REMs in REM sleep in children with breath-holding spells. The authors hypothesized that because REMs in REM sleep are presumed to be generated in the brain stem, a functional brainstem disturbance may be involved in the occurrence of breath-holding spells (Kohyama et al 2000).
Some children with breath-holding spells appear to be able to voluntarily hold their breath beyond the point at which most individuals feel an overwhelming urge to breathe. However, ventilatory chemosensitivity (increase in breathing in response to hypercapnia or hypoxia) is similar in individuals with and without a history of cyanotic breath-holding in infancy (Anas et al 1985).
The presence of lower hemoglobin values in children with breath-holding spells (Holowach and Thurston 1963; Bhatia et al 1990) and improvement in or amelioration of spells with oral iron therapy (Lombroso and Lerman 1967; Colina and Abelson 1995; Daoud et al 1997; Tam and Rash 1997; Zubcevic et al 2000), suggests that anemia may be a contributing factor. The study by Daoud and colleagues further suggests that iron deficiency, with or without anemia, may adversely affect autonomic function (Daoud et al 1997).