Authors: Gozde Erdemir, Ahsan N. Moosa
Categories: AIAN Review, Epileptic spasms, West syndrome, hypsarrhythmia, infantile spasms
Source: Annals of Indian Academy of Neurology
Epileptic spasms are a unique, age-dependent manifestation of epilepsies in infancy and early childhood, commonly occurring as part of infantile epileptic spasms syndrome. Developmental stagnation and subsequent decline may occur in children with epileptic spasms, partly due to the abundant high-amplitude interictal epileptiform and slow wave abnormalities. Early recognition and treatment of epileptic spasms, along with the reversal of the electroencephalography (EEG) findings, are critical for improving outcomes. Recognizing hypsarrhythmia and its variations is key to confirming the diagnosis. The various patterns of hypsarrhythmia are not etiology specific, but could indicate the severity of the disease. Several scoring systems have been proposed to improve the inter-rater reliability of recognizing hypsarrhythmia and to assess EEG progress in response to treatment. Ictal patterns during spasms are brief and composed of slow waves, sharp transients, fast activity, and voltage attenuation, either in isolation or more commonly as a combination of these waveforms. Ictal patterns are commonly diffuse, but may be lateralized to one hemisphere in children with structural etiology. A subset of patients with epileptic spasms has a surgically remediable etiology, with readily identifiable lesions on neuroimaging in most cases. Asymmetry in epileptic spasms, concurrent focal seizures, and asymmetric interictal and ictal EEG findings may be present, but a lack of focality in electrophysiological findings is not uncommon. Intracranial EEG features of epileptic spasms have been described, but the utility of intracranial EEG monitoring in surgical candidates with overt focal epileptogenic lesions on magnetic resonance imaging is questionable, and surgery could be performed using noninvasive data.
Keywords: Epileptic spasms, infantile spasms, hypsarrhythmia, West syndrome
Epileptic spasms are a distinctive seizure type that typically occur during infancy as part of infantile epileptic spasms syndrome (IESS), but can also occur in younger children.[1] Epileptic spasms most commonly start in infancy and cease by age 5 years in majority, but may persist in older children and young adults rarely; the new occurrence of epileptic spasms after 5 years of age is extremely rare. The estimated incidence of IESS is 30/100,000 liveborn infants, accounting for 10% of epilepsies starting before 3 years of age.[2] Epileptic spasms occur as a feature of epileptic encephalopathy and despite advances in recognition and treatment, epileptic spasms carry a poor prognosis; only 15%–25% of individuals with epileptic spasms achieve a normal developmental outcome.[3,4,5]
The onset of spasms often coincides with a noticeable plateauing of development, followed by regression in development if the disease is untreated and progressive. Developmental problems are attributed in part to pervasive occurrence of epileptiform discharges and electroencephalography (EEG) disorganization, and hence the categorization as “epileptic encephalopathy.” The triad of features that include epileptic spasms, developmental stagnation or regression, and a distinct EEG pattern called hypsarrhythmia is classically referred to as West syndrome. However, as all patients with epileptic spasms do not exhibit all three features, the more encompassing term IESS is recommended to include all children with epileptic spasms.[1] Early recognition and treatment are crucial to minimize cognitive and neurologic deficits.[5,6] Therefore, timely diagnosis and management are essential.
Epileptic spasms are characterized by unique clinical and EEG features, which we will discuss in this review, focusing on their electroclinical aspects.
Epileptic spasms are characterized by sudden, brief flexion or extension of the axial and/or proximal extremities, usually occurring in clusters and, less commonly, as isolated events. Epileptic spasms are frequently observed upon awakening and rarely occur when the patient is in deep sleep.[7]
The individual movements in the epileptic spasms typically last 1–2 sec and are rarely longer in older children. Epileptic spasms are different from myoclonic seizures, which are rapid and shock-like jerky movements lasting less than 300–400 msec.[8] Tonic seizures are sustained tonic stiffening lasting several seconds, but epileptic spasms are shorter than tonic seizures.[8] It is important to differentiate epileptic spasms from myoclonic jerks and tonic seizures, as the treatments vary significantly. King et al.[9] described three phases in various combinations in epileptic these include a brief myoclonic component, a slightly sustained tonic phase, and a period of relative lack of movement. Variations in spasms are a result of varying degrees of these components, some with jerky quality, others with classical spasms with a “hold,” and yet others with a pause (arrest or freeze) in activity. Occasionally, complex motor activity can occur during the spasms; gelastic spasms have been rarely reported.[10,11]
Spasms are categorized as flexor, extensor, or mixed based on their predominant involvement of ventral or dorsal axial muscle groups.[7,9,12] In flexor spasms, there is flexion of the axial muscles (truck, neck) with variable degree of arm involvement with adduction and forward elevation, and flexion at the hip. Extension of the neck and trunk with extension of the extremities occurs with extensor spasms. Mixed spasms are most frequent with flexion of the axial muscles and extension of the legs and arm. In one study of 5042 spasms in 24 infants, 42% were mixed, 33% were flexor, and 22% were extensor spasms. Patients may have more than one type of spasm.[7] A minority manifest as an “arrest” of baseline motor activity. Contractions during spasms usually involve bilateral muscle groups symmetrically; however, asymmetric spasms may occur. Asymmetric spasms are seen in children with structural lesions. Asymmetric spasms and focal features like eye and head deviation can provide valuable information for lateralization in patients with surgically treatable causes.[13,14,15,16,17,18] However, severe weakness in the extremities can lead to false lateralization, as these areas may be less affected during a spasm. Alternating spasms during a cluster have been reported in a child with Aicardi syndrome.[19]
Eye movements during epileptic spasms, such as upward deviation or with jerky, nystagmoid movements, are seen in 55%–60% of seizures.[7,9] Respiratory changes are also frequent (in 60%), but changes in heart rate are uncommon.[7,9] Vocalizations, hiccups, head nod, grimacing, and tongue/mouth movements can occur. Subtle spasms limited to a body part can be seen in children undergoing treatment. These spasms can occur in eyes, neck, laryngeal muscles, or diaphragmatic muscles without clear involvement of the trunk or limbs.[7,9,20] A diagnosis may be obvious on review of a cluster of such events, but frequently needs video EEG for confirmation.
Spasms may occur sporadically, but occur in clusters in over two-thirds of patients, with two or more spasms in a cluster.[7] Spasms could occur as frequently as every 4–5 sec in a cluster. In a cluster, the intensity of spasms often progressively increases (crescendo) at the onset and then decrease toward the end of the cluster.[7,9] Clusters tend to occur after an arousal from sleep, particularly in the first 30 min after arousal; occurrence of spasms in sleep is distinctly unusual and is always accompanied or preceded by arousal.[9] The duration of a cluster varies from patient to patient, and it usually lasts several minutes.[9] Other than increased occurrence of clusters during sleep–wake transition, there are no consistent triggers for spasms. Loud noise has been reported to be a trigger in some, mediated by alterations in arousal by the stimuli.
Alternation of awareness in young infants during a cluster is not readily assessable.[7,8,9] Irritability and cry may occur in between spasms.[7,8,9,21,22] Older children with subtle spasms may be subdued or appear confused, and sometimes, the subtle spasms during this period of altered responsiveness many be underrecognized.
Focal seizures can also occur and may coincide with spasms, especially in cases with a structural etiology. Previous studies on epilepsy surgery in children with epileptic spasms showed that 23%–87% of the patients had concurrent focal seizures.[13,14,15,16,17,18] Focal seizures may precede the onset of spasms or appear after the remission of spasms.[23] In some patients, a focal seizure could end in a cluster of spasms.
Several epileptic and nonepileptic motor spells may resemble epileptic spasms. As discussed earlier, myoclonic seizures and brief tonic seizures have some overlapping features with epileptic spasms. In some cases, clear distinction between them could be difficult based on a single event. If occurring in clusters, with interictal findings of hypsarrhythmia and ictal features compatible with spasms, we recommend considering them as epileptic spasms and institute appropriate treatment, as the effective therapeutic options for epileptic spasms are specific and often not used outside of the spasms. Underdiagnosis of epileptic spasms may result in delay and suboptimal care.
Nonepileptic conditions that mimic epileptic spasms include nonepileptic myoclonus, benign spasms or variations of shuddering spells, spasticity-related movements, and benign sleep myoclonus.[24,25,26] A careful analysis of the symptomatology and a normal interictal EEG may be sufficient in the majority to rule out epileptic spasms. In some children, a video EEG would be required to confirm the diagnosis.
Epileptic spasms can occur secondary to a variety of etiologies including perinatal ischemic brain injury, malformations of cortical development, and a host of genetic conditions.[27,28,29] Occasionally, the cause is considered idiopathic after extensive testing, and some children with an excellent response to treatment may recover without lasting neurologic deficits. Certain conditions like Cyclin-Dependent Kinase-Like 5 (CDKL5) disease and tuberous sclerosis have a high propensity to manifest as epileptic spasms.[30,31] Conversely, certain genetic conditions such as SCN1A are less likely to manifest with epileptic spasms.
The term hypsarrhythmia was first introduced by Gibbs et al.[32] in 1952 to describe the typical interictal EEG pattern observed in West syndrome. Hypsarrhythmia in its original description is a highly disorganized “chaotic” EEG pattern, characterized by high-amplitude (>200–300 μv) multifocal slow waves in delta range and multifocal high-amplitude sharp waves and spikes, with no recognizable physiologic rhythms, as shown in Figures 1 and 2.[32,33,34] These patterns were described to be nearly continuous and infrequently synchronizing. Within a few years, it was recognized that several patients with infantile spasms and extremely abnormal EEG failed to meet all the features described by Gibbs et al. A scoring system was proposed to improve the recognition of EEG findings.[34]
Figure 1 Hypsarrhythmia, generalized. This EEG shows abundant high-amplitude multifocal spikes and slow waves. Thin arrows point to three different regions with spikes, and thick arrowhead points to multifocal slow waves. (EEG shown in a 15-sec epoch, sensitivity at 15 μV, high-frequency filter [HFF] 70 Hz, low-frequency filter [LFF] 1.6 Hz). EEG = electroencephalography
Figure 2 Hypsarrhythmia in sleep. This EEG shows abundant high-amplitude multifocal spikes and slow waves with periods of decrement (arrowheads). (EEG shown in a 15-sec epoch, sensitivity at 20 μV, HFF 70 Hz, LFF 0.53 Hz). EEG = electroencephalography
Hrachovy et al.[35] described several variations of hypsarrhythmia after reviewing 290 polygraphic records of 67 children with epileptic spasms. They termed these variations as “modified hypsarrhythmia.”[35] These variations include the
Figure 3 Modified hypsarrhythmia, with increased interhemispheric synchronization. This EEG shows repetitive diffuse synchronous bursts of high-amplitude spikes and polyspikes. This child had epileptic spasms and tonic seizures. (EEG shown in a 15-sec epoch, sensitivity at 15 μV, HFF 70 Hz, LFF1.6 Hz). EEG = electroencephalography
Figure 4 Modified hypsarrhythmia, hemi-hypsarrhythmia. This EEG shows frequent high-amplitude sharp waves and spikes in the left hemisphere, maximal in the posterior regions. This child had extensive dysplasia in the left posterior quadrant. (EEG shown in 15-sec epoch, sensitivity at 10 μV, HFF 70 Hz, LFF 1.6 Hz). EEG = electroencephalography
Hypsarrhythmia may be state dependent in less-severe cases and present in only a small segment of sleep. Hypsarrhythmia is most prominent during non-REM sleep and decreases during REM sleep. In rare cases, abnormal findings may be more prominent when the child is awake. Physiologic rhythms, such as posterior background and sleep spindles, may be variably present in less-severe cases. In some cases, hypsarrhythmia may not be present despite ongoing epileptic spasms.[37]
Hypsarrhythmia could notably abate in the first few minutes of awakening from sleep.[35] Sometimes, this may be followed by a cluster of epileptic spasms, but other times, hypsarrhythmia gradually emerges without spasms. In addition, hypsarrhythmia could abate during a cluster of spasms, also termed “relative normalization” of EEG.[35] While reviewing continuous long-term EEG in children with hypsarrhythmia, it is important to recognize this relative normalization and review these portions of EEG carefully for occurrence of subtle or overt spasms.
Variations from typical hypsarrhythmia are common and are seen in over two-thirds of children.[38] Etiological correlations and variations of hypsarrhythmia are not consistent, except for hemi-hypsarrhythmia, occurring with structural lesions. Of note, surgically remediable etiologies of epileptic spasms can manifest with any type of hypsarrhythmia.[18] Severity of hypsarrhythmia has been correlated with developmental outcomes.[38]
Hypsarrhythmia is typically age dependent and tends to resolve as children grow older.[39] However, it may emerge to a range of EEG patterns such as slow spike and wave activity seen in Lennox–Gastaut syndrome, focal/multifocal epileptiform discharges, diffuse/focal slowing, and others.
While the description of hypsarrhythmia has remained unchanged since its original characterization, not all patients exhibit typical EEG findings as mentioned above. Consequently, the determination of hypsarrhythmia shows poor inter-rater reliability.[40] To address this issue, various rating scales have been proposed over many decades to standardize hypsarrhythmia scoring and monitor treatment response.
The first scoring system was developed in 1960 by Bower and Jeavons.[34] This grading scale categorized EEG findings based on voltage, organization, synchronicity, and regional distribution of spikes and slow waves. It consisted of nine grades, with 9 being normal and 1 indicating the most severe abnormalities, as shown in Table 1. Subsequently, few other scoring systems have been proposed to improve the inter-rater agreement on the classification of EEG findings.[41] A recent scoring system, proposed in 2021 by Mytinger et al.,[42] is known as Burden of Amplitudes and Epileptiform Discharges (BASED) score and is shown in Table 2. Initially created in 2015 based on a prospective study comparing EEGs of children with epileptic spasms before and after adrenocorticotropic hormone (ACTH) treatment, the BASED score showed improved interobserver agreement.[43] Observers could accurately identify remission with an overall accuracy of 95%. Mytinger et al.[44] reported that normal young children can exhibit background waves exceeding 300 μV in the occipital regions during sleep. Therefore, in the revised 2021 BASED score, the authors excluded channels containing occipital and midline electrodes due to these physiologic high-amplitude waves. These scoring systems are particularly useful in serial assessment of patients during their course of therapy.
As the spasms are short in duration, the concurrent ictal findings are also brief and may be underrecognized by less-experienced readers. Early studies had polygraphic recording with concurrent electromyography (EMG) activity to correlate with the spasms. In 1979, Kellaway et al.[7] noted that ictal EEG findings in epileptic spasms varied from patient to patient and described 11 different patterns after reviewing 5042 spasms in 24 infants, as shown in Table 3. The first three patterns listed in the table were the most common and were noted in 67% of all spasms. These patterns may vary from patient to patient and from spasm to spasm within a cluster as well. These patterns could be viewed as variable combinations of sharp waves, slow waves, fast activity, and attenuation. Some of the selected patterns are shown in Figures 5 and 6. The most common pattern was found to be a generalized slow wave transient followed by voltage attenuation/electrodecrement of background activity across all regions.[7,12,45,46,47] Contrary to popular knowledge, isolated attenuation of EEG occurs only in about 12% of spasms.
Figure 5 Ictal EEG: common ictal patters of epileptic spasms. (a) Generalized burst with sharp waves and slow transients, lasting 1 sec, concurrent with the spasms. (b) Burst of generalized delta transient lasting 1.5 sec. (c) A burst of fast activity overriding a delta transient, followed by low-amplitude fast activity and attenuation of baseline rhythms. In (a and b), note a pause in EMG activity in the temporal channels during the burst as many children may have subtle loss of tone in the facial muscles during the spasm. In (c), the clinical spasms (not shown) were subtle with a brief pause in activity. EEG = electroencephalography, EMG = electromyography
Figure 6 Ictal EEG: asymmetric ictal patters during epileptic spasms. (a) Short bust of spikes followed by sharply contoured delta activity intermixed with spikes lateralized to the left hemisphere; the delta transient toward the end of the burst is more diffuse. (b) Bursts of fast overriding delta activity over the “left” posterior quadrant followed by attenuation of baseline frequencies. (c) A combination of fast activity, spikes, and slow transient lateralized to the left hemisphere, maximum in the posterior quadrant. EEG = electroencephalography
As noted earlier, interictal hypsarrhythmia may disappear during a cluster of spasms. Presence of hypsarrhythmia in between spasms was thought to be a good prognostic factor based on some studies.[12,48]
The type of ictal patterns was not found to correlate with the specific etiologies.[12,46] Patients with the focal lesions causing epileptic spasms can have diffuse and symmetric ictal findings.[18,49] However, ictal patterns in surgical candidates may help with lateralization or localization as well. If the fast activity is part of the ictal pattern, it tends to be seen more often in posterior head regions, irrespective of the location and extent of epileptogenic zone.
Epileptogenic lesions that occur in early life could manifest as the syndrome of infantile epileptic spasms. Malformations of cortical development and encephalomalacia related to perinatal or prenatal ischemic or hemorrhagic injury are the most frequent causes.[13,14,15,16,17,18] The locations of the lesions may have some influence of the age of onset of epileptic spasms, with the earliest onset associated with occipitally located lesions and later onset with frontal lesions.[50] EEG findings in these children could be diffuse, but frequently show focal abnormalities. In the Cleveland Clinic series of 70 children, ictal patterns were diffuse and nonlateralized in 44% of them.[17] In other series, diffuse, nonlocalizing ictal patterns were noted in about two-thirds of patients.[14,16] Ictal patterns described earlier could be seen as lateralized to the affected hemisphere, frequently maximum in the posterior regions. Samples of lateralized ictal patterns are shown in Figure 6.
In children with large areas of porencephaly or encephalomalacia, the epileptiform abnormalities may appear paradoxically worse in the healthier hemisphere.[18,35] This occurs because of loss of cortical tissue in the affected hemisphere leading to an asymmetric expression of the diffuse abnormality, higher over the side with more cortical tissue. Thus, the EEG abnormalities in surgical candidates could be categorized as nonlocalizing, localizing, and, at times, false localizing.[18]
Epileptic spasms could be asymmetric, providing lateralizing signs during seizures. Coexistent focal seizures may assist with localization and have been reported in 23%–87% of patients in surgical series; focal seizures are seen less often when children undergo surgery at a younger age.[13,14,15,16,17] Abnormal neurologic findings such as hemiparesis are common in children with large hemispheric lesions and epileptic spasms.
Ictal intracranial EEG patterns have been reported from a few surgical series. Children with epileptic spasms secondary to epileptogenic lesions evident on magnetic resonance imaging (MRI) could be selected for surgery without the use of intracranial EEG monitoring.[17] In other series, intracranial EEG monitoring has been performed in 20%–65% of surgically treated cases.[13,14,15,16] Intracranial EEG patterns during the spasms were characterized by a diffuse burst of slow waves, often accompanied by low-voltage fast activity that can precede, follow, or superimpose the slow wave. This is very similar to the patterns seen on scalp in their waveform characteristics. In addition, these patterns are often more focal, and when combined with interictal focal anomalies, they can help in localization of the epileptogenic zone.[13,14,15,51,52] These findings are reported to correlate with the location of the epileptogenic lesions noted on brain MRI.
Asano et al.[53] demonstrated that epileptic spasms can be associated with a focal “leading” spike that precedes a fast-wave burst at frequencies of 30 Hz and above, which typically involves widespread brain regions, including the motor or premotor cortex, possibly within 100 msec. In another report of five patients, ictal high-frequency oscillations (HFOs) were noted 100–300 msec before the EMG-detected spasms.[54] Occurrence of preceding spikes and sharp waves was inconsistent, but HFO with superimposed slow waves occurred during spasms in all patients. In two patients, the ictal pattern had three short HFO without overt clinical signs, HFO with slow wave with clinical spasm, and sustained spasm for up to 4 sec with sustained HFO without slow waves.[54] Improvements in the sampling rate of recording systems over the past decade have allowed Nariai et al.[52] to observe that the spectral frequencies of “leading” spikes and fast-wave bursts during spasms both reach the range of HFOs at 80–200 Hz. Consequently, the ictal propagation of HFOs to the Rolandic cortex was found to be temporally associated with body jerking during epileptic spasms.[52] These authors also described a phenomenon called “ictal doughnut phenomenon.” During the spasms, most ictal HFOs seem to disappear in the “seizure onset” regions, but continue to be augmented at the surrounding sites. This phenomenon is interpreted as seizure termination at the onset zone and propagation in other regions, resulting in a doughnut shape in the topographic image.[52]
In conclusion, the characteristic semiology and frequent epileptiform discharges on interictal EEG aid in prompt diagnosis of IESS. Early recognition and treatment, along with EEG reversal, are vital for improving developmental outcomes. Ictal patterns are brief diffuse or focal, featuring slow waves, sharp transients, fast activity, and voltage attenuation, either in isolation or in various combinations. Some patients have surgically remediable etiologies, with identifiable lesions on neuroimaging. Asymmetry in spasms and EEG findings may occur, but a lack of focality is not uncommon.
Nil.
There are no conflicts of interest.