Severe Neonatal Epilepsy with Suppression-Burst Pattern (Early Epileptic Encephalopathy); Erratic Myoclonus. A 5-day-old boy born full term without complications who presented with hypotonia, apnea, irritability, and jitteriness. He was found to have frequent erratic myoclonus and myoclonic seizures. MRI was unremarkable. EEG shows suppression-burst (S-B) pattern and subclinical electrographic focal seizures (not shown). It also shows no significant changes during erratic myoclonus (open arrow). An extensive metabolic work-up was negative.

There are two severe neonatal epilepsies with S-B pattern, Ohtahara syndrome (OS) and early myoclonic encephalopathy (EME). The EEG shows bursts, lasting several seconds, of polyspikes alternating with very low-voltage activity, this combination being called “suppression bursts.” The S-B pattern may be asymmetric, affecting mainly the side of the cortical malformation, hemimegalencephaly, focal cortical dysplasia, Aicardi syndrome, olivary-dentate dysplasia, or schizencephaly.^1–3 The onset of seizures in OS is within the first 2–3 months but most commonly within the first 10 days. The main type of seizure in OS is the tonic spasm. Myoclonic seizures and erratic myoclonus are rare. A majority of cases of OS are associated with structural brain abnormalities, including porencephaly, hydrocephalus, hemimegalencephaly, and lissencephaly. No familial case of OS have been reported.

EME is characterized by an early onset in the neonatal period with the main seizure types of erratic and massive myoclonus and partial seizures. The most common cause of EME is metabolic disease.

The causes of OS are symptomatic or organic; the causes of EME can be genetic, metabolic, or entirely unknown. OS causes tonic spasms and partial seizures. EME causes myoclonic and partial seizures. The EEG of OS contains periodic S-B and is irrespective of waking and sleeping, while EME may have S-B only during sleep. OS commonly transitions to West syndrome. EME transition to West syndrome is transient, if there is any transition at all. The EEG course of S-B in OS is that they turn into hypsarrhythmia in 3–6 months. The EME S-B course is long lasting.^4,5 However, the distinction between these two conditions may be difficult because brief spasms are difficult to distinguish from myoclonus. The distinction between S-B and hypsarrhythmia with extreme fragmentation in sleep also is difficult in many cases because in OS, the S-B evolves into the more continuous asynchronous spike- and slow-wave activity of hypsarrhythmia.³

Severe Neonatal Epilepsy with Suppression-Burst Pattern; Ohtahara Syndrome. A 1-week-old boy with a history of frequent tonic spasms starting on the first day of life with subsequent developmental regression, spastic quadriparesis, and intractable infantile spasms. Serial neuroimaging studies showed progressive cerebral atrophy. (A) CT performed at 10 months of age. (B) Axial T1-weighted image performed at 2½ years of age. The patient died at 2½ years of age. After intensive investigation, including autopsy, no specific metabolic or degenerative disease was found. EEG performed at 1 week of age shows suppression-burst (S-B) pattern. (Courtesy of Dr. B. Miller, Department of Neurology, The Children’s Hospital, Denver, CO.)

Ohtahara syndrome is a very rare and devastating form of epileptic encephalopathy of very early infancy. Onset of seizures is mainly by 1 month of age and often within the first 10 days of life, sometimes prenatally or during the first 2–3 months after birth. Characteristic clinico-EEG features are tonic spasms and, less commonly, erratic focal motor seizures and hemiconvulsion with S-B pattern in the EEG occurring in both sleep and waking states. Although the etiologies of Ohtahara syndrome are heterogeneous, prenatal brain pathology such as a malformation of cortical development is suspected in most cases and metabolic disorders are rare. Evolution into West syndrome is often observed in surviving cases.^4,6

Unilateral Suppression-Burst Pattern (Ohtahara Syndrome); Hemimegalencephaly. A 19-day-old boy born at 35 weeks GA who started having seizures in utero (hiccup and increased fetal movement) and developed postnatal seizure at 1 week of age, described as left facial twitching and eye deviation and epileptic nystagmus with fast component to the left side. The seizures, at times, were continuous. MRI shows right hemimegalencephaly. EEG demonstrates suppression-burst (S-B) pattern over the right hemisphere. She underwent right functional hemispherectomy at 2 months of age and has been seizure-free for 3 years.

Out of 44 patients with hemimegalencephaly, 35% had neurocutaneous syndromes. Almost all patients had mental retardation and hemiparesis. Ninety-three percent had epileptic seizures, which first appeared within a month in 40%. Twenty-five percent underwent functional hemispherectomy, which resulted in fairly good seizure control and improved development. There is a correlation between the onset of epilepsy and the degree of clinical severity of motor deficit and intellectual level.⁷

The interictal EEG in hemimegalencephaly demonstrates many abnormalities, especially high-amplitude spikes and spike-wave complexes over the damaged hemisphere in the first weeks or months of life^8,9 and unilateral suppression burst (S-B).^8,10,11 Hoefer et al.¹² first described hypsarrhythmia with S-B pattern. The association of this pattern with epileptic spasms justifies the diagnosis of Ohtahara syndrome.¹³ S-B pattern in Ohtahara syndrome is generated from the subcortical structures and caused by a subcortical-cortical regulation disorder, which is also influenced by cortical lesions.¹¹ Asymmetric S-B pattern can also be seen in cortical malformations, focal cortical dysplasia, Aicardi syndrome, olivary-dentate dysplasia, and schizencephaly.^1–3

Early Myoclonic Encephalopathy (EME); Pyridoxine Dependency. A 7-day-old girl with intermittent irritability, jitteriness, lethargy, and myoclonic jerks. A subsequent gene test confirmed the diagnosis of pyridoxine dependency. Her MRI was unremarkable. Her initial EEG (as shown) demonstrates diffuse suppression-burst pattern. After an administration of intravenous pyridoxine, the patient showed dramatic improvement in both her clinical symptoms and EEG. During her subsequent neurology visits, she continued to have no seizure and had normal developmental milestones. Her EEGs performed at 1 and 3 months of age were appropriate for age.

EME is a very rare epileptic syndrome characterized by myoclonus with onset of seizures in the neonatal period. The EEG shows suppression-burst pattern. Metabolic diseases, especially nonketotic hyperglycinemia, are usually the causes of EME. Malformation of cortical development is an uncommon etiology. Pyridoxine dependency was reported in one patient with EME who had complete recovery after treatment with pyridoxine. Almost all patients with EME have a very poor prognosis.⁴

Early Myoclonic Encephalopathy (EME) due to Pyridoxine dependency; Focal Clonic Seizure. (Same patient as in Figure 7-4) EEG shows a run of spikes and sharp waves in the right parieto-temporal region. The patient had focal clonic jerks of his left hand time-locked with spikes and sharp waves.

Focal clonic seizures in the newborn always show a close relationship to electrographic seizures. They can be seen in both structural abnormalities such as stroke or in a variety of metabolic diseases.¹⁴

Partial seizures are an almost constant feature in EME and tend to appear shortly after erratic myoclonus. Epileptic spasms are rarely seen early in the course of EME.⁴

Early Myoclonic Encephalopathy (EME) due to Pyridoxine dependency; Response to Treatment. (Same patient as in Figure 7-4) This EEG was performed at 13 months of age. The patient continues to be on vitamin B6 supplementation for pyridoxine dependency and has done extremely well. He has had normal developmental milestones and has been seizure-free. The EEG shows bilateral synchronous and relatively symmetric sleep spindles, which is normal for 13 months. No epileptiform activity is noted.

West Syndrome; Diffuse Cerebral Atrophy due to Severe Hypoxic Ischemic Encephalopathy (HIE). A 5-month-old boy born 27 weeks GA with severe HIE who developed West syndrome at 4 months of age. EEG during wakefulness shows typical hypsarrhythmia.

The average incidence of infantile spasms is 1 in 3225 live births. The highest incidence correlates with higher geographic latitudes. The age of onset of infantile spasms varies from the first week of life to more than 3 years of age, with the average onset at 6 months. Most cases (94%) begin within the first year of life. Positive family history for epilepsy ranges from 1% to 7%.¹⁵ Gibbs and Gibbs¹⁶ defined the term hypsarrhythmia as follows: “…random high voltage slow waves and spikes. These spikes vary from moment to moment, both in duration and in location. At times they appear to be focal, and a few seconds later they seem to originate from multiple foci. Occasionally the spike discharge becomes generalized, but it never appears as a rhythmically repetitive and highly organized pattern that could be confused with a discharge of the petit mal or petit mal variant type. The abnormality is almost continuous, and in most cases it shows as clearly in the waking as in the sleeping record.”

Five variants of hypsarrhythmia were defined as follows: (1) hypsarrhythmia with increased interhemispheric synchronization (35%); (2) asymmetric hypsarrhythmia (12%); (3) hypsarrhythmia with a consistent focus of abnormal discharge (26%); (4) hypsarrhythmia with episodes of voltage attenuation (11%); and (5) hypsarrhythmia with little spike or sharp activity (7%).^17,18 Transient alterations of the hypsarrhythmia occur throughout the day in relation to the sleep state. During non-rapid eye movement (NREM) sleep, the voltage of the background activity typically increases, and there is a tendency for grouping of the multifocal spike- and sharp-wave activity, often resulting in a periodic pattern.^19,20 Electrodecremental episodes frequently occur during NREM sleep. On arousal from NREM sleep, there is also typically a reduction in amplitude or complete disappearance of the hypsarrhythmic pattern that may persist for a few seconds to many minutes. The hypsarrhythmic pattern may also disappear during a cluster of spasms but immediately returns after cessation of the spasms.¹⁷ As with the clinical spasms, hypsarrhythmia characteristically disappears with increasing age.²¹ A variety of patterns may be seen when hypsarrhythmia disappears, including diffuse slowing, focal or multifocal spikes and sharp waves, monorhythmic background activity, focal slowing, asymmetric background activity, slow spike and slow-wave activity, and diffuse high-voltage fast activity.²² Rarely, the EEG may be normal.

Although hypsarrhythmia and its variants are the most common EEG patterns seen in infantile spasms, other interictal patterns may occur, including focal or multifocal spikes and sharp waves, abnormally slow or fast rhythms, diffuse slowing, focal slowing, focal depression, paroxysmal slow or fast bursts, a slow spike and wave pattern, continuous spindling or, rarely a normal pattern. These patterns may occur singly or in various combinations.¹⁵

Hypsarrhythmia; Infantile Spasms secondary to Periventricular Leukomalacia (PVL). A 7-month-old girl with infantile spasms caused by periventricular leukomalacia (PVL). The patient was born 30 weeks GA with severe HIE with subsequent moderately severe developmental delay and spastic diplegia. She had her first seizure at 3 months of age. MRI shows multiple small periventricular cysts (arrow), decreased white matter volume, thinning of the corpus callosum, and absence of the septum pellucidum, consistent with PVL. Interictal EEG activity demonstrates a chaotic mixture of asynchronous, very high-voltage polymorphic delta slowing and multifocal sharp waves, which is characteristic of hypsarrhythmia. Spike-wave activity is seen predominantly in bilateral parietal-occipital regions. West syndrome is a common complication of severe PVL and correlates strongly with the finding of bilateral parietal-occipital dominant irregular polyspike-wave activity.²³

Asymmetric Hypsarrhythmia; Cystic Encephalomalacia due to Intrauterine Stroke. A 9-month-old right-handed boy with a history of antithrombin 3 deficiency with resultant intrauterine right middle cerebral artery stroke. At 7 months of age, he developed clusters of spells with bilateral upper extremity extension and left-sided deviation of his head. EEG shows asymmetrical hypsarrhythmia characterized by voltage asymmetry with amplitude higher in the right hemisphere.

Asymmetric hypsarrhythmia (hemihypsarrhythmia or unilateral hypsarrhythmia), first described by Ohtahara²⁴ is characterized by hypsarrhythmia, with a consistent amplitude asymmetry between the two hemispheres. Asymmetric hypsarrhythmia is always associated with underlying structural abnormalities of the brain, most commonly seen in large cystic or atrophic defects of one hemisphere, such as porencephaly or encephalomalacia, tuberous sclerosis, Aicardi syndrome, hemimegalencephaly, and other malformations of cortical development.^25–29 Asymmetric hypsarrhythmia can also occur in bilateral structural lesions that were more abnormal in the area of the greater EEG abnormality.³⁰

Hypsarrhythmia may be maximal over either the more abnormal or the more normal hemisphere.³¹ Asymmetric hypsarrhythmia and asymmetric ictal EEG changes during infantile spasms often occurred together: each always indicated the side of a focal or asymmetric structural cerebral lesion.³⁰

Asymmetric Infantile Spasms; Asymmetric Hypsarrhythmia. A 4-month-old left-handed boy with normal developmental milestones who developed asymmetric infantile spasms characterized by clusters of brief tonic contractions of the muscles of the trunk, neck, and limbs, that gradually relaxed over 1–3 sec. Persistent asymmetric muscle contraction of limbs and neck, described as head turning to the right side with left arm extension and right arm flexion, was noted. Axial and coronal T2-weighted MRIs show left hippocampal atrophy (arrows). An interictal EEG shows hypsarrhythmia with a consistent amplitude asymmetry between hemispheres, compatible with “asymmetric hypsarrhythmia” with consistent left parietal epileptiform discharges (large arrow). Interictal PET scan (not shown) demonstrated hypometabolism in the left temporal region. The patient was in remission after 4 days of ACTH treatment and had normal developmental milestones after that.

In the series by Kellaway et al.,³² only 0.6% of spasms were asymmetric. Consistent asymmetry of epileptic spasms, especially when associated with asymmetry of ictal/interictal EEG discharges, is supportive evidence for an underlying focal structural abnormality.³³ Persistent asymmetric hypsarrhythmia is always associated with underlying structural brain abnormalities. However, it should be noted that the hypsarrhythmia can be more prominent over either the more abnormal or the more normal hemisphere.¹⁵

Hypsarrhythmia with Increased Interhemispheric Synchronization; Symptomatic Late onset Epileptic Spasm Associated with Trisomy 21.

A 2-year-old boy with trisomy 21 (mosaic) and mild global developmental delay and hypotonia who recently developed clusters of symmetric epileptic spasms. He responded well to ACTH. EEG shows hypsarrhythmia with increased interhemispheric synchronization.

Hypsarrhythmia with increased interhemispheric synchronization was seen in 35% of hypsarrhythmia variants.¹⁸ The classic hypsarrhythmia, multifocal spikes and sharp waves, and the diffuse asynchronous slow wave activity are replaced or intermixed with activity that demonstrates a significant degree of interhemispheric synchrony and symmetry. The EEG evolution can take place over weeks to months. This EEG pattern sometimes appears only intermittently with classic hypsarrhythmia.^31,34 Most infants with hypsarrhythmia will have some degree of synchronization of the background activity if the condition persists for many months or years. This is particularly true of those infants who exhibit a transition to Lennox-Gastaut syndrome.³¹

Asymmetric Infantile Spasms; Asymmetric Hypsarrhythmia with Increased Interhemispheric Synchronization. (Same patient as in Figure 7-11)

EEG during sleep shows three variants of hypsarrhythmia, including suppression-burst pattern, asymmetric hypsarrhythmia, and consistent focus of abnormal discharges.

Hrachovy et al. describe five hypsarrhythmia variants: hypsarrhythmia with increased interhemispheric synchronization, asymmetric hypsarrhythmia, hypsarrhythmia with a consistent focus of abnormal discharge, hypsarrhythmia with episodes of voltage attenuation, and hypsarrhythmia with little spikes or sharp activity. These patterns may occur in various combinations. Hypsarrhythmia with a consistent focus of abnormal discharge and asymmetric hypsarrhythmia are associated with focal or lateralized structural lesions.^15,17

Asymmetric Hypsarrhythmia with a Consistent Focus of Abnormal Discharge; Asymmetric Infantile Spasm. (Same patient as in Figure 7-11) An interictal EEG at 4 months of age shows consistent epileptiform activity in the left centro-parietal and centro-parietal vertex regions (arrow) and asymmetric hypsarrhythmia, maximal in the left hemisphere. These findings are highly supportive of an epileptic focus caused by a structural abnormality in the left centro-parietal vertex region, which is concordant with the MRI and PET scan finding performed at 4 years of age when the patient started having focal seizures. Review of earlier video-EEG evaluation is extremely helpful in the identification of epileptic focus.³⁵

Asymmetric Infantile Spasms; Diffuse Electrodecrement with Focal Onset. (Same patient as in Figure 7-11) Ictal EEG during a typical asymmetric epileptic spasm shows a burst of low-voltage beta activity in the left midtemporal (solid arrow) and a spike in the left centro-parietal region (arrow), immediately prior to bilateral synchronous sharp activity, diffuse electrodecremental event, and the epileptic spasm.

Asymmetric ictal patterns frequently occurring in patients with asymmetric epileptic spasms are correlated with focal or lateralized structural abnormalities.^15,30,36

Asymmetric Epileptic Spasms; Focal Cortical Dysplasia (FCD). (Same patient as in Figure 7-11) After the remission of infantile spasms (IS), the patient had normal developmental milestones with minimal focal neurological deficits that included pathologic left handedness, mild atrophy of the right thumb, mild right optic apraxia, asymmetric tonic neck refl ex, and hyperrefl exia/ dorsifl exion of the right side. EEGs performed every 6 months were within normal limits. At 3. years of age, the patient developed epileptic spasms similar to the IS he had when he was 4 months old. (A) Axial inversion recovery MRI shows blurring of the gray-white matter junction and thickened cortex in the left mesial parietal region (arrow). (B) Coronal T2-weighted MRI shows thickened cortex in the left lateral/mesial parietal region (arrow). The MRI continued to show left hippocampal atrophy (not shown). Interictal EEG shows frequent and, at times, periodic sharp waves and frequent polymorphic delta slowing, maximal in the left parietal region. This finding is compatible with the hypsarrhythmia with consistent left parietal spikes seen at 4 months of age (Figure 7-12).

Cerebral maturation begins in the central regions and then extends to the occipital regions before occurring in the frontal lobes.^37,38. Theoretically, lesions in the central and occipital regions would produce seizures earlier than those in the frontal region. Developmental process may play a role in clinical seizure expression and propagation of seizure activity. Cerebral lesions located in critical areas of brain maturation may have a role in the genesis of IS. Occipital lesions are found to be associated with the earliest onset of spasms, whereas frontal lesions are rare and associated with latest spasm onset.^39,40

Patients with IS caused by FCD frequently develop partial seizures that can precede, be simultaneous with, or follow the cluster of epileptic spasms. Spasms can be easily controlled by ACTH or Vigabatrin. EEG epileptic foci tend to persist after spontaneous disappearance of the hypsarrhythmic pattern or after successful treatment. When spasms disappear, patients are left with focal epilepsy that is intractable to medical treatment, in contrast with IS. Antiepileptic drug (AED) treatment seems to be able to prevent the diffuse paroxysmal activity outside of the FCD that causes secondary generalization such as in IS, but the intrinsic epileptogenicity of the FCD is poorly aff ected by the AED.^15,41

High-Voltage, Frontal-Dominant, Generalized Slow Wave Transient; Symptomatic West syndrome and Asymmetric Epileptic Spasm. (Same EEG tracing as in Figure 7-11) EEG during a cluster of asymmetric epileptic spasms described as brief asymmetric tonic stiffening of arms and legs with left-sided predominance (arrow head) reveals lateralized high-voltage delta slow activity in the left hemisphere with positive polarity delta slowing, maximal at the P3 electrode (arrow).

Eleven different ictal patterns were identified: (1) a high-voltage, frontal-dominant, generalized slow-wave transient followed by a period of attenuation; (2) a generalized sharp- and slow-wave complex; (3) a generalized sharp- and slow-wave complex followed by a period of voltage attenuation; (4) a period of voltage attenuation only; (5) a generalized slow transient only; (6) a period of attenuation with superimposed fast activity; (7) a generalized slow-wave transient followed by a period of voltage attenuation with superimposed fast activity; (8) a period of attenuation with rhythmic slow activity; (9) fast activity only; (10) a sharp- and slow-wave complex followed by a period of voltage attenuation with superimposed fast activity; and (11) a period of voltage attenuation with superimposed fast activity followed by rhythmic slow activity. The most common pattern observed was an episode of voltage attenuation (electrodecremental episode). The duration of ictal events ranged from 0.5 to 106 sec, with the longer episodes being associated with the arrest phenomenon. However, there was no close correlation between specific ictal EEG patterns and specific types of clinical events.³²

No significant correlation was found between the various types of ictal EEG patterns and underlying cause (cryptogenic versus symptomatic), subsequent seizure control, or prognosis for developmental outcome.⁴²

As with interictal EEG patterns, an asymmetric ictal pattern, regardless of type, does correlate with focal or lateralized structural brain lesions.^30,43 The most common patterns noted were higher amplitude fast activity and/or more pronounced voltage attenuation on the side of the lesion. Asymmetric spasms frequently occur in patients with asymmetric ictal patterns.¹⁵ A high-voltage, frontal-dominant, generalized slow-wave transient is a common ictal EEG onset seen in infantile spasm. In this patient, lateralized diffuse high-voltage biphasic delta activity in the left hemisphere indicates a lateralized epileptic focus/structural abnormality in the left hemisphere. The positive sharp wave at P3 indicates a deep epileptic focus corresponding to the focal cortical dysplasia seen in the left mesial parieto-frontal region (arrow).

Subdural EEG During Asymmetric Epileptic Spasms; High-Frequency Oscillations (HFOs). (Same patient as in Figure 7-11) Subdural EEG recording during a cluster of similar asymmetric epileptic spasms as in Figure 7-16 (arrow head) shows high-voltage delta slow activity with a positive polarity at the PG55 electrode, which is approximately at the same location as the P3 electrode in scalp EEG. What is missing in the scalp EEG recording is a brief run of low-voltage 70- to 80-Hz gamma activity both preceding and superimposed on the delta slowing (open arrow).

High-frequency oscillations (HFOs), characterized by very fast activity, ranging from 80 to 150 Hz, are noted at the epileptic focus in neocortical epilepsy during subdural EEG recordings.⁴⁴ Similar gamma activity ranging from 50-100 Hz is also detected on the scalp EEG during epileptic spasms.⁴⁵ Recent findings suggest that HFOs ranging between 100 and 500 Hz might be closely linked to epileptogenesis.⁴⁶

In humans, physiologic oscillations generally showed a frequency range between 80 and 160 Hz (“ripples”) in hippocampus.^47,48 Pathological ripples were also observed.⁴⁹ The differentiation between pathological and physiological events remains unclear.⁵⁰

HFOs between 250 and 500 Hz, called fast ripples, have been recorded from normal rodent and human brains.^51–53 It was hypothesized that they are related to somatosensory stimulation and sensory information processing.^54,55 Fast ripples in mesial temporal structures were more epileptogenic than ripples.⁵⁶

Ripples and fast ripples (250–500 Hz) occur frequently during interictal epileptiform discharges (IEDs) and may reflect pathological hypersynchronous events. In general, these HFOs are seen more frequently during non-rapid eye movement (NREM) sleep compared to rapid eye movement (REM) sleep or wakefulness.⁴⁸ Recently, it has been shown that HFOs may also be recorded from intracranial macroelectrodes.^57,58 During ictal recordings, HFOs could be identified and occurred mostly in the region of primary epileptogenesis and less frequently in areas of secondary spread.⁵⁷

The recent study showed that HFOs are an important electrophysiological manifestation of the epileptic tissue. They are partially correlated with the spiking region and with the seizure-onset zone (SOZ). Ripples and fast ripples behaved in parallel, increasing in the SOZ and spiking regions, but fast ripples were more specific to the SOZ region than ripples.⁴⁶

Symptomatic West Syndrome and Asymmetric Epileptic Spasm; Focal Cortical Dysplasia, Left Mesial Fronto-Parietal. (Same patient as in Figure 7-10 to 7-17) (A) MRI: blurred gray-white matter junction with cortical thickening in the left mesial fronto-parietal region. (B) Interictal PET: hypometabolism, left fronto-parietal region.(C) Resection of epileptogenic zone in the same area.

West Syndrome caused by Type 1 Neurofibromatosis. A 5-month-old boy with a family history of neurofibromatosis who had normal developmental history and presented with 3 weeks of epileptic spasms. His EEG shows hypsarrhythmia. He responded well with ACTH. At a last follow-up visit at 3 years of age, he was seizure-free and had only mild developmental delay.

Neurofibromatosis type 1 (NF1) is one of the most common autosomal dominant disorders with a prevalence of 1 in 4000. Seizures may be relatively uncommon in NF1 and are not always explained by underlying brain lesions. Infantile spasms (IS) are the most frequent cause of epilepsy in infancy, with incidence rates ranging from 2 to 5 per 10,000 live births. IS occurs in NF1 with a frequency (0.76%), 10- to 20-fold higher than that reported in the general population.⁵⁹ The frequency of West syndrome (WS) in NF1 clearly exceeds the frequency of WS in the general population.^60,61 Although the combination of IS and NF1 is not coincidental, it is an unusual event in NF1 compared to other neurocutaneous syndromes.

Generally, the outcome is favorable.⁶² Most patients had normal psychomotor development before spasms (14 of 15).⁶⁰ Predictors of a good outcome include the following: (1) symmetrical spasms without associated partial seizures; (2) typical hypsarrhythmia; (3) good response to corticoid therapy.⁶⁰ Infantile spasms caused by NF1 have several characteristics similar to idiopathic WS in profile and evolution: symmetrical spasms without partial seizures and without intellectual deficit, but with good response to corticotherapy and good long-term outcome.⁶⁰ Another report found the opposite outcome.⁶³ Some studies showed intermediate outcome.⁵⁹ MRIs of NF1 patients with IS showed high-signal foci in the brain, either subcortical or higher brainstem and central cerebral regions, after the age of 3 years.⁵⁹

Infantile Spasm; Diffuse Electrodecremental Pattern (EDP) with Low-Voltage Fast Activity. A 6-month-old girl with infantile spasms. The work-up was unremarkable. Interictal EEG shows hypsarrhythmia. Ictal EEG during her typical spasm demonstrates diffuse electrodecrement (*). Note diffuse attenuation of background activity at the onset of epileptic spasm. Four seconds later, during the tonic phase, diffuse low-voltage fast activity with posterior predominance (arrow) followed by more pronounced diffuse background attenuation is noted. At the end of electrodecrement (**), the patient starts to move and cry.

West Syndrome with Asymmetric Epileptic Spasms; Focal Cortical Dysplasia Associated with Cobalamin C Deficiency. A 4-month-old boy with global developmental delay who presented with asymmetric epileptic spasms with tonic stiffening greater on the right side, with or without high-pitch cry. MRI shows possible focal cortical dysplasia (FCD) in the left frontal region (white arrow). EEG during one of his typical seizures demonstrates diffuse attenuation of background activity (electrodecrement) with superimposed low-voltage beta activity.

After treatment with zonisamide, the patient developed hyperthermia and apnea. He was intubated and was admitted from the ED to the PICU. He developed very frequent asymmetric epileptic spasms with persistent epileptic focus in the left hemisphere. Emergency ictal SPECT showed hyperperfusion in the left frontal region concordant with the location of FCD seen in the MRI (black arrow). He underwent emergency invasive EEG monitoring followed by resection of the epileptogenic zone in the left frontal region. The patient has been free of disabling seizures since the resection of the FCD and surrounding epileptogenic zone. Pathology confirmed the diagnosis of mild FCD.

Asymmetric epileptic spasms are correlated with structural abnormalities, especially FCD in over 90% of cases. Functional modalities such as interictal PET and ictal SPECT play important roles in identification of epileptic foci.⁶⁴ Although FCD can be seen in rare neurometabolic diseases such as nonketotic hyperglycinemia or cerebrohepatorenal syndrome, it has never been reported in cobalamin c deficiency. Underlying neurometabolic disease is not an absolute contraindication for epilepsy surgery.

Outcomes after surgery, cortical resection, or hemispherectomy in infants with catastrophic focal epilepsy are very good. About 75–78% are seizure-free or have at least a 90% seizure reduction.^65,66

Life-saving epilepsy surgery for status epilepticus caused by cortical dysplasia has been reported.⁶⁷

Hypsarrhythmia Variant: Consistent Focus of Abnormal Discharge; Focal Cortical Dysplasia Due to Cobalamin c Deficiency. (Same patient as in Figure 7-21) EEG during sleep shows high-voltage delta slowing intermixed with multifocal spikes and sharp waves with a consistent focus of polyspikes in the left occipital region (arrow).

Hypsarrhythmia with a consistent focus of abnormal discharge is seen in 26% of hypsarrhythmia variants¹⁸ and characterized by a distinct focus of spike, polyspike, or sharp-wave activity superimposed on a typical hypsarrhythmic background, and in some cases, focal electrographic seizure discharges may occur.

Such foci tend to persist after spontaneous disappearance of the hypsarrhythmic pattern or after successful treatment.¹⁵

Hypsarrhythmia Variant: Consistent Focus of Abnormal Discharge; Focal Cortical Dysplasia Due to Cobalamin c Deficiency. (Same patient as in Figure 7-21) EEG performed during one of his typical asymmetric epileptic spasms described as rapid stiffening of the arms and legs, greater on the right side. The EEG shows a burst of diffuse biphasic delta activity (arrow) followed by a diffuse lateralized electrodecremental event with superimposed low-voltage beta activity in the left hemisphere with occipital predominance (double arrows). Three seconds later, there is a run of sharp waves in the left occipital region (open arrow).

Hypsarrhythmia with a consistent focus of abnormal discharge is seen in 26% of hypsarrhythmia variants¹⁸ and characterized by a distinct focus of spike, polyspike, or sharp-wave activity superimposed on a typical hypsarrhythmic background, and in some cases, focal electrographic seizure discharges may occur. Such foci tend to persist after spontaneous disappearance of the hypsarrhythmic pattern or after successful treatment.¹⁵

West Syndrome with Asymmetric Epileptic Spasms; Focal Cortical Dysplasia Associated with Cobalamin c Deficiency. (Same patient as in Figure 7-21 to 7-23) A 4-month-old boy with asymmetric epileptic spasms associated with cobalamin c deficiency. He developed seizure, hyperthermia, and apnea and was intubated. He developed NCSE. Emergency ictal SPECT shows hyperperfusion in the left frontal region concordant with the MRI (black arrow). EEG during the SPECT injection (open arrow) showed ictal activity arising from the left frontal region during the versive seizure. He underwent emergency invasive EEG monitoring followed by resection of epileptogenic zone in the left frontal region. The patient has been free of disabling seizures since the surgery. Pathology confirmed the diagnosis of mild FCD.

Epileptic spasms (ES) in some patients with West syndrome (WS) may be triggered by an epileptic focus in the neocortex. A leading spike can be used as a marker of the trigger zone for ES.⁶⁸ However, a study of WS by ictal SPECT demonstrates that the origin of hypsarrhythmia and ES may be different. Hypsarrhythmia appears to originate from cortical lesions, whereas the subcortical structures may be primarily responsible for the ES.⁶⁹ Lee et al. proposed a model in which the brainstem was implicated as the source of hypsarrhythmia and ES.⁷⁰ Asymmetric epileptic spasms are correlated with structural abnormalities, especially FCD in over 90% of cases. Functional modalities such as interictal PET and ictal SPECT play important roles in identification of epileptic foci.^64,71

Although focal cortical dysplasia can be seen in rare neurometabolic diseases such as nonketotic hyperglycinemia or cerebrohepatorenal syndrome, it has never been reported in cobalamin c deficiency. Underlying neurometabolic disease is not an absolute contraindication for epilepsy surgery.

Outcomes after surgery, cortical resection, or hemispherectomy in infants with catastrophic focal epilepsy are very good. About 75–78% are seizure-free or have at least a 90% seizure reduction.^65,66 Life-saving epilepsy surgery for status epilepticus caused by cortical dysplasia has been reported.⁶⁷

Asymmetric Hypsarrhythmia (Hemihypsarrhythmia) (Ipsilateral); Intraventricular Hemorrhage with Subsequent Left cerebral Hemiatrophy. A 9-month-old girl with a history of a new-onset asymmetric infantile spasm due to grade 4 IVH. Her seizures were described as clusters of subtle spells of head and eyes deviating to the right side without definite flexor or extensor spasms, lasting for approximately 1 sec. (A) CT image during an acute IVH shows dilatation of lateral ventricles, intraventricular hemorrhages with abnormally hypodense areas surrounding them (presumably infarct or edematous) with left-sided predominance, and intraparenchymal hemorrhage in the left occipital region. (B) CT image at 6 months of age shows diffuse cerebral atrophy, greater on the left, with VP shunt placement into the temporal horn of the left lateral ventricle. EEG demonstrates chaotic, very high-voltage polymorphic delta slowing intermixed with multifocal sharp waves in the left hemisphere, with relatively normal background activity in the right hemisphere. These findings are termed “asymmetric hypsarrhythmia.”

Asymmetric hypsarrhythmia is also referred to as hemihypsarrhythmia or unilateral hypsarrhythmia and is characterized by the presence of hypsarrhythmia with a consistent amplitude asymmetry between hemispheres. Asymmetric hypsarrhythmia is always associated with underlying structural abnormalities of the brain. However, it should be noted that the hypsarrhythmic activity may be maximal over either the more abnormal or the more normal hemisphere.³¹ It is more commonly seen in patients with malformation of cortical development. The presence of asymmetric hypsarrhythmia and other variant hypsarrhythmic patterns is more common than previously thought and generally does not correlate with prognosis.⁷¹ In children with leukomalacia and in patients with localized porencephalic lesions, the outcome of epilepsy appears to be better than in patients with diffuse cerebral lesions or in children with extensive porencephalic cysts, particularly those involving the frontal lobe.⁷³ Atrophy of midbrain and pons and the presence of bilateral parieto-occipital polyspike-wave discharges on follow-up EEGs were strongly correlated with the development of West syndrome.^74,75

Hemihypsatthythmia; Herpes Simplex Encephalitis. A 4-year-old boy with intractable epilepsy caused by herpes simplex encephalitis at 2 years of age. His seizure is described as “very frequent clusters of asymmetric tonic spasms with left-sided predominance accompanied by head and eye deviation to the left side, with or without horizontal nystagmus with fast component to the left side.” MRI showed severe encephalomalacia of the entire right hemisphere with mild left cerebral atrophy. Interictal EEG shows a hypsarrhythmic pattern over the left hemisphere with severe background suppression and multifocal sharp waves over the right hemisphere. This EEG pattern is compatible with left hemihypsarrhythmia. The patient showed significant improvement of seizures after the right functional hemispherectomy. Brain pathology can be lateralized to either ipsilateral or contralateral hemihypsarrhythmia.³¹

Infections are considered to be etiological factors in 10% of patients with infantile spasms (congenital or acquired cytomegalovirus (CMV), congenital rubella, herpes simplex virus, enterovirus, adenovirus, meningococcus, pneumococcus, pertussis, and unknown agents). The outcome of children with infectious etiology is poor.⁷⁶ herpes simplex virus (HSV-1) and varicella-zoster virus (VZV) are the most common causes of sporadic encephalitis in adults and children, respectively.⁷⁷ Sixty-one percent of children have early seizures and an associated poor outcome.⁷⁸

Unilateral Paroxysmal Fast Activity (PFA); Infantile Spasms. (Same patient as in Figure 7-26) A 4-year-old boy with intractable infantile spasms caused by herpes simplex encephalitis at 2 years of age. His seizures were described as very frequent clusters of asymmetric epileptic spasms with head and eyes deviating to the left side with nystagmus. EEG during sleep shows left hemihypsarrhythmia with bursts of diffuse high-voltage fast activity (20–24/sec), compatible with unilateral PFA (arrow) over the left hemisphere, with no clinical accompaniment except bradycardia noted in the ECG channel (double arrows). Absence of PFA in the right hemisphere may be due to severe damage to the neocortex, which is an important substrate in generating PFA.

Although PFA is very common in the EEG of Lennox-Gastaut syndrome, it can also be seen in infantile spasms,¹⁵ progressive partial epilepsy, and atypical generalized epilepsy.⁷⁹ The minimal substrate for the production of seizures consists of spike-wave/polyspike-wave complexes and runs of fast activity in the neocortex.⁸⁰

Hemihypsatthythmia; Herpes Simplex Encephalitis: EEG Normalization after Hemispherectomy. (Same patient as in Figure 7-26) EEG performed 1 month after the right hemispherectomy reveals resolution of hemihypsarrythmia in the left hemisphere. The patient was almost seizure-free for 6 months before developing recurrent epileptic spasms.

Asymmetric Epileptic Spasms; Post right Hemispherectomy. (Same patient as in Figure 7-26) After the right hemispherectomy, at 5 years of age, the patient showed a significant decrease in epileptic spasms with seizure reduction greater than 90%. He continues having some daily epileptic spasms that no longer occur in clusters. His seizure is described as rapid jerking of both arms and legs, greater on the left side, with head and eyes deviating to the left side, lasting for 2–5 sec. EEG during the seizure demonstrates diffuse biphasic delta slowing followed by a diffuse electrodecremental event with superimposed low-voltage beta activity, more prominent in the left hemisphere. Clinical seizures were compatible with epileptic focus lateralizing to the right hemisphere, although the EEG shows the predominant electrodecremental event in the left hemisphere. Persistent postoperative seizures after the functional hemispherectomy could be associated with residual insular cortex. In selected cases, repeated surgery was required.^81,82

MRI in Aicardi Syndrome. Aicardi syndrome is a genetic disorder transmitted as an X-linked dominant trait with hemizygous lethality in males. It is characterized by a triad of infantile spasms, agenesis of the corpus callosum, and chorioretinal lacunae. Other features include malformations of cortical development (polymicrogyria, periventricular heterotopia, focal cortical dysplasia), intracranial/interhemispheric cysts, papillomas of the choroid plexuses, gross hemispheric asymmetry, coloboma of the optic disc, microphthalmia, and vertebral and costal anomalies.²⁸

(A, B, C) Axial T2-weighted MRIs show microphthalmia (double arrows), periventricular heterotopia (arrow), polymicrogyria with schizencephaly (large arrow), and absence of corpus callosum (curved arrow). (D, E) Axial T1-weighted MRIs demonstrate interhemispheric and intraventricular cysts (arrow), focal cortical dysplasia (double arrows), and papilloma of chloroid plexus (large arrow). (F) Sagittal T1-weighted MRI shows focal cortical dysplasia (arrow) and a Dandy-Walker cyst (*).

“Split Brain” EEG; Aicardi Syndrome. (Same patient as in Figure 7-30) A 4-month-old girl with Aicardi syndrome. Interictal EEG shows bursts of high-amplitude spikes, sharp and slow waves separated by intervals of low-amplitude EEG. This suppression-burst pattern is almost always asymmetric, and the paroxysmal bursts may be unilateral or, when bilateral, may arise independently from both hemispheres. This is called a “split brain” EEG, which suggests impaired interhemispheric connection caused by an absence of corpus callosum.²⁸

Focal Transmantle Dysplasia; Focal low Voltage Fast Activity and Slow Direct Current (DC) Shift. A 21-day-old male child who started having seizures described as eye deviation to the right and left-sided tonic-clonic seizures starting at 1 week of life. The seizures evolved into asymmetric epileptic spasms. MRI shows focal transmantle dysplasia in the left parieto-temporal region. EEG during the asymmetric epileptic spasm (stronger on the right side), demonstrates low-voltage fast activity mixed with polyspikes during the spasm (arrow), followed by a negative “slow DC shift” at F7 (underline).

An asymmetric paroxysmal fast activity discharge or a sharp transient was consistently associated with asymmetric spasms, and the side with the stronger spasm contractions is contralateral to structural lesions.^33,83

An ictal slow DC shift is a slow and sustained change in EEG voltage resulting from a change in the function or interaction of neurons, glia, or both.^84,85 Ictal slow baseline shifts could be recorded with DC amplifiers. They were not seen with conventional EEG systems. When the high-pass filter was opened to 0.01–0.1 Hz, ictal baseline shifts were present in the scalp and in intracranially recorded seizures and may have localizing value.^86–89

Usually scalp-recorded ictal DC shifts are not successfully recorded because movements during clinical seizures could cause artifacts. They are highly specific but low in sensitivity. Ictal DC shifts were seen in 14–40% of recorded seizures and their sensitivity varied.^86,90,91 Scalp-recorded DC shifts were detected when seizures were clinically intense, while no slow shifts were observed in small seizures.⁸⁶ They were restricted to 1–2 electrodes, very closely related to the onset of low-voltage fast activity and electrodecrement.⁹²

Aicardi’s Syndrome with Focal Cortical Dysplasia. A 14-month-old right-handed girl with asymmetric infantile spasms resulting from Aicardi syndrome. MRI shows extensive focal cortical dysplasia in the right hemisphere, especially in the posterior quadrant (arrow head). Interictal EEG (left) shows asynchrony between both cerebral hemispheres, suppression of background EEG activity, and diffuse low-voltage beta activity in the right hemisphere (arrow). Ictal EEG (above) during one of her typical asymmetric epileptic spasms, which came in clusters, shows diffuse electrodecrement with no definite epileptic focus. Ictal SPECT during this seizure shows hyperperfusion in the right temporal region corresponded to the focal cortical dysplasia (double arrows). The patient underwent a partial right functional hemispherectomy and has been seizure-free.

Asymmetric infantile spasms have been found to be more frequent than previously considered.^33,93 They were seen in 25% in the study performed at the UCLA, and it was suggested that the spasms are generated by a cortical epileptogenic region that involves the primary sensorimotor area.

Hemihypsarrhythmia (Contralateral). A 6-month-old-boy who is an ex-38-week twin with a past history of left subdural hemorrhage at 5 days of age. He was found to have a remote left middle cerebral artery (MCA) stroke at that time. He developed global developmental delay and right hemiparesis. At 5 months of age, he started having clusters of asymmetric epileptic spasms with more intense jerking on the right side and with occasional head deviation to the right side. He failed very high dose of topiramate. (A) Axial T2-weighted MRI at 7 days of age shows extensive subdural hematoma (SDH) over the left hemisphere with mass effect and focal encephalomalacia in the left temporal region. (B) Axial T2-weighted MRI at 6 months of age shows resolution of SDH, which is transformed to a subdural hygroma, left temporal encephalomalacia, and left cerebral atrophy, especially in the posterior region. Interictal EEG shows hypsarrythmia over the right hemisphere, marked background suppression over the left hemisphere, and frequent bursts of low-voltage beta activity in the left posterior temporal region (arrow).

Asymmetric hypsarrhythmia is also referred to as hemihypsarrhythmia or unilateral hypsarrhythmia and is characterized by hypsarrhythmia with a consistent amplitude asymmetry between both hemispheres. Asymmetric hypsarrhythmia is always associated with focal or lateralized structural abnormalities. Hypsarrhythmia can be maximal over either the more abnormal or the more normal hemisphere.¹⁵ Consistent low-voltage beta activity may represent intrinsic epileptogenicity in the left posterior temporal region.

Neuroimages Before Functional Hemispherectomy. (A) Interictal FDG (2-dehydroxy-fluoro-D-glucose)-PET images show hypometabolism in the left

parieto-temporo-occipital region. FDG-PET provides a measure of regional cerebral glucose utilization. Interictal PET and ictal PET (or frequent interictal spiking during tracer uptake period) will show decreased and increased utilization of glucose, respectively. These findings are correspond to epileptic foci. (B) Axial T2-weighted MRI after the left functional hemispherectomy.