INTRODUCTION AND TERMINOLOGY — Infantile spasms are an age-specific epileptic disorder of infancy and early childhood. Children with infantile spasms typically exhibit epileptic spasms along with the electroencephalographic (EEG) pattern known as hypsarhythmia. Infantile spasms were described first by West in 1841 . The triad of spasms, arrest of psychomotor development, and hypsarhythmia is known as West syndrome.
The International League Against Epilepsy has adopted the term "infantile epileptic spasms syndrome (IESS)" to encompass infants presenting with epileptic spasms, with or without fulfilling all of the criteria for West syndrome .
Infantile spasms are an age-specific subset of epileptic spasms. Epileptic spasms can occur in the older patient population as late-onset spasms, as a seizure type in severe epileptic encephalopathies, and in periodic spasms.
The clinical features and diagnosis of infantile spasms are reviewed here. The etiology and pathogenesis, and management and prognosis are discussed separately. (See "Infantile epileptic spasms syndrome: Etiology and pathogenesis" and "Infantile epileptic spasms syndrome: Management and prognosis".)
CLINICAL FEATURES — Infantile epileptic spasms syndrome (IESS), also known as "infantile spasms,” is characterized by epileptic spasms with onset in infancy or early childhood that are usually associated with the electroencephalographic (EEG) pattern of hypsarhythmia, and also developmental regression .
Age of onset — The majority (90 percent) of affected children with infantile spasms present at less than one year of age, typically between 3 and 12 months. The syndromic diagnosis of IESS is applicable if the onset is between 1 month to 2 years of age (figure 1) . Epileptic spasms that present before one month of age should raise concern for other early-onset developmental and epileptic encephalopathies, which are categorized as separate epilepsy syndromes. The true age of onset may be uncertain because infantile spasms may be initially mistaken for other conditions, such as hyperirritability, exaggerated startle responses, and/or colic . (See 'Differential diagnosis' below.)
Infantile spasms — Infantile spasms can involve the muscles of the neck, trunk, and extremities . They are usually symmetric and synchronous, but there can be variant clinical patterns. Two phases of muscle activity typically occur. The first phase consists of sudden, brief contractions of one or more muscle groups. This is followed by a longer tonic phase. The initial phasic contraction lasts less than two seconds. The less intense tonic contraction that follows usually is 2 to 10 seconds in duration. Less often, phasic contraction lasts less than 0.5 seconds and occurs without a tonic phase .
Three clinical types of spasms have been characterized using time-synchronized video and polygraphic recording [5,6]:
●Flexor spasms consist of sudden flexion of the neck, trunk, arms, and legs, and contraction of the abdominal muscles. The latter may be severe enough to cause the torso to jackknife at the waist. The intensity of the contraction and the number of muscle groups involved vary in different attacks and from infant to infant.
●Extensor spasms consist of abrupt extension of the neck and trunk, with abduction or adduction of the arms or legs.
●Mixed flexor-extensor spasms usually consist of flexion of the neck, trunk, and arms, and extension of the legs. Less commonly, they involve flexion of the legs and extension of the arms.
In one report, 5042 infantile spasms in 24 infants were classified as flexor, extensor, and mixed flexor-extensor in 33.9, 22.5, and 42 percent, respectively . Most infants have more than one type of spasm.
The extent and intensity of seizures vary . The ictal event can range from a precipitous, massive contraction of flexor and/or extensor muscles of the neck, trunk, and extremities to an evanescent contraction confined to the rectus abdominis muscles or a brief head nod or subtle eye rolling. Body position can affect the type of spasm.
Motor arrest, or episodes of attenuated responsiveness, sometimes occurs after the spasm and can last as long as 90 seconds. These episodes also can occur independently as a seizure without a preceding motor spasm. Deviation of the eyes or rhythmic nystagmoid eye movements occurs in approximately 55 percent of seizures . Asymmetric spasms occur almost exclusively in patients with focal brain lesions.
Changes in respiratory pattern occur frequently during spasms. Changes in heart rate are rare. A cry or scream frequently occurs after an attack, but it is not considered to be part of the seizure .
Most spasms (80 percent) occur in clusters consisting of 2 to 125 spasms at a rate of as many as 13 per minute . The intensity and frequency of the spasms in each cluster often increase progressively to a peak, then decline until they stop (a crescendo-decrescendo pattern). Although the average duration of an individual spasm is 4 to 10 seconds, a cluster may last for several minutes . Different seizure types may occur within a cluster. Parents may observe a behavioral change at the onset of clusters.
Spasms occur more frequently in the waking state and in the daytime . Clusters tend to occur following arousal, rather than during sleep . One video-EEG monitoring study noted that spasms in younger patients (<3 years) were more frequent between 9 am to noon and between 3 pm to 6 pm, while older children have spasms mostly between 6 am and 9 am . The sleep pattern in affected infants is characterized by frequent arousals during the night. Photic stimulation, handling, feeding, or loud sounds do not precipitate spasms, although they may appear to do so [5,6].
Recognition and accurate reporting of spasms can be difficult for both parents and medical personnel [5,6]. Although massive muscular contractions are easy to recognize, brief contractions confined to the abdominal muscles may be detectable only with video-EEG monitoring. Single spasms and even some clusters may be short lived and can occur on arousal from sleep when the infant is not observed. When parental reports of seizure activity have been compared with video-EEG monitoring, most parents underestimated seizure frequency by 5- to 10-fold .
Other clinical manifestations — Neurodevelopmental delay and/or regression with motor and cognitive manifestations is evident in most patients.
Seizure types other than spasms occur in one-third to one-half of patients with infantile spasms [10,11]. These include focal clonic seizures.
Clinical course — Infantile spasms typically progress through several stages .
●During the initial stage, spasms may occur infrequently and be isolated and relatively mild. Abrupt developmental regression may begin in infants who previously were normal.
●In the next stage, which is the most severe, spasms increase in frequency and appear in series or clusters. As peak activity is reached, hundreds of spasms may occur in a 24-hour period. Developmental regression or arrest is most pronounced during this stage.
●The third stage is characterized by a progressive and sustained decrease in the frequency and severity of spasms, which may be rapid or gradual. Resolution of spasms may be followed by the appearance of other types of seizures.
In a retrospective review of 44 children with untreated infantile spasms, the cumulative spontaneous remission rate of spasms was 2 percent at one month, 5 percent at three months, and 25 percent at 12 months . In most patients, spasms disappear by age three to four years . Other seizure types frequently emerge and persist, and permanent neurodevelopmental disability is common. (See "Infantile epileptic spasms syndrome: Management and prognosis".)
DIFFERENTIAL DIAGNOSIS — The differential diagnosis of infantile epileptic spasms syndrome (IESS) includes colic, gastroesophageal reflux, excessive startles, exaggerated Moro reflexes, repetitive body arching, spasticity, benign myoclonus of early infancy, benign neonatal sleep myoclonus, tonic reflex seizures of early infancy, and self-limited and progressive myoclonic epilepsies [5,6,9]. These conditions also may occur in patients who previously had or currently have infantile spasms.
Visual observation alone often cannot distinguish infantile spasms from other normal and abnormal infant behaviors [5,6]. The random, often abrupt, uncoordinated movements of infants with brain damage may be especially difficult to differentiate from infantile spasms [5,6]. Video-electroencephalography (EEG) monitoring is usually necessary to differentiate these conditions from infantile spasms, evaluate the persistence or recurrence of infantile spasms, or identify other seizures (eg, myoclonic) [5,9].
Benign myoclonus of early infancy — Benign myoclonus of early infancy is a rare condition characterized by brief series of nonepileptic spasms that occur during wakefulness [14-16]. The episodes are characterized by tonic and/or myoclonic activity of the truncal or limb musculature. Spasms typically result in flexion, extension, or abduction of the arms and rarely involve the legs. The neck musculature often is involved with flexor or extensor components and/or aversive jerking movements of the head. Given the wide variability in nonepileptic paroxysmal motor manifestations seen in this condition, some experts use the term Fejerman syndrome for this condition to avoid ambiguity with infantile spasms . (See "Nonepileptic paroxysmal disorders in infancy", section on 'Benign myoclonus of infancy'.)
In contrast to infantile spasms, infants with benign myoclonus of early infancy have normal neurologic examinations, EEGs, and development. The myoclonic episodes typically resolve before the child reaches two years of age and no other seizures develop.
Sleep myoclonus — Benign neonatal sleep myoclonus is characterized by abnormal jerky movements that occur only during sleep . The myoclonus is bilateral, synchronous, and repetitive and affects the distal parts of the upper extremities causing flexion of the fingers, wrists, and elbows, with occasional dorsiflexion of the ankle. In contrast to infantile spasms, infants with sleep myoclonus present within the first week of life and have a normal neurologic examination and EEG. The disorder resolves spontaneously during the child's first year, often within the first three months, with no sequelae. (See "Nonepileptic paroxysmal disorders in infancy", section on 'Benign neonatal sleep myoclonus'.)
Tonic reflex seizures of early infancy — Tonic reflex seizures of early infancy is a nonepileptic movement disorder that presents at one to three months of age . Affected infants have episodes of generalized tonic contraction with extension of all limbs, accompanied by apnea and cyanosis and lasting 3 to 10 seconds. In the initial description, the episodes occurred only when the infants were awake and held in a vertical position . They were provoked by shaking or tactile stimulation. This disorder is distinguished from infantile spasms by the normal ictal and interictal EEGs. The prognosis is good, with spontaneous resolution within one to two months.
Electroencephalography — In an infant with onset of epileptic spasms between the ages of 1 and 24 months (typically 3 to 12 months), the diagnosis of infantile epileptic spasms syndrome (IESS) is confirmed by electroencephalography (EEG) (table 1) . A full EEG evaluation should be of sufficient duration to capture an ictal event and include a full sleep-wake cycle . The recommended approach is an overnight inpatient 24-hour video-EEG. However, if this is not possible, a four- to five-hour EEG study may be sufficient in most cases . Prolonged or repeated monitoring may be required if the initial evaluation is not diagnostic.
Hypsarhythmia — Most affected patients have an interictal EEG pattern known as hypsarhythmia (figure 2). This EEG pattern is a defining feature of infantile spasms [2,3]. The classic pattern of hypsarhythmia consists of very high-voltage, random, slow waves and spikes in all cortical areas [3,22,23]. The spikes vary in duration and location. They appear to originate from one part of the cortex at one moment, then from another or from multiple foci a few seconds later. The spike discharges occasionally are generalized but never are rhythmically repetitive or highly organized, as is the pattern in childhood absence epilepsy, for example. The chaotic appearance of hypsarhythmia suggests significant cortical dysfunction .
Hypsarhythmia is usually seen in the early stages of infantile spasms and can precede the onset of spasms . In some cases, clinical spasms may precede the onset of hypsarhythmia. Longitudinal studies using prolonged monitoring show a highly variable and dynamic EEG pattern . The initial multifocal and chaotic pattern evolves into a more organized pattern known as "modified" or "atypical" hypsarhythmia, which is characterized by features such as greater hemispheric synchronization and symmetry. Variations of this EEG pattern include hypsarhythmia with increased interhemispheric synchronization, an asymmetric pattern, a consistent focus of abnormal discharge, episodes of attenuation (electrodecremental response), and hypsarhythmia composed primarily of high-voltage slow activity with little sharp-wave or spike activity [25,26]. The hypsarrhythmic pattern may disappear with hormonal therapy while the spasms persist [9,25]. Hypsarhythmia tends to disappear later in childhood, sometimes evolving into other abnormal EEG patterns .
The hypsarhythmia pattern changes with the state of the patient, and varies if the infant is awake or in slow-wave quiet (non-rapid eye movement [REM]) or active (REM) sleep [6,9,25]. Patients with hypsarhythmia often have very reduced amounts of non-REM sleep, and as a result, long-term monitoring studies may be required in some cases to capture hypsarhythmia. Of note, hypsarhythmia may only be seen in up to 60 percent of children with epileptic spasms [27,28], and there is poor inter-rater reliability to diagnose hypsarhythmia on EEG .
Due to poor inter-rater reliability for diagnosing hypsarhythmia, some authors have proposed EEG scoring scales and have used the term "epileptic encephalopathy" instead of hypsarhythmia for scoring. The 2021 BASED (Burden of AmplitudeS and Epileptiform Discharges) score was designed to account for the burden of epileptiform discharges and background slowing to help determine whether epileptic encephalopathy is present in the setting of infantile spasms . The 2021 BASED score is not validated or widely used in clinical practice but shows a good inter-rater reliability and can be considered to monitor treatment response.
Other interictal patterns in patients with infantile spasms include focal or multifocal spikes and sharp waves, diffuse or focal slowing, paroxysmal slow or fast bursts, and slow spike and wave . These may occur singly or in combination; the latter EEG features suggest evolution towards Lennox-Gastaut syndrome. It is rare for the interictal EEG to appear normal.
Ictal EEG — An ictal EEG in patients with infantile spasms typically shows a high-voltage, slow-wave transient followed by attenuation of activity (figure 2). Variations in these EEG events do not predict the type of spasm (flexor, extensor, or mixed). Episodes of generalized attenuation (electrodecremental response) also may occur in both waking and sleeping states without clinical evidence of a seizure.
Immediately after either a clinical or electrographic seizure, the EEG sometimes shows a marked decrease of abnormal activity (figure 2) [5,25]. It may transiently appear normal for age. No consistent clinical changes are seen during these periods.
Lateralized findings — Focal or lateralized EEG findings may indicate the presence of a structural brain lesion [26,31]. In one report of 77 patients with infantile spasms, 38 percent had focal or lateralized features on video-EEG . Unilateral hypsarhythmia and asymmetric ictal EEG changes often occurred together. Both of these features consistently indicated the side of a focal or asymmetric structural cerebral lesion that was visible on computed tomography (CT) or magnetic resonance imaging (MRI) of the brain.
Asymmetric EEG changes occur with asymmetric infantile spasms, which is uncommon. Lateralized hypsarhythmia also occurs with bilateral structural lesions that are more severe on one side.
ETIOLOGIC EVALUATION — Clinical evaluation, magnetic resonance imaging (MRI) of the brain, and early screening for genetic/inherited disorders are important components of the etiologic evaluation of children diagnosed with infantile epileptic spasms syndrome (IESS). With contemporary neuroimaging and metabolic and genetic testing, a cause can be identified in the majority (65 to 80 percent) of infants with newly diagnosed infantile spasms [32,33]. (See "Infantile epileptic spasms syndrome: Etiology and pathogenesis", section on 'Etiology'.)
Neuroimaging — Neuroimaging studies should be performed in all patients with infantile spasms to identify lesions associated with the disorder, as this may influence treatment decisions [3,20,34-36].
MRI is the preferred imaging study for all patients with infantile spasms [3,20]. Children younger than one year require special MRI sequences due to immature myelination patterns; these should include high-resolution coronal and axial T2-weighted sequences, along with sagittal, axial, and coronal T1-weighted sequences . Ideally, MRI should be obtained prior to the initiation of therapy, which can sometimes cause imaging changes. If MRI is normal and no other etiology is identified, then repeat imaging at six-month intervals is recommended, particularly if there is not an expected treatment response or if there is clinical deterioration.
MRI may detect cerebral malformations, cerebral atrophy, delayed myelination, and other focal lesions not visible on CT scan . MRI also may provide information regarding prognosis, especially with regard to motor development. Patients with normal findings on MRI have better outcomes compared with those with lesions .
Computed tomography (CT) may demonstrate cerebral atrophy, ventricular enlargement, calcium deposits, tubers, or encephalomalacia. However, CT has a limited role in patients with infantile spasms due to the higher sensitivity of MRI .
Most patients with infantile spasms and symmetric hypsarhythmia have diffuse structural brain diseases that are not lateralized. They rarely have focal or lateralizing features visible on imaging studies. Positron emission tomography (PET) may help identify an etiology in these cases, as illustrated by a study of 140 affected patients referred for evaluation . A specific disease or syndrome was diagnosed at presentation in 9 percent. CT and/or MRI detected lesions in 21 percent of cases without a clinical diagnosis. Among the 97 patients whose underlying condition remained uncertain, PET scanning detected unifocal or multifocal abnormalities in 92 (95 percent). Specialized MRI studies, including magnetization transfer imaging and magnetic resonance spectroscopy, may also identify lesions not visible on a standard MRI.
Metabolic and genetic testing — In the approximately one-third of patients without an obvious cause despite clinical evaluation, electroencephalography (EEG), and MRI, metabolic and genetic testing is useful and can establish an etiology in an additional 10 to 15 percent of cases .
Studies that can establish a metabolic etiology include, among others :
●Urine for organic acids
●Serum for lactate and amino acids
●Cerebrospinal fluid analysis of neurotransmitters, lactic acid, amino acids, folate metabolites, glucose, and glycine
Genetic testing, including whole-exome sequencing, improves the diagnostic yield in infantile spasms . In a study of 44 children with unexplained infantile spasms, whole-exome sequencing was superior to targeted resequencing for identifying potential disease-causing genetic variations . Pathogenic mutations identified in these patients included STXBP1, CASK, ALG13, PNPO, and ADSL. This study demonstrates that infantile spasms are genetically heterogeneous, with a major contribution of de novo mutations.
In a prospective multicenter study that included 251 infants with newly diagnosed infantile spasms, the highest-yield genetic study was the epilepsy gene panel, which resulted in an etiologic diagnosis in 31 percent of patients tested but was performed in <25 percent of infants . Array comparative genomic hybridization (aCGH) was performed in 55 percent of patients and had an etiologic yield of 11 percent. The investigators concluded that a cost-effective evaluation in patients without an obvious cause after clinical history, physical examination, and MRI includes serum lactate, serum amino acids, urine organic acids, and aCGH, followed by an epilepsy gene panel if the microarray is not definitive. Whole-exome sequencing should be considered when all of these studies are unrevealing, but cost may be a limiting factor and larger studies are needed to determine the diagnostic yield.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Seizures and epilepsy in children".)
SUMMARY AND RECOMMENDATIONS
●Clinical features – Infantile spasms, also known as infantile epileptic spasms syndrome (IESS), represent an age-specific convulsive disorder of infancy and early childhood. The triad of infantile spasms, arrest of psychomotor development, and hypsarhythmia is known as West syndrome. (See 'Introduction and terminology' above and 'Clinical features' above.)
•Most children with infantile spasms present between three and seven months of age; onset after 18 months is rare. (See 'Age of onset' above.)
•Spasms are usually symmetric contractions of flexor or extensor axial or limb muscles. They vary in pattern, intensity, duration, and extent. Most spasms occur in clusters of 2 to more than 100 over one to several minutes. (See 'Infantile spasms' above.)
•Spasm or spasm clusters may be unrecognized when they are brief and involve limited musculature. Parents typically underestimate seizure frequency by a factor of 5 to 10. (See 'Infantile spasms' above.)
●Diagnosis – The diagnosis of IESS in an infant with onset of epileptic spasms between the ages of 1 to 24 months (typically 3 to 12 months) is confirmed by electroencephalography (EEG) (table 1). (See 'Diagnosis' above.)
•The EEG should be of sufficient duration to capture an ictus as well as the characteristic interictal pattern of hypsarhythmia. The recommended approach is an overnight, 24-hour, inpatient video-EEG monitoring study. (See 'Electroencephalography' above.)
•Hypsarhythmia on interictal EEG (figure 2) is an important feature of IESS but may not be present in all cases. The classic pattern of hypsarhythmia consists of very high-voltage, random, slow waves and spikes in all cortical areas. The spikes vary in duration and location. Hypsarhythmia varies with the sleep-wake cycle. (See 'Hypsarhythmia' above.)
●Etiologic evaluation – Determining the etiology of IESS is critical to directing treatment and informing prognosis. (See 'Etiologic evaluation' above.)
•Neuroimaging studies should be performed in all patients with infantile spasms; a magnetic resonance imaging (MRI) is the preferred imaging study because it may detect cerebral malformations, cerebral atrophy, delayed myelination, and other focal lesions not visible on CT scan. (See 'Neuroimaging' above.)
•Further metabolic and genetic testing should be performed if an etiology is not identified after clinical evaluation that includes EEG and MRI. (See 'Metabolic and genetic testing' above.)
•The etiology of infantile spasms is reviewed in detail separately. (See "Infantile epileptic spasms syndrome: Etiology and pathogenesis".)
ACKNOWLEDGMENT — The editorial staff at UpToDate acknowledges Daniel G Glaze, MD, who contributed to an earlier version of this topic review.
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