Breath-holding spells

INTRODUCTION — 

Breath-holding spells (BHS) are frightening but innocuous episodic events that can affect infants and young children. The two clinical types are cyanotic and pallid. Both types are typically preceded or provoked by an injury or emotional upset. Brief unresponsiveness, loss of consciousness, or seizures may result.

This topic will review BHS. Other nonepileptic paroxysmal disorders in infants and children (table 1) are reviewed separately. (See "Nonepileptic paroxysmal disorders in neonates and infants" and "Nonepileptic paroxysmal disorders in children".)

PATHOGENESIS — 

The pathogenesis of BHS events is not clear. Some studies support a primary role for dysfunction of the autonomic nervous system [1-3]. Iron deficiency anemia is more prevalent in children with BHS compared with controls and might contribute to the occurrence of BHS and the underlying dysautonomia [3-6]. An association between BHS and other types of anemia, including transient erythroblastopenia of childhood (TEC), has also been described [7]. Other possible mechanisms include vagally mediated cardiac inhibition and delayed myelination of the brainstem [8,9].

A family history of BHS is present in 20 to 35 percent of patients, and an autosomal dominant trait has been reported in some families [10,11].

EPIDEMIOLOGY — 

BHS are relatively common events in otherwise healthy infants and young children.

Most children (80 to 90 percent) with these spells have their first episode between 6 and 18 months of age [8,10]. However, onset may occur from the neonatal period to five years of age [12]. The prevalence of BHS in this age group ranges from 0.1 to 4.6 percent in different studies [8,13-16].

CLINICAL MANIFESTATIONS

Common features across subtypes — BHS occur only during wakefulness and have the following characteristic features:

●Trigger – Almost all BHS are associated with precipitating factors, typically an emotion (eg, anger, frustration, fear), pain, or minor head trauma.

●Apnea – Involuntary apnea at end of expiration is a defining feature of BHS.

●Color change – The two clinical types of BHS are cyanotic and pallid, based upon the color of the face or lips during a spell. Both family members and individual children can demonstrate both types (mixed), but usually one predominates [10]. (See 'Cyanotic breath-holding spells' below and 'Pallid breath-holding spells' below.)

●Crying – Crying often precedes the color change in cyanotic BHS, while crying may be minimal or "silent" in pallid BHS [8].

●Unresponsiveness and/or loss of consciousness – These are common (but not universal) features of BHS, and are considered markers of severe spells [16].

●Seizure semiology – BHS may be accompanied by atonic, tonic, tonic-clonic, and/or myoclonic seizure activity [16].

●Duration of spell – Most BHS last from 10 to 60 seconds [8].

●Recovery period – Recovery from a BHS often occurs quickly without a postictal phase, but a significant proportion of BHS cases have a postictal phase of tiredness, confusion, or decreased responsiveness lasting 15 to 30 minutes or longer [16].

Cyanotic breath-holding spells — In the cyanotic variety, the child becomes angry or upset in response to a reprimand or a mild injury [17]. The precipitant is often minimal, even trivial. There is a brief period of crying, typically followed quickly by breath-holding in forced expiration with apnea and cyanosis, often followed by collapse with limpness and loss of consciousness. Cyanosis can appear faster than expected with simple breath-holding, and the loss of tone is often striking. The sequence is quite stereotyped and reproducible.

If the apnea is prolonged, there may be other clinical manifestations, including decorticate or decerebrate posturing. A few children have generalized motor seizures characterized by increased tone followed by loss of tone or clonic activity and prolonged postictal unconsciousness [18,19]. Status epilepticus has been reported.

A significant minority of children (15 to 25 percent) have multiple episodes daily [10,17]. Most children have one to six spells per week.

Pallid breath-holding spells — Pallid infantile syncope is less common than the cyanotic variety and is more likely to be mistaken for a seizure. The child typically loses consciousness after a minor fall or blow to the head or upper body [15,17]. Often, this history is not volunteered by the family or caregivers and must be elicited by direct questioning. The loss of consciousness may be delayed up to 30 seconds after the minor trauma, obscuring the connection between the two events. The child then stops breathing and becomes pale, diaphoretic, and limp. If the episode lasts more than a few seconds, this is followed by generalized increased tone of the trunk and extremities and occasionally low-amplitude clonus. Tongue biting and incontinence can occur when seizures are associated with a BHS. The entire episode lasts less than one minute, but the child is confused and/or sleepy for several minutes afterward.

The event is caused by cardiac bradycardia. If simultaneous electroencephalography (EEG) monitoring is performed, hypersynchronous, high-amplitude slowing may be seen, followed by flattening if the episode is prolonged.

EVALUATION AND DIAGNOSIS

Making the diagnosis — The diagnosis of BHS is based upon the clinical history and is made in an infant or young child with one or more spells matching the characteristic features of BHS (algorithm 1) [8]. Home cell phone or baby monitor video recordings can aid in confirming the diagnosis.

There is no confirmatory diagnostic test, and testing for other conditions is not required for infants with typical BHS. A history of any provocation (eg, head injury, crying) should be elicited, as this is typical for BHS but not epileptic seizures. Prominent color change (pallor or cyanosis) also suggests BHS rather than seizures. (See 'Differential diagnosis' below.)

Evaluation for anemia — Since iron deficiency anemia is associated with BHS, evaluation with complete blood count and serum ferritin is warranted [7,16,20]. A blood lead level should also be measured in children who are found to be anemic if it has not been done recently. (See "Iron deficiency in infants and children <12 years: Screening, prevention, clinical manifestations, and diagnosis".)

Role for other investigations — Most infants and young children with BHS and a normal physical and neurologic examination do not require any additional studies. In particular, EEG is not indicated in typical BHS, and electrocardiography (ECG) is infrequently indicated [16,21]. However, a more in-depth cardiac evaluation, particularly for prolonged QT syndrome, may be warranted if the episodes are prolonged or frequent, precipitated by startle or other nontraumatic stimuli, or if a family history of syncope or sudden death exists [22]. Video-EEG monitoring can be helpful in difficult cases when BHS have atypical features and are difficult to distinguish from epileptic seizures. (See 'Differential diagnosis' below.)

DIFFERENTIAL DIAGNOSIS — 

The differential diagnosis of BHS includes the following:

●Epilepsy – Some BHS are accompanied by convulsive activity, which is typically brief (<1 minute in most cases) and associated with a short or no postictal recovery period. Seizures are usually longer than one minute with a postictal phase lasting minutes to hours. A key distinguishing feature is that seizures with epilepsy are unprovoked, whereas seizures with BHS are nearly always triggered by a precipitating factor (anger, fear, minor trauma) that is usually obvious to observers. Unlike epileptic seizures, BHS are associated with crying and color change (cyanosis or pallor) prior to loss of consciousness or seizure activity, and BHS are not associated with an aura, tongue biting, or incontinence and never occur during sleep.

●Hyperekplexia – Hyperekplexia (stiff baby syndrome or startle disease) is a rare genetic disorder characterized by generalized stiffness during wakefulness, exaggerated startle reflex, and nocturnal myoclonus, features that are not seen with BHS. Severe attacks may interfere with breathing. (See "Nonepileptic paroxysmal disorders in neonates and infants", section on 'Hyperekplexia'.)

●Syncope – Syncope is defined as a sudden, brief loss of consciousness associated with a loss of postural tone with spontaneous recovery. Note that pallid BHS is a form of syncope. Other causes of syncope should be considered in the differential diagnosis of BHS, including vasovagal syncope (including reflex precipitants such as swallowing, hair grooming, and micturition), cardiac arrhythmias (eg, long QT syndrome), congenital heart disease, and orthostatic hypotension. (See "Causes of syncope in children and adolescents".)

●Brief resolved unexplained event (BRUE) in infancy – BRUE is not a specific diagnosis but a description of a sudden, brief, resolved episode characterized by an unexpected change in breathing, appearance, or behavior (ie, cyanosis or pallor; absent, decreased, or irregular breathing; marked change in tone [hyper- or hypotonia]; and/or an altered level of responsiveness) (table 2). The history and physical examination of infants who have experienced BRUE should identify features that suggest a specific cause of the event (eg, choking/laryngospasm or an upper respiratory infection) or characteristics that suggest a higher risk for having a serious underlying disease. The evaluation and management of BRUE are reviewed in detail separately. (See "Acute events in infancy including brief resolved unexplained event (BRUE)".)

MANAGEMENT

Education and reassurance — BHS with loss of consciousness or seizure activity are frightening to witness but are typically benign. Education and reassurance of the family and caregivers about the innocuous nature of the spells is the mainstay of management [8]. Family and caregivers should be instructed in positioning and noninvasive maneuvers to maintain the airway and prevent aspiration in patients with BHS who have loss of consciousness or seizure activity [8]. Antiseizure medications are not indicated [8]. They are not helpful in reducing the BHS and may or may not prevent secondary anoxic seizures if these are frequent [10,23].

Iron supplementation — For infants and children with BHS and iron deficiency, we treat with iron supplementation using ferrous sulfate. Some experts treat all children who have BHS with iron supplementation, including those without iron deficiency. Additional measures include dietary counseling to ensure adequate intake of iron and avoid dietary risk factors such as excessive milk intake. (See "Iron deficiency in infants and children <12 years: Screening, prevention, clinical manifestations, and diagnosis".)

●Dose – A typical dose is oral ferrous sulfate 3 mg/kg given once daily in the morning or between meals. (See "Iron deficiency in infants and children <12 years: Screening, prevention, clinical manifestations, and diagnosis", section on 'Empiric trial of iron therapy' and "Iron deficiency in infants and children <12 years: Treatment".)

The duration of treatment should be individualized according to the improvement of clinical episodes and the anemia.

●Efficacy – Iron supplementation in individuals with iron deficiency or iron deficiency anemia appears to reduce the frequency of BHS. In a meta-analysis of two trials with 87 children, reduction or resolution of BHS was more frequent with iron supplementation compared with placebo or no treatment (91 versus 14 percent; odds ratio 76.5; 95% CI 15.7-373.7) [24]. However, confidence in these results is reduced by methodologic limitations regarding uncertain allocation concealment in both trials and lack of blinding in one trial. In observational studies, iron supplementation has been associated with complete remission of spells in 32 to 52 percent of patients with BHS [11,20,25,26].

Although not well studied, iron supplementation has also been associated with improvement in BHS in children without iron deficiency [24,26,27].

Other interventions — Although high-quality evidence is lacking, other interventions have been tried for patients with severe and/or frequent BHS that are refractory to iron supplementation [8]. As examples, several retrospective studies and case reports suggest that theophylline treatment may reduce the frequency of BHS [28-31]. Piracetam treatment (not available in the United States) was associated with a reduced frequency of BHS in three small trials (one unblinded) [13,32,33]. In rare patients with severe attacks of pallid infantile syncope associated with prolonged, severe bradycardia or asystole, atropine and cardiac pacing have been employed [10,34,35].

PROGNOSIS — 

The prognosis for children with BHS is excellent [8]. The median age of remission is four years; virtually all children stop having episodes by eight years of age [2,10,17,36]. Neurologic development is normal [37]. However, limited evidence suggests that children with BHS may have an increased frequency of syncopal events later in life [10,16,38,39]. (See "Causes of syncope in children and adolescents", section on 'Breath holding spells'.)

SUMMARY AND RECOMMENDATIONS

●Epidemiology – Breath-holding spells (BHS) are relatively common events in otherwise healthy infants and young children. The age of onset ranges from the neonatal period to five years of age, but usually occurs between 6 and 18 months of age. (See 'Epidemiology' above.)

●Clinical manifestations – BHS occur only during wakefulness and have the following characteristic features (see 'Clinical manifestations' above):

•Trigger – Almost all BHS are associated with precipitating factors, typically an emotion (eg, anger, frustration, fear), pain, or minor head trauma.

•Apnea – Apnea at end of expiration is a defining feature of BHS.

•Color change – The two clinical types of BHS are cyanotic and pallid, based upon the color of the face or lips during a spell. (See 'Cyanotic breath-holding spells' above and 'Pallid breath-holding spells' above.)

•Crying – Crying often precedes the color change in cyanotic BHS but may be minimal or "silent" in pallid BHS.

•Unresponsiveness and/or loss of consciousness – These are common (but not universal) features of BHS.

•Seizure semiology – BHS may be accompanied by atonic, tonic, tonic-clonic, and/or myoclonic seizure activity.

•Duration of spell – Most BHS last from 10 to 60 seconds.

•Recovery period – Recovery often occurs quickly with a brief or no postictal phase, but a considerable proportion of cases have a postictal phase lasting 15 to 30 minutes or longer.

●Evaluation and diagnosis – The diagnosis of BHS is based upon the clinical history (algorithm 1). There is no confirmatory diagnostic test. Since iron deficiency anemia is associated with BHS, evaluation with complete blood count and serum ferritin is warranted. Most infants and young children with BHS and a normal physical and neurologic examination do not require any additional studies. (See 'Evaluation and diagnosis' above.)

●Differential diagnosis – The differential diagnosis of BHS includes epilepsy, hyperekplexia, syncope, and brief resolved unexplained event (BRUE) in infancy. (See 'Differential diagnosis' above.)

●Management – The management of BHS involves education, reassurance, and iron supplementation (algorithm 1).

•Education and reassurance – BHS with loss of consciousness or seizure activity are frightening to witness but are typically benign. Education and reassurance of the family and caregivers about the innocuous nature of the spells is the mainstay of management. (See 'Education and reassurance' above.)

•Iron supplementation – For infants and children with BHS and iron deficiency, we treat with iron supplementation using ferrous sulfate. (See 'Iron supplementation' above and "Iron deficiency in infants and children <12 years: Screening, prevention, clinical manifestations, and diagnosis" and "Iron deficiency in infants and children <12 years: Treatment".)

●Prognosis – The prognosis for children with BHS is excellent. The median age of remission is four years, and virtually all children stop having episodes by eight years. Neurologic development is normal. (See 'Prognosis' above.)