Electroencephalographic characteristics of Dravet syndrome

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1 DRAVET SYNDROME Electroencephalographic characteristics of Dravet syndrome *Michelle Bureau and ybernardo Dalla Bernardina *Centre Saint Paul, Hôpital Henri Gastaut, Marseille, France; and yu.o.c. Neuropsichiatria Infantile Azienda Ospedaliera Universitaria Integrata, Policlinico G.B. Rossi, Verona, Italy SUMMARY In Dravet syndrome, interictal and ictal electroencephalography (EEG) recording may remain misleading, and are not specifically altered. Moreover, there is a great polymorphism of clinical and EEG seizure types. Some can be observed in other epileptic syndromes, but others are more specific particularly the peculiar unilateral seizures, the falsely generalized seizures, probably with a focal onset, and the unstable seizures. In some cases, the ictal manifestations are characterized by the persistent predominant recurrence of convulsive seizures, often induced by body temperature increase, eventually associated with partial complex seizures. The myoclonic events, absences with myoclonic component, obtundation status, and photosensitivity and/or pattern sensitivity are absent or appear relatively late and recur transiently for short periods. In these cases interictal EEG is characterized by the persistent paucity of paroxysmal discharges. In other cases, on a background of convulsive seizures and body temperature sensitivity, one may find a variable association of (1) myoclonic seizures of different types, (2) a strong sensitivity to light and pattern stimulations, with early onset and persistent in time. In these cases, interictal paroxysms and spontaneous and induced (intermittent photic stimulation, patterns, and eye closure) stimulation tend to appear early and to be frequent and persistent during the evolution. According to these electroclinical patterns it is possible to divide the population into two subsets, both sharing common genetic mechanisms but with a different clinical outcome. KEY WORDS: EEG, Electroclinical seizures, Dravet syndrome, Myoclonic seizures, Nonconvulsive status, Photosensitivity. In Dravet syndrome (DS) there are no specific interictal electroencephalography (EEG) features, and the seizures are very different and polymorphous according to the age and probably to the different subsets of subjects. Nevertheless both interictal and ictal features change progressively with the evolution, and it is this progressive modification that often suggests the diagnosis. For this reason, we will first consider the interictal EEG at onset and during the evolution, and then the EEG features of the different seizure types. Address correspondence to Michelle Bureau, Centre Saint Paul, Hôpital Henri Gastaut, 300 bd de Sainte Marguerite, 13009, Marseille, France. michelle-bureau@wanadoo.fr Wiley Periodicals, Inc. ª 2011 International League Against Epilepsy Interictal EEG Onset Before the end of the first year of life, during wakefulness, background activity is normal. In some cases, a 4 5 Hz rhythmic theta activity can be noticed over the rolandic areas and the vertex (Dalla Bernardina et al., 1982; Hurst, 1987; Giovanardi-Rossi et al., 1991). At the end of the first year of life this peculiar theta activity appears in most cases and persists throughout the followup (Ohki et al., 1997). During sleep, the EEG shows a normal organization with patterns that are physiologic for age. A diffuse or unilateral slowing of the background activity may be observed if the EEG is performed shortly after a prolonged seizure. According to most authors (Oguni et al., 2001; Dravet et al., 2005a), the paroxysmal abnormalities are observed rarely during both wakefulness and sleep. Nevertheless in some cases brief discharges of 13

2 14 M. Bureau and B. Dalla Bernardina diffuse spike-waves (SWs) can be recorded; in one third of the subjects followed in Verona similar paroxysms were recorded in the first year of life. Moreover, in approximately 25% of the cases, the EEGs show generalized SWs elicited by intermittent photic stimulation, a most unusual finding at this age (Dalla Bernardina et al., 1982; Dravet et al., 1992). Steady state Between the second and the fifth years of life, the EEG changes show a progressive increase of paroxysmal abnormalities. During wakefulness, background activity remains normal in 50% of the cases or shows a slight slowing. In the remaining cases, background activity becomes slow and poorly organized. Slowing of the background activity is a fluctuating finding, probably because it is caused by the frequency and duration of the different types of seizures and the different pharmacologic treatments. A precise evaluation of the true incidence and frequency of the paroxysmal EEG abnormalities depends on the number and duration of the EEG recordings, because the paroxysms can fluctuate according to the different conditions (spontaneous fluctuation, seizure trend, and pharmacologic treatment). Probably the lack of repeated EEG recordings can explain why some authors (Hattori et al., 2008) conclude that EEG does not help an early diagnosis of DS. Moreover, the limits between interictal and ictal paroxysms can be difficult to assess in the absence of long-lasting video-eeg polygraphic recordings. Even following numerous and accurate recordings, in some cases there are no paroxysmal EEG abnormalities. Paroxysmal EEG abnormalities are constituted by generalized SWs, isolated or in brief bursts, predominating on the frontocentral regions. In many cases there are brief discharges of fast polyspike waves (PSWs), diffuse or involving mainly the frontocentral regions, induced by eye closure (Fig. 1). Often associated with these generalized paroxysms there are also focal and multifocal abnormalities such as fast spikes or polyspikes, involving asynchronously the frontocentral or centrotemporal and vertex regions, and sometimes even the posterior regions (Fig. 2). There is no relation between the site of these paroxysms and that of seizures, probably because EEG abnormalities represent a fragment of the diffuse discharges rather than true focal abnormalities. Generalized SW discharges are more frequent when myoclonic fits are also frequent. A strong photosensitivity persists in a large proportion of cases, with or without associated clinical events (eyelid Figure 1. B.C. is a 17-month-old patient. At awakening, there are brief bursts of SWs induced by opening and closing of the eyes while crying. During sleep, there is a recurrence of brief discharges of diffuse SWs. Note the predominance of the fast polyspike component on the frontocentral regions and vertex.

3 EEG Characteristics of Dravet Syndrome 15 Figure 2. B.C. is a 3-year-old patient. Notice the great variability in morphology and topography of the paroxysmal abnormalities according to different conditions of vigilance. During active wakefulness with recurrent forced blinking, there are frequent brief discharges of SWs or fast polyspikes predominating on the anterior regions, frequently associated with eyelid myoclonus. At rest with eyes closed there is posterior predominance of the paroxysms. During sleep, there are frequent fast SWs or polyspikes, greatly varying in amplitude and topography, evoking multifocal paroxysms. myoclonia, generalized myoclonic jerks). Eye closure, television, and fixation of patterns elicit subclinical or clinical discharges of spikes and SWs in 25% of the cases. In other cases there is a spontaneous fluctuation of photosensitivity. Sleep is usually well structured, with physiologic patterns and normal cyclic organization, except when several seizures occur during the night. In general it is exceptional not to identify non rapid eye movement (NREM) and REM sleep. The generalized, as well as localized, paroxysms are enhanced or simply appear. In rare cases, the interictal EEG shows fast rhythms sometimes followed by a decremental event and PSWs very similar to those recorded in Lennox-Gastaut syndrome (LGS). In some cases there is an important activation of the focal anomalies particularly over the frontal regions, bilaterally or with hemispheric predominance. Long-term evolution The characteristics of background activity fluctuate, depending on the number and severity of seizures. Persistently normal background activity is observed in approximately 42% of the cases for Dravet et al. (2009) and in 65% for Akiyama et al. (2010). In these cases we can observe a peculiar strong increase of the theta activity in the central regions and the vertex elicited by the eye closure. This activity is particularly enhanced in patients showing an intense cortical tremor with motor deterioration. In 19 25% of cases, the generalized SWs decrease and in some cases disappear. The photosensitivity decreases progressively (Akiyama et al., 2010); nevertheless in some cases it can persist (in 12% of the Verona patients older than 18). The cyclic organization of the sleep remains normal in 70% of patients with several sleep recordings, and in the remaining cases it is possible to distinguish the NREM from REM sleep. The focal and multifocal abnormalities often appear only during sleep. As reported by Nabbout et al. (2008), in some cases during slow sleep there is an unusual pattern constituted by a subcontinuous sequence of diffuse slow bi-triphasic spikes predominating at the frontocentral regions. This pattern sometimes persists until adulthood and is not necessarily associated with tonic seizures (Fig. 3). From the onset, throughout the evolution, the interictal pattern varies considerably according to the different treatments and probably because of differences in the seizure threshold among patients. Ictal EEG Subjects with DS, in most cases, have multiple seizure types during the course of the disease.

4 16 M. Bureau and B. Dalla Bernardina Figure 3. S.A. is a 23-year-old patient. Persistence of diurnal falsely generalized seizures 1 2 times a month. Myoclonic seizures disappeared at the age of 16 years and photosensitivity at the age of 18. From the age of 16 years, there is persistence, during slow sleep, of this pattern of subcontinuous bi-triphasic waves in the absence of tonic seizures. Unilateral seizures Unilateral seizures are one of the most common seizures at onset; often, if not quickly treated they are long-lasting and constitute an epileptic status. True hemiclonic seizures, corresponding to the description by Gastaut et al. (1974), are rare and are observed in children younger than 3 years of age. The ictal discharge is characterized by rhythmic (2 3/s) bilateral slow waves, with higher amplitude on the hemisphere contralateral to the clinical seizure. On this side only, they are intermixed with 10/s recruiting rhythms, usually predominant in posterior scalp areas. This discharge is followed by a brief flattening, and then by delta slowing, with higher amplitude on the affected hemisphere. On the opposite side, physiologic rhythms intermixed with slow waves, reappear. At this time, a unilateral motor deficit is noted that is not permanent in any case. In the remaining cases, the EEG pattern is variable with a focal onset over the frontal or frontocentral region on one hemisphere, or more bilateral, but always predominant over the frontal areas. The discharge can be constituted by pseudo-rhythmic spike and waves, contralateral to the clinical seizure, periodically interrupted by a 1- to 2-s flattening. Polygraphic recordings can show a strict correlation between EEG paroxysms and jerks, but in many cases a consistent relation between muscle jerks and EEG discharges is difficult to recognize. Spontaneous termination of the seizure is generally abrupt. In some cases the seizure can be preceded by isolated massive jerks related to generalized SW discharges starting several minutes before the unilateral seizure onset. These seizures can be on either side in the same patient; this alternating pattern can be a clue for the diagnosis of DS. Falsely generalized seizures According to Dravet et al. (2005a,b), two peculiar types of convulsive seizures are considered typical of the DS: the falsely generalized seizures and the unstable seizures. The falsely generalized seizures are characterized by a complicated semiology with some degree of discrepancy between clinical and EEG phenomena. The description reported by the family seems to correspond to a generalized tonic clonic seizure (GTCS), even if the seizures are generally shorter, but accurate observation under videopolygraphic EEG recording demonstrates that they are not primarily generalized, neither at the onset nor at the offset, and that they differ from one patient to another. They occur especially during NREM sleep. The EEG discharge is always bilateral but according to various modalities. One pattern consists of bilateral abnormalities from onset, such as a slow spike or an SW, sometimes followed by a brief attenuation, and then fast activities intermixed with slow waves, still more or less bilateral (Fig. 4) in contrast with the clinical events. In a different pattern, the abnormalities are initially bilateral but become and remain asymmetric during the seizure. In some cases they are bilateral but asymmetric at their very onset. The postictal EEG shows either a diffuse flattening or slowing. Sometimes the end of the seizure is not easy to recognize and the child continues to sleep. This asymmetry in the EEG during the GTCS has also been described by Kanazawa (1992) and Ogino (1986). As observed for unilateral

5 EEG Characteristics of Dravet Syndrome 17 Figure 4. A falsely generalized seizure in a 5-year and 6-month-old boy. Top: At onset a generalized slow spike followed by a low voltage theta activity followed by bilateral fast activity of higher voltage over the left hemisphere. Note on the EMG recording that a slight bilateral tonic contraction begins 2 s after the EEG onset, remits, and then is followed by an irregular tonic contraction associated with a vibratory aspect. Bottom: 40 s later there are diffuse SWs associated with bilateral myoclonus that becomes progressively asynchronous and stops on the left deltoid earlier than on the right muscles. At the end of the seizure, note the absence of a flattening but the presence of high-voltage delta waves. seizures, even these seizures can be preceded several minutes by isolated massive jerks, increasing progressively in frequency until the onset of the convulsive event. In these cases the electrographic seizure onset is more generalized, and frequently the initial tonic phase is almost immediately mixed with clonic jerks, realizing a vibratory aspect similar to that described by Ogihara et al. (1994). Unstable seizures The unstable seizures are characterized by the topographic changes of the ictal EEG discharge in the same seizure. The EEG discharge involves irregularly different parts of the brain. It can start in one localized area of one hemisphere and then spread to the entire hemisphere, either asymmetrically to the two hemispheres, or to another area of the same hemisphere or to the opposite hemisphere, and then return to the firstly involved hemisphere. The end of the discharge can occur either in this hemisphere or contralaterally (Fig. 5). But the ways of propagation are variable from one seizure to another in the same patient, even in the same recording. The relationship between the clinical

6 18 M. Bureau and B. Dalla Bernardina Figure 5. An unstable seizure occurring during NREM sleep in a 3-year-old boy. Top: brief diffuse lowering of voltage intermixed on the right hemisphere with fast activity, and then spikes and slow waves evident only on the right hemisphere during 10 s followed by a more or less rhythmic activity around 10 Hz on the right centroparietal area. Twenty seconds after the onset of that activity a similar activity appears on the left frontocentrotemporal region. Bottom: continuation of the seizure; the activity is progressively associated with slow waves on the left hemisphere, becoming slower at the end of the seizure. (A) cough, (B) nothing noted, (C) slight diffuse tremor, (D) deviation of eyes and head to the right, and (E) no deficit. manifestations and the accompanying EEG is not always clear. Myoclonic seizures Myoclonic manifestations in DS have been reported to be heterogeneous and include nonepileptic myoclonus (Dalla Bernardina et al., 1982; Oguni et al., 2001; Dravet et al., 2005a, 2009). The myoclonic seizures can be isolated or grouped in brief bursts of two or three jerks. Generally they predominate on the arms but can involve the axial muscles and the neck. The polygraphic EEG recording shows generalized SWs or multiple SWs, at 3 Hz or more, with higher voltage on the frontocentral areas and on the vertex. These discharges can be similar to those observed in benign myoclonic epilepsy of infancy (BMEI) (Fig. 6), even if, like documented by Hirano et al. (2009), the jerks are characterized predominantly by extensor postural changes of the trunk and upper limbs. According to Guerrini et al. (2005) the generalized jerks appear to originate from the spreading of central myoclonic activity. Nevertheless the neurophysiologic mechanism underlying the jerks remains speculative. Their duration is usually brief (1 3 s) but they can recur in longer series (up to 10 s). The electromyography (EMG) can show postmyoclonic inhibition corresponding to a head drop. Myoclonic status is

7 EEG Characteristics of Dravet Syndrome 19 Figure 6. Two bursts of generalized SWs accompanied by myoclonic jerks, followed by a discharge of slow waves. On the left a 14-month-old boy with benign myoclonic epilepsy of infancy and on the right a 5 year-old girl with a DS. Recording: 15 lv/mm, 15 mm/s. rare (Dravet et al., 2005a), but in many cases the recurrence in clusters of myoclonic jerks can culminate into a convulsive seizure. The massive jerks are frequently mixed with numerous asynchronous and arrhythmic distal jerks manifested as twitching of fingers, often difficult to correlate with an obvious EEG paroxysm and consequently difficult to differentiate only polygraphically from nonepileptic myoclonus (Fig. 7). Atypical absence seizures They can be divided into atypical absence seizures with impaired consciousness only and those with a more or less obvious myoclonic component. In these cases the myoclonic attack consists of a successive myoclonic twitching involving mainly the head, eyelids, and sometimes the arms, and it can result in a rhythmic retropulsion of the head. In both seizure types the EEG recording shows generalized, irregular SWs at Hz. The myoclonic phenomenon can be very mild and isolated during the SW bursts and so, in the absence of a polygraphic recording, it can remain unrecognized. However, occasionally, absences with rhythmic, generalized SWs at 3 Hz, similar to those observed in the absences of childhood absence epilepsy, have been recorded. Ohmori et al. (2001) recorded atypical absences with either predominance or onset of the SWs in the occipital regions. In a few subjects an absence status can be observed, this status appears in a progressive manner with a fluctuating consciousness disturbance in absence of motor manifestations. They are characterized by a subcontinuous sequence of slow PSWs fluctuating in amplitude, diffuse on both hemispheres, with an anterior predominance. They are of long duration; they can disappear spontaneously during sleep, but can reappear at awakening if the sleep duration is brief. Focal seizures Simple partial seizure (SPS) of motor type or, more frequently, complex partial seizures (CPS), with prominent autonomic symptoms, occur in % of patients in the largest series reported by Dravet et al. (2005a,b), but they are seldom illustrated (Ohki et al., 1997; Ohmori et al., 2001; Caraballo & Fejerman, 2006). The CPS consist mainly of eye deviation, pallor, cyanosis, respiratory changes, drooling, discrete oral automatisms, hypotonia sometimes with eyelids, and/or a few distal myoclonic jerks. They last from one to a few minutes; when of longer duration, CPS can evolve into a unilateral motor or secondary generalized seizure. Because of the paucity of the motor symptoms, this seizure can be erroneously interpreted as an atypical absence. Nevertheless it is invariably followed by a significant somnolence, and this can help the differential diagnosis. Ictal EEG is constituted by a rhythmic sequence of fast poly-s intermitted by theta activity during the last part of the seizure involving, for the duration of the seizure, the temporoparietooccipital region of one hemisphere or more rarely a frontal region. Although the CPS are reported by most authors, SPS are

8 20 M. Bureau and B. Dalla Bernardina Figure 7. De Za. M. is a 2-year and 9-month-old child. Note on the EEG the frequent discharges of diffuse or bilateral frontal polyspikes and waves intermingled with subcontinuous theta activity. On the EMG recording, there is subcontinuous myoclonic jerks of different intensity and topography, sometimes clearly time locked to EEG paroxysms, especially during ILS. Figure 8. An obtundation status in a 2-year and 4-month-old boy. Diffuse slow and sharp waves. On the right, a burst of SW is accompanied by brief staring. On the EMG recording, note a slight increase of the muscular tone and arrhythmic, erratic, segmentary myoclonic jerks.

9 EEG Characteristics of Dravet Syndrome 21 reported only by a few (Giovanardi-Rossi et al., 1991; Yakoub et al., 1992; Wang et al., 1996; Sarisjulis et al., 2000; Caraballo & Fejerman, 2006); both partial seizure types can secondarily generalize. Obtundation status Obtundation status represents a relatively characteristic symptom reported in all the series (Dalla Bernardina et al., 1987; Oguni et al., 2001; Dravet et al., 2005a). These statuses are generally long-lasting; they appear preferentially in the morning at awakening and are characterized by obtundation with poor responsivity and erratic myoclonus, involving mainly the fingers and orobuccal muscles with drooling, and intercalated by isolated and randomly recurrent massive jerks. When persistent in the evening they can interfere with falling asleep. Convulsive seizures could initiate, occur during, or terminate this type of status. The EEG is usually characterized by one diffuse dysrhythmia of slow waves, intermixed with focal and diffuse spikes (Fig. 8), sharp waves, and SWs, of higher voltage in the anterior regions and the vertex, without time correspondence between the spikes and the myoclonic jerks except during the intercalated myoclonic fits. This aspect was also described by Ohmori et al. (2001). Other EEG aspects were described by Oguni et al. (2001): pseudorhythmic diffuse high-amplitude, irregular slow waves, gradually slowing down in frequency, and bursts of bilateral, diffuse high-voltage slow waves, occasionally notched with small spikes. Strong sensory stimulation can transiently interrupt the status. This status must be distinguished from another type of nonconvulsive status reported by Wakai et al. (1996) and Oguni et al. (2001), under the term of complex partial status because of the clinical symptomatology evoking complex partial seizures characterized on the EEG by irregular unilateral SW complexes, predominantly in the occipitotemporal area or by continuous posterior localized, irregular slow waves or SWs. Tonic seizures Tonic seizures are unusual in this syndrome. They are rarely described by the parents and are detected mainly by sleep EEG recordings. They have variable electroclinical features. They resemble the axial tonic seizures of the LGS, sometimes with a myoclonic component, but are usually sporadic and rarely repeated during the same recording. In the Dravet series the ictal EEG can show several aspects: (1) a fast rhythm, which is directly diffuse of high voltage, stopping abruptly, followed by slight and brief postictal sufferance signs; (2) a flattening, generally of brief duration (2 3 s); or (3) a rapid recruiting rhythm sometimes interrupted by a flattening, followed by slow waves or irregular diffuse SWs. The polygraphic study Figure 9. H. B. is a 2 year and 6 month old. Different electroclinical brief seizures are induced by ILS. Note the progressive increase from the first to the third seizures of the clinical symptoms according to the progressive topographic extension of the ictal discharges. In all cases the initial EEG response to stimulation is bilateral.

10 22 M. Bureau and B. Dalla Bernardina confirms the clinical signs: If the initial contraction is a true tonic contraction, some seconds later it can change into a vibratory aspect intermixed with myoclonias. Only in rare cases is the interictal sleep EEG analogous to that in the LGS (rapid rhythms and multiple SWs). In a recent study, Nabbout et al. (2008) recorded tonic seizures in five patients, underscoring the unusual EEG features of these patients with DS. Reflex seizures Body temperature increase sensitivity In many of the patients with DS it is possible to observe seizures induced by different conditions of stimulation. The most frequent condition is constituted by body temperature increase sensitivity. It is well known that fever can trigger the seizures nearly habitually. In fact not only fever, but also immersion in hot water or intense physical exercise, especially in the summer, can also trigger seizures. In these cases the most frequent seizures are characterized by recurrent myoclonic jerks that in some cases can culminate into a convulsive seizure or by the abrupt onset of a convulsive seizure. Photosensitivity and pattern sensitivity A significant number of subjects (64% of Verona subjects) show a peculiar photosensitivity or pattern sensitivity, appearing between the age of 9 months and 9 years. Photic stimulation and pattern stimulation can induce different kinds of seizures: 1. Most frequently isolated or recurrent massive jerks if the stimulus persists, associated with isolated or recurrent generalized SW discharges. These manifestations can stop spontaneously or can culminate into a generalized convulsive seizure. 2. Generalized clonic or vibratory generalized seizures associated to the abrupt appearance of diffuse discharges of fast PSWs. A unilateral seizure was provoked by patterns in one case of the Dravet et al. (2005b) series. 3. Partial complex seizures related with a hemispheric or more localized discharge of SWs or polyspikes. These different ictal patterns can be observed even in the same patient (Fig. 9). The pattern stimulation generally induces massive jerks and if the stimulus persists they can culminate into a convulsive event. Finally, subjects having a strong photosensitivity and/or pattern sensitivity frequently present a peculiar tendency to self stimulation, by repetitive eye blinking, while staring at a bright source or at a pattern. Photogenic self-induced absences and/or myoclonic jerks were firstly documented by Takahashi et al. (1995). In these subjects, in adult age, eye closure can also precipitate cortical tremor and distal myoclonus related with a peculiar Figure 10. V.M. is a 13-year old. Following eye closure, there is appearance of an enhanced fast activity intermingled with fast spikes/polyspikes predominating on frontocentral regions and vertex. Note the concomitant increasing of the cortical tremor and small distal myoclonic jerks. The electroclinical and polygraphic pattern is stopped by eyes opening.

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