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Symptomatology of infantile spasms
Brain & Development 23 (2001) 453–466 www.elsevier.com/locate/braindev
Review article
Symptomatology of infantile spasms Kazuyoshi Watanabe*, Tamiko Negoro, Akihisa Okumura Department of Pediatrics, Nagoya University Graduate School of Medicine, 65 Tsurumai, Showa-ku, Nagoya 466-8550, Japan Received 9 May 2001; received in revised form 28 May 2001; accepted 31 May 2001
Abstract Epileptic spasms in West syndrome consist of a brief phasic contraction followed by a gradually relaxing tonic component, associated with typical ictal electroencephalographic (EEG) patterns. Three different EEG patterns are associated with a clinical spasm: fast wave bursts, high voltage slow waves (HVS), and desynchronization, occurring in this order. HVS are consistently seen and correspond to a clinical spasm, but usually preceded by fast wave bursts, which may be associated with an inhibition of muscle activity. Epileptic spasms can be classified into: symmetric spasms, asymmetric/asynchronous spasms, focal spasms, spasms with partial seizures, subtle spasms, spasms preceded by brief atonia, or subclinical spasms. Although clinical spasms are usually symmetric, ictal fast waves are always localized, and the following slow waves are not bilaterally synchronous and generalized, suggesting a focal cortical origin of spasms. q 2001 Elsevier Science B.V. All rights reserved. Keywords: Infant; Epilepsy; Infantile spasms; West syndrome; Electroencephalogram
1. Introduction The term ‘infantile spasms’ has long been used to denote a seizure type as well as an epileptic syndrome, but it is important to differentiate the classification of seizure types from that of epilepsies. The term ‘spasms’ should be used to denote a seizure type, as spasms are seen not only in West syndrome but also in many other syndromes, and not only in infants but also in older children. West syndrome is defined by the association of spasms in cluster and hypsarrhythmia. 2. Clinical and electrical delineation of epileptic spasms Epileptic spasms have not been satisfactorily defined. The report of the Workshop on infantile spasms describes that spasms designate a special type of epileptic seizure that involves the axial musculature – in flexion, extension or mixed – and that often occurs in clusters [1]. But nothing more definitive was stated as to the duration, extent or mode of muscle contraction or associated ictal electroencephalographic (EEG) changes. Kellaway et al. [2] studied infants with infantile spasms aged 1–43 months, and stated that the muscle activity in infantile spasms consisted of two phases with an initial phasic contraction lasting less than 2 s, followed by a less intense tonic contraction lasting from 2 to 10 s. Sometimes * Corresponding author. Tel.: 181-52-744-2297; fax: 181-52-744-2974. E-mail address: [email protected] (K. Watanabe).
the tonic phase was not present and the attack consisted of a phasic muscular contraction lasting less than 0.5 s. King et al. [3] reported that spasms were composed of one or more of the following: a brief myoclonic contraction, a more prolonged tonic contraction, and/or an arrest of activity. The most common types were myoclonic–tonic and myoclonic alone, but some showed tonic type alone. They studied 13–54month-old patients with intractable spasms, and some of them must have been in the transitional stage to Lennox– Gastaut syndrome. Fusco and Vigevano [4] studied patients aged 2–12 months, and defined an epileptic spasm as a characteristic muscular contraction that lasts from 1 to 2 s, and reaches a peak more slowly than a myoclonic jerk, but more rapidly than a tonic seizure, and then decreases equally quickly and appears polygraphically as a kind of ‘rhombos’. However, a spasm usually consists of an initial brief phasic contraction followed by a gradually relaxing tonic component of varying duration [5]. A close look at the surface electromyogram (EMG) discloses that muscular contraction usually reaches a peak quickly and sustains for a brief period, but decreases more slowly, resembling the shape of a tadpole (Fig. 1). Haga et al. [6] investigated ictal features of spasms in patients with newly diagnosed West syndrome before adrenocorticotropical hormonal (ACTH) therapy. A cluster of spasms was defined as a group of spasms consisting of two or more spasms occurring at intervals less than 60 s apart. The number of spasms per cluster was 19, the duration of one cluster 282 s, and the interval between each spasm 23 s on average, but they varied greatly. As the duration of the relax-
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Fig. 1. Ictal polygram of a spasm. Muscular contraction reaches a peak quickly and sustains for a brief period and decreases slowly. Note also a preceding muscular inhibition in the biceps muscle associated with fast wave bursts, and following high voltage slow wave bursts associated with a spasm.
ing phase was variable, the duration of an initial phasic muscle contraction was analyzed, which was 0.65 s with a range from 0.3 to 1.6 s. There was no significant difference in the flexor, extensor, mixed types and other ictal manifestations between cryptogenic and symptomatic cases, except for focal features, which were seen only in the symptomatic group. Although some spasms are very brief and clinically appear indistinguishable from myoclonic seizures, ictal EEGs of spasms are different from those associated with myoclonic seizures. Thus, ictal EEGs are important for the diagnosis of spasms. Usually three different EEG patterns are associated with a clinical spasm: high voltage slow wave complex, fast wave bursts, and desynchronization. The slow wave complex corresponds to a clinical spasm and was observed in all cases [4,6]. Fusco and Vigevano [4] reported that the onset of the contraction correlated with that of the slow wave on the vertex, where it was positive in polarity. The slow wave, however, is not an initial ictal discharge, and is usually preceded by fast wave bursts. As slow waves are of high amplitude and obscure other EEG components such as fast waves, we analyzed ictal EEGs in detail with digital EEGs [7]. A low pass filter at 0.5 Hz with reduction of the sensitivity disclosed that the slow wave complex is usually polyphasic, displaying negative–positive–negative deflection, reminiscent of an elongated sharp and slow wave complex, where the positive wave is the most prominent (Fig. 2). The slow waves are bilateral but asynchronous, not diffuse but more widespread than the
fast wave burst. The most prominent initial positive wave occurs at Pz, Fz/Pz , or Fz with laterality (Fig. 3). The muscle contraction of a spasm begins at the onset of the descending slope of the positive component and reaches a peak at the peak of the positivity and decreases with the ascending slope. A study with surface EMG disclosed that muscle contraction occurred initially in mentalis, then rectus abdominis, triceps, and then quadriceps femoris muscles in this order (Fig. 4). Thus, axial muscles seem to contract earlier than limb muscles, and cephalad muscles earlier than caudal muscles. The fast wave burst is an initial ictal discharge followed by the slow wave complex. It occurs alone or is followed by the slow wave and correlates with motionless stare, never corresponding to a clinical spasm [4]. Panzica et al. [8] reported that it was associated with subtle seizures preceding the onset of spasm series but also appeared to occur with behavioral spasms. The fast wave burst was observed in 50% [4], 62% [6], or 72% [7]. We also found it in 72% in our recent study using digital EEGs. The frequency of the fast wave burst was 14–16 Hz [4], or 17.5 ^ 2.1 Hz [7]. Fast wave bursts occur generally at the beginning or end of a cluster [4]. Our recent study using a low pass filter at 15 Hz disclosed that fast wave bursts occurred mainly in the left or right occipital, posterior temporal and parietal area [7] (Fig. 5). They were initially asymmetric, but later occurred more diffusely on both sides in the whole series of a cluster (Fig. 5). Although they are not observed in all cases, they should be a leading discharge triggering spasms and an associated slow wave complex. Panzica et al. [8] evaluated the characteristics of the ictal EEG event accompanying infantile spasms using a bivariate autoregressive parametric model. The analysis of the fast wave burst present in the 500 ms EEG epochs preceding spasm onset revealed that the burst had rather low interhemispheric coherence values and asymmetric amplitude on homologous EEG derivations. The highest power peak was found most frequently in the fronto-central area and least frequently in the parieto-occipital area. It persisted briefly after spasm onset, reaching a higher coherence value. The interhemispheric time difference ranged from 9.1 to 14.3 ms (11.4 ^ 1.9) in the epoch preceding spasm onset. They concluded that the data obtained from the analysis of the ictal EEG events, compared with clinical and interictal EEG features, indicate that an asymmetric EEG pattern mainly consisting of a rhythmic burst of fast activity consistently preceded both symmetric and asymmetric spasms, thus suggesting a localized cortical origin of the ictal discharge giving rise to the spasms. We found similar fast wave bursts during rapid eye movement (REM) sleep in 35% of patients with West syndrome and observed in some cases that they continued to occur periodically until clinical spasms appeared and the patient awoke [9]. The same phenomenon was reported by Hrachovy et al. [10]. This fast wave burst occurred during REM sleep in 50% of cases in our later study [11]. Infantile spasms seem to start subclinically in REM sleep and this
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Fig. 2. Ictal polygram of a spasm. Left: low pass filter at 1.6 Hz. Right: low pass filter at 0.5 Hz with reduced sensitivity. The slow wave complex is polyphasic, consisting of negative–positive–negative deflection with prominent positivity. The contraction of the deltoid muscle begins on the descending slope of the positive wave.
agrees well with the fact that infantile spasms occur often immediately after awakening. Desynchronization or decremental activity appeared in 69% of the patients studied by Fusco and Vigevano [4] and 62% of our previous series [6]. It always appeared after the clinical spasm and never accompanied by an ictal manifestation, considered to be a postictal rather than an ictal phase. Less frequently, slow sharp and slow wave complex was observed in association with a clinical spasm [2,6]. But Fusco and Vigevano [4] never found them as the counterpart of a clinical spasm. It is different from that seen in myoclonic seizures, but takes a form of elongated sharp and slow wave complex. An analysis with a low pass filter at 0.5 Hz and reduced sensitivity showed that the sharp and slow wave complex was essentially similar to the polyphasic slow wave complex with prominent positivity as mentioned above (Fig. 6). Predominantly, the clusters occurred soon after arousal from sleep. Because of frequent awakenings, the number of seizures occurring at night was similar to the diurnal number [2]. Spasms characteristically occur in a cluster that evolves in a crescendo–decrescendo manner. The intensity of spasms in each cluster often increases to a peak, then progressively decreases until they stop [2]. Spasms gradu-
ally become stronger, and quite violent at the peak, and then the intensity diminishes until they become subtle again, terminating as subclinical discharges without discernible movements on video (Fig. 7). The surface EMG may show subclinical contraction without visible movements on video. When the spasms are weak, interspasm EEG shows hypsarrhythmia, but as the spasms become stronger, interspasms hypsarrhythmia disappears, and then reappears as the spasms become weaker again towards the end of a cluster (Fig. 7). Thus, interspasms hypsarrhythmia, which has been claimed to be a characteristic of idiopathic West syndrome [12,13], depends rather on the intensity of spasms, not on the etiology. Epileptic spasms are seen in Ohtahara syndrome, West syndrome, Lennox–Gastaut syndrome, other symptomatic generalized epilepsies, epilepsy with periodic spasms, and severe epilepsy with multiple independent spike foci. Seizures resembling spasms are also seen in patients with symptomatic localization-related epilepsy (LRE) [14]. Spasms also occur in non-epileptic benign infantile spasms [15]. It has not been completely elucidated whether or not spasms in West syndrome are the same as in other syndromes in all respects. The seizures occurring in series in Lennox–Gastaut syndrome and other generalized epilepsies in older children clinically greatly resembled infantile
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Fig. 3. Ictal polygram of spasms during a cluster. The most prominent initial positive wave occurs at Pz-P3 on the left and Fz-F3 on the right.
spasms, and the ictal EEG changes were reported to be identical to those that occur with infantile spasms [16,17]. Clustering is most characteristic in West syndrome and tends to be less frequent in other syndromes. In the study by King et al. [3] who examined older patients with intractable spasms, 47% of spasms occurred in clusters, whereas Kellaway et al. [2] who studied younger patients reported that 78% occurred in clusters. Other seizure types such as tonic seizures usually coexist and are more marked in Lennox–Gastaut syndrome. 3. Classification of epileptic spasms in West syndrome Spasms have been classified into flexor, extensor and mixed flexor/extensor type [2]. But there is no significant difference among these types in the etiology, seizure or psychomotor outcome of West syndrome [4,6]. Thus, this classification does not aid in the diagnosis of etiology, decision of treatment option, monitoring of therapeutic effect, or prognostication. Therefore, a classification based mainly on the topography and extent of muscle contraction is proposed (Table 1). 3.1. Symmetric spasms Symmetric spasms are those in which both sides of the body appear to be involved with equal intensity at the same time or only axial musculature was involved. Gaily et al. [18] found symmetric spasms in 57% of all recorded
spasms. Spasms in cryptogenic West syndrome is always symmetric, but the reverse is not always true, and symmetric spasms are seen not only in cryptogenic West syndrome but also in symptomatic West syndrome. In patients with symptomatic West syndrome having symmetric spasms, brain lesions are usually diffuse, not lateralized [19]. In Down syndrome, spasms were symmetric with symmetric hypsarrhythmia [20]. Spasms are mostly symmetric also in neurofibromatosis type I [21]. Even in patients with symmetric spasms, a focal lesion can be found. Haginoya et al. [22] reported a patient having symmetrical spasms in whom the left hemisphere was virtually completely defective and showed focal hypsarrhythmia in the right frontal cortex. Even in cryptogenic West syndrome with normal neurodevelopmental status and normal magnetic resonance imaging (MRI) having symmetric spasms, focal glucose hypometabolism may be found at the onset [23]. 3.2. Asymmetric spasms Infantile spasms were classically considered symmetric [24], but asymmetric spasms have been found to be more frequent than was previously considered. Asymmetric spasms are spasms involving only one side of the body or distinctly stronger on one side than the other. Gaily et al. [18] found asymmetric spasms in 25% of all recorded spasms in children younger than 5 years of age. They calculated the ratio of asymmetric/asynchronous spasms to all recorded spasms. Forty-eight percent of the patients had
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Fig. 4. Ictal polygram of a spasm. Muscle contraction occurs sequentially in the mentalis, rectus abdominis, triceps, quadriceps femoris muscle in that order.
only symmetric spasms. The other patients could be divided into minority-asymmetry/asynchrony group and majorityasymmetry/asynchrony group, the latter comprising 20% of the patients. On the contrary, Kellaway et al. [2] reported asymmetric spasms in 4% of their patients which accounted for only 0.6% of the total spasms. Donat et al. [16] considered asymmetric spasms present if they were observed in 75% of artifact-free seizures recorded and found asymmetric spasms in 10% of their patients. Fusco and Vigevano [4] noted asymmetric spasms in 22% of their patients. Haga et al. [25] defined asymmetric spasms as those that were dominant on one side of the body throughout an entire series of spasms, excluding those showing asymmetry transiently, and found asymmetric spasms in 16% of their patients. Spasms asymmetric only in the initial part of a cluster or only a part of multiple clusters of the same patient was not considered asymmetric spasms, taking the influence of body posture into consideration. Asymmetric spasms may be consistent or alternating. In those associated with a unilateral or focal lesion, asymmetric spasms were constantly
dominant on the side contralateral to the abnormal hemisphere, i.e., on the paralytic side when the patient had hemiplegia. In those combined with preceding partial seizures, clusters of spasms were influenced by preceding partial seizures. When the predominant side of a preceding partial seizure changed from one seizure to another, the predominant side of spasms changed alternately in each series in conformity with that of the preceding partial seizure (Fig. 8). The ictal EEG of spasms exhibited more pronounced fast wave bursts or slow waves with either left or right hemisphere accentuation in accordance with the side of the preceding focal discharges. Asymmetric spasms always indicate symptomatic etiology whereas symmetric spasms are seen in both symptomatic and cryptogenic cases [4,6,19]. But asymmetric spasms were observed in only 17% of patients with symptomatic West syndrome [6]. Fusco and Vigavano [4] found asymmetric spasms in 40% of patients with symptomatic West syndrome which was defined as those showing contraction asymmetric on the two sides of the body. Not
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Fig. 5. Ictal polygram of spasms with a low pass filter at 15 Hz. Fast wave bursts initially occurred most prominently in the right occipital and posterior temporal area (left), but more diffusely 15 min later (right) in the same cluster.
all patients with focal cortical lesions display asymmetric spasms. Only 29% of patients with a focal lesion were reported to have asymmetric spasms [26]. Donat et al. [19] found focal or lateralized features in 38% of consecutive patients with infantile spasms. Unilateral hypsarrhythmia and asymmetric ictal EEG changes during spasms often occurred together: each always indicated the side of a focal or asymmetric structural cerebral lesion that was visible on neuroimaging studies and was usually large. Clinically asymmetric spasms were less common, always occurred in the presence of asymmetric ictal EEG changes, and did not appear to have additional localizing value. Lateralized hypsarrhythmia, with or without asymmetric spasms, occurred in the presence of bilateral structural lesions that were more abnormal in the area of the greater EEG abnormality. Patients with symmetric hypsarrhythmia and infantile spasms rarely had focal/lateralized lesions visible on imaging studies. Kramer et al. [27] investigated focal features including partial seizures, hemiparesis, focal radiologic findings, asymmetric spasms, and lateralized hypsarrhythmia in patients with West syndrome. Sixty-six percent had such asymmetric manifestations, which had significant association with asymmetric brain pathology, but did not correlate with age of onset and outcome.
3.3. Asynchronous spasms Gaily et al. [18] investigated behavioral and EEG asymmetry and asynchrony in patients with infantile spasms younger than 5 years of age, but hypsarrhythmia was present only in 7% of them. They defined asynchronous spasms as those involving one side of the body before the other. The EEG was defined as symmetric if the spasms-associated EEG event was bilateral and synchronous between the hemispheres, and there was a ,50% difference in amplitude between the sides, or no spasms-related changes were seen. EEG asymmetry was considered present if the EEG event associated with behavioral spasms was unilateral or had at least twice as high amplitude on one side as on the other. A spasms-associated EEG change was defined as asynchronous when one side preceded the other by at least 100 ms. Of the recorded spasms, 25% were asymmetric and 7% were asynchronous. Most asymmetric or asynchronous spasms were associated with an ictal EEG discharge that was contralateral to the behaviorally more involved side. In 20% of the patients, more than half of the recorded spasms were asymmetric or asynchronous. Baseline EEG, magnetic resonance imaging, positron emission tomography, and neurological examination revealed structural and functional
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Fig. 6. Ictal polygram of a spasm with a low pass filter at 0.5 Hz and reduced sensitivity. The sharp and slow wave complex resembles the polyphasic slow wave complex with prominent positivity. Low pass filter: 1.6 Hz in the left, 0.5 Hz in the middle, and 10.0 Hz in the right.
brain abnormalities that involved the contralateral central region significantly more often in the children with .50% spasm asymmetry or asynchrony than in the other children. Partial seizures with lateralized motor behavior also occurred frequently in these children. The findings suggest that asymmetric and asynchronous spasms are generated by a cortical epileptogenic region that involves the primary sensorimotor area.
this was considered a variant of West syndrome, some may argue that this is a type of LRE. Donat and Wright [29] reported a patient having focal spasms associated with contralataral porencephalic cyst, which later evolved into bilaterally symmetric typical spasms, but an EEG at the time of focal spasms was not available.
3.4. Focal spasms
Partial seizures (PS) may be combined with epileptic spasms (ES) in a single seizure in patients with West syndrome [30–40]. The sequence of seizures is variable; PS followed several seconds later by spasms in cluster, alternation of PS and spasms in cluster starting with PS, PS gradually replaced by ES in cluster with overlapping of the two, and most infrequently ES followed by PS. Most frequently, PS are followed by ES in cluster, which seem to be triggered by foregoing PS. The epileptic spasms are bilateral but often asymmetric. In patients with symmetric spasms, the spasms tend to show some laterality during or just after a partial seizure, but gradually became symmetric in the later parts of the clusters. The interictal EEG often shows asymmetric hypsarrhythmia. The clinical manifestation preceding PS consists of star-
Focal spasms usually consist of brief focal muscular contraction, but lateral eye deviation or lateral head jerk may be seen. They are associated with ictal EEG discharges characteristic of a spasm. Focal spasms may be associated with generalized hypsarrhythmia interictally. We reported an infant who had clusters of focal spasms of the right arm associated with hypsarrhythmia without definite asymmetry on interictal EEGs [28]. Ictal EEGs showed fast wave bursts superimposed on slow waves most markedly in the left central region. Subsequent EEGs after cessation of spasms with ACTH treatment disclosed focal polyspike and waves in the same region. MRI revealed findings suggestive of delayed myelination in the left frontal region. Although
3.5. Spasms combined with partial seizures
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Fig. 7. Ictal polygram of a cluster of spasms. S: Subclinical spasm. Number in circle: the sequential number of a spasm in a cluster. Subclinical spasm is a subclinical contraction noted on EMG without visible movements on video. Before the onset of a clinical cluster, a brief contraction is noted on the mentalis muscle associated with a typical slow wave complex without visible movements on video. As the cluster progresses with stronger spasms, interspasm hypsarrhythmia disappears. Toward the end of the cluster, spasms become weaker, and interspasm hypsarrhytmia reappears, and then subclinical spasms occur again. The extent of muscle involvement gradually decreases with sequential subclinical spasms toward the end of the cluster, as shown in the two subclinical spasms at the end.
Table 1 Classification of epileptic spasms I. Type of spasms 1. Symmetric spasms 2. Asymmetric/asynchronous spasms 3. Focal spasms 4. Spasms with partial seizures (a) Spasms combined with partial seizures in a single seizure (b) Spasms preceded by partial seizures in the clinical course 5. Subtle spasms 6. Spasms preceded by brief atonia 7. Subclinical spasms II. Ictal phenomena associated with spasms (collected from literature by Lacy and Penry, 1976 [24]) Scream, cry, laughter, pallor, cyanosis, flushing, sweating, pupillary dilation, hiccups, tears, facial grimace, smile, confused, frightened facial expression, fluttering of eyelids, staring, rolling up of eyes, lateralizing eye movements, nystagmus, tremulousness of extremities, respiratory arrest, incontinence
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Fig. 8. Ictal polygram of spasms in cluster following a partial seizure. Upper figure: left occipital focal rhythmic discharges were followed by HVS on the left side associated with spasms with the patient turning toward the left. Lower figure: right occipital discharges were followed by HVS in the right side associated with spasms with the patient turning toward the right.
ing, cessation of movements, flushing, automatisms, increased limb tone, laughter, tonic eye and head deviation, clonic movements, tonic posturing of single limbs, fencing, posturing, or facial twitching [32–34]. The origin of focal seizure discharges is variable, involving any regions of both hemispheres [33,34,40], although central and temporal regions were most frequent, and frontal areas least frequent [41]. Carrazana et al. [34] reported three patients with complete agenesis of the corpus callosum who had PS– ES, which argues against interhemispheric callosal spread of focal discharges resulting in the generalized spasms. They also reported that 6 of the 16 infants with PS–ES had a favorable outcome with surgical cortical resections. This group of patients supports a model in which the spasms, although probably generated at a subcortical level, are facilitated or possibly induced by focal discharges from cortical pathology. Plouin et al. [36] noted PS in 31(42%) of 74 of patients with West syndrome (51% of patients with symptomatic cases, 33% of cryptogenic cases) during 24-h ambulatory EEG recordings. In 14 infants (19%), PS were immediately followed by a cluster of spasms consisting of a single ictal event. Kubota et al. [40] also found such combinations in 8
(18%) of 45 patients with West syndrome studied with simultaneous video-EEG monitoring. Hrachovy et al. [38], however, reported that the coupling of focal electrical seizure discharges (FS) and spasms was significant in only 3% of 96 patients with West syndrome, and concluded that, in some instances, apparent couplings of FS and spasms are best explained by chance coincidence. Kubota et al. [40] studied the long-term clinical course in 8 patients who had PS followed by ES with a close temporal association (PS–ES). PS–ES were preceded by PS in the clinical course in six of the eight cases. PS–ES disappeared or was replaced by other types of seizures in 1–34 months. They were followed by PS alone or together with other types of seizures in six of the eight cases. Thus, epilepsy with PS– ES often starts as LRE and evolves into LRE in most of the patients. The period during which the patients showed PS– ES was transient. It should be classified into undetermined epilepsy with both focal and generalized seizures according to the current International Classification, but is closer to LRE rather than generalized epilepsy. The clinical course is similar to epilepsy with continuous spike-waves during slow sleep, in which the EEG shows transient generalization of paroxysmal discharges during the course of LRE. In a few
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cases, however, it may evolve into Lennox–Gastaut syndrome [34]. A long-term follow-up study showed that all cases of epilepsy with PS–ES were severely mentally retarded [37,40]. Compared with patients without PS–ES, those with PS–ES more often had organic brain lesions of prenatal origin, other types of seizures before the onset of ES, asymmetric hypsarrhythmia on the EEG, and poor psychomotor outcome [40]. In periodic spasms reported by Gobbi et al. [42], spasms occur periodically with focal electrical discharges, but interictal EEGs do not show hypsarrhythmia. 3.6. Spasms preceded by partial seizures in the course of epilepsy Infantile spasms may be preceded or followed by PS in the course of epilepsy [43–45]. The occurrence of PS before onset of spasms usually indicates prenatal etiology [46]. In
Aicardi syndrome, PS usually precede spasms by 1–6 weeks. Most patients with tuberous sclerosis presenting with PS in the first month of life progress to infantile spasms. In patients with lissencephaly, epilepsy may be manifested by early PS before spasms occur. Patients with hemimegalencephaly often have their first seizures within 3 months of life, especially in the first days of life, and present with PS and asymmetric spasms, and asymmetric or unilateral hypsarrhythmia. In a follow-up study of infants with epilepsies of neonatal onset, we identified a subgroup of symptomatic LRE with transient West syndrome [47]. Thirteen (45%) of 29 infants with symptomatic LRE of neonatal onset developed West syndrome, which was followed by LRE in five (38%) of them. 3.7. Subtle spasms Subtle seizure phenomena may occur alone or together
Fig. 9. Ictal polygram of a spasm. A brief muscular inhibition is noted in the mentalis muscle immediately before a spasm.
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Fig. 10. Ictal polygram of a spasm. A brief muscular inhibition is noted in the right biceps muscle, which is associated with fast wave bursts. This is followed by a spasm associated with HVS.
with typical spasms in association with electrical discharges characteristic of typical spasms. Contractions of the facial muscles, eye opening or closure, eye movements (upward, downward or nystagmoid movements, adduction), head nodding, shoulder shrugging, grimace, yawn, motion arrest, or motionless stare [29]. Eye movements may occur independently from infantile spasms and precede the development of infantile spasms by weeks. Most of the variants appear to be fragments or limited expressions of more typical spasms. They may coexist with typical infantile spasms, representing natural variability or resulting from a change in level of consciousness, time or medication that modifies the clinical expression of the spasms [29]. Some patients may show typical spasms in the waking state but have subtle variants during sleep. Subtle spasms may occur weeks before typical spasms begin to occur or after they resolve spontaneously. Subtle spasms tend to occur at the onset and offset of the cluster. Subtle spasms may also be observed after ACTH or other treatments. 3.8. Spasms preceded by brief atonia We previously reported brief atonia associated with slow sharp waves at the beginning of a burst observed during
abnormal tonic posture in an infant with Ohtahara syndrome [48]. This was sometimes followed by tonic spasms. The duration of the muscular inhibition ranged from 100 to 400 ms, which is longer than a myoclonic jerk. We later observed the same phenomenon in infants with West syndrome. Each spasm is preceded by a brief muscular inhibition, which may manifest only in muscles in continuous contraction (Figs. 9 and 10). This muscle inhibition may occur in association with the fast wave burst not followed by clinical spasms (Fig. 11). The patient seems to have motion arrest on video, which may be assessed as a subclinical spasm, or a subtle spasm called motion arrest. This corresponds to a related epileptic silent period reported by Tassinari et al. (1968) [49] or epileptic negative myoclonus [50,51], although it is longer in duration than a myoclonic jerk. 3.9. Subclinical spasms Ictal discharges characteristic of spasms may occur in cluster without discernible movements, although subtle seizures barely detectable on video may be present as mentioned above. Shewmon [5] stated that he came across subclinical electrographic spasms on several occasions
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Fig. 11. Ictal polygram of a subclinical spasm. A brief muscular inhibition is noted on the right biceps muscle in association with fast wave bursts. This is not followed by clinical spasms and the patient is noted to have motion arrest on video.
during video/EEG monitoring and described them as follows. The epileptiform discharges disappear and the background assumes a lower-amplitude, faster, non-descript pattern. Soon the characteristic ictal discharges appear – typically high amplitude slow waves with overriding rhythmic fast activity, each lasting 1–2 s – and these repeat approximately every 10 s. But the child does not awaken, and no discernible movement accompanies any of the discharges, although subtle seizures barely detectable on video may be present. The patient seems to have gone into REM sleep in view of the background EEG change and have been displaying periodic fast wave bursts as we previously reported [9]. Some of the patients may wake up to have frank spasms. Subclinical spasms may also occur at the onset and the end of a cluster, as mentioned above (Figs. 7 and 11). Therefore, the boundary between subtle and subclinical spasms is difficult to fix because of the limitation of video-EEG polygraphy and our ability of observation.
4. Are spasms generalized seizures? Infantile spasms have been placed in generalized
seizures, and West syndrome in generalized epilepsies. Meanwhile, localization-related epilepsies (LREs) are defined as epileptic disorders in which seizure semiology or findings at investigation disclose a localized origin of the seizures [52]. Focal or unilateral lesions are found not infrequently in West syndrome. Some investigators consider infantile spasms a type of LRE when they are abolished by resection of a focal lesion [53]. However, localized cortical lesions found in West syndrome cannot be a direct origin of epileptic spasms, since their site is quite heterogeneous [54]. Moreover, seizures in West syndrome with a focal cortical lesion do not show a focal onset of paroxysmal discharges from the site of the lesion. Secondary generalization from the original focus cannot be considered an explanation of epileptic spasms because ictal discharges do not propagate as seen in usual secondarily generalized partial seizures in which initial focal paroxysmal discharges are followed by generalization of paroxysmal discharges. Most investigators consider that epileptic spasms originate in the brainstem, but there has been no definite evidence for it [55]. As mentioned above, ictal EEGs do not show bilaterally synchronous generalized discharges even in cryptogenic West syndrome with symmetric spasms, but display a
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positive slow wave maximally at Fz/Pz in accordance with spasms. This may suggest the supplementary motor area as a generator of spasms. Cortical stimulation of this area produces proximal, segmental, unilateral or bilateral, tonic postural movements [56]. Some frontal lobe seizures occur frequently in clusters. But this cannot explain all. There are many unanswered questions. How will the mesial frontal area be triggered by lesions in various areas? What do fast wave bursts stand for? Apart from neurophysiological consideration, it may be useful to classify epilepsy with spasms with a localized lesion into LRE from a practical viewpoint, as intractable cases can be treated surgically.
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[50] Guerrini R, Dravet C, Genton P, Bureau M, Roger J, Rubboli G, et al. Epileptic negative myoclonus. Neurology 1993;43:1078–1083. [51] Tassinari CA, Rubboli G, Parmeggiani L, Valzania F, Plasmati R, Riguzzi P, et al. Epileptic negative myoclonus. In: Fahn S, Hallet M, Lueders H, Marsden CD, editors. Advances in neurology, vol. 67. Negative motor phenomenaPhiladelphia, PA: Lippincott-Raven, 1995. pp. 181–197. [52] Commission on Classification and Terminology of the International League against Epilepsy. Proposal for revised classification of epilepsies and epileptic syndromes. Epilepsia 1989;30:389–399. [53] Acharya JN, Wyllie E, Lu¨ ders HO, Kotagal P, Lancman M, Coelho M. Seizure symptomatology in infants with localization-related epilepsy. Neurology 1997;48:189–196. [54] Koo B, Hwang P. Localization of focal cortical lesions influences age of onset of infantile spasms. Epilepsia 1996;37:1068–1071. [55] Watanabe K. Recent advances and some problems in the delineation of epileptic syndromes in children. Brain Dev 1996;18:423–437. [56] Soo NK. Mesial frontal epilepsy. Epilepsia 1998;39(Suppl 4):S49– S61.
Review article
Symptomatology of infantile spasms Kazuyoshi Watanabe*, Tamiko Negoro, Akihisa Okumura Department of Pediatrics, Nagoya University Graduate School of Medicine, 65 Tsurumai, Showa-ku, Nagoya 466-8550, Japan Received 9 May 2001; received in revised form 28 May 2001; accepted 31 May 2001
Abstract Epileptic spasms in West syndrome consist of a brief phasic contraction followed by a gradually relaxing tonic component, associated with typical ictal electroencephalographic (EEG) patterns. Three different EEG patterns are associated with a clinical spasm: fast wave bursts, high voltage slow waves (HVS), and desynchronization, occurring in this order. HVS are consistently seen and correspond to a clinical spasm, but usually preceded by fast wave bursts, which may be associated with an inhibition of muscle activity. Epileptic spasms can be classified into: symmetric spasms, asymmetric/asynchronous spasms, focal spasms, spasms with partial seizures, subtle spasms, spasms preceded by brief atonia, or subclinical spasms. Although clinical spasms are usually symmetric, ictal fast waves are always localized, and the following slow waves are not bilaterally synchronous and generalized, suggesting a focal cortical origin of spasms. q 2001 Elsevier Science B.V. All rights reserved. Keywords: Infant; Epilepsy; Infantile spasms; West syndrome; Electroencephalogram
1. Introduction The term ‘infantile spasms’ has long been used to denote a seizure type as well as an epileptic syndrome, but it is important to differentiate the classification of seizure types from that of epilepsies. The term ‘spasms’ should be used to denote a seizure type, as spasms are seen not only in West syndrome but also in many other syndromes, and not only in infants but also in older children. West syndrome is defined by the association of spasms in cluster and hypsarrhythmia. 2. Clinical and electrical delineation of epileptic spasms Epileptic spasms have not been satisfactorily defined. The report of the Workshop on infantile spasms describes that spasms designate a special type of epileptic seizure that involves the axial musculature – in flexion, extension or mixed – and that often occurs in clusters [1]. But nothing more definitive was stated as to the duration, extent or mode of muscle contraction or associated ictal electroencephalographic (EEG) changes. Kellaway et al. [2] studied infants with infantile spasms aged 1–43 months, and stated that the muscle activity in infantile spasms consisted of two phases with an initial phasic contraction lasting less than 2 s, followed by a less intense tonic contraction lasting from 2 to 10 s. Sometimes * Corresponding author. Tel.: 181-52-744-2297; fax: 181-52-744-2974. E-mail address: [email protected] (K. Watanabe).
the tonic phase was not present and the attack consisted of a phasic muscular contraction lasting less than 0.5 s. King et al. [3] reported that spasms were composed of one or more of the following: a brief myoclonic contraction, a more prolonged tonic contraction, and/or an arrest of activity. The most common types were myoclonic–tonic and myoclonic alone, but some showed tonic type alone. They studied 13–54month-old patients with intractable spasms, and some of them must have been in the transitional stage to Lennox– Gastaut syndrome. Fusco and Vigevano [4] studied patients aged 2–12 months, and defined an epileptic spasm as a characteristic muscular contraction that lasts from 1 to 2 s, and reaches a peak more slowly than a myoclonic jerk, but more rapidly than a tonic seizure, and then decreases equally quickly and appears polygraphically as a kind of ‘rhombos’. However, a spasm usually consists of an initial brief phasic contraction followed by a gradually relaxing tonic component of varying duration [5]. A close look at the surface electromyogram (EMG) discloses that muscular contraction usually reaches a peak quickly and sustains for a brief period, but decreases more slowly, resembling the shape of a tadpole (Fig. 1). Haga et al. [6] investigated ictal features of spasms in patients with newly diagnosed West syndrome before adrenocorticotropical hormonal (ACTH) therapy. A cluster of spasms was defined as a group of spasms consisting of two or more spasms occurring at intervals less than 60 s apart. The number of spasms per cluster was 19, the duration of one cluster 282 s, and the interval between each spasm 23 s on average, but they varied greatly. As the duration of the relax-
0387-7604/01/$ - see front matter q 2001 Elsevier Science B.V. All rights reserved. PII: S 0387-760 4(01)00274-1
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Fig. 1. Ictal polygram of a spasm. Muscular contraction reaches a peak quickly and sustains for a brief period and decreases slowly. Note also a preceding muscular inhibition in the biceps muscle associated with fast wave bursts, and following high voltage slow wave bursts associated with a spasm.
ing phase was variable, the duration of an initial phasic muscle contraction was analyzed, which was 0.65 s with a range from 0.3 to 1.6 s. There was no significant difference in the flexor, extensor, mixed types and other ictal manifestations between cryptogenic and symptomatic cases, except for focal features, which were seen only in the symptomatic group. Although some spasms are very brief and clinically appear indistinguishable from myoclonic seizures, ictal EEGs of spasms are different from those associated with myoclonic seizures. Thus, ictal EEGs are important for the diagnosis of spasms. Usually three different EEG patterns are associated with a clinical spasm: high voltage slow wave complex, fast wave bursts, and desynchronization. The slow wave complex corresponds to a clinical spasm and was observed in all cases [4,6]. Fusco and Vigevano [4] reported that the onset of the contraction correlated with that of the slow wave on the vertex, where it was positive in polarity. The slow wave, however, is not an initial ictal discharge, and is usually preceded by fast wave bursts. As slow waves are of high amplitude and obscure other EEG components such as fast waves, we analyzed ictal EEGs in detail with digital EEGs [7]. A low pass filter at 0.5 Hz with reduction of the sensitivity disclosed that the slow wave complex is usually polyphasic, displaying negative–positive–negative deflection, reminiscent of an elongated sharp and slow wave complex, where the positive wave is the most prominent (Fig. 2). The slow waves are bilateral but asynchronous, not diffuse but more widespread than the
fast wave burst. The most prominent initial positive wave occurs at Pz, Fz/Pz , or Fz with laterality (Fig. 3). The muscle contraction of a spasm begins at the onset of the descending slope of the positive component and reaches a peak at the peak of the positivity and decreases with the ascending slope. A study with surface EMG disclosed that muscle contraction occurred initially in mentalis, then rectus abdominis, triceps, and then quadriceps femoris muscles in this order (Fig. 4). Thus, axial muscles seem to contract earlier than limb muscles, and cephalad muscles earlier than caudal muscles. The fast wave burst is an initial ictal discharge followed by the slow wave complex. It occurs alone or is followed by the slow wave and correlates with motionless stare, never corresponding to a clinical spasm [4]. Panzica et al. [8] reported that it was associated with subtle seizures preceding the onset of spasm series but also appeared to occur with behavioral spasms. The fast wave burst was observed in 50% [4], 62% [6], or 72% [7]. We also found it in 72% in our recent study using digital EEGs. The frequency of the fast wave burst was 14–16 Hz [4], or 17.5 ^ 2.1 Hz [7]. Fast wave bursts occur generally at the beginning or end of a cluster [4]. Our recent study using a low pass filter at 15 Hz disclosed that fast wave bursts occurred mainly in the left or right occipital, posterior temporal and parietal area [7] (Fig. 5). They were initially asymmetric, but later occurred more diffusely on both sides in the whole series of a cluster (Fig. 5). Although they are not observed in all cases, they should be a leading discharge triggering spasms and an associated slow wave complex. Panzica et al. [8] evaluated the characteristics of the ictal EEG event accompanying infantile spasms using a bivariate autoregressive parametric model. The analysis of the fast wave burst present in the 500 ms EEG epochs preceding spasm onset revealed that the burst had rather low interhemispheric coherence values and asymmetric amplitude on homologous EEG derivations. The highest power peak was found most frequently in the fronto-central area and least frequently in the parieto-occipital area. It persisted briefly after spasm onset, reaching a higher coherence value. The interhemispheric time difference ranged from 9.1 to 14.3 ms (11.4 ^ 1.9) in the epoch preceding spasm onset. They concluded that the data obtained from the analysis of the ictal EEG events, compared with clinical and interictal EEG features, indicate that an asymmetric EEG pattern mainly consisting of a rhythmic burst of fast activity consistently preceded both symmetric and asymmetric spasms, thus suggesting a localized cortical origin of the ictal discharge giving rise to the spasms. We found similar fast wave bursts during rapid eye movement (REM) sleep in 35% of patients with West syndrome and observed in some cases that they continued to occur periodically until clinical spasms appeared and the patient awoke [9]. The same phenomenon was reported by Hrachovy et al. [10]. This fast wave burst occurred during REM sleep in 50% of cases in our later study [11]. Infantile spasms seem to start subclinically in REM sleep and this
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Fig. 2. Ictal polygram of a spasm. Left: low pass filter at 1.6 Hz. Right: low pass filter at 0.5 Hz with reduced sensitivity. The slow wave complex is polyphasic, consisting of negative–positive–negative deflection with prominent positivity. The contraction of the deltoid muscle begins on the descending slope of the positive wave.
agrees well with the fact that infantile spasms occur often immediately after awakening. Desynchronization or decremental activity appeared in 69% of the patients studied by Fusco and Vigevano [4] and 62% of our previous series [6]. It always appeared after the clinical spasm and never accompanied by an ictal manifestation, considered to be a postictal rather than an ictal phase. Less frequently, slow sharp and slow wave complex was observed in association with a clinical spasm [2,6]. But Fusco and Vigevano [4] never found them as the counterpart of a clinical spasm. It is different from that seen in myoclonic seizures, but takes a form of elongated sharp and slow wave complex. An analysis with a low pass filter at 0.5 Hz and reduced sensitivity showed that the sharp and slow wave complex was essentially similar to the polyphasic slow wave complex with prominent positivity as mentioned above (Fig. 6). Predominantly, the clusters occurred soon after arousal from sleep. Because of frequent awakenings, the number of seizures occurring at night was similar to the diurnal number [2]. Spasms characteristically occur in a cluster that evolves in a crescendo–decrescendo manner. The intensity of spasms in each cluster often increases to a peak, then progressively decreases until they stop [2]. Spasms gradu-
ally become stronger, and quite violent at the peak, and then the intensity diminishes until they become subtle again, terminating as subclinical discharges without discernible movements on video (Fig. 7). The surface EMG may show subclinical contraction without visible movements on video. When the spasms are weak, interspasm EEG shows hypsarrhythmia, but as the spasms become stronger, interspasms hypsarrhythmia disappears, and then reappears as the spasms become weaker again towards the end of a cluster (Fig. 7). Thus, interspasms hypsarrhythmia, which has been claimed to be a characteristic of idiopathic West syndrome [12,13], depends rather on the intensity of spasms, not on the etiology. Epileptic spasms are seen in Ohtahara syndrome, West syndrome, Lennox–Gastaut syndrome, other symptomatic generalized epilepsies, epilepsy with periodic spasms, and severe epilepsy with multiple independent spike foci. Seizures resembling spasms are also seen in patients with symptomatic localization-related epilepsy (LRE) [14]. Spasms also occur in non-epileptic benign infantile spasms [15]. It has not been completely elucidated whether or not spasms in West syndrome are the same as in other syndromes in all respects. The seizures occurring in series in Lennox–Gastaut syndrome and other generalized epilepsies in older children clinically greatly resembled infantile
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Fig. 3. Ictal polygram of spasms during a cluster. The most prominent initial positive wave occurs at Pz-P3 on the left and Fz-F3 on the right.
spasms, and the ictal EEG changes were reported to be identical to those that occur with infantile spasms [16,17]. Clustering is most characteristic in West syndrome and tends to be less frequent in other syndromes. In the study by King et al. [3] who examined older patients with intractable spasms, 47% of spasms occurred in clusters, whereas Kellaway et al. [2] who studied younger patients reported that 78% occurred in clusters. Other seizure types such as tonic seizures usually coexist and are more marked in Lennox–Gastaut syndrome. 3. Classification of epileptic spasms in West syndrome Spasms have been classified into flexor, extensor and mixed flexor/extensor type [2]. But there is no significant difference among these types in the etiology, seizure or psychomotor outcome of West syndrome [4,6]. Thus, this classification does not aid in the diagnosis of etiology, decision of treatment option, monitoring of therapeutic effect, or prognostication. Therefore, a classification based mainly on the topography and extent of muscle contraction is proposed (Table 1). 3.1. Symmetric spasms Symmetric spasms are those in which both sides of the body appear to be involved with equal intensity at the same time or only axial musculature was involved. Gaily et al. [18] found symmetric spasms in 57% of all recorded
spasms. Spasms in cryptogenic West syndrome is always symmetric, but the reverse is not always true, and symmetric spasms are seen not only in cryptogenic West syndrome but also in symptomatic West syndrome. In patients with symptomatic West syndrome having symmetric spasms, brain lesions are usually diffuse, not lateralized [19]. In Down syndrome, spasms were symmetric with symmetric hypsarrhythmia [20]. Spasms are mostly symmetric also in neurofibromatosis type I [21]. Even in patients with symmetric spasms, a focal lesion can be found. Haginoya et al. [22] reported a patient having symmetrical spasms in whom the left hemisphere was virtually completely defective and showed focal hypsarrhythmia in the right frontal cortex. Even in cryptogenic West syndrome with normal neurodevelopmental status and normal magnetic resonance imaging (MRI) having symmetric spasms, focal glucose hypometabolism may be found at the onset [23]. 3.2. Asymmetric spasms Infantile spasms were classically considered symmetric [24], but asymmetric spasms have been found to be more frequent than was previously considered. Asymmetric spasms are spasms involving only one side of the body or distinctly stronger on one side than the other. Gaily et al. [18] found asymmetric spasms in 25% of all recorded spasms in children younger than 5 years of age. They calculated the ratio of asymmetric/asynchronous spasms to all recorded spasms. Forty-eight percent of the patients had
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Fig. 4. Ictal polygram of a spasm. Muscle contraction occurs sequentially in the mentalis, rectus abdominis, triceps, quadriceps femoris muscle in that order.
only symmetric spasms. The other patients could be divided into minority-asymmetry/asynchrony group and majorityasymmetry/asynchrony group, the latter comprising 20% of the patients. On the contrary, Kellaway et al. [2] reported asymmetric spasms in 4% of their patients which accounted for only 0.6% of the total spasms. Donat et al. [16] considered asymmetric spasms present if they were observed in 75% of artifact-free seizures recorded and found asymmetric spasms in 10% of their patients. Fusco and Vigevano [4] noted asymmetric spasms in 22% of their patients. Haga et al. [25] defined asymmetric spasms as those that were dominant on one side of the body throughout an entire series of spasms, excluding those showing asymmetry transiently, and found asymmetric spasms in 16% of their patients. Spasms asymmetric only in the initial part of a cluster or only a part of multiple clusters of the same patient was not considered asymmetric spasms, taking the influence of body posture into consideration. Asymmetric spasms may be consistent or alternating. In those associated with a unilateral or focal lesion, asymmetric spasms were constantly
dominant on the side contralateral to the abnormal hemisphere, i.e., on the paralytic side when the patient had hemiplegia. In those combined with preceding partial seizures, clusters of spasms were influenced by preceding partial seizures. When the predominant side of a preceding partial seizure changed from one seizure to another, the predominant side of spasms changed alternately in each series in conformity with that of the preceding partial seizure (Fig. 8). The ictal EEG of spasms exhibited more pronounced fast wave bursts or slow waves with either left or right hemisphere accentuation in accordance with the side of the preceding focal discharges. Asymmetric spasms always indicate symptomatic etiology whereas symmetric spasms are seen in both symptomatic and cryptogenic cases [4,6,19]. But asymmetric spasms were observed in only 17% of patients with symptomatic West syndrome [6]. Fusco and Vigavano [4] found asymmetric spasms in 40% of patients with symptomatic West syndrome which was defined as those showing contraction asymmetric on the two sides of the body. Not
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Fig. 5. Ictal polygram of spasms with a low pass filter at 15 Hz. Fast wave bursts initially occurred most prominently in the right occipital and posterior temporal area (left), but more diffusely 15 min later (right) in the same cluster.
all patients with focal cortical lesions display asymmetric spasms. Only 29% of patients with a focal lesion were reported to have asymmetric spasms [26]. Donat et al. [19] found focal or lateralized features in 38% of consecutive patients with infantile spasms. Unilateral hypsarrhythmia and asymmetric ictal EEG changes during spasms often occurred together: each always indicated the side of a focal or asymmetric structural cerebral lesion that was visible on neuroimaging studies and was usually large. Clinically asymmetric spasms were less common, always occurred in the presence of asymmetric ictal EEG changes, and did not appear to have additional localizing value. Lateralized hypsarrhythmia, with or without asymmetric spasms, occurred in the presence of bilateral structural lesions that were more abnormal in the area of the greater EEG abnormality. Patients with symmetric hypsarrhythmia and infantile spasms rarely had focal/lateralized lesions visible on imaging studies. Kramer et al. [27] investigated focal features including partial seizures, hemiparesis, focal radiologic findings, asymmetric spasms, and lateralized hypsarrhythmia in patients with West syndrome. Sixty-six percent had such asymmetric manifestations, which had significant association with asymmetric brain pathology, but did not correlate with age of onset and outcome.
3.3. Asynchronous spasms Gaily et al. [18] investigated behavioral and EEG asymmetry and asynchrony in patients with infantile spasms younger than 5 years of age, but hypsarrhythmia was present only in 7% of them. They defined asynchronous spasms as those involving one side of the body before the other. The EEG was defined as symmetric if the spasms-associated EEG event was bilateral and synchronous between the hemispheres, and there was a ,50% difference in amplitude between the sides, or no spasms-related changes were seen. EEG asymmetry was considered present if the EEG event associated with behavioral spasms was unilateral or had at least twice as high amplitude on one side as on the other. A spasms-associated EEG change was defined as asynchronous when one side preceded the other by at least 100 ms. Of the recorded spasms, 25% were asymmetric and 7% were asynchronous. Most asymmetric or asynchronous spasms were associated with an ictal EEG discharge that was contralateral to the behaviorally more involved side. In 20% of the patients, more than half of the recorded spasms were asymmetric or asynchronous. Baseline EEG, magnetic resonance imaging, positron emission tomography, and neurological examination revealed structural and functional
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Fig. 6. Ictal polygram of a spasm with a low pass filter at 0.5 Hz and reduced sensitivity. The sharp and slow wave complex resembles the polyphasic slow wave complex with prominent positivity. Low pass filter: 1.6 Hz in the left, 0.5 Hz in the middle, and 10.0 Hz in the right.
brain abnormalities that involved the contralateral central region significantly more often in the children with .50% spasm asymmetry or asynchrony than in the other children. Partial seizures with lateralized motor behavior also occurred frequently in these children. The findings suggest that asymmetric and asynchronous spasms are generated by a cortical epileptogenic region that involves the primary sensorimotor area.
this was considered a variant of West syndrome, some may argue that this is a type of LRE. Donat and Wright [29] reported a patient having focal spasms associated with contralataral porencephalic cyst, which later evolved into bilaterally symmetric typical spasms, but an EEG at the time of focal spasms was not available.
3.4. Focal spasms
Partial seizures (PS) may be combined with epileptic spasms (ES) in a single seizure in patients with West syndrome [30–40]. The sequence of seizures is variable; PS followed several seconds later by spasms in cluster, alternation of PS and spasms in cluster starting with PS, PS gradually replaced by ES in cluster with overlapping of the two, and most infrequently ES followed by PS. Most frequently, PS are followed by ES in cluster, which seem to be triggered by foregoing PS. The epileptic spasms are bilateral but often asymmetric. In patients with symmetric spasms, the spasms tend to show some laterality during or just after a partial seizure, but gradually became symmetric in the later parts of the clusters. The interictal EEG often shows asymmetric hypsarrhythmia. The clinical manifestation preceding PS consists of star-
Focal spasms usually consist of brief focal muscular contraction, but lateral eye deviation or lateral head jerk may be seen. They are associated with ictal EEG discharges characteristic of a spasm. Focal spasms may be associated with generalized hypsarrhythmia interictally. We reported an infant who had clusters of focal spasms of the right arm associated with hypsarrhythmia without definite asymmetry on interictal EEGs [28]. Ictal EEGs showed fast wave bursts superimposed on slow waves most markedly in the left central region. Subsequent EEGs after cessation of spasms with ACTH treatment disclosed focal polyspike and waves in the same region. MRI revealed findings suggestive of delayed myelination in the left frontal region. Although
3.5. Spasms combined with partial seizures
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Fig. 7. Ictal polygram of a cluster of spasms. S: Subclinical spasm. Number in circle: the sequential number of a spasm in a cluster. Subclinical spasm is a subclinical contraction noted on EMG without visible movements on video. Before the onset of a clinical cluster, a brief contraction is noted on the mentalis muscle associated with a typical slow wave complex without visible movements on video. As the cluster progresses with stronger spasms, interspasm hypsarrhythmia disappears. Toward the end of the cluster, spasms become weaker, and interspasm hypsarrhytmia reappears, and then subclinical spasms occur again. The extent of muscle involvement gradually decreases with sequential subclinical spasms toward the end of the cluster, as shown in the two subclinical spasms at the end.
Table 1 Classification of epileptic spasms I. Type of spasms 1. Symmetric spasms 2. Asymmetric/asynchronous spasms 3. Focal spasms 4. Spasms with partial seizures (a) Spasms combined with partial seizures in a single seizure (b) Spasms preceded by partial seizures in the clinical course 5. Subtle spasms 6. Spasms preceded by brief atonia 7. Subclinical spasms II. Ictal phenomena associated with spasms (collected from literature by Lacy and Penry, 1976 [24]) Scream, cry, laughter, pallor, cyanosis, flushing, sweating, pupillary dilation, hiccups, tears, facial grimace, smile, confused, frightened facial expression, fluttering of eyelids, staring, rolling up of eyes, lateralizing eye movements, nystagmus, tremulousness of extremities, respiratory arrest, incontinence
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Fig. 8. Ictal polygram of spasms in cluster following a partial seizure. Upper figure: left occipital focal rhythmic discharges were followed by HVS on the left side associated with spasms with the patient turning toward the left. Lower figure: right occipital discharges were followed by HVS in the right side associated with spasms with the patient turning toward the right.
ing, cessation of movements, flushing, automatisms, increased limb tone, laughter, tonic eye and head deviation, clonic movements, tonic posturing of single limbs, fencing, posturing, or facial twitching [32–34]. The origin of focal seizure discharges is variable, involving any regions of both hemispheres [33,34,40], although central and temporal regions were most frequent, and frontal areas least frequent [41]. Carrazana et al. [34] reported three patients with complete agenesis of the corpus callosum who had PS– ES, which argues against interhemispheric callosal spread of focal discharges resulting in the generalized spasms. They also reported that 6 of the 16 infants with PS–ES had a favorable outcome with surgical cortical resections. This group of patients supports a model in which the spasms, although probably generated at a subcortical level, are facilitated or possibly induced by focal discharges from cortical pathology. Plouin et al. [36] noted PS in 31(42%) of 74 of patients with West syndrome (51% of patients with symptomatic cases, 33% of cryptogenic cases) during 24-h ambulatory EEG recordings. In 14 infants (19%), PS were immediately followed by a cluster of spasms consisting of a single ictal event. Kubota et al. [40] also found such combinations in 8
(18%) of 45 patients with West syndrome studied with simultaneous video-EEG monitoring. Hrachovy et al. [38], however, reported that the coupling of focal electrical seizure discharges (FS) and spasms was significant in only 3% of 96 patients with West syndrome, and concluded that, in some instances, apparent couplings of FS and spasms are best explained by chance coincidence. Kubota et al. [40] studied the long-term clinical course in 8 patients who had PS followed by ES with a close temporal association (PS–ES). PS–ES were preceded by PS in the clinical course in six of the eight cases. PS–ES disappeared or was replaced by other types of seizures in 1–34 months. They were followed by PS alone or together with other types of seizures in six of the eight cases. Thus, epilepsy with PS– ES often starts as LRE and evolves into LRE in most of the patients. The period during which the patients showed PS– ES was transient. It should be classified into undetermined epilepsy with both focal and generalized seizures according to the current International Classification, but is closer to LRE rather than generalized epilepsy. The clinical course is similar to epilepsy with continuous spike-waves during slow sleep, in which the EEG shows transient generalization of paroxysmal discharges during the course of LRE. In a few
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cases, however, it may evolve into Lennox–Gastaut syndrome [34]. A long-term follow-up study showed that all cases of epilepsy with PS–ES were severely mentally retarded [37,40]. Compared with patients without PS–ES, those with PS–ES more often had organic brain lesions of prenatal origin, other types of seizures before the onset of ES, asymmetric hypsarrhythmia on the EEG, and poor psychomotor outcome [40]. In periodic spasms reported by Gobbi et al. [42], spasms occur periodically with focal electrical discharges, but interictal EEGs do not show hypsarrhythmia. 3.6. Spasms preceded by partial seizures in the course of epilepsy Infantile spasms may be preceded or followed by PS in the course of epilepsy [43–45]. The occurrence of PS before onset of spasms usually indicates prenatal etiology [46]. In
Aicardi syndrome, PS usually precede spasms by 1–6 weeks. Most patients with tuberous sclerosis presenting with PS in the first month of life progress to infantile spasms. In patients with lissencephaly, epilepsy may be manifested by early PS before spasms occur. Patients with hemimegalencephaly often have their first seizures within 3 months of life, especially in the first days of life, and present with PS and asymmetric spasms, and asymmetric or unilateral hypsarrhythmia. In a follow-up study of infants with epilepsies of neonatal onset, we identified a subgroup of symptomatic LRE with transient West syndrome [47]. Thirteen (45%) of 29 infants with symptomatic LRE of neonatal onset developed West syndrome, which was followed by LRE in five (38%) of them. 3.7. Subtle spasms Subtle seizure phenomena may occur alone or together
Fig. 9. Ictal polygram of a spasm. A brief muscular inhibition is noted in the mentalis muscle immediately before a spasm.
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Fig. 10. Ictal polygram of a spasm. A brief muscular inhibition is noted in the right biceps muscle, which is associated with fast wave bursts. This is followed by a spasm associated with HVS.
with typical spasms in association with electrical discharges characteristic of typical spasms. Contractions of the facial muscles, eye opening or closure, eye movements (upward, downward or nystagmoid movements, adduction), head nodding, shoulder shrugging, grimace, yawn, motion arrest, or motionless stare [29]. Eye movements may occur independently from infantile spasms and precede the development of infantile spasms by weeks. Most of the variants appear to be fragments or limited expressions of more typical spasms. They may coexist with typical infantile spasms, representing natural variability or resulting from a change in level of consciousness, time or medication that modifies the clinical expression of the spasms [29]. Some patients may show typical spasms in the waking state but have subtle variants during sleep. Subtle spasms may occur weeks before typical spasms begin to occur or after they resolve spontaneously. Subtle spasms tend to occur at the onset and offset of the cluster. Subtle spasms may also be observed after ACTH or other treatments. 3.8. Spasms preceded by brief atonia We previously reported brief atonia associated with slow sharp waves at the beginning of a burst observed during
abnormal tonic posture in an infant with Ohtahara syndrome [48]. This was sometimes followed by tonic spasms. The duration of the muscular inhibition ranged from 100 to 400 ms, which is longer than a myoclonic jerk. We later observed the same phenomenon in infants with West syndrome. Each spasm is preceded by a brief muscular inhibition, which may manifest only in muscles in continuous contraction (Figs. 9 and 10). This muscle inhibition may occur in association with the fast wave burst not followed by clinical spasms (Fig. 11). The patient seems to have motion arrest on video, which may be assessed as a subclinical spasm, or a subtle spasm called motion arrest. This corresponds to a related epileptic silent period reported by Tassinari et al. (1968) [49] or epileptic negative myoclonus [50,51], although it is longer in duration than a myoclonic jerk. 3.9. Subclinical spasms Ictal discharges characteristic of spasms may occur in cluster without discernible movements, although subtle seizures barely detectable on video may be present as mentioned above. Shewmon [5] stated that he came across subclinical electrographic spasms on several occasions
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Fig. 11. Ictal polygram of a subclinical spasm. A brief muscular inhibition is noted on the right biceps muscle in association with fast wave bursts. This is not followed by clinical spasms and the patient is noted to have motion arrest on video.
during video/EEG monitoring and described them as follows. The epileptiform discharges disappear and the background assumes a lower-amplitude, faster, non-descript pattern. Soon the characteristic ictal discharges appear – typically high amplitude slow waves with overriding rhythmic fast activity, each lasting 1–2 s – and these repeat approximately every 10 s. But the child does not awaken, and no discernible movement accompanies any of the discharges, although subtle seizures barely detectable on video may be present. The patient seems to have gone into REM sleep in view of the background EEG change and have been displaying periodic fast wave bursts as we previously reported [9]. Some of the patients may wake up to have frank spasms. Subclinical spasms may also occur at the onset and the end of a cluster, as mentioned above (Figs. 7 and 11). Therefore, the boundary between subtle and subclinical spasms is difficult to fix because of the limitation of video-EEG polygraphy and our ability of observation.
4. Are spasms generalized seizures? Infantile spasms have been placed in generalized
seizures, and West syndrome in generalized epilepsies. Meanwhile, localization-related epilepsies (LREs) are defined as epileptic disorders in which seizure semiology or findings at investigation disclose a localized origin of the seizures [52]. Focal or unilateral lesions are found not infrequently in West syndrome. Some investigators consider infantile spasms a type of LRE when they are abolished by resection of a focal lesion [53]. However, localized cortical lesions found in West syndrome cannot be a direct origin of epileptic spasms, since their site is quite heterogeneous [54]. Moreover, seizures in West syndrome with a focal cortical lesion do not show a focal onset of paroxysmal discharges from the site of the lesion. Secondary generalization from the original focus cannot be considered an explanation of epileptic spasms because ictal discharges do not propagate as seen in usual secondarily generalized partial seizures in which initial focal paroxysmal discharges are followed by generalization of paroxysmal discharges. Most investigators consider that epileptic spasms originate in the brainstem, but there has been no definite evidence for it [55]. As mentioned above, ictal EEGs do not show bilaterally synchronous generalized discharges even in cryptogenic West syndrome with symmetric spasms, but display a
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positive slow wave maximally at Fz/Pz in accordance with spasms. This may suggest the supplementary motor area as a generator of spasms. Cortical stimulation of this area produces proximal, segmental, unilateral or bilateral, tonic postural movements [56]. Some frontal lobe seizures occur frequently in clusters. But this cannot explain all. There are many unanswered questions. How will the mesial frontal area be triggered by lesions in various areas? What do fast wave bursts stand for? Apart from neurophysiological consideration, it may be useful to classify epilepsy with spasms with a localized lesion into LRE from a practical viewpoint, as intractable cases can be treated surgically.
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