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An unexpected EEG course in Dravet syndrome
Epilepsy Research (2008) 81, 90—95
journal homepage: www.elsevier.com/locate/epilepsyres
SHORT COMMUNICATION
An unexpected EEG course in Dravet syndrome Rima Nabbout a,b,c,∗, Isabelle Desguerre a, Sandra Sabbagh a, Christel Depienne d, Perrine Plouin e, Olivier Dulac a,b,c, Catherine Chiron a,b,c a
´pilepsies rares, APHP, Necker-Enfants Malades Hospital, Department of Neuropediatrics, Centre de r´ ef´ erence e 149 rue de S` evres, Paris F-75743, France b Inserm, U663, Paris F-75015, France c University Paris Descartes, Paris F-75005, France d Inserm, U679, Hˆ opital de la Piti´ e Salpˆ etri` ere, 47 boulevard de l’Hˆ opital, Paris F-75013, France e APHP, Necker-Enfants Malades Hospital, Clinical Neurophysiology, 149 Rue de S` evres, Paris F-75743, France Received 29 September 2007; received in revised form 20 April 2008; accepted 22 April 2008 Available online 6 June 2008
KEYWORDS Dravet syndrome; Severe myoclonic epilepsy in infancy; EEG; Tonic seizures; Lennox—Gastaut syndrome
Summary A puzzling EEG pattern combining frontal slow bi—tri spikes followed or not by slow waves when awake and activated by sleep with 5—10 s discharges of 8—9 Hz spikes in a minority of adolescents with Dravet syndrome (DS) was recorded in the context of stable seizure and cognitive status, and unchanged antiepileptic medication. Tonic seizures were frequently reported in patients with this EEG pattern (3/5). This EEG pattern could suggest that of Lennox—Gastaut syndrome (LGS) but it exhibits clear differences and therefore should not be considered as a change into LGS but as a previously overlooked unusual pattern in the adolescent course of DS. © 2008 Elsevier B.V. All rights reserved.
Introduction Dravet syndrome (DS) is characterized by the occurrence in infancy of long lasting clonic seizures often triggered by fever, and the later appearance of myoclonic seizures (Dravet, 1978). Although seizures tend to become shorter in the second decade, the overall pattern does not change sig-
∗ Corresponding author at: Department of Neuropediatrics, Cen´pilepsies rares, Necker-Enfants Malades Hospital, tre de r´ ef´ erence e APHP, 149 rue de S` evres, 75743 Paris Cedex 15, France. Tel.: +33 144492695; fax: +33 142192692. E-mail addresses: [email protected], [email protected] (R. Nabbout).
nificantly in adolescence. The EEG is normal during the first year of life but an excess of theta rhythms and generalized and multifocal spike and waves (SW) appear progressively. Between 5 and 10 years of age, diffuse theta activity affects about two-third of the patients but generalized spikes and SW often tend to disappear. Focal spikes in central and vertex areas with a diffusion to temporal and posterior areas can be recorded mainly during sleep, and sleep organization usually remains normal (Dravet et al., 2005). Contrasting with its extensive analysis in childhood, the EEG phenotype in adolescence remains poorly described. We encountered an unexpected EEG pattern during the follow-up of adolescent DS patients in the context of stable seizure and cognitive status, and unchanged antiepileptic medication. This EEG pattern raises the issue of a
0920-1211/$ — see front matter © 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.eplepsyres.2008.04.015
An unexpected EEG course in Dravet syndrome Table 1
91
Clinical and molecular genetic characteristic of the patients
Patient
DD
NP
SC
FM
PEB
Age of onset Age First seizure Type Duration Fever association Vaccine association Interictal EEG PMD AED (after 1st seizure) Other reported seizures’ types Myoclonic attacks Myoclonic status GTCS Unilateral motor Atypical absences Partial seizures Tonic (age of onset-end) Fever sensitivity Seizures in clusters Treatment (onset-end) VPA CLB STP TPM CBZ VGB LTG Ketogenic diet Vagal stimulator Language Psychomotor delay SCN1A mutations
7m 12 y
4.5 m 16 y
4m 15 y
3.5 m 17 y
3m 11 y
GTC 20 min Yes No nl nl VPA
GC/GTC 25 min Yes No nl nl VPA
Clonic unilat 20 min Yes No nl nl No
Clonic unilat 20 min Yes Yes nl nl VPA
GC 1 h 30 min Yes Yes nl nl No
Yes No Yes No No No 3—5 y ++ Yes
Yes No Yes No No No 7— +++ Yes
Yes No Yes Yes Yes Yes 3.5—5 y + No
Yes No Yes Yes No Yes No ++ Yes
Yes Yes Yes Yes Yes Yes No ++ Yes
11 m— 2.5 y— 2.5 y— 7 y— No No No No No No Severe c4582—1G > T
5, 5 m— 5 y— 7 y— No No No 5—5, 5 y No No Complex S Moderate c.3880—1G > T
4 m— 14 m— 1.5—3, 5 y§ 4 y— 6—9 m* No No Yes§§ No Simple S Moderate c.3733C > T, p.Arg1245X
4 m— 2 y— 2.5—11 y 11 y— No 5—15 m* 5—6 y* No No No Severe No
4 m— 1 y— 2 y—? 5 y— No No No Yes Yes** No Severe No
GTC = generalized tonic—clonic, GC = generalized clonic, S = sentence, nl = normal, m = month, y = year, PMD = psychomotor development, § = increasing frequency of tonic seizures, * = increasing frequency of myoclonic seizures, §§ = ketogenic diet with short term efficacy but poor tolerability, ** = vagal nerve stimulation with no efficacy % of seizures provoked by fever: + = 25%, ++ = 50%, +++ = 75%
possible change in the type of syndrome affecting a subgroup of patients with DS, or a previously overlooked age-related pattern in DS.
2 years. Five of these eight patients underwent awake and sleep recording with video polygraphy including muscular recording.
Results (Table 1) Patients and methods All patients with DS followed at our institution systematically undergo a search for SCN1A mutation and at least one standard EEG every other year. For the patients who exhibit a clear change in either the clinical or the EEG pattern, we perform sleep recording with concomitant video and electromyography, provided parental acceptance is obtained. We reviewed the serial EEGs of all our patients with DS followed prospectively until the age of at least 10 years. For those with unusual EEG tracings, we reviewed the clinical course and treatment schedule. Of 82 patients followed at our institution for DS, 52 were over 10 years. We identified in eight sporadic frontal biphasic or triphasic spikes, which may be followed by slow waves on the awake tracing. Their age at the time of the study ranged from 11 to 17 years. For each patient, 6—8 tracings had been performed since the age of
Bifrontal spikes and SW were recorded in the waking state, beginning between 7 and 10 years of age. This pattern consisted of bilateral stereotyped bi- or triphasic spikes of high amplitude. Spikes were (i) during awake recording, mainly frontal and eventually asymmetrical, and either isolated or repeated at 1—2 Hz (Fig. 1A) and (ii) during slow sleep, more diffuse although with frontal predominance, and almost continuous (Fig. 1B). In addition, both awake and sleep recordings exhibited high amplitude spikes discharges of 2—3 s at 10 Hz followed by a rhythmic sequence of 5 Hz spikes before spikes became sporadic and irregular, not exceeding 1 Hz. The whole sequence lasted almost 15 s. The high frequency discharge (10—11 Hz) may last up to 8 s with spikes remaining at the same frequency and amplitude
92
R. Nabbout et al.
Figure 1 Frontal triphasic spikes and polyspikes mainly on the left hemisphere followed or not by a slow wave on the awake record (A) and their activation during sleep (B). The EEG background is slow and does not show any physiologic element during sleep.
(Fig. 2). Although spikes exhibited clear activation during sleep, becoming nearly continuous, the overall structure of each spike remained bi- or triphasic as on the awake tracing (Fig. 1). All five patients presented with a typical pattern of Dravet syndrome and SCN1A mutations were found in three of them (Table 1).
The first seizure had been febrile and prolonged, between 3 and 7 months of age. Initial psychomotor development, first interictal EEGs, and brain MRI were normal. All patients exhibited different seizure types: myoclonic (5/5), generalized clonic (5/5), unilateral (3/5), partial (3/5) and atypical absences (2/5). Tonic seizures had affected three children. Two (DD and SC) presented tonic seizures described
Figure 2 Awake EEG with a sequence of high amplitude spikes discharges lasting 2—3 s, abruptly followed by a rhythmic 4 Hz sequence of spikes, then spikes become sporadic and irregular, not exceeding 1 Hz. The whole sequence lasts almost 15 s. Although spikes are mixed with slow waves they do not have the ‘‘classical’’ spike wave aspect.
An unexpected EEG course in Dravet syndrome
93
Figure 3 Two ictal events: tonic contraction involving mostly the face on awakening. Although EMG artefacts prevent adequate EEG analysis a high amplitude bilateral spike is followed by a left hemispheric discharge of slow waves and spike waves, a sequence that cannot be classified, according to the International classification (A). Subclinical burst of slow spikes in sleep from the same patient’s video polygraphy recording, corresponding to no clinical or EMG changes (B).
by parents earlier on between 3 and 5 years of age that had not recurred later when we recorded the presently described EEG pattern. The first had nocturnal seizures not registered but reported by the parents. Tonic seizures in the second were mainly nocturnal and were filmed by the parents; it occurred rarely during awakening but did not provoke falls. The third (NP) had rare tonic seizures mainly on awakening since the age of 7 years. All patients presented with moderate to severe cognitive impairment. Three patients had experienced seizure worsening with inadequate AEDs many years prior to the occurrence of the presently reported EEG pattern. No change had occurred in AED treatment or cognition during the previous 6 months of this EEG pattern finding. Regarding seizures, three patients (DD, SC and FM) were in a stable situation with seizures clustering every 2—3 months. The two others (NP and PEB) had experienced a moderate increase in seizure frequency few months earlier with in one patient (PEB) an episode of myoclonic status 1 month before the first recording of this EEG pattern. The other (NP) had increased GTCS. She still had concomitantly unclassified seizures with tonic features registered on awakening and not associated with this pattern although both occurred independently on the same polygraphy recordings (Fig. 3).
Discussion We report a particular EEG pattern in the adolescent course of DS. It combines frontal biphasic or triphasic spikes, which may be followed by slow waves on the awake tracing by slow
waves when awake that are activated by sleep with 5—10 s subclinical discharges of 8—9 Hz spikes. To our knowledge, this is the first report of such findings in DS. The issue is whether it expresses a particular pattern in a subgroup of patients with DS or a switch to Lennox—Gastaut syndrome (LGS). Although suggestive of LGS, the pattern we report exhibits clear differences: (i) spikes tend to be triphasic instead of biphasic, (ii) subclinical discharges are slower (at 8—9 Hz) than in LGS, (iii) there are no polyspikes in sleep, and (iv) discharges that mimic tonic discharges show no recruiting pattern and no clinical tonic or EMG features on video EEG awaking and sleeping records (Fig. 4) (Beaumanoir and Blume, 2005). Our patients had all clinical and EEG characteristics of DS with SCN1A mutations in three of them. This phenotype is clearly distinct from LGS in which, among other differences, no fever sensitivity is reported and tonic seizures are the hallmark that persists into adult life. In addition, the age of occurrence of this EEG pattern is later than the usual age of onset of LGS (Beaumanoir and Blume, 2005). The evolution of various epilepsy syndromes into LGS is well established. West syndrome is the most frequent preceding condition, but patients have exhibited infantile spasms and the EEG is abnormal from seizure onset (Beaumanoir and Blume, 2005). A pattern reminiscent of LGS may also affect the course of epilepsy with myoclonic—astatic seizures, characterized by the occurrence of cognitive decline, slow spike waves and tonic seizures (Kaminska et al., 1999), a condition earlier known as the myoclonic variant of LGS (Beaumanoir, 1981; Aicardi
94
R. Nabbout et al.
Figure 4 To illustrate the difference between the sleep pattern we describe in adolescent with Dravet syndrome (A) and of an adolescent with Lennox—Gastaut syndrome (B).
and Levy-Gomes, 1988; Roger et al., 1989). This worsening often results from inappropriate treatment, particularly with carbamazepine (Beaumanoir and Blume, 2005). In our series, EEG worsening did not correspond to any AED change and it persisted despite clinical improvement. Three patients had experienced seizure worsening when given inadequate AED treatment, but this had occurred several years prior to the first recording of the presently reported EEG pattern. In addition, patients with this EEG pattern did not differ from the other DS patients followed at our institution. They had the same clinical characteristics and psychomotor course. Their response to AEDs is identical: relative efficacy of valproate and clobazam in association with stiripentol and topiramate, but worsening with carbamazepine and lamotrigine. Genetic findings are also similar to that of our previously reported DS cohort (Nabbout et al., 2003). Nevertheless, the relatively high proportion of patients with sporadic tonic seizures in this small DS series (3/5) is intriguing. Tonic seizures were not mentioned in the first description of the syndrome (Dravet et al., 1992) and are reported as very unusual in the latest report (9 of 105) (Dravet et al., 2005). This is consistent with the finding in our series since 12 patients over 82 presented tonic seizures. This number could however be underestimated since only few patients underwent sleep video EEG recordings. This apparently rare EEG pattern (10—15%: it was suspected in 8 of 52 DS patients aged over 8 years with the full pattern recorded in the five who underwent sleep EEG)
is likely underestimated because (i) it is not always associated with clinical worsening and discharges usually remain without clinical manifestation, (ii) it mainly appears relatively late in the course of the disease (after 7 years), when most patients tend to no longer undergo serial EEGs anymore since the clinical condition appears to be stable, and (iii) it is better identified on sleep EEG, a procedure rarely performed in preadolescents and adolescents with persisting non-surgical epilepsy and major cognitive and behaviour troubles. We could identify no potential mechanism of this unusual finding, and additional data regarding the circumstances of occurrence and course will be necessary in order to formulate valuable hypotheses. Nevertheless, whatever the mechanism, the occurrence of frontal slow spikes and discharges mimicking tonic discharges in the course of DS should not be considered as a change in the type of syndrome but as a characteristic of the disease that requires further investigation, particularly regarding the long term course of sleep EEG. Of special importance might be the risk of switching drug treatment to lamotrigine, a drug registered for LGS but known to exacerbate seizure frequency in patients with DS (Guerrini et al., 1998).
Acknowledgments The authors wish to thank the patients and their families for their participation. They are also grateful to Delphine
An unexpected EEG course in Dravet syndrome Coste-Zeitoun, MD, and St´ ephane Chabrier, MD, for their collaboration.
References Aicardi, J., Levy-Gomes, A., 1988. The Lennox—Gastaut syndrome: clinical and electroencephalographic features. In: Niedermeyer, E., Degen, R. (Eds.), The Lennox—Gastaut Syndrome. Alan R Liss, New York, pp. 25—46. Beaumanoir, A., 1981. Les limites du syndrome de Lennox—Gastaut. Revue d’EEG et de Neurophysiologie 11, 468—473. Beaumanoir, A., Blume, W., 2005. The Lennox—Gastaut syndrome. In: Roger, J., Bureau, M., Dravet, C., Genton, P., Tassinari, C.A., Wolf, P. (Eds.), Epileptic Syndromes in Infancy, Childhood and Adolescence, 4th ed. John Libbey, London, pp. 125—148. ´pilepsies graves de l’enfant. Vie M´ Dravet, C., 1978. Les e edicale 8, 548. Dravet, C., Bureau, M., Guerrini, R., Giraud, N., Roger, J., 1992. Severe myoclonic epilepsy in infancy. In: Roger, J., Bureau, M.,
95 Dravet, C., Dreifuss, F.E., Perret, A., Wolf, P. (Eds.), Epileptic Syndromes in Infancy, Childhood and Adolescence, 2nd ed. John Libbey, London, pp. 75—88. Dravet, C., Bureau, M., Oguni, H., Fukuyama, Y., Cokar, O., 2005. Severe myoclonic epilepsy in infancy (Dravet syndrome). In: Roger, J., Bureau, M., Dravet, C., Genton, P., Tassinari, C.A., Wolf, P. (Eds.), Epileptic Syndromes in Infancy, Childhood and Adolescence, 4th ed. John Libbey, London, pp. 89—114. Guerrini, R., Dravet, C., Genton, P., Belmonte, A., Kaminska, A., Dulac, O., 1998. Lamotrigine and seizure aggravation in severe myoclonic epilepsy. Epilepsia 39, 508—512. Kaminska, A., Ickowicz, A., Plouin, P., Bru, M.F., Dellatolas, G., Dulac, O., 1999. Delineation of cryptogenic Lennox—Gastaut syndrome and myoclonic astatic epilepsy using multiple correspondence analysis. Epilepsy Res. 36, 15—29. Nabbout, R., Gennaro, E., Dalla Bernardina, B., et al., 2003. Spectrum of SCN1A mutations in severe myoclonic epilepsy of infancy. Neurology 60, 1961—1967. Roger, J., Bureau, M., Dravet, C., 1989. The Lennox—Gastaut syndrome. Clev. Clin. J. Med. 56 (S2), 172—177.
journal homepage: www.elsevier.com/locate/epilepsyres
SHORT COMMUNICATION
An unexpected EEG course in Dravet syndrome Rima Nabbout a,b,c,∗, Isabelle Desguerre a, Sandra Sabbagh a, Christel Depienne d, Perrine Plouin e, Olivier Dulac a,b,c, Catherine Chiron a,b,c a
´pilepsies rares, APHP, Necker-Enfants Malades Hospital, Department of Neuropediatrics, Centre de r´ ef´ erence e 149 rue de S` evres, Paris F-75743, France b Inserm, U663, Paris F-75015, France c University Paris Descartes, Paris F-75005, France d Inserm, U679, Hˆ opital de la Piti´ e Salpˆ etri` ere, 47 boulevard de l’Hˆ opital, Paris F-75013, France e APHP, Necker-Enfants Malades Hospital, Clinical Neurophysiology, 149 Rue de S` evres, Paris F-75743, France Received 29 September 2007; received in revised form 20 April 2008; accepted 22 April 2008 Available online 6 June 2008
KEYWORDS Dravet syndrome; Severe myoclonic epilepsy in infancy; EEG; Tonic seizures; Lennox—Gastaut syndrome
Summary A puzzling EEG pattern combining frontal slow bi—tri spikes followed or not by slow waves when awake and activated by sleep with 5—10 s discharges of 8—9 Hz spikes in a minority of adolescents with Dravet syndrome (DS) was recorded in the context of stable seizure and cognitive status, and unchanged antiepileptic medication. Tonic seizures were frequently reported in patients with this EEG pattern (3/5). This EEG pattern could suggest that of Lennox—Gastaut syndrome (LGS) but it exhibits clear differences and therefore should not be considered as a change into LGS but as a previously overlooked unusual pattern in the adolescent course of DS. © 2008 Elsevier B.V. All rights reserved.
Introduction Dravet syndrome (DS) is characterized by the occurrence in infancy of long lasting clonic seizures often triggered by fever, and the later appearance of myoclonic seizures (Dravet, 1978). Although seizures tend to become shorter in the second decade, the overall pattern does not change sig-
∗ Corresponding author at: Department of Neuropediatrics, Cen´pilepsies rares, Necker-Enfants Malades Hospital, tre de r´ ef´ erence e APHP, 149 rue de S` evres, 75743 Paris Cedex 15, France. Tel.: +33 144492695; fax: +33 142192692. E-mail addresses: [email protected], [email protected] (R. Nabbout).
nificantly in adolescence. The EEG is normal during the first year of life but an excess of theta rhythms and generalized and multifocal spike and waves (SW) appear progressively. Between 5 and 10 years of age, diffuse theta activity affects about two-third of the patients but generalized spikes and SW often tend to disappear. Focal spikes in central and vertex areas with a diffusion to temporal and posterior areas can be recorded mainly during sleep, and sleep organization usually remains normal (Dravet et al., 2005). Contrasting with its extensive analysis in childhood, the EEG phenotype in adolescence remains poorly described. We encountered an unexpected EEG pattern during the follow-up of adolescent DS patients in the context of stable seizure and cognitive status, and unchanged antiepileptic medication. This EEG pattern raises the issue of a
0920-1211/$ — see front matter © 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.eplepsyres.2008.04.015
An unexpected EEG course in Dravet syndrome Table 1
91
Clinical and molecular genetic characteristic of the patients
Patient
DD
NP
SC
FM
PEB
Age of onset Age First seizure Type Duration Fever association Vaccine association Interictal EEG PMD AED (after 1st seizure) Other reported seizures’ types Myoclonic attacks Myoclonic status GTCS Unilateral motor Atypical absences Partial seizures Tonic (age of onset-end) Fever sensitivity Seizures in clusters Treatment (onset-end) VPA CLB STP TPM CBZ VGB LTG Ketogenic diet Vagal stimulator Language Psychomotor delay SCN1A mutations
7m 12 y
4.5 m 16 y
4m 15 y
3.5 m 17 y
3m 11 y
GTC 20 min Yes No nl nl VPA
GC/GTC 25 min Yes No nl nl VPA
Clonic unilat 20 min Yes No nl nl No
Clonic unilat 20 min Yes Yes nl nl VPA
GC 1 h 30 min Yes Yes nl nl No
Yes No Yes No No No 3—5 y ++ Yes
Yes No Yes No No No 7— +++ Yes
Yes No Yes Yes Yes Yes 3.5—5 y + No
Yes No Yes Yes No Yes No ++ Yes
Yes Yes Yes Yes Yes Yes No ++ Yes
11 m— 2.5 y— 2.5 y— 7 y— No No No No No No Severe c4582—1G > T
5, 5 m— 5 y— 7 y— No No No 5—5, 5 y No No Complex S Moderate c.3880—1G > T
4 m— 14 m— 1.5—3, 5 y§ 4 y— 6—9 m* No No Yes§§ No Simple S Moderate c.3733C > T, p.Arg1245X
4 m— 2 y— 2.5—11 y 11 y— No 5—15 m* 5—6 y* No No No Severe No
4 m— 1 y— 2 y—? 5 y— No No No Yes Yes** No Severe No
GTC = generalized tonic—clonic, GC = generalized clonic, S = sentence, nl = normal, m = month, y = year, PMD = psychomotor development, § = increasing frequency of tonic seizures, * = increasing frequency of myoclonic seizures, §§ = ketogenic diet with short term efficacy but poor tolerability, ** = vagal nerve stimulation with no efficacy % of seizures provoked by fever: + = 25%, ++ = 50%, +++ = 75%
possible change in the type of syndrome affecting a subgroup of patients with DS, or a previously overlooked age-related pattern in DS.
2 years. Five of these eight patients underwent awake and sleep recording with video polygraphy including muscular recording.
Results (Table 1) Patients and methods All patients with DS followed at our institution systematically undergo a search for SCN1A mutation and at least one standard EEG every other year. For the patients who exhibit a clear change in either the clinical or the EEG pattern, we perform sleep recording with concomitant video and electromyography, provided parental acceptance is obtained. We reviewed the serial EEGs of all our patients with DS followed prospectively until the age of at least 10 years. For those with unusual EEG tracings, we reviewed the clinical course and treatment schedule. Of 82 patients followed at our institution for DS, 52 were over 10 years. We identified in eight sporadic frontal biphasic or triphasic spikes, which may be followed by slow waves on the awake tracing. Their age at the time of the study ranged from 11 to 17 years. For each patient, 6—8 tracings had been performed since the age of
Bifrontal spikes and SW were recorded in the waking state, beginning between 7 and 10 years of age. This pattern consisted of bilateral stereotyped bi- or triphasic spikes of high amplitude. Spikes were (i) during awake recording, mainly frontal and eventually asymmetrical, and either isolated or repeated at 1—2 Hz (Fig. 1A) and (ii) during slow sleep, more diffuse although with frontal predominance, and almost continuous (Fig. 1B). In addition, both awake and sleep recordings exhibited high amplitude spikes discharges of 2—3 s at 10 Hz followed by a rhythmic sequence of 5 Hz spikes before spikes became sporadic and irregular, not exceeding 1 Hz. The whole sequence lasted almost 15 s. The high frequency discharge (10—11 Hz) may last up to 8 s with spikes remaining at the same frequency and amplitude
92
R. Nabbout et al.
Figure 1 Frontal triphasic spikes and polyspikes mainly on the left hemisphere followed or not by a slow wave on the awake record (A) and their activation during sleep (B). The EEG background is slow and does not show any physiologic element during sleep.
(Fig. 2). Although spikes exhibited clear activation during sleep, becoming nearly continuous, the overall structure of each spike remained bi- or triphasic as on the awake tracing (Fig. 1). All five patients presented with a typical pattern of Dravet syndrome and SCN1A mutations were found in three of them (Table 1).
The first seizure had been febrile and prolonged, between 3 and 7 months of age. Initial psychomotor development, first interictal EEGs, and brain MRI were normal. All patients exhibited different seizure types: myoclonic (5/5), generalized clonic (5/5), unilateral (3/5), partial (3/5) and atypical absences (2/5). Tonic seizures had affected three children. Two (DD and SC) presented tonic seizures described
Figure 2 Awake EEG with a sequence of high amplitude spikes discharges lasting 2—3 s, abruptly followed by a rhythmic 4 Hz sequence of spikes, then spikes become sporadic and irregular, not exceeding 1 Hz. The whole sequence lasts almost 15 s. Although spikes are mixed with slow waves they do not have the ‘‘classical’’ spike wave aspect.
An unexpected EEG course in Dravet syndrome
93
Figure 3 Two ictal events: tonic contraction involving mostly the face on awakening. Although EMG artefacts prevent adequate EEG analysis a high amplitude bilateral spike is followed by a left hemispheric discharge of slow waves and spike waves, a sequence that cannot be classified, according to the International classification (A). Subclinical burst of slow spikes in sleep from the same patient’s video polygraphy recording, corresponding to no clinical or EMG changes (B).
by parents earlier on between 3 and 5 years of age that had not recurred later when we recorded the presently described EEG pattern. The first had nocturnal seizures not registered but reported by the parents. Tonic seizures in the second were mainly nocturnal and were filmed by the parents; it occurred rarely during awakening but did not provoke falls. The third (NP) had rare tonic seizures mainly on awakening since the age of 7 years. All patients presented with moderate to severe cognitive impairment. Three patients had experienced seizure worsening with inadequate AEDs many years prior to the occurrence of the presently reported EEG pattern. No change had occurred in AED treatment or cognition during the previous 6 months of this EEG pattern finding. Regarding seizures, three patients (DD, SC and FM) were in a stable situation with seizures clustering every 2—3 months. The two others (NP and PEB) had experienced a moderate increase in seizure frequency few months earlier with in one patient (PEB) an episode of myoclonic status 1 month before the first recording of this EEG pattern. The other (NP) had increased GTCS. She still had concomitantly unclassified seizures with tonic features registered on awakening and not associated with this pattern although both occurred independently on the same polygraphy recordings (Fig. 3).
Discussion We report a particular EEG pattern in the adolescent course of DS. It combines frontal biphasic or triphasic spikes, which may be followed by slow waves on the awake tracing by slow
waves when awake that are activated by sleep with 5—10 s subclinical discharges of 8—9 Hz spikes. To our knowledge, this is the first report of such findings in DS. The issue is whether it expresses a particular pattern in a subgroup of patients with DS or a switch to Lennox—Gastaut syndrome (LGS). Although suggestive of LGS, the pattern we report exhibits clear differences: (i) spikes tend to be triphasic instead of biphasic, (ii) subclinical discharges are slower (at 8—9 Hz) than in LGS, (iii) there are no polyspikes in sleep, and (iv) discharges that mimic tonic discharges show no recruiting pattern and no clinical tonic or EMG features on video EEG awaking and sleeping records (Fig. 4) (Beaumanoir and Blume, 2005). Our patients had all clinical and EEG characteristics of DS with SCN1A mutations in three of them. This phenotype is clearly distinct from LGS in which, among other differences, no fever sensitivity is reported and tonic seizures are the hallmark that persists into adult life. In addition, the age of occurrence of this EEG pattern is later than the usual age of onset of LGS (Beaumanoir and Blume, 2005). The evolution of various epilepsy syndromes into LGS is well established. West syndrome is the most frequent preceding condition, but patients have exhibited infantile spasms and the EEG is abnormal from seizure onset (Beaumanoir and Blume, 2005). A pattern reminiscent of LGS may also affect the course of epilepsy with myoclonic—astatic seizures, characterized by the occurrence of cognitive decline, slow spike waves and tonic seizures (Kaminska et al., 1999), a condition earlier known as the myoclonic variant of LGS (Beaumanoir, 1981; Aicardi
94
R. Nabbout et al.
Figure 4 To illustrate the difference between the sleep pattern we describe in adolescent with Dravet syndrome (A) and of an adolescent with Lennox—Gastaut syndrome (B).
and Levy-Gomes, 1988; Roger et al., 1989). This worsening often results from inappropriate treatment, particularly with carbamazepine (Beaumanoir and Blume, 2005). In our series, EEG worsening did not correspond to any AED change and it persisted despite clinical improvement. Three patients had experienced seizure worsening when given inadequate AED treatment, but this had occurred several years prior to the first recording of the presently reported EEG pattern. In addition, patients with this EEG pattern did not differ from the other DS patients followed at our institution. They had the same clinical characteristics and psychomotor course. Their response to AEDs is identical: relative efficacy of valproate and clobazam in association with stiripentol and topiramate, but worsening with carbamazepine and lamotrigine. Genetic findings are also similar to that of our previously reported DS cohort (Nabbout et al., 2003). Nevertheless, the relatively high proportion of patients with sporadic tonic seizures in this small DS series (3/5) is intriguing. Tonic seizures were not mentioned in the first description of the syndrome (Dravet et al., 1992) and are reported as very unusual in the latest report (9 of 105) (Dravet et al., 2005). This is consistent with the finding in our series since 12 patients over 82 presented tonic seizures. This number could however be underestimated since only few patients underwent sleep video EEG recordings. This apparently rare EEG pattern (10—15%: it was suspected in 8 of 52 DS patients aged over 8 years with the full pattern recorded in the five who underwent sleep EEG)
is likely underestimated because (i) it is not always associated with clinical worsening and discharges usually remain without clinical manifestation, (ii) it mainly appears relatively late in the course of the disease (after 7 years), when most patients tend to no longer undergo serial EEGs anymore since the clinical condition appears to be stable, and (iii) it is better identified on sleep EEG, a procedure rarely performed in preadolescents and adolescents with persisting non-surgical epilepsy and major cognitive and behaviour troubles. We could identify no potential mechanism of this unusual finding, and additional data regarding the circumstances of occurrence and course will be necessary in order to formulate valuable hypotheses. Nevertheless, whatever the mechanism, the occurrence of frontal slow spikes and discharges mimicking tonic discharges in the course of DS should not be considered as a change in the type of syndrome but as a characteristic of the disease that requires further investigation, particularly regarding the long term course of sleep EEG. Of special importance might be the risk of switching drug treatment to lamotrigine, a drug registered for LGS but known to exacerbate seizure frequency in patients with DS (Guerrini et al., 1998).
Acknowledgments The authors wish to thank the patients and their families for their participation. They are also grateful to Delphine
An unexpected EEG course in Dravet syndrome Coste-Zeitoun, MD, and St´ ephane Chabrier, MD, for their collaboration.
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