Infantile spasms, also known as infantile epileptic encephalopathy (IEE), is a severe form of childhood epilepsy that typically manifests within the first year of life and appears to be tied to a particular neurodevelopmental period. A high-amplitude, chaotic interictal electroencephalographic (EEG) background, known as hypsarrhythmia, is often seen in association with infantile spasms. In the wake of infantile spasms, the majority of children are left with significant cognitive delay. The triad of infantile spasms, developmental arrest or regression, and the characteristic EEG background of hypsarrhythmia has been dubbed West syndrome, after the English physician William West, who first provided a detailed description of spasms in 1841, as seen in his 4-month-old son.¹ The broader term epileptic spasms is sometimes used to denote events of a similar semiology that tend to present in a slightly older age range and are not associated with hypsarrhythmia on EEG.

The incidence of infantile spasms has been estimated to be between 0.25 and 0.42 per 1000 live births, with a slight predilection toward male infants over female.² Higher geographic latitudes have been noted to be associated with a higher incidence of infantile spasms, although the extent to which this relationship may be due to environmental versus ethnic factors is unknown. The prevalence of infantile spasms ranges from 0.14 to 0.52 per 1000 children.³ Individuals tend to be affected sporadically by the disorder; only 1 to 7% of patients with infantile spasms have a family history of any type of epilepsy.

Infantile spasms typically appear abruptly between the ages of 3 months and 1 year, with the peak age of onset ∼4 to 6 months and 90% of onsets prior to 12 months of age.⁴ Only 8% of children present after 2 years of age.^4,5 Early onset is generally associated with increased mortality and poorer overall prognosis. Other seizure types, particularly partial seizures in cases of symptomatic infantile spasms, may precede, occur concurrently with, or follow the spasms. During the transitional period between infantile spasms and other seizure types, within one seizure episode a cluster of spasms may culminate in a focal seizure. The reverse may also be true, with an initial partial seizure triggering a series of spasms. In addition, the individual spasms may take on partial or tonic features, with asymmetric limb or head movements.

Normal neurologic development is often reported prior to the onset of infantile spasms, although children whose spasms are symptomatic of other underlying causes may exhibit a baseline delay. However, a global decline becomes evident with the appearance of spasms. A marked decrease is commonly present in social interaction and responsiveness to sensory, particularly visual, stimuli. In line with these autistic tendencies, language delay is often seen later in development. In addition, axial hypotonia is reflective of a similar decline in motor functioning.

Although infantile spasms may occasionally persist into childhood, and in rare cases into adulthood, the spasms typically cease within a few years, with or without treatment. Of affected children, 17 to 54% transition to Lennox-Gastaut syndrome (LGS), which is manifested by multiple seizure types and an EEG with slow spike-wave background. Correspondingly, 20 to 40% of children with LGS have a history of infantile spasms.⁶ In addition, spontaneous remission of infantile spasms has been reported in up to 25% of patients within 1 year of onset.⁷

In spite of the self-limited nature of the spasms themselves, the overall prognosis of infantile spasms is often quite poor, with early studies from the 1960s of untreated patients reporting 75 to 96% with subsequent mental retardation.^5,8 At 20 to 35 years of follow-up, only 17% of patients treated for infantile spasms in the 1960s and 1970s had normal intelligence in a Finnish study. An additional 7% had slightly impaired intelligence.⁴ The bulk of those patients with good outcome occurred in the small subset of patients who had normal development prior to spasm onset and no apparent epileptogenic etiology. In studies of cryptogenic spasms, 67 to 71% of such children whose spasms resolved with treatment had normal intelligence upon neuropsychological assessment at 5 to 10 years of age.^6,9 For those with symptomatic infantile spasms, the outcome is largely dependent on their underlying pathology.

Aicardi Syndrome

Infantile spasms may be seen in association with other severe epilepsies of infancy. Aicardi syndrome is an X-linked dominant disorder of female children, who present with retinal malformations, agenesis of the corpus callosum, and infantile spasms. The pathognomonic eye findings of chorioretinal lacunae consist of round white or pinkish patches, often with pigmented rims, which range in size from 1/10th to several optic disk diameters. Other ophthalmologic abnormalities may also be associated, the most common of which is a coloboma of the optic disk. In addition to callosal agenesis, other malformations of cortical development may be seen, including cortical dysplasia, periventricular heterotopias, and polymicrogyria. In addition, intracranial cystic formations are quite common, with choroid plexus cysts seen in >50% of cases, as well as occasional cysts of the arachnoid and dura mater.¹⁰ Cysts may also be seen in the third ventricle, in rare cases becoming large enough to compress the cerebral aqueduct, resulting in obstructive hydrocephalus. Choroid plexus papillomas have also been reported.

Extraneurologic abnormalities are also often seen, the most common of which are rib and vertebral malformations. Missing or bifurcated ribs may be seen uni- or bilaterally. Butterfly vertebrae and hemivertebrae frequently contribute to problems with scoliosis, which may require orthopedic correction.

The typical EEG background of Aicardi syndrome is a high-amplitude burst-suppression pattern, which, due to the absence of the corpus callosum, is asynchronous and asymmetric between hemispheres. Classic hypsarrhythmia is seen in only 18% of cases.¹¹

The outcome of Aicardi syndrome is generally quite poor. The seizures are usually refractory to treatment, and the majority of patients suffer severe global developmental delay.

Ohtahara Syndrome

Ohtahara syndrome, also known as early infantile epileptic encephalopathy (EIEE), is characterized by severe developmental delay, the onset of tonic seizures within the first few months of life, and an EEG background pattern of burst suppression encompassing both wakefulness and sleep. The age of onset for EIEE is earlier than for infantile spasms and usually is in the first 3 months after birth. In some cases, intrauterine seizure onset is retrospectively suspected based on episodes of violent fetal movement.¹² Daily seizure burden is extremely high, with clusters of 10 to 20 events occurring up to 20 times per day. Each tonic seizure may last for up to 10 sec. Focal motor and asymmetric tonic seizures may also be seen, but myoclonic seizures are uncommon. The interictal background is characterized by 1 to 3 sec bursts of 150 to 350 μV high-amplitude activity, with admixed multifocal spikes. The interburst interval typically lasts between 2 and 5 sec and is nearly flat.

With time, Ohtahara syndrome often transitions into West syndrome. Like infantile spasms, there is no unifying underlying pathology. Severe structural brain malformations are common, although other etiologies, such as inborn errors of metabolism, have also been reported. The seizures are initially intractable to a gamut of treatments, although seizure control is often attained by school age. Unfortunately, the developmental prognosis is generally dismal, with 25% mortality within the first 2 years of life, and severe cognitive and motor delay in those who survive to later ages.¹³ In some cases of focal cortical dysplasia, surgical resection has resulted in some developmental improvement.^14,15

A related syndrome known as early myoclonic encephalopathy (EME) is characterized by erratic, fragmented myoclonus in association with other seizure types, including partial motor seizures, major myoclonus, and infantile spasms. EME is otherwise similar to EIEE, with early age of onset, intractability, and an interictal EEG background of burst suppression.

The syndrome of infantile spasms may result from a wide variety of conditions. Cryptogenic spasms, in which an underlying structural, genetic, or metabolic etiology cannot be determined in a previously developmentally normal child, constitute only 20% of patients. With continued development of neuroimaging and other diagnostic techniques, this category will inevitably continue to diminish.

The majority of spasms are therefore symptomatic from a variety of congenital or acquired brain abnormalities. A substantial proportion of patients are found to have underlying malformations of cortical development. Other processes affecting the infant brain in a diffuse or multifocal manner may also lead to spasms, including tuberous sclerosis, hypoxic-ischemic encephalopathy, Down syndrome, neonatal hypoglycemia, trauma, intraventricular hemorrhage, and biochemical abnormalities, including pyridoxine deficiency. Interestingly, focal brain insults such as ischemic strokes and focal cortical dysplasias also have been implicated.

Although infantile spasms may stem from postnatal insults, they generally do not appear in the acute period after brain injury. The latency period typically lasts several months, but it may range between 6 weeks and 11 months.¹⁶

In addition to this list of potential etiologies, mutations of the ARX (aristaless-related homeobox) gene have been associated with X-linked infantile spasms in male infants.¹⁷ Interestingly, a wide array of phenotypes have been linked to derangements of this gene, including X-linked lissencephaly with abnormal genitalia, Proud syndrome (agenesis of the corpus callosum with abnormal genitalia), Partington syndrome (mental retardation with mild distal dystonia), X-linked mental retardation with or without seizures, and infantile spasms associated with status dystonicus.^18–25 Female carriers are generally asymptomatic, although agenesis of the corpus callosum may be seen in association with some severe ARX mutations.

Several models have been proposed for the pathophysiological basis of infantile spasms. In many hypotheses, considerable attention has been paid to the potential role of subcortical and brainstem structures. In light of the diffuse and symmetric nature of the EEG patterns that are commonly associated with infantile spasms (e.g., hypsarrhythmia and generalized paroxysmal fast activity), the brainstem nuclei, with their extensive connections to widespread cortical structures, have been particularly attractive candidates.

After observing disturbed sleep patterns in patients with infantile spasms, including a decrease in rapid eye movement (REM) sleep and total sleep time,²⁶ Hrachovy and Frost proposed a model implicating disturbances in the relationship between noradrenergic, serotonergic, and cholinergic neurons of the brainstem, involving some of the pontine centers that regulate the sleep cycle.²⁷ The clinical appearance of spasms may result from intermittent disruption of descending pontine projections governing spinal reflexes, whereas dysfunction in widespread ascending pontine projections would account for the cognitive decline and chaotic EEG background. This theory is supported by the finding of decreased serotonin metabolites in the cerebrospinal fluid of patients with infantile spasms, in comparison to age-matched controls.²⁸ In addition, only infants who responded clinically and electrographically to hormonal treatment also show improvement in REM sleep time.²⁶

This brainstem dysfunction model stems in part from the observation of cases in which brainstem pathology is discovered in the absence of cortical lesions. However, numerous studies have also reported the reverse (i.e., cortical pathology without brainstem defects). Therefore, it has been suggested that infantile spasms result from the dysfunctional or poorly regulated interaction between cortical and subcortical structures. Positron emission tomography (PET) studies have demonstrated focal cortical hypometabolism, as well as symmetric hypermetabolism in the lenticular nuclei and brainstem in some infants with infantile spasms, in comparison to age-matched controls.²⁹ Based on these findings, focal or diffuse cortical lesions have been postulated to lead to dysfunctional interactions with the brainstem raphe nuclei at a critical stage of development. In this model, widespread projections from the raphe are thought to produce the clinical and EEG pattern of West syndrome. Specifically, serotonergic raphe-cortical projections are posited to produce the EEG pattern of hypsarrhythmia, and descending spinal pathways from either the raphe or closely associated reticular activating system were thought to generate the semiology of infantile spasms. PET activation of the lentiform nucleus would be the result of raphe-striatal connections to the putamen. Interestingly, the onset of infantile spasms was coincidentally noted in 15% of patients with Down syndrome who received 5-hydroxytryptophan (5-HTP), a precursor to serotonin, for the treatment of hypotonia.³⁰ Unfortunately, trials of antiserotonergic medications such as tetrabenazine (a serotonin and catecholamine depleter), methysergide (a serotonin receptor blocker), and alpha-methyparatyrosine (a competitive inhibitor of tyrosine hydroxylase) produced only minimal improvements at best.^31,32

In a similar cortical-subcortical interaction model, Lado and Moshé proposed that the spasms phenotype may be produced by the combination of either increased cortical excitability coupled with impaired brainstem modulation of the cortex, or increased epileptogenic potential from the brainstem coupled with impaired cortical modulation.³³ The necessity of proconvulsant dysfunction in both regions would explain why only some infants with similar patterns of injury or malformation develop infantile spasms.

The last model is based on a hypothesis of developmental desynchronization. In this model, infantile spasms are thought to be the final common pathway that results when several maturational processes that typically interact and develop in concert instead develop at different rates. Although the desynchronization may initially be unnoticeably minor, the gap may widen such that a cohesive neurologic system does not develop.³⁴ If the nervous system is able to respond and correct the desynchronized systems through the activation of other regulatory mechanisms, the problem may resolve, producing the phenomenon of spontaneous remission of infantile spasms. However, the defects are irreparable in most instances, which results in intractable spasms and global neurologic delay.

In any given case, the particular systems at fault may vary based on the patient’s underlying pathology. For instance, the serotonergic and cholinergic systems both have widespread projections and therefore must work in tandem in the normal maturing brain. The serotonergic system undergoes substantial changes during development, with significant decreases in receptor binding in the pontine, midbrain, and interpeduncular regions during the fetal and childhood periods.^35,36 Any process that retards this receptor downregulation during a period of rapid development would quickly disrupt the balance between the serotonergic system and other neurotransmitter systems with which it interacts. Another example would be the process of synaptogenesis, which is also rendered vulnerable to potential developmental desynchronization by rapid maturational changes. Synaptic density grows progressively from the third trimester of gestation through infancy. Accelerated increases are noted at 2 to 3 months after birth, before plateauing ∼3 to 9 months of age.³⁷ Any insult resulting in a delay in synaptogenesis would eventually affect other maturational systems dependent on a critical level of synaptic density, thereby initiating the process that may lead to the syndrome of infantile spasms.³⁸

Interictal

Hypsarrhythmia (Figure 17-1) was a term first coined in 1952 by Gibbs and Gibbs.³⁹ It is the hallmark background pattern seen in infantile spasms and part of the definition of West syndrome.⁴⁰ By strict definition, hypsarrhythmia consists of three abnormalities: high-amplitude background (>200μV), disorganization of the background, and multifocal independent spike discharges (three independent, bilateral, and noncontiguous discharge foci). This pattern is typically continuous during the wake state, occasionally fragmented during sleep, and typically not seen during REM sleep, although REM sleep is still abnormal.⁴¹ However, hypsarrhythmia can have many variations. It can be asymmetric, have frequent focal discharges, display inter- or intrahemispheric synchrony, and have generalized or lateralized voltage attenuation or even a pattern of burst suppression. The etiology of infantile spasms does not dictate the characteristics of hypsarrhythmia outside of the symptomatic group. Asymmetric hypsarrhythmia is often seen with focal lesions such as cortical dysplasia or tuberous sclerosis. In some reports, up to 30% of children never actually have hypsarrhythmia as the background.^41–43 A study evaluating the interictal spike discharges in hypsarrhythmia demonstrated a number of interesting characteristics: the discharges were most frequently multifocal and dominant over the posterior head regions; interspasm spikes were much less frequent than interictal spikes; and the dominant location of interspasm spikes, not interictal spikes, coincided with the focal underlying lesion in symptomatic spasms.⁴⁴

Modified hypsarrhythmia (Figure 17-2) is used when variations of the typical findings as described above are seen.⁴⁵ This may actually be a precursor to or the evolution of hypsarrhythmia. Others have commented that the EEG change may be a crescendo-decrescendo pattern, possibly starting with a normal EEG and progressing to modified hypsarrhythmia, returning to hypsarrhythmia and again modified hypsarrhythmia, and finally ending with a variety of patterns. Early evaluation of the EEG patterns in term and preterm infants with hypoxic-ischemic encephalopathy did show that the progression of multifocal epileptiform discharges may indicate the future progression of infantile spasms, particularly in preterm infants.⁴⁶ An evaluation of 19 preterm infants with cystic periventricular leukomalacia (PVL) who were divided into two groups, those with and without paroxysmal discharges, found that 70% of those with discharges developed West syndrome, and none of those without discharges developed the syndrome.⁴⁷ Nearly all of the patients who developed West syndrome were considered to have severe PVL on imaging.