EEG patterns suggestive of AS
EEG patterns suggestive of AS were observed in 47 EEGs of 25 (96.2%) of 26 patients. Only one patient had repeatedly normal EEGs [five examinations from the ages of 1 to 5 years (one examination/year)]. This patient had a uniparental disomy and so far has not had seizures.
To analyze the frequency with which these patterns occurred, we took into account only those patients who had the suggestive EEG patterns. Therefore the number of patients considered was 25.
The delta pattern occurred in 41 EEGs [ages from 0.4 to 21.2 years (mean, 5.7 years)] of 22 (88%) of 25 patients who had an EEG suggestive of AS. Some inter- and intraindividual variations, regarding mainly morphology and distribution, were observed. We were able to classify them in four variants:
: Runs of high-amplitude, generalized, irregular delta waves, without spatial organization, associated with multifocal epileptiform discharges, characterized by spikes or sharp waves of moderate amplitude. This variant, although resembling a hypsarrhythmic pattern, had a predominance of slow waves over the epileptiform discharges. No correlation with sleep/wake cycle was noticed. This variant was seen in three EEGs [obtained at the ages of 0.4, 1.2, and 1.3 years (mean, 0.9 years)] of two (9.1%) of 22 patients (Fig. 1A
Ill-defined slow spike and wave variant:
Runs of regular, quasi-rhythmic, high-amplitude delta activity, with generalized distribution, usually with predominance over anterior regions, and with superimposed epileptiform discharges (spikes or sharp waves), ranging from moderate to low amplitude, occurring either on the descending or on the ascending phase of the slow wave. As observed in other variants of the delta pattern, a clear predominance of the slow-wave component is seen over the epileptiform activity, forming a complex with a peculiar morphology, characterized by a slow wave, with notched
appearance (Fig. 1B
). These features were registered in 32 EEGs [1.2–16.7 years (mean, 5.2 years)] of 16 (72.7%) of 22 patients;
Runs of monomorphic, rhythmic, and regular delta waves, with moderate amplitude, over anterior regions, or generalized with an evident predominance over these regions, with low-amplitude sharp waves (Fig. 1C
), on the descending phase of the slow wave in nine EEGs [1–16.7 years (mean, 6 years)] of five (22.7%) of 22 patients; and
Runs of regular, high-amplitude, delta activity, with generalized distribution, usually with anterior predominance, and with none or rare epileptiform discharges (Fig. 2
). This variant occurred in 24 EEGs [1–21.2 years (mean, 4.9 years)] of 15 (68.2%) of 22 patients.
Figure 1. A: Patient 11 (1 yr 2 mo). During sleep recording, we observed continuous, generalized, >250 μV, irregular delta waves mixed with spikes and sharp waves in a multifocal distribution with variable amplitude. No fragmentation was noted. Sens, 10 μV/mm; TC, 0.3; HFF, 70; PS, 30 mm/s. B: Patient 9 (3 yr). During wakefulness and sleep, this child had prolonged trains of high-amplitude, generalized delta waves with superimposed low-amplitude epileptiform discharges, giving the slow wave a notched aspect. In this variant, the epileptiform discharge was usually seen on the downslope of the slow wave, closer to the subsequent delta wave than to that preceding it. This variant is associated with another delta variant (triphasic-like pattern). Sens, 15 μV/mm; TC, 0.3; HFF, 70; PS, 30 mm/s. C: Patient 19 (7 yr). During sleep phase II, bursts of regular, rhythmic, and monomorphic delta waves with moderate amplitude, over the anterior regions with triphasic aspect. Sens, 10 μV/mm; TC, 0.3; HFF, 70; PS, 30 mm/s.
Figure 2. Patient 19 (1 yr 4 mo). Although the child was awake and playing with a toy over his head, we observed an almost continuous activity constituted of high-amplitude, quasi-rhythmic 2- to 3-Hz waves with generalized distribution. Random and very low amplitude epileptiform discharges occurred during the entire tracing. Sens, 15 μV/mm; TC, 0.3; HFF, 70; PS, 30 mm/s.
Download figure to PowerPoint
These variants of delta pattern did not change during sleep (phases I and II).
Delta pattern bursts varied in duration from 1 s to continuous or almost continuous. They occurred in prolonged bursts (>10 s) in 14 patients, as continuous or quasi-continuous, in five of these.
The theta pattern was observed in 14 EEGs [1.2–7 years (mean, 3.8 years)] of eight (32%) of 25 patients and was characterized by 4- to 7-Hz activity, of high amplitude (>150 μV), and with a regular, rhythmic, sinusoidal, and monotonous morphology. This pattern had a variable distribution, being observed as generalized in four EEGs of three patients, and over the posterior regions (Fig. 3A), in 14 EEGs of eight patients, of which three were asymmetric. This pattern occurred in bursts that lasted from 2 to 10 s (mean, 7 s) and was continuous in one EEG, during wakefulness and sleep. Morphology, distribution, frequency, and occurrence of this pattern were not related to the sleep/wake cycle (Fig. 3B) and were not blocked by eye-opening during awake periods.
Figure 3. Patient 19 (7 yr). Theta pattern (>200 μV), monotonous, rhythmic, and regular activity during wakefulness (A) and sleep (B) over the posterior regions. Sens, 15 μV/mm; TC, 0.3; HFF, 70; PS, 30 mm/s.
Posterior discharges were seen in 31 EEGs [1–16.7 years (mean, 5.3 years)] of 19 (76%) of 25 patients and were observed as:
Figure 4. Patient 11 (3 yr 2 mo). Posterior discharges characterized by bursts of sharp activity in a theta range (4–6 Hz) with notched appearance. Sens, 15 μV/mm; TC, 0.3; HFF, 70; PS, 30 mm/s.
Download figure to PowerPoint
These posterior discharges were usually seen in short runs, except for five patients, who had bursts >10 s.
Passive eye closure was carried out in 29 EEGs, but posterior discharges, elicited by this procedure, were observed in only one patient.
Association of more than one EEG pattern suggestive of AS was obtained in 31 EEGs of 20 (80%) of 25 patients. The most frequent associations were: delta and posterior discharges in 11 (42.3%) of 25 patients; delta and theta in two (7.7%); and theta and posterior discharges in one (3.8%) of 25 patients. Association of the three patterns in the same tracing or in serial EEGs was present in four (15.4%) patients.
The delta pattern and posterior discharges were observed in all ages (from 4 months to 22 years), and in all groups (DEL, UPD, and NEG), despite the milder phenotype in some patients. The theta pattern was the only one that was age related, being observed in those younger than 8 years, and only in patients with DEL. The correlation of these abnormalities with distinctive genetic mechanisms is part of another study.
In the 22 patients with genetic confirmation, suggestive EEG patterns preceded the genetic diagnosis in 16 (72.7%). Moreover, in all patients without genetic confirmation, the EEG was able to corroborate the clinical diagnosis.
The age at clinical diagnosis ranged from 2 to 17 years 2 months (mean, 4.9 years; median, 3.8 years). Analysis of EEG tracings of 15 patients who had EEGs performed before the clinical diagnosis of AS revealed that nine (60%) had suggestive EEG patterns. Their ages when the EEG was obtained ranged from 5 months to 15 years 11 months (mean, 4.4 years; median, 2.4 years). In the EEGs of six patients, we could observe an early age at onset (before age 3 years) for suggestive EEG features of AS: one before the first year, three after the first but before the second year, and two patients younger than 3 years. The interval between the presence of suggestive EEG and the clinical diagnosis ranged from 3 months to 4 years 9 months (mean, 1.6 years; median, 1.2 years).
Other EEG abnormalities
Interictal epileptiform discharges occurred in 21 EEGs of 12 (46.2%) of 26 patients. They were characterized by spike/sharp waves over frontal regions in five (41.7%), frontocentral in four (33.3%), temporal in three (25%), posterior quadrant in six (50%), and multifocal in five (41.7%) of 12 patients. These discharges were nonspecific and did not constitute a novel EEG feature for the diagnosis of AS.
Seizures were recorded in eight (30.8%) of 26 patients during prolonged V-EEG studies and were characterized by slow spike-and-wave complexes in five patients, with concomitant atypical absence status. In one patient, we observed sharp theta activity over the right occipital region during a complex partial seizure, with sustained head and eye deviation to the left, and in other two patients, a generalized tonic–clonic event, with EEG correlate.