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Overnight polygraphic study of Lennox-Gastaut syndrome
Overnight Polygraphic Study of Lennox-Gastaut Syndrome Hideki Horita, MD, Koumei Kumagai, MD and Kihei Maekawa, MD
Nine children with Lennox-Gastaut syndrome, aged 2-14 years, were studied by overnight polygraphy for one night. Percentage of sleep period time (SPT) for stage rapid eye movement (REM) and REM density during REM sleep decreased in Lennox-Gastaut syndrome as compared with control. Alpha rhythm was seen in only 3 cases and sleep spindles in only 6 cases. The effect of sleep-wake or REM-non-REM (NREM) sleep rhythm on the rate of generalized epileptiform discharges varied with the individual. Ictal discharges with or without clinical tonic seizures observed in 5 children appeared during NREM sleep and awakening in the morning, and in 2 of these cases they also occurred frequently during the NREM sleep of the first sleep cycle. Subclinical ictal discharges were also seen during REM sleep in the early morning in one case who was 2 years old. The Lennox-Gastaut syndrome is assumed to involve a considerable degree of brain stem dysfunction. Key words: Lennox-Gastaut syndrome, overnight polygraphic study, tonic seizure, slow spike-wave. Horita H, Kumagai K, Maekawa K. Overnight polygraphic study of Lennox-Gastaut syndrome. Brain Dev 1987;9:627-35
Lennox-Gastaut syndrome (LGS) is a childhood epileptic encephalopathy with poor response to antiepileptic drugs. Children with LGS have the following characteristics: atypical absence, myoclonic, atonic, and tonic seizures in varying combinations; interictal diffuse slow spike-wave discharges on the EEG; psychomotor retardation and a variety of neurologic deficits [1, 2] . It is well-known that epileptic seizures and epileptiform EEG activity are subject to biorhythmic modulation, especially the slee-wake cycle [3-5]. The main purpose of this study is to elucidate electrophysiologically the relation between slee-wake rhythm and ictal or interictal discharges of LGS. SUBJECTS AND METHODS Nine children (5 males, 4 females) with LGS, ranging in
From the Division of Neurology, Saitama Children's Medical Center, Iwatsuki (HH); Division of Pediatrics, Kanagawa Rehabilitation Center, Atsugi (KK); Department of Pediatrics, Jikei University School of Medicine, Tokyo (KM). Received for publication: April 13, 1987. Accepted for pUblication: June 24,1987. Correspondence address: Dr. Hideki Horita, Division of Neurology, Saitama Children's Medical Center, 2100 Magome, Iwatsuki, Saitama 339, .(apan.
age from 7 to 14 years except for the 2-year-old Case 1, were studied. All children had had atypical absence, myoclonic, atonic, and tonic seizures in varying combinations with interictal diffuse slow spike-wave discharges on the EEG. Three children (Cases 1,6, and 9) had a history of West syndrome. Brain CT was available in 7 children, exhibiting brain atrophy in 5 cases. The DQ or IQ was low at 10-55 in all· children, and motor function was also severely retarded in Cases 1, 7, and 9 (Table 1). A 11year-old epileptic child without mental retardation who had been administered anticonvulsants (phenobarbital and phenytoin) for generalized tonic-clinic seizures was added to the study as a control. The natural sleep was recorded polygraphically for one night. The noise (sound from inside and outside of the body), EEG, EOG (horizontal direction), EMG (mentalis and biceps brachii or triceps brachii muscles), respirogram and ECG were monitored. EEG electrodes were placed on 6 regions including the central and occipital areas. Analysis of records was made every minute, and the APSS scoring system [6] was employed for judging the sleep stages. But non-rapid eye movement (NREM) sleep could not be subdivided because of frequent epileptiform discharges. The rapid eye movement (REM) density was used as the index for expressing the rate of REMs in REM sleep. This was shown as the ratio of segments involving horizontal eye movements against the total number of segments after the REM periods were divided into one-
Table 1 Summa ry of cases Interictal EEG
Presumptive etiology
IQ DQ
Brain CT
Age
Sex
Seizure type
2y6m
M
Tonic, myoclon ic
Unknow n
Slow sp-w
2
7y7m
F
Tonic, atypical absence, secondarily GTe
Unknow n
Slow sp-w
Normal
55
3
8y5m
F
Tonic, atonic
Unknow n
Slow sp-w
Mild brain atrophy
40
4
9yOm
F
Tonic, atonic, myoclon ic, atypical absence
Unknow n
Slow sp-w
Dilatation of lateral ventricles
39
5
9y8m
M
Tonic, atonic, myoclon ic
Forced abortion
Slow sp-w
Diffuse brain atrophy
20
6
10y5m
M
Tonic, atypical absence
Unknow n
Slow sp-w, multiple sp-w
7
10y7m
M
Tonic, atonic, myoclon ic, secondarily GTe
Prematu re, toxemia
Slow sp-w
Diffuse brain atrophy
10
8
12yOm
M
Tonic, myoclon ic
Unknow n
Slow sp-w
Normal
40
9
14y3m
F
Tonic, myoclon ic
Prematu re
Slow sp-w, sp in rt 0
Dilatatio n of It lateral ventricle
15
Case
15
25
GTe: generalized tonic-clonic, sp-w: spike and wave.
DSW
o
50
I
Case 1 1:::<:;:;::<·>:···· ,
100% D SNREM I
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% 30
15
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Fig 1 Percentage of SPT for each sleep stage. Average SPT of all cases is 529.9 ± 64.3 minutes. 0
0
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second segments. The children were maintained on their usual anticonvulsant medication (phenobarbital, phenytion, sodium valproate, benzodiazepines, etc).
Fig 2 REM density. Case numbers are arranged in order of the degree of DQ or IQ.
RESULTS Percentage of sleep period time (SPT) spent in each sleep stage and REM density The percentage for stage REM in all the cases except Case 1 (mean, 11.8 ± 2.9%) was lower than those in the control and in the normal 8 children aged 7-13 [7] (mean, 17.8%
and 20.4 ± 6.3%, respectively). The percentage for stage REM in Case 1 aged 2 (17.9%) was also lower than that in the age-matched normal children (28.7%) [8] (Fig 1). REM density in all the cases except Case 1 (mean, 7.0 ± 5.1%) was lower than that in the control (28.2%). REM density in the Case 1 (2.2%) was markedly lower than that
628 Brain & Develop ment, Vol 9, No 6, 1987
in the normal children of the same age group (20%) [9]. There was no positive correlation between the degree of DQ or IQ and REM density (Fig 2). Basic activity The presence or absence of alpha rhythm and sleep spindles varied with the patient. Three cases (Cases 2, 6, and 8) had both alpha rhythm and sleep spindles; the
Table 2 Basic activity Basic activity Case Alpha rhythm
Sleep spindles
+
+
2
3
+
4
+
5
+
6
+
+
+
+
7 8 9
other 3 cases (Cases 3,4, and 5) had no alpha rhythm but sleep spindles; and the remaining 3 cases had neither alpha rhythm nor sleep spindles. The amount of sleep spindles was small in Cases 3 and 5. On the whole, the abnormality of basic activity tended to be remarkable in the cases with severe psychomotor retardation (Table 2). Sleep states and epileptifonn discharges During NREM sleep diffuse slow spike-waves became more irregular - often replaced by multiple spike-waves in 8 cases-than during wakefulness and REM sleep. Suppression-burst EEG pattern similar to that in West syndrome was observed during NREM sleep in Case 1, the 2-year-old. The generalized epileptiform discharges including slow spike-waves and multiple spike-waves were neither increased nor decreased among wakefulness, NREM sleep and REM sleep in Cases 3, 8, and 9; increased in Cases 2 and 6 and decreased in Case 4 during NREM sleep as compared with wakefulness and REM sleep; increased similarly during NREM and REM sleeps as compared with wakefulness in Case 7; and increased in Case 5 and decreased in Case 1 during REM sleep as compared with wakefulness and NREM sleep. The effect of sleep-wake or REM-NREM sleep rhythm on the rate of generalized epileptiform discharges varied with the individual (Table 3).
Table 3 Sleep states and interictal epileptiform discharges Case
2 3 4
5 6
7
8 9
Epileptiform discharges StageNREM
Stage W
Stage REM
Slow sp-w
Slow sp-w, suppression-burst
Slow sp-w
(++)
(++)
(+)
Slow sp-w
Slow sp-w, multiple sp-w,
Slow sp-w
(+)
(+++)
(+)
Slow sp-w
Slow sp-w, multiple sp-w
Slow sp-w
(++)
(++)
(++)
Slow sp-w
Slow sp-w, multiple sp-w
Slow sp-w
(+++)
(++)
(+++)
Slow sp-w
Slow sp-w, mUltiple sp-w, multiple sp in posterior area
Slow sp-w
(+)
(+)
(+++)
Slow sp-w
Slow sp-w, multiple sp-w
Slow sp-w
(+)
(++)
(+)
Slow sp-w
Slow sp-w, multiple sp-w
Slow sp-w, multiple sp-w
(+)
(+++)
(+++)
Slow sp-w
Slow sp-w, multiple sp-w
Slow sp-w
(+)
(+)
(+)
Slow sp-w
Slow sp-w, multiple sp-w
Slow sp-w
(+++)
(+++)
(+++)
+, ++, and +++ indicate discharge rates under 20%, 20-50%, and above 50% of tracing, respectively.
Horita et al: Lennox-Gastaut syndrome 629
Poly grams in ictal discharges and in EEG discharges similar to ictal ones During overnight polygraphic recordings, clinical seizures observed only in the 5 children (Cases 1, 5, 7, 8, and 9) were all tonic type. Five types of polygrams were noticed: 3 in the ictal discharges with or without clinical manifestation, 2 in the EEG discharges similar to ictal ones.
1) Polygrams in ictal discharges Clinical seizure (C): During a tonic seizure, EEG showed a diffuse rhythmic fast activity at 8-17 Hz, 50-200 "N, associated with remarkable muscular contraction, apnea or irregular respiration and tachycardia. Nystagmus was also noticed in Cases 1 and 9. The duration of tonic seizure was 6-30 seconds (Fig 3 left, Fig 4 left, Fig 5). The
Fig 3 Polygrams in the ictal discharges of Case 1. Left: C. Right: S in stage REM.
-ECG
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630 Brain & Development, Vol 9, No 6, 1987
---4--+---H-I----f----4--J-+-.-i---+--+_+__
fast activity was sometimes followed by spike-wave at 1.5-2.5 Hz. In Case 9, the diffuse de synchronization was associated with the tonic seizure instead of the rhythmic fast activity (Fig 6). Subclinical seizure (SC): EEG showed a diffuse rhythmic fast activity at 8-15 Hz, 60-200 IN accompanied with feeble muscular contraction, apnea or irregular respi-
Noise
ration and tachycardia without obvious clinical manifestation. No nystagmus was observed in any of the cases. The fast activity lasting 4-7 seconds was sometimes followed by spike-wave at 1.5-3 Hz. The SC was recognized in Cases 1, 5, and 8 with clinical seizures during the recordings (Fig 4 middle). Seizure activity (S): The same rhythmic fast activity at
stage NREM
---------- - -------
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TK
9 y~m'____ _
Fig 5 Polygram of the other type C in Case 5, indicating longer duration and stronger intensity than that in Fig 4.
Fig 6 Polygram showing the type C with desynchronized EEG pattern in Case 9.
Horita et al: Lennox-Gastaut syndrome 631
8-15 HZ, 50-200 J.lV as in the C and SC was recognized without obvious clinical manifestation. Coincidentally, muscular contraction was not confirmed, but irregular
respiration was frequently observed. The fast activity last· ing 2-6 seconds was sometimes followed by spike·wave at 1.5-3 Hz. The S was recognized in Cases 1, 5, and 8 with
~bra.sin. R~sp.
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ECG,
Fig 7 Polygrams in the EEG discharges similar to ictal ones. Left: LRD with irregular respiration in Case 3. Right: SRD in l..-ase 4.
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Fig 8 Sleep profile and the occurrence time of ictal discharges and EEG discharges similar to ictal ones in one overnight record.
632 Brain & Development, Vol 9, No 6, 1987
clinical seizures during the recordings (Fig 3 right, Fig 4 right). 2) Polygrams in EEG discharges similar to ictal ones Long rapid discharge (LRD): EEG showed a diffuse rapid discharge at 8-15 Hz, 100-200 J.LV lasting 2-6 seconds. The changes of respiration and pulse rate were noticed when the duration of rapid discharge was long, but muscular contraction and clinical seizure were not confirmed. The LRD was recognized in Cases 3 and 6 without clinical seizures during the recordings (Fig 7 left). Short rapid discharge (SRD): EEG showed a 10-18 Hz, 50-200 J.LV diffuse rapid discharge lasting 0.8-2 seconds, not associated with the changes of respiration and muscular contraction. The SRD was recognized in Cases 4 and 6 without clinical seizures and in Case 9 with the ictal de synchronization pattern during the recordings (Fig 7 right).
Sleep states and ictal discharges or EEG discharges similar to ictal ones Fig 8 shows the occurrence time of the ictal discharges and the EEG discharges similar to ictal ones in one overnight record. The clinical seizures appeared frequently after awakening in the morning in Case 1, and occasionally during NREM sleep and immediately after awakening in the early morning in Cases 7 and 9. But in Cases 5 and 8, the clinical seizures were frequently observed during NREM sleep in the first sleep cycle, though they appeared infrequently during NREM sleep and awakening in the early morning. The SC and S in Case 1 were recognized during NREM and REM sleeps in the early morning. The SC and S in Cases 5 and 8 were recognized frequently during NREM sleep of the first sleep cycle, and not confirmed during REM sleep. The LRD and SRD appeared only during NREM sleep without preferred time zone. DISCUSSION Sleep states and REM density The REM sleep was decreased in the children of LGS as compared with control subjects, even if the effect of anticonvulsants on sleep was evaluated [10, 11] , as described by Ohtahara [12] and Amir et al [11]. The reduction of REM sleep has been observed in the children of earlyinfantile epileptic encephalopathy with suppression-burst (ElEE), West syndrome [3, 9] and other intractable epilepsy with mental retardation [10]. And also the decrement of REM sleep has been reported in mentally retarded children including those with Down's syndrome [13-15]. It is of interest to note that the reduction of REM sleep is closely related with mental subnormality. It is reported that tonic seizures, if frequent, can disrupt sleep organization owing to a decrease or disappearence of
REM sleep and stages 3 and 4 [16,17]. But the reduction of REM sleep in our study could not be ascribed only to the clinical tonic seizures during sleep because REM sleep decreased in children both with and without clinical'seizures during overnight recordings. The low level of REM density may indicate dysfunction of the REM sleep mechanism, because REMs are the main phasic event during REM periods. Feinberg et al [13] reported that a positive relation was found between the amount of eye movement during REM sleep and estimates of intellectual level in a group of retarded adults. In our previous study [9, 10], REM density remarkably declined in the children of EIEE, West syndrome, and other intractable epilepsy with mental retardation. From these observations, it is deduced that the pons regulating the REM sleep mechanism [18] is functionally damaged in LGS. Basic activity In this study, the alpha rhythm during wakefulness was observed in only 3 cases and the sleep spindles were seen in only 6 cases. The abnormality of basic activity tended to be remarkable in the cases with severe psychomotor retardation. Markand [2] reported that over two-thirds of 83 patients with LGS had moderate to markedly slow basic activity during wake EEG, and sleep spindles were usually absent in these patients though sleep spindles were present in 13 of 58 patients. He also reported that there was a correlation between the severity of mental subnormality and degree of slowing of the basic EEG activity. The absence of sleep spindles is reportedly observed in 50% of severely handicapped children [19], and in our previous study [10] on intractable epilepsy with mental retardation, neither alpha rhythm nor sleep spindles were recognized in 2 of 4 cases. Because alpha rhythm and sleep spindles are derived from the thalamus and propagated through the thalamocortical pathway [20], these findings may indicate that dysfunction of the thalamo-cortical system is present in LGS particularly in that with severe psychomotor subnormality. Sleep states and interictal epileptiform discharges It has been reported that in the patients with LGS, slow spike-wave discharges become irregular and are sometimes replaced by polyspike and wave discharges during NREM sleep, and that all types of paroxysmal discharges increase markedly during NREM sleep and decrease dramatically during REM sleep [1, 12, 16, 21]. It is a common observation that diffuse epileptiform discharges such as hypsarhythmia increase during NREM sleep and decrease markedly during REM sleep [3-5,9]. But in this study, there was no regular relationship between the sleep states and amount of interictal epilepti-
Horita et al: Lennox-Gastaut syndrome 633
form discharges as only 3 out of all 9 cases had the reduction of all types of discharges during REM sleep as compared with NREM sleep. In order to elucidate this discrepancy between the present study and previous reports, the difference between the cases with and without the reduction of epileptiform discharges during REM sleep (Cases 1,2,6 and Cases 3, 4,5,7,8,9, respectively) was investigated. Percentage of SPT for stage REM in the patients divided by that in the normal children was lower in the latter than in the former (mean, 0.53 ± 0.12 and 0.69 ± 0.09, respectively). The brain CT showed no abnormal finding in the former, but brain atrophy in 5 of the latter 6 cases. From these results, it is assumed that the suppressive effect on epileptiform discharges in REM sleep was poor in the cases with severe brain damage. The variable response of epileptiform discharges to sleep states may indicate the heterogeneous genesis of epileptiform activity in LGS. The suppression-burst pattern of EEG during NREM sleep in Case 1 could be explained as follows: the suppression-burst pattern during NREM sleep in West syndrome [9, 22] was successively observed because this case was LGS just subsequent to West syndrome. Polygrams in ictal discharges and in the EEG discharges similar to ictal ones Tonic seizures and their EEG pattern are one of the main signs of the LGS. Three types of generalized synchronous and symmetrical EEG patterns may occur during a tonic seizure [21, 23, 24]: (1) simple flattening (desynchronization) of all activity throughout an attack; (2) very rapid activity (20 ± 5 Hz), initially of low voltage and then progressively increasing in amplitude to 50 to 100 pV; and (3) rhythmic discharge at about 10Hz, identical to that of the tonic phase of tonic-clonic seizure (epileptic recruiting rhythm) except that it may be of high amplitude from the onset. It is postulated that the simple flattening (de synchronization) originates in the midbrain tegmental reticular formation [23}. The rhythmic discharge at 10 Hz (recruiting rhythm) is believed to be derived from the thalamic reticular structures and mediated by the nonspecific diffuse thalamic projection systems [23]. In our overnight polygraphic recordings,4 out of 5 cases with tonic seizures had the type 2 or 3, and one had the type 1. According to the previous reports [21, 23], the tonic contraction during sleep can persist, but it is usually either absent or very much reduced in intensity and topography. Although reduced in intensity, autonomic changes such as transient tachycardia and brief apnea usually persist during sleep, even when the seizures are strictly subclinical. In this study, Cases 1, 5, and 8 showed a similar finding. Ohtahara et al [24] reported that a specific wave form "rapid rhythm" at 10-12 Hz, 50-100 JJ.V was observed without clinical seizure during moderate to deep
634 Brain & Development, Vol 9, No 6, 1987
sleep but not observed during REM sleep, and that this rapid rhythm was observed in 21 of 74 patients (28.4%). The LRD and SRD in our study, coinciding with "rapid rhythm," might be closely related to the clinical tonic seizure because the changes of respiration and pulse rate were noticed under the long duration of LRD. Sleep states and ictal discbarges or the EEG discharges similar to ictal ones Concerning the relationship between sleep and clinical seizures in LGS, the following description was given by previous authors [1,2,21,23,25]: All types of seizures appear during both sleep and wakefulness. Tonic seizures usually are much more frequent during NREM sleep than during wakefulness but never occur during REM sleep. The clinical manifestation of tonic seizures are often less dramatic in sleep and can be easily overlooked. Rarely, ictal EEG pattern is observed during sleep without any clinical correlates. In our study, the ictal discharges with or without obvious clinical manifestation of tonic seizures occurred during NREM sleep and awakening in the early morning, and in 2 cases occurred frequently also during NREM sleep of the first sleep cycle. In the child aged 2, the subclinical ictal discharges (SC and S) occurred not only in NREM sleep, but also in REM sleep. We suggest that the subclinical ictal discharges appearing during REM sleep in West syndrome [3, 26] were successively recognized because this child was LGS just subsequent to West syndrome. It is assumed that the ictal discharges start to occur only in NREM sleep along with brain maturation or progress of the illness. The LRD and SRD similar to "rapid rhythm" was recognized during NREM sleep without the special time zone of occurrence. These results suggest that the occurrence of tonic seizures and their ictal discharges are subject to the sleepwake and REM-NREM sleep rhythms controlled in the brain stem.
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Horita et al: Lennox-Gastaut syndrome 635
Nine children with Lennox-Gastaut syndrome, aged 2-14 years, were studied by overnight polygraphy for one night. Percentage of sleep period time (SPT) for stage rapid eye movement (REM) and REM density during REM sleep decreased in Lennox-Gastaut syndrome as compared with control. Alpha rhythm was seen in only 3 cases and sleep spindles in only 6 cases. The effect of sleep-wake or REM-non-REM (NREM) sleep rhythm on the rate of generalized epileptiform discharges varied with the individual. Ictal discharges with or without clinical tonic seizures observed in 5 children appeared during NREM sleep and awakening in the morning, and in 2 of these cases they also occurred frequently during the NREM sleep of the first sleep cycle. Subclinical ictal discharges were also seen during REM sleep in the early morning in one case who was 2 years old. The Lennox-Gastaut syndrome is assumed to involve a considerable degree of brain stem dysfunction. Key words: Lennox-Gastaut syndrome, overnight polygraphic study, tonic seizure, slow spike-wave. Horita H, Kumagai K, Maekawa K. Overnight polygraphic study of Lennox-Gastaut syndrome. Brain Dev 1987;9:627-35
Lennox-Gastaut syndrome (LGS) is a childhood epileptic encephalopathy with poor response to antiepileptic drugs. Children with LGS have the following characteristics: atypical absence, myoclonic, atonic, and tonic seizures in varying combinations; interictal diffuse slow spike-wave discharges on the EEG; psychomotor retardation and a variety of neurologic deficits [1, 2] . It is well-known that epileptic seizures and epileptiform EEG activity are subject to biorhythmic modulation, especially the slee-wake cycle [3-5]. The main purpose of this study is to elucidate electrophysiologically the relation between slee-wake rhythm and ictal or interictal discharges of LGS. SUBJECTS AND METHODS Nine children (5 males, 4 females) with LGS, ranging in
From the Division of Neurology, Saitama Children's Medical Center, Iwatsuki (HH); Division of Pediatrics, Kanagawa Rehabilitation Center, Atsugi (KK); Department of Pediatrics, Jikei University School of Medicine, Tokyo (KM). Received for publication: April 13, 1987. Accepted for pUblication: June 24,1987. Correspondence address: Dr. Hideki Horita, Division of Neurology, Saitama Children's Medical Center, 2100 Magome, Iwatsuki, Saitama 339, .(apan.
age from 7 to 14 years except for the 2-year-old Case 1, were studied. All children had had atypical absence, myoclonic, atonic, and tonic seizures in varying combinations with interictal diffuse slow spike-wave discharges on the EEG. Three children (Cases 1,6, and 9) had a history of West syndrome. Brain CT was available in 7 children, exhibiting brain atrophy in 5 cases. The DQ or IQ was low at 10-55 in all· children, and motor function was also severely retarded in Cases 1, 7, and 9 (Table 1). A 11year-old epileptic child without mental retardation who had been administered anticonvulsants (phenobarbital and phenytoin) for generalized tonic-clinic seizures was added to the study as a control. The natural sleep was recorded polygraphically for one night. The noise (sound from inside and outside of the body), EEG, EOG (horizontal direction), EMG (mentalis and biceps brachii or triceps brachii muscles), respirogram and ECG were monitored. EEG electrodes were placed on 6 regions including the central and occipital areas. Analysis of records was made every minute, and the APSS scoring system [6] was employed for judging the sleep stages. But non-rapid eye movement (NREM) sleep could not be subdivided because of frequent epileptiform discharges. The rapid eye movement (REM) density was used as the index for expressing the rate of REMs in REM sleep. This was shown as the ratio of segments involving horizontal eye movements against the total number of segments after the REM periods were divided into one-
Table 1 Summa ry of cases Interictal EEG
Presumptive etiology
IQ DQ
Brain CT
Age
Sex
Seizure type
2y6m
M
Tonic, myoclon ic
Unknow n
Slow sp-w
2
7y7m
F
Tonic, atypical absence, secondarily GTe
Unknow n
Slow sp-w
Normal
55
3
8y5m
F
Tonic, atonic
Unknow n
Slow sp-w
Mild brain atrophy
40
4
9yOm
F
Tonic, atonic, myoclon ic, atypical absence
Unknow n
Slow sp-w
Dilatation of lateral ventricles
39
5
9y8m
M
Tonic, atonic, myoclon ic
Forced abortion
Slow sp-w
Diffuse brain atrophy
20
6
10y5m
M
Tonic, atypical absence
Unknow n
Slow sp-w, multiple sp-w
7
10y7m
M
Tonic, atonic, myoclon ic, secondarily GTe
Prematu re, toxemia
Slow sp-w
Diffuse brain atrophy
10
8
12yOm
M
Tonic, myoclon ic
Unknow n
Slow sp-w
Normal
40
9
14y3m
F
Tonic, myoclon ic
Prematu re
Slow sp-w, sp in rt 0
Dilatatio n of It lateral ventricle
15
Case
15
25
GTe: generalized tonic-clonic, sp-w: spike and wave.
DSW
o
50
I
Case 1 1:::<:;:;::<·>:···· ,
100% D SNREM I
.............. :<.:<.:.;.;::.;.;:::;:~ . .................. <>:.:.:<::::.;~
Case 2 1
(::::::.....
Case 3 1
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Case 4 11:::::»>:',' Case 5 1 1::::::: .. <........ . Case 6 1 f;:::>:«>.....
~S~M
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... "':":::::».:::::;:;:::::;:;::::::::;:®@ L;::.::·:::<····· Case 7 1 Case 8 11;::::::::::>·<······ ............... ..........;.;.: ... :::::::::.;.. :::::::::::::::::::::~ Case 9
% 30
15
.............. :<"':::::::::::::::::::;:::::::::::::<::::::~ ............ >.:>::::::::::::~
Fig 1 Percentage of SPT for each sleep stage. Average SPT of all cases is 529.9 ± 64.3 minutes. 0
0
0
0
0
0
0
0
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0
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second segments. The children were maintained on their usual anticonvulsant medication (phenobarbital, phenytion, sodium valproate, benzodiazepines, etc).
Fig 2 REM density. Case numbers are arranged in order of the degree of DQ or IQ.
RESULTS Percentage of sleep period time (SPT) spent in each sleep stage and REM density The percentage for stage REM in all the cases except Case 1 (mean, 11.8 ± 2.9%) was lower than those in the control and in the normal 8 children aged 7-13 [7] (mean, 17.8%
and 20.4 ± 6.3%, respectively). The percentage for stage REM in Case 1 aged 2 (17.9%) was also lower than that in the age-matched normal children (28.7%) [8] (Fig 1). REM density in all the cases except Case 1 (mean, 7.0 ± 5.1%) was lower than that in the control (28.2%). REM density in the Case 1 (2.2%) was markedly lower than that
628 Brain & Develop ment, Vol 9, No 6, 1987
in the normal children of the same age group (20%) [9]. There was no positive correlation between the degree of DQ or IQ and REM density (Fig 2). Basic activity The presence or absence of alpha rhythm and sleep spindles varied with the patient. Three cases (Cases 2, 6, and 8) had both alpha rhythm and sleep spindles; the
Table 2 Basic activity Basic activity Case Alpha rhythm
Sleep spindles
+
+
2
3
+
4
+
5
+
6
+
+
+
+
7 8 9
other 3 cases (Cases 3,4, and 5) had no alpha rhythm but sleep spindles; and the remaining 3 cases had neither alpha rhythm nor sleep spindles. The amount of sleep spindles was small in Cases 3 and 5. On the whole, the abnormality of basic activity tended to be remarkable in the cases with severe psychomotor retardation (Table 2). Sleep states and epileptifonn discharges During NREM sleep diffuse slow spike-waves became more irregular - often replaced by multiple spike-waves in 8 cases-than during wakefulness and REM sleep. Suppression-burst EEG pattern similar to that in West syndrome was observed during NREM sleep in Case 1, the 2-year-old. The generalized epileptiform discharges including slow spike-waves and multiple spike-waves were neither increased nor decreased among wakefulness, NREM sleep and REM sleep in Cases 3, 8, and 9; increased in Cases 2 and 6 and decreased in Case 4 during NREM sleep as compared with wakefulness and REM sleep; increased similarly during NREM and REM sleeps as compared with wakefulness in Case 7; and increased in Case 5 and decreased in Case 1 during REM sleep as compared with wakefulness and NREM sleep. The effect of sleep-wake or REM-NREM sleep rhythm on the rate of generalized epileptiform discharges varied with the individual (Table 3).
Table 3 Sleep states and interictal epileptiform discharges Case
2 3 4
5 6
7
8 9
Epileptiform discharges StageNREM
Stage W
Stage REM
Slow sp-w
Slow sp-w, suppression-burst
Slow sp-w
(++)
(++)
(+)
Slow sp-w
Slow sp-w, multiple sp-w,
Slow sp-w
(+)
(+++)
(+)
Slow sp-w
Slow sp-w, multiple sp-w
Slow sp-w
(++)
(++)
(++)
Slow sp-w
Slow sp-w, multiple sp-w
Slow sp-w
(+++)
(++)
(+++)
Slow sp-w
Slow sp-w, mUltiple sp-w, multiple sp in posterior area
Slow sp-w
(+)
(+)
(+++)
Slow sp-w
Slow sp-w, multiple sp-w
Slow sp-w
(+)
(++)
(+)
Slow sp-w
Slow sp-w, multiple sp-w
Slow sp-w, multiple sp-w
(+)
(+++)
(+++)
Slow sp-w
Slow sp-w, multiple sp-w
Slow sp-w
(+)
(+)
(+)
Slow sp-w
Slow sp-w, multiple sp-w
Slow sp-w
(+++)
(+++)
(+++)
+, ++, and +++ indicate discharge rates under 20%, 20-50%, and above 50% of tracing, respectively.
Horita et al: Lennox-Gastaut syndrome 629
Poly grams in ictal discharges and in EEG discharges similar to ictal ones During overnight polygraphic recordings, clinical seizures observed only in the 5 children (Cases 1, 5, 7, 8, and 9) were all tonic type. Five types of polygrams were noticed: 3 in the ictal discharges with or without clinical manifestation, 2 in the EEG discharges similar to ictal ones.
1) Polygrams in ictal discharges Clinical seizure (C): During a tonic seizure, EEG showed a diffuse rhythmic fast activity at 8-17 Hz, 50-200 "N, associated with remarkable muscular contraction, apnea or irregular respiration and tachycardia. Nystagmus was also noticed in Cases 1 and 9. The duration of tonic seizure was 6-30 seconds (Fig 3 left, Fig 4 left, Fig 5). The
Fig 3 Polygrams in the ictal discharges of Case 1. Left: C. Right: S in stage REM.
-ECG
t~-----f-~ --i,~---I~--l~ -I-~ ~ .......,I-+--+---f..---.-t_~
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------
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Fig 4 Polygrams in the ictal discharges of Case 5. Left: C. Middle: Sc. Right: S.
630 Brain & Development, Vol 9, No 6, 1987
---4--+---H-I----f----4--J-+-.-i---+--+_+__
fast activity was sometimes followed by spike-wave at 1.5-2.5 Hz. In Case 9, the diffuse de synchronization was associated with the tonic seizure instead of the rhythmic fast activity (Fig 6). Subclinical seizure (SC): EEG showed a diffuse rhythmic fast activity at 8-15 Hz, 60-200 IN accompanied with feeble muscular contraction, apnea or irregular respi-
Noise
ration and tachycardia without obvious clinical manifestation. No nystagmus was observed in any of the cases. The fast activity lasting 4-7 seconds was sometimes followed by spike-wave at 1.5-3 Hz. The SC was recognized in Cases 1, 5, and 8 with clinical seizures during the recordings (Fig 4 middle). Seizure activity (S): The same rhythmic fast activity at
stage NREM
---------- - -------
-610
TK
9 y~m'____ _
Fig 5 Polygram of the other type C in Case 5, indicating longer duration and stronger intensity than that in Fig 4.
Fig 6 Polygram showing the type C with desynchronized EEG pattern in Case 9.
Horita et al: Lennox-Gastaut syndrome 631
8-15 HZ, 50-200 J.lV as in the C and SC was recognized without obvious clinical manifestation. Coincidentally, muscular contraction was not confirmed, but irregular
respiration was frequently observed. The fast activity last· ing 2-6 seconds was sometimes followed by spike·wave at 1.5-3 Hz. The S was recognized in Cases 1, 5, and 8 with
~bra.sin. R~sp.
____
~
~
, , , I -rr I 'I 111
ECG,
Fig 7 Polygrams in the EEG discharges similar to ictal ones. Left: LRD with irregular respiration in Case 3. Right: SRD in l..-ase 4.
CaN 1
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I ..J'L...L,'L..I.'J...jl " ,_ _' " -_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _- ' - -_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ __ I________-'LJ.-'-_ _
SeizIn LRO)
ea..
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gil
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Fig 8 Sleep profile and the occurrence time of ictal discharges and EEG discharges similar to ictal ones in one overnight record.
632 Brain & Development, Vol 9, No 6, 1987
clinical seizures during the recordings (Fig 3 right, Fig 4 right). 2) Polygrams in EEG discharges similar to ictal ones Long rapid discharge (LRD): EEG showed a diffuse rapid discharge at 8-15 Hz, 100-200 J.LV lasting 2-6 seconds. The changes of respiration and pulse rate were noticed when the duration of rapid discharge was long, but muscular contraction and clinical seizure were not confirmed. The LRD was recognized in Cases 3 and 6 without clinical seizures during the recordings (Fig 7 left). Short rapid discharge (SRD): EEG showed a 10-18 Hz, 50-200 J.LV diffuse rapid discharge lasting 0.8-2 seconds, not associated with the changes of respiration and muscular contraction. The SRD was recognized in Cases 4 and 6 without clinical seizures and in Case 9 with the ictal de synchronization pattern during the recordings (Fig 7 right).
Sleep states and ictal discharges or EEG discharges similar to ictal ones Fig 8 shows the occurrence time of the ictal discharges and the EEG discharges similar to ictal ones in one overnight record. The clinical seizures appeared frequently after awakening in the morning in Case 1, and occasionally during NREM sleep and immediately after awakening in the early morning in Cases 7 and 9. But in Cases 5 and 8, the clinical seizures were frequently observed during NREM sleep in the first sleep cycle, though they appeared infrequently during NREM sleep and awakening in the early morning. The SC and S in Case 1 were recognized during NREM and REM sleeps in the early morning. The SC and S in Cases 5 and 8 were recognized frequently during NREM sleep of the first sleep cycle, and not confirmed during REM sleep. The LRD and SRD appeared only during NREM sleep without preferred time zone. DISCUSSION Sleep states and REM density The REM sleep was decreased in the children of LGS as compared with control subjects, even if the effect of anticonvulsants on sleep was evaluated [10, 11] , as described by Ohtahara [12] and Amir et al [11]. The reduction of REM sleep has been observed in the children of earlyinfantile epileptic encephalopathy with suppression-burst (ElEE), West syndrome [3, 9] and other intractable epilepsy with mental retardation [10]. And also the decrement of REM sleep has been reported in mentally retarded children including those with Down's syndrome [13-15]. It is of interest to note that the reduction of REM sleep is closely related with mental subnormality. It is reported that tonic seizures, if frequent, can disrupt sleep organization owing to a decrease or disappearence of
REM sleep and stages 3 and 4 [16,17]. But the reduction of REM sleep in our study could not be ascribed only to the clinical tonic seizures during sleep because REM sleep decreased in children both with and without clinical'seizures during overnight recordings. The low level of REM density may indicate dysfunction of the REM sleep mechanism, because REMs are the main phasic event during REM periods. Feinberg et al [13] reported that a positive relation was found between the amount of eye movement during REM sleep and estimates of intellectual level in a group of retarded adults. In our previous study [9, 10], REM density remarkably declined in the children of EIEE, West syndrome, and other intractable epilepsy with mental retardation. From these observations, it is deduced that the pons regulating the REM sleep mechanism [18] is functionally damaged in LGS. Basic activity In this study, the alpha rhythm during wakefulness was observed in only 3 cases and the sleep spindles were seen in only 6 cases. The abnormality of basic activity tended to be remarkable in the cases with severe psychomotor retardation. Markand [2] reported that over two-thirds of 83 patients with LGS had moderate to markedly slow basic activity during wake EEG, and sleep spindles were usually absent in these patients though sleep spindles were present in 13 of 58 patients. He also reported that there was a correlation between the severity of mental subnormality and degree of slowing of the basic EEG activity. The absence of sleep spindles is reportedly observed in 50% of severely handicapped children [19], and in our previous study [10] on intractable epilepsy with mental retardation, neither alpha rhythm nor sleep spindles were recognized in 2 of 4 cases. Because alpha rhythm and sleep spindles are derived from the thalamus and propagated through the thalamocortical pathway [20], these findings may indicate that dysfunction of the thalamo-cortical system is present in LGS particularly in that with severe psychomotor subnormality. Sleep states and interictal epileptiform discharges It has been reported that in the patients with LGS, slow spike-wave discharges become irregular and are sometimes replaced by polyspike and wave discharges during NREM sleep, and that all types of paroxysmal discharges increase markedly during NREM sleep and decrease dramatically during REM sleep [1, 12, 16, 21]. It is a common observation that diffuse epileptiform discharges such as hypsarhythmia increase during NREM sleep and decrease markedly during REM sleep [3-5,9]. But in this study, there was no regular relationship between the sleep states and amount of interictal epilepti-
Horita et al: Lennox-Gastaut syndrome 633
form discharges as only 3 out of all 9 cases had the reduction of all types of discharges during REM sleep as compared with NREM sleep. In order to elucidate this discrepancy between the present study and previous reports, the difference between the cases with and without the reduction of epileptiform discharges during REM sleep (Cases 1,2,6 and Cases 3, 4,5,7,8,9, respectively) was investigated. Percentage of SPT for stage REM in the patients divided by that in the normal children was lower in the latter than in the former (mean, 0.53 ± 0.12 and 0.69 ± 0.09, respectively). The brain CT showed no abnormal finding in the former, but brain atrophy in 5 of the latter 6 cases. From these results, it is assumed that the suppressive effect on epileptiform discharges in REM sleep was poor in the cases with severe brain damage. The variable response of epileptiform discharges to sleep states may indicate the heterogeneous genesis of epileptiform activity in LGS. The suppression-burst pattern of EEG during NREM sleep in Case 1 could be explained as follows: the suppression-burst pattern during NREM sleep in West syndrome [9, 22] was successively observed because this case was LGS just subsequent to West syndrome. Polygrams in ictal discharges and in the EEG discharges similar to ictal ones Tonic seizures and their EEG pattern are one of the main signs of the LGS. Three types of generalized synchronous and symmetrical EEG patterns may occur during a tonic seizure [21, 23, 24]: (1) simple flattening (desynchronization) of all activity throughout an attack; (2) very rapid activity (20 ± 5 Hz), initially of low voltage and then progressively increasing in amplitude to 50 to 100 pV; and (3) rhythmic discharge at about 10Hz, identical to that of the tonic phase of tonic-clonic seizure (epileptic recruiting rhythm) except that it may be of high amplitude from the onset. It is postulated that the simple flattening (de synchronization) originates in the midbrain tegmental reticular formation [23}. The rhythmic discharge at 10 Hz (recruiting rhythm) is believed to be derived from the thalamic reticular structures and mediated by the nonspecific diffuse thalamic projection systems [23]. In our overnight polygraphic recordings,4 out of 5 cases with tonic seizures had the type 2 or 3, and one had the type 1. According to the previous reports [21, 23], the tonic contraction during sleep can persist, but it is usually either absent or very much reduced in intensity and topography. Although reduced in intensity, autonomic changes such as transient tachycardia and brief apnea usually persist during sleep, even when the seizures are strictly subclinical. In this study, Cases 1, 5, and 8 showed a similar finding. Ohtahara et al [24] reported that a specific wave form "rapid rhythm" at 10-12 Hz, 50-100 JJ.V was observed without clinical seizure during moderate to deep
634 Brain & Development, Vol 9, No 6, 1987
sleep but not observed during REM sleep, and that this rapid rhythm was observed in 21 of 74 patients (28.4%). The LRD and SRD in our study, coinciding with "rapid rhythm," might be closely related to the clinical tonic seizure because the changes of respiration and pulse rate were noticed under the long duration of LRD. Sleep states and ictal discbarges or the EEG discharges similar to ictal ones Concerning the relationship between sleep and clinical seizures in LGS, the following description was given by previous authors [1,2,21,23,25]: All types of seizures appear during both sleep and wakefulness. Tonic seizures usually are much more frequent during NREM sleep than during wakefulness but never occur during REM sleep. The clinical manifestation of tonic seizures are often less dramatic in sleep and can be easily overlooked. Rarely, ictal EEG pattern is observed during sleep without any clinical correlates. In our study, the ictal discharges with or without obvious clinical manifestation of tonic seizures occurred during NREM sleep and awakening in the early morning, and in 2 cases occurred frequently also during NREM sleep of the first sleep cycle. In the child aged 2, the subclinical ictal discharges (SC and S) occurred not only in NREM sleep, but also in REM sleep. We suggest that the subclinical ictal discharges appearing during REM sleep in West syndrome [3, 26] were successively recognized because this child was LGS just subsequent to West syndrome. It is assumed that the ictal discharges start to occur only in NREM sleep along with brain maturation or progress of the illness. The LRD and SRD similar to "rapid rhythm" was recognized during NREM sleep without the special time zone of occurrence. These results suggest that the occurrence of tonic seizures and their ictal discharges are subject to the sleepwake and REM-NREM sleep rhythms controlled in the brain stem.
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Horita et al: Lennox-Gastaut syndrome 635