Nonepileptic paroxysmal disorders in infancy

INTRODUCTION — Epilepsy is a condition characterized by an underlying susceptibility for recurrent seizures. The term "seizure" refers to a transient occurrence of signs and/or symptoms due to abnormal excessive neuronal activity of the brain.

Paroxysmal events are common in infancy. In one population-based cohort, they occurred in 9 percent of those in the first year of life [1]. While seizures and epilepsy are commonly considered in the differential, these make up a small fraction (<10 percent) of these events.

Neonates and infants exhibit nonepileptic paroxysmal episodes that differ from those encountered in older children and adults (table 1). These may be difficult to differentiate from epileptic events because of the overlapping clinical features as well as the difficulty in interpreting neonatal and infant electroencephalograms (EEG). It is important for clinicians to be aware of and recognize the transient nonepileptic events that resemble seizures in order to avoid unnecessary treatment and to institute the correct treatment when required.

This topic reviews nonepileptic paroxysmal events in the neonate and infant. The differential diagnosis of epilepsy in other age groups is reviewed separately. (See "Nonepileptic paroxysmal disorders in children" and "Nonepileptic paroxysmal disorders in adolescents and adults".)

NEONATES (BIRTH TO ONE MONTH OF AGE) — Healthy neonates commonly exhibit a variety of paroxysmal movements including nonconjugate eye movements, sucking movements without associated eye abnormalities, and sleep-related myoclonus. These normal behaviors as well as the pathologic conditions discussed below can be difficult to distinguish from epileptic seizures, which can also have somewhat subtle manifestations. Electroencephalography (EEG), particularly video-EEG monitoring, can be invaluable in distinguishing among these entities. In one study of neonates, 90 percent of abnormal movements suspicious for seizures were found to be nonepileptic on EEG recording [2]. (See "Clinical features, evaluation, and diagnosis of neonatal seizures".)

Apnea — Apnea, or a pause in breathing for >20 seconds, is usually not due to an epileptic seizure, particularly if apnea is the sole manifestation. Apneic episodes are common in premature infants during active sleep and are believed to be due to brainstem immaturity. (See "Management of apnea of prematurity".)

Compared with epileptic seizures, episodes of nonepileptic apnea are more likely to include bradycardia and typically do not include tachycardia or significant alterations in blood pressure, body temperature, or skin color [3-8]. A few jerking movements may occur, but the baby does not convulse. An epileptic seizure should be suspected if apnea is accompanied by eye closure or opening, eye deviation, mouth movement, hypertension, or tachycardia.

When apnea occurs in older infants, it may represent a brief resolved unexplained event (BRUE). The history and physical examination in 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)".)

Jitteriness — Jitteriness is a common movement seen in the neonatal period, typically observed as an excessive response to stimulation such as touch or loud noise [3,9,10]. Jitteriness is often associated with drug withdrawal, hypocalcemia, hypoglycemia, and hypoxic-ischemic encephalopathy, conditions that can also produce seizures.

It has a tremulous quality, with a back-and-forth oscillation of equal amplitude and frequency. In contrast to seizures, the child is typically awake during the events and no associated autonomic disturbance is evident. The movement can be lessened by consoling the child, removing the stimulus, or relaxing the affected limb, interventions that do not affect seizure activity. The provocation of events by stimulus is also atypical for seizures. In addition, head or eye deviation during an episode suggests seizure.

Benign neonatal sleep myoclonus — Benign neonatal sleep myoclonus, also called benign sleep myoclonus of infancy, refers to a phenomenon of repetitive myoclonic jerks that occur during non-rapid eye movement (NREM) sleep in the first few weeks of life and resolve spontaneously by two to three months [11-15]. The jerks are typically bilateral, symmetric movements of the arms and/or legs.

Features that help distinguish these myoclonic jerks from epileptic events include [11-14]:

●Absence of autonomic disturbances

●Myoclonic jerks occurring only while asleep

●Normal EEG

●Neurologic and developmental examination

Unlike epileptic seizures, the movements of benign neonatal sleep myoclonus will cease when the baby is aroused. Neonates with severe cerebral dysfunction can also have myoclonic jerks, but these typically occur with a stimulus, or upon wakening or falling asleep.

Hyperekplexia — Hyperekplexia (stiff baby syndrome or startle disease) is a rare genetic disease that has been associated with pathogenic variants in various genes, often affecting glycine receptors [16-18]. (See "Hyperkinetic movement disorders in children", section on 'Hyperekplexia'.)

The disease is characterized by a triad of generalized stiffness while awake, nocturnal myoclonus, and an exaggerated startle reflex. These features are often apparent at birth [17]. Episodes of hypertonia or tonic spasms occur upon awakening or with auditory or tactile stimuli. When severe, these may interfere with breathing and can even cause hypoxic brain injury [19]. Attacks may be resolved by manual flexion of the neck or hips [20]. All these features are atypical for epileptic seizures.

These tonic spasms can also cause older infants to fall suddenly in response to surprise, sensory stimuli, strong emotion, or stress [17]. As a result, walking is often delayed. The spasms lessen in severity and usually disappear as the child grows older, but an excessive startle response may persist throughout life, elicited even by minor visual, auditory, or tactile stimuli.

Clonazepam, a gamma-aminobutyric acid (GABA) receptor agonist, appears to be effective for alleviating hypertonia and apneic episodes [17,18,20]. Phenobarbital, phenytoin, diazepam, and sodium valproate also have been cited in the literature as effective therapies for hypertonia and/or abnormal startle response.

Others — A sodium channelopathy causing episodic laryngospasm, along with face and limb myotonia, has been described in three neonates, each carrying a de novo pathogenic variant in the muscle sodium channel gene SCN4A [21]. Treatment with carbamazepine and mexiletine was successful in eliminating attacks in two cases.

INFANTS (ONE MONTH TO ONE YEAR OF AGE) — The differential diagnosis of epileptic seizures in infancy includes events with a broad range of underlying pathologies. Although clinical symptomatology helps to differentiate these from epileptic seizures, electroencephalography (EEG), particularly video-EEG monitoring, can be invaluable in the diagnosis [22-24]. (See "Seizures and epilepsy in children: Clinical and laboratory diagnosis".)

Breath-holding spells — Breath-holding spells are common events in infants and young children from six months to six years of age [25-28]. Most children (80 to 90 percent) with these spells have their first episode before 18 months of age [29]. Rarely, the first presentation occurs in the neonatal period [30].

The pathogenesis of these syncopal events is not clear. Some studies support a primary role for dysfunction of the autonomic nervous system [26,27,31]. Iron deficiency anemia is more prevalent in children with breath-holding spells compared with controls and might contribute to the occurrence of breath-holding spells and the underlying dysautonomia [31-34]. An association between breath-holding spells and other types of anemia, including transient erythroblastopenia of childhood (TEC), has also been described [35].

A family history of breath-holding spells is present in 20 to 35 percent of patients, and an autosomal dominant trait has been reported in some families [29,36].

The two clinical types of breath-holding spells are cyanotic and pallid. Both family members and individual children can demonstrate both types, but usually one predominates [29].

Cyanotic breath-holding spells — In the cyanotic variety, the child becomes angry or upset in response to a reprimand or a mild injury [28]. 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, which is then often followed by collapse with limpness and loss of consciousness. Cyanosis can appear faster than anticipated with simple breath-holding, and the loss of tone often is 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 [37,38]. Status epilepticus has been reported.

A significant minority of children (15 to 25 percent) have multiple episodes daily [28,29]. 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 [28]. 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, often with incontinence and occasionally low-amplitude clonus. 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. Events may be reproduced with 10 seconds of ocular pressure during electrocardiogram (ECG) monitoring, which produces a typical attack with a profound bradycardia, even asystole, usually lasting 5 to 10 seconds [28]. Cases have been described in which the heartbeat did not return for 30 seconds. If simultaneous EEG monitoring is performed, hypersynchronous, high-amplitude slowing may be observed, followed by flattening if the episode is prolonged.

Diagnosis — There is no diagnostic test that confirms the diagnosis of breath-holding spells. These may be difficult to distinguish from epileptic seizures. A history of any provocation (eg, head injury, crying) should be elicited, as this is typical for breath-holding spells but not epileptic seizures. Prominent color change (pallor or cyanosis) also suggests breath-holding spells rather than seizures. As with other nonepileptic events, video-EEG monitoring can be helpful in difficult cases.

Other causes of syncope also should be considered. 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, a more in-depth cardiac evaluation, particularly for prolonged QT syndrome, is indicated [39]. (See "Causes of syncope in children and adolescents".)

Because iron deficiency anemia is highly associated with breath-holding spells, evaluation with complete blood count and serum ferritin is warranted in these children [35,40]. 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".)

Prognosis and treatment — The prognosis for children with breath-holding spells is excellent [29]. The median age of remission is four years; virtually all children stop having episodes by eight years [27-29,41]. Neurologic development is normal [42].

Iron supplementation in individuals with iron deficiency or iron deficiency anemia appears to reduce the frequency of breath-holding attacks, according to observational studies and one clinical trial [36,40,43,44]. Complete remission of spells reportedly occurs in 32 to 52 percent. A typical dose is 5 to 6 mg/kg per day of elemental iron given in three divided doses using ferrous sulphate [40]. The duration of treatment should be individualized according to the improvement of clinical episodes and the anemia. The value of iron supplementation in children with breath-holding spells who are not anemic has not been well studied [44].

Theophylline treatment may also reduce the frequency of breath-holding spells, as suggested by the findings of several retrospective reports [45-47].

Antiseizure medications are not helpful in reducing the breath-holding spells and may or may not prevent secondary anoxic seizures if these are frequent [29,48]. The gamma-aminobutyric acid (GABA)-derivative piracetam (40 or 50 mg/kg per day in two divided doses) was shown in two randomized trials (one unblinded) to reduce the frequency of breath-holding spells [49,50]. Piracetam is not available in the United States.

In rare patients with severe attacks of pallid infantile syncope associated with prolonged, severe bradycardia or asystole, atropine and cardiac pacing have been employed to reduce the frequency of spells [29,51,52].

Jitteriness — Mild degrees of jitteriness are common in healthy infants [53]. More severe jitteriness can interfere with feeding and other aspects of normal infant care.

Benign myoclonus of infancy — Benign myoclonus of infancy is also known as benign nonepileptic infantile spasms. The spasms can manifest as myoclonus, spasms with brief tonic contractions, shuddering, and/or atonia (negative myoclonus) [54]. Spasms occur in clusters, frequently at mealtime. First occurring at three to eight months of age, these clusters increase in intensity and severity over weeks or months and then remit spontaneously at two to three years of age [55,56].

The clinical features of these attacks may be clinically indistinguishable from other types of progressive infantile spasms associated with developmental delay and epileptic seizures, although they typically occur only while awake [54,55,57].

Benign myoclonus of infancy can be identified by a normal EEG and normal neurologic development without subsequent epilepsy. (See "Infantile epileptic spasms syndrome: Clinical features and diagnosis".)

Sleep-related rhythmic movement disorder — Rhythmic movements such as nocturnal head banging, body rocking, and head rolling typically occur in children younger than one year of age as they try to fall asleep [12,58,59]. They also can be present in deep sleep and in wakefulness. Episodes usually begin in infancy and resolve by five years of age, but can persist into adult life. The characteristic nature of the movements is not typical for epilepsy, and patients often can be directed to stop the movements, which is generally not true for an epileptic seizure. (See "Sleep-related movement disorders in childhood", section on 'Rhythmic movement disorder'.)

Shuddering attacks — Shuddering attacks usually begin in infancy, less commonly in childhood. These brief episodes of altered muscle tone often manifest as a rapid tremor of the head, shoulder, and trunk reminiscent of a "shudder" or "shiver" from a chill. There may be stiffening, flexion, and elevation of the arms with a low-amplitude tremor [60]. If seated, the child may lean in one direction or even fall. The child may stare, appear to be unaware of the surroundings, and then promptly return to the task at hand [61].

The episodes last a few seconds and can occur multiple times a day [60,62]. The spells often occur with feeding or when the child is excited or distressed, suggesting they are a pattern of stimulus overflow in a young child. They never occur during sleep and virtually never when being held and cuddled.

The EEG during the spells is normal [60,61]. Neurologic and developmental examinations also are normal.

The episodes may continue at lower frequency into the second half of the first decade and can, on rare occasions, cause the child to fall in the middle of activities such as playing ball. Occasionally, a family history of benign essential tremor exists, but the children themselves do not have a chronic tremor [63]. The spells spontaneously resolve by the second decade without treatment.

Sandifer syndrome — Sandifer syndrome refers to the intermittent paroxysmal spells of generalized stiffening and opisthotonic posturing that are caused by gastroesophageal reflux in infants [64,65]. The posturing likely reflects a pain response to acidic reflux into the esophagus [62]. These spells may be associated with apnea, staring, and minimal jerking of the extremities [66]. A careful history will reveal that these spells are associated with feedings, usually occurring within 30 minutes following a meal. Sandifer syndrome can be seen in otherwise healthy children as well as children with hypotonia and tracheomalacia.

If the history suggests Sandifer syndrome, a gastroesophageal work-up should be considered [62,65]. Treatment of gastroesophageal reflux reduces the frequency and severity of attacks. (See "Clinical manifestations and diagnosis of gastroesophageal reflux disease in children and adolescents" and "Management of gastroesophageal reflux disease in children and adolescents" and "Acquired torticollis in children", section on 'Sandifer syndrome'.)

Dystonia — Dystonia is an abnormal posture due to sustained contraction of both the agonist and antagonist muscle groups. A dystonic posture may be generalized or focal; examples include opisthotonic posturing, torticollis, and oculogyric crisis.

A common etiology of dystonia in infants is an acute reaction to a drug such as metoclopramide, phenothiazines, or haloperidol. (See "Hyperkinetic movement disorders in children", section on 'Acute dystonic reaction'.)

Benign paroxysmal torticollis in infancy — This is an idiopathic disorder, characterized by periods of an abnormal, sustained posture of the head and neck in which the head tilts to one side, with the face rotated toward the opposite side. The events begin and end suddenly, with a duration between a few hours and a few days. The child is alert and responsive during an attack. (See "Acquired torticollis in children", section on 'Benign paroxysmal torticollis'.)

Episodes usually first occur in the first three months of life and may recur at varying intervals, resolving by the age of three years in most cases [67-69]. EEG and neurologic examinations are normal, as is subsequent neurologic development; any delays in motor development improve with resolution of episodes [69]. No treatment is required.

A relationship between this disorder and migraine is suggested. A family history of migraines is common in children with this disorder and they may develop migraine later in life [68,69]. In one family, benign paroxysmal torticollis appeared to be associated with inheritance of a pathogenic variant in the CACN1A gene, which is also linked to familial hemiplegic migraine [70].

Abnormal eye movements — Oculomotor apraxia is a condition with impaired saccadic eye movements in which the child will turn their head suddenly to move the direction of gaze. These peculiar rapid head movements are rarely mistaken for epileptic seizure. Oculomotor apraxia may be seen in ataxia-telangiectasia and lysosomal diseases. (See "Ataxia-telangiectasia", section on 'Differential diagnosis'.)

Spasmus nutans consists of a triad of nystagmus, head nodding (titubation), and head tilt. When the symptoms fluctuate during the day, they may be confused with epileptic seizures. Consciousness is not impaired. The onset is usually the first few months of life and resolves by five years of age. (See "Pendular nystagmus", section on 'Spasmus nutans'.)

Opsoclonus consists of rapid, erratic, involuntary conjugate eye movements ("dancing eyes"). These eye movements are usually associated with myoclonus and ataxia, also described as dancing eyes-dancing feet syndrome. Most cases occur between ages 6 and 18 months. Fifty percent of cases are related to an underlying neoplasm, especially neuroblastoma [71,72]. (See "Clinical presentation, diagnosis, and staging evaluation of neuroblastoma" and "Hyperkinetic movement disorders in children", section on 'Myoclonus'.)

SUMMARY

●Overview – The differential diagnosis of epileptic seizures in neonates and infants includes a variety of benign, physiologic phenomena as well as pathologic conditions (table 1). Some of these conditions can persist into childhood and longer. (See 'Introduction' above.)

●Distinction from seizures – Clinical features of the events, the setting in which they occur, and the presence or absence of provocation help distinguish these events from epileptic seizures. The history and physical examination should probe for associated features including change in vital signs, color change, autonomic disturbances, loss of consciousness, and head and eye deviation. In challenging cases, electroencephalography (EEG), particularly video-EEG monitoring, is useful in the diagnostic evaluation. (See "Clinical features, evaluation, and diagnosis of neonatal seizures" and "Seizures and epilepsy in children: Clinical and laboratory diagnosis".)

●Neonates – Healthy neonates commonly exhibit a variety of physiologic paroxysmal movements during both wakefulness and sleep. Pathologic conditions in neonates that can have overlapping features or be difficult to distinguish from epileptic seizures include apnea, jitteriness, benign neonatal sleep myoclonus, and hyperekplexia. (See 'Neonates (birth to one month of age)' above.)

●Infants

•Breath holding – Breath-holding spells are common events in infants and young children from six months to six years of age that can be mistaken for epileptic seizures. The two clinical types are cyanotic and pallid. Both types are typically preceded or provoked by an injury or emotional upset. (See 'Breath-holding spells' above.)

•Sleep-related disorders – Benign myoclonus of infancy and sleep-related rhythmic movement disorder should be considered when events are confined to sleep or the transitions between wakefulness and sleep. (See 'Benign myoclonus of infancy' above and 'Sleep-related rhythmic movement disorder' above.)

•Shuddering attacks – Shuddering attacks last a few seconds and often occur with feeding or when the child is excited or distressed, suggesting they are a pattern of stimulus overflow in a young child. (See 'Shuddering attacks' above.)

•Increased muscle tone – Nonepileptic events that involve stiffening or sustained changes in head or limb tone and posture include Sandifer syndrome, which occurs in response to gastroesophageal reflux, and dystonias, which include a variety of conditions that produce paroxysmal eye and/or head movements. (See 'Sandifer syndrome' above and 'Dystonia' above and 'Abnormal eye movements' above.)

●Older children and adolescents – Separate topics discuss paroxysmal movement disorders in older age groups. (See "Nonepileptic paroxysmal disorders in children" and "Nonepileptic paroxysmal disorders in adolescents and adults".)