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Lennox–Gastaut syndrome in adulthood: Clinical and EEG features
Epilepsy Research (2010) 89, 271—277
journal homepage: www.elsevier.com/locate/epilepsyres
Lennox—Gastaut syndrome in adulthood: Clinical and EEG features Edoardo Ferlazzo a,∗, Marina Nikaronova b, Domenico Italiano a, Michelle Bureau c, Charlotte Dravet c,d, Tiziana Calarese c,e, Danielle Viallat c, Margarethe Kölmel b, Placido Bramanti a, Lorenzo De Santi a, Pierre Genton c a
IRCCS Centro Neurolesi ‘‘Bonino-Pulejo’’, Via Palermo, SS 113, C.da Casazza, 98124 Messina, Italy Danish Epilepsy Centre, Dianalund, Denmark c Centre Saint-Paul, Hôpital Henri Gastaut, Marseille, France d Division of Child Neurology and Psychiatry, Policlinco A. Gemelli, Rome, Italy e Division of Child Neurology and Psychiatry, University of Messina, Messina, Italy b
Received 26 November 2009; received in revised form 12 January 2010; accepted 18 January 2010 Available online 10 February 2010
KEYWORDS Lennox—Gastaut syndrome; Adults; Seizures; EEG
∗
Summary Purpose: We performed a retrospective study to investigate seizure, EEG, social and cognitive outcome in adult LGS subjects. Methods: We retrospectively evaluated 27 LGS patients aged 40—59 years. We assessed in particular the evolution of different seizure types and EEG findings, as well as cognitive and social outcome. Results: During the early stages of the disease, all patients presented tonic seizures (TS) during wakefulness and sleep, 20/27 had atypical absences (AA), more rarely other seizure types. EEG showed slow background activity in 21/27 patients, diffuse slow spike-wave discharges (DSSW) during wakefulness in 22/27, and bursts of diffuse fast rhythms (DFR) in sleep in all patients. At last observation, 11 patients only had TS during wakefulness, but all still presented TS during sleep; AA persisted in 6 patients. EEG showed normal BA in 12/27 patients; only 7/27 still presented DSSW. On the contrary, sleep EEG showed the persistence of DFR in all. A moderate to severe cognitive impairment was observed in 26/27 patients. Conclusions: In adult LGS patients TS during sleep remain the major seizure type; moreover, a standard waking EEG may be normal. Thus, polysomnography represents the most important mean of investigation also in adult LGS patients. © 2010 Elsevier B.V. All rights reserved.
Corresponding author. Tel.: +39 090 3656748; fax: +39 090 3656749. E-mail address: [email protected] (E. Ferlazzo).
0920-1211/$ — see front matter © 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.eplepsyres.2010.01.012
272
Introduction Lennox—Gastaut syndrome (LGS) is a severe epileptic encephalopathy beginning between 1 and 8 years of age, with a peak between 3 and 5 years. It represents from 3 to 10% of all childhood epilepsies (Genton and Dravet, 2007). The prevalence of LGS is estimated between 1 and 2% of all epileptic patients (Heiskala, 1997). This clinical entity has classically been defined by the triad of multiple, drug-resistant seizure types, mainly tonic, atonic, and atypical absences (AA), with tonic seizures (TS) during sleep as a constant feature; diffuse slow spike-wave discharges (DSSW) during wakefulness and bursts of diffuse fast rhythms (DFR) at 10—20 Hz during sleep on the EEG; progressive mental deterioration and behaviour disorder, occurring after seizure onset (Genton and Dravet, 2007; Arzimanoglou et al., 2009). LGS can evolve from West syndrome or from unspecified epilepsies, or it may represent the first seizure disorder. LGS usually occurs in patients with various preexisting types of brain damage, including perinatal hypoxic ischemia, antenatal or perinatal vascular accidents, cerebromeningeal infections, brain malformations and migration disorders (most of symptomatic forms), but it may also occur in patients without pre-existing history or signs of brain lesion (Dulac and NGuyen, 1993; Beaumanoir and Blume, 2005; Arzimanoglou et al., 2009). Despite the well-defined clinical and neurophysiologic characteristics of LGS in childhood, longitudinal studies evaluating the electroclinical features in adulthood are still lacking. Authors investigating the long-term (>10 years follow-up) LGS outcome (OllerDaurella, 1973; Roger et al., 1987; Beaumanoir and Blume, 2005), showed that ∼50% of patients retain all typical clinical and EEG features. Both cryptogenic and symptomatic LGS subjects may on the contrary evolve toward symptomatic generalized epilepsies, severe epilepsy with multiple independent spike foci, or localization-related epilepsies (Oguni et al., 1996). The aim of our study is to evaluate the clinical and EEG characteristics of adult subjects with typical LGS. We then tried to retrospectively assess how seizures and EEG features evolved as compared to the early stages of disease.
Methods Patients The population study was composed of consecutive adult patients with typical LGS, followed at the Hôpital Henri Gastaut (Centre Saint-Paul), Marseille, France, and at the Danish Epilepsy Centre, Dianalund, Denmark. All subjects came at our observation from the early stages of disease (first 5—10 years of disease), between 1960 and 1976. The diagnosis of LGS was based on the following criteria: multiple generalized seizure types including TS; DSSW or DFR on the EEG; mental deterioration associated with the onset of epilepsy. All patients were retrospectively evaluated with special regard to the evolution of different seizure types and EEG findings, as well as cognitive and social outcome. Data from each patient were collected with full details of seizure types and frequency, antiepileptic treatment and response to therapy, neuropsychological assessment, ictal and interictal EEG findings during wakefulness and sleep, neuroradiological findings. Information about seizure types and frequency were obtained from epilepsy diaries, relatives’ descriptions and EEG and video-EEG analysis. Additional clinical data collected
E. Ferlazzo et al. included gender, personal antecedents including perinatal asphyxia, head injury, encephalitis and meningitis, age at seizure onset, delay between seizure onset and diagnosis of epilepsy, follow-up duration. Seven clinicians (C.D., P.G., M.B., D.V., E.F., M.N., M.K.), conducted personal interviews with patients (when possible) or their relatives. All patients had undergone several EEG examinations during wakefulness and sleep over the years, with no less than one polysomnography recording including at least surface EMG of deltoid muscles. Neuropsychological evaluation was based on assessment of verbal and performance intelligence by means of Wechsler Intelligence Scale for Children or Wechsler Adult Intelligence Scale, although in most patients cognitive impairment was too severe to allow formal testing.
Statistical analysis Statistical analysis, comparing the presence of TS and other seizure types, as well as EEG features (i.e., DSSW and DFR during wakefulness and sleep), in the early stages of the disease and at last follow-up, was performed by Fisher’s exact test and SPSS version 13.0 running on Mac OSX. Differences were considered statistically significant at p < 0.05.
Results Patients We collected 27 patients (12 M and 15 F) aged from 40 to 59 years (average 45.2 years). Clinical and neuroradiological data are summarized in the Table 1 . Epilepsy aetiology was clearly symptomatic in 8 cases and cryptogenic in 19. Five patients with symptomatic LGS had a previous West syndrome (#7, 10, 13, 18, 25). No patient evolved from Ohtahara syndrome. Age at LGS onset varied between 1.5 and 8 years (mean 3.6 years). The mean age at first evaluation was 9.5 years (range 2—18 years), the mean duration of follow-up was 35.7 years (range 22—47 years).
Seizure evolution During the early stages of disease, all patients had TS during both wakefulness and sleep, 20/27 had AA, 12/27 atonic seizures (AS), 9/27 generalized tonic-clonic seizures (GTCS), 7/27 myoclonic and 3/27 also focal seizures. Moreover, 15 patients experienced episodes of tonic or absence status epilepticus (Graphic 2). At the end of follow-up, TS during wakefulness were present only in 11/27 patients (p < 0.0001), whereas all subjects still had TS during sleep (Graphic 1). AA persisted only in 6/27 patients (p < 0.0001), AS in 4 (p = 0.035). The remaining seizure types were not significantly reduced at last follow-up (Graphic 2). One patient (#22) also had psychogenic seizures. Absence or tonic status epilepticus were not reported to occur in any patient at last follow-up (p < 0.0001) (Graphic 2).
EEG evolution At disease onset, EEG showed slow background activity (BA) in 21/27 subjects, and DSSW during wakefulness in 22/27 patients (Graphic 3). Bursts of DFR during sleep were observed in all patients who underwent sleep EEG (24/27)
Clinical and neuroradiological findings in our LGS series.
Patients (sex) Age at onset (years)
Age at first observ.
Age at last f-up
Neuroimaging
Actual situation
AED in early stages
AED at last f-up
1 (M)
8
18
47
MRI: diffuse cortical atrophy
VPA, CLB, ESM
VPA, FLB
2 (F)
2
10
44
MRI: diffuse cortical atrophy
VPA, PB
VPA, LTG, LEV
3 (F) 4 (F)
3 1,5
9 8
48 40
CT: normal MRI: diffuse cortical atrophy
VPA, CBZ, PB VPA, ESM, CLB
VPA, LEV, CLB LTG, TPM, CLB
5 (F)
4
11
57
CT: normal
VPA, CBZ, CLB
LTG, LEV
6 (F)
1.5
5
47
MRI: cerebellar atrophy
PB, PTH
VPA, LTG, CLB
7 (M)
3
40
MRI: cortical atrophy
VPA, ESM, CZP
VPA, LEV, ESM
8 (M)
7 months West syndrome, LGS age 3 1.5
Severe MR, aggressiveness, institutionalized Severe MR, institutionalized, aggressiveness Moderate MR, lives at home Severe MR, aggressiveness, hyperactivity, institutionalized Severe MR, somnolence, institutionalized Severe MR, ataxia, institutionalized Severe MR, institutionalized
11
41
MRI: normal
VPA, PB
CBZ, TPM, GVG
9 (F)
4
6
40
MRI: left hemisphere atrophy
VPA, CZP
LEV, VPA, OXC
10 (F)
5 months West syndrome, LGS age 4 7 2
15
41
MRI: left occipital polymicrogyria
Severe MR, hyperactivity, institutionalized Severe MR, hyperactivity, aggressiveness, institutionalized Severe MR, hyperactivity, lives at home
VPA, CLB
CBZ, LEV, CLB
17 17
59 45
CT: normal CT: diffuse cortical atrophy
PB, PTH, ESM VPA, ESM
VPA, LTG VPA, LTG, LEV
2
40
MRI: diffuse cortical atrophy
Moderate MR, lives at home Severe MR, aggressiveness; institutionalized Severe MR, autism, institutionalized
VPA, ESM, CLB
LEV, TPM
8 13 12 7
42 42 49 40
MRI: MRI: MRI: MRI:
VPA, CBZ, CZP VPA ETS, VPA, PRM, CBZ VPA, NTZ
LTG, TPM PHT, CZP, PB LTG, PB, VPA, CZP LTG, TPM, CLB
2
46
MRI: normal
Severe MR, lives at home Severe MR, lives at home Severe MR, lives at home Severe MR, aggressiveness, somnolence, lives with parents Severe MR, ataxia, institutionalized
PB, CBZ, CLN, NTZ,
PHT, LTG, PB, CLB
9
47
CT: diffuse atrophy
40 51
MRI: normal CT: posterior cranial fossa cyst
PB, ETS, CBZ, PHT, CLN VPA, CLB, PB ACTH, PB, PHT, ETS, CBZ, VPA
FLB, LTG, VPA, CLB, PB
12 12
Severe MR, aggressiveness, institutionalized Mild MR, married with a son Moderate MR, ataxia, lives in family
11 (M) 12 (M) 13 (F)
14 15 16 17
(M) (M) (F) (M)
18 (F)
4 months West syndrome, LGS age 4 1.5 4 2 4
19 (F)
14 months West Syndrome; LGS age 2 5
20 (F) 21 (M)
6 2
normal normal moderate diffuse atrophy right frontal lesion
Lennox–Gastaut syndrome in adulthood
Table 1
CBZ, LTG VPA, LTG, FLB
273
57 27 (M)
10 5
26 (M)
CBZ: carbamazepine, CLB: clobazam, CZP: clonazepam, ESM: ethosuximide, FLB: felbamate, GVG: vigabatrin, LEV: levetiracetam, LTG: lamotrigine, MR: mental retardation, NZP: nitrazepam, OXZ: oxcarbazepine, PB: phenobarbital, PHT: phenitoin, PRM: primidone, TPM: topiramate, VPA: valproate.
PHT, PB, LTG
LEV, LTG, NZP, PRM
PHT, CBZ, VPA, CLB, NTZ PB, PHT, CBZ Moderate MR, somnolence, institutionalized Moderate MR, lives with parents, sheltered employment MRI: left parietal vascular malformation MRI: cortical diffuse atrophy with ventricular expansion 45
ACTH, PB, PHT, CBZ, VPA CT: normal 43
5 months West Syndrome; LGS age 4 6 25 (F)
2
40 2 24 (F)
8
49 5 1.5 23 (M)
6
CBZ, CLB, VPA VPA, PHT, ACTH, PB
LTG, VPA, CBZ
LTG, CBZ, ESM FB, PHT
VPA, PHT, CLB, PB
Moderate MR, aggressiveness, lives in family Deaf and dumb, right hemiparesis, severe MR, institutionalized Severe MR, aggressiveness, lives in family Severe MR, aggressiveness, somnolence, institutionalized 8 22 (F)
18
40
MRI: corpus callosus agenesis, diffuse cortical atrophy. MRI: left hemisphere atrophy (post meningo-encephalitis) MRI: diffuse cortical atrophy
AED in early stages Actual situation Neuroimaging Age at last f-up Age at first observ. Age at onset (years) Patients (sex)
Table 1 (Continued )
PHT, PB, CLB
E. Ferlazzo et al.
AED at last f-up
274
(Graphic 3 and Fig. 1). Only 8 patients, mostly symptomatic, presented focal epileptic abnormalities. At last observation, BA was slow only in 15/27 patients while it was normal in 12 (p = 0.014) (see Fig. 1). Moreover, only 7/27 patients still presented DSSW during wakefulness (p < 0.0001) whereas all patients still presented DFR during sleep (Graphic 3 and Fig. 1).
Cognitive outcome As to mental status, 26/27 patients presented moderate to severe cognitive impairment at last observation; 12 patients also presented behaviour disorders (mostly hyperactivity and aggressiveness). Fifteen patients were institutionalized, while 12 lived with their family. One patient only (#20) had mild cognitive impairment and was married with a child; she only presented rare TS during sleep.
Discussion In this study we evaluated the electroclinical features of adult patients with typical LGS, who had been followed in our epilepsy centres for an average period of 35 years. Previous reports evaluating seizure outcome in LGS are difficult to compare since inclusion criteria were often different. Longitudinal studies (Ohtsuka et al., 1990; Ignatowicz et al., 1994; Oguni et al., 1996) showed that ∼2/3 of LGS subjects have an unfavourable outcome with seizure persistence over the years. In a >10-year follow-up study on 102 LGS patients, Yagi (1996) found that TS, especially during sleep, were the most resistant seizure type and persisted in nearly all patients; in addition, 20% of his patients also had AA or astatic seizures and only 8% were seizure-free. Our data furthermore confirm the evolution pattern of seizures in LGS patients during a longer follow-up. Indeed, in our series, daytime seizures (TS, AA and AS) significantly reduced over the years, while TS persisted mainly during sleep. Our findings have relevant clinical significance. Since daytime TS and AS may disappear over the years, adult LGS subjects may not retain the same tendency to fall as compared to child or youth, thus making heavy or specific (i.e., rufinamide, callosotomy, etc.) treatments to prevent drop attacks, questionable or unnecessary in some patients. Several studies (Ohtsuka et al., 1990; Yagi, 1996; Oguni et al., 1996; Rantala and Putkonen, 1999; Goldsmith et al., 2000) showed no significant difference between cryptogenic and symptomatic cases in terms of evolution of seizure types or frequency, EEG findings, or response to treatment. Symptomatic LGS patients tend to have more seizure types, but cryptogenic aetiology did not decrease the risk of poor outcome (Rantala and Putkonen, 1999; Goldsmith et al., 2000). Our results are in accordance with those findings. Indeed, no prognostic difference among symptomatic or cryptogenic LGS patients was present in our series. Furthermore, 3/8 symptomatic patients presented focal seizures or EEG abnormalities. Previous reports have attempted to analyze the evolution of EEG abnormalities in LGS over time. In Yagi’s LGS series (1996), DSSW during waking disappeared first, but multiple spike-and-wave complexes or DFR during sleep remained
Lennox–Gastaut syndrome in adulthood
275
Figure 1 Patient 5, standard EEG and polysomnographic recordings performed at the age of 48 years. Clinically, she presented only TS during sleep. In the early stages of the disease she experienced diurnal and nocturnal TS, GTCS, atonic seizures, rare tonic status epilepitcus with waking EEG showing slow background activity at 7 Hz along with frequent DSSW. (A) Standard waking EEG was normal [background activity in the alpha range, bilateral, symmetric, predominant over the posterior head regions, well reacting to eye opening (blue line)]. (B) Polysomnographic recordings including EEG, EMG 1: right deltoid, EMG 2: left deltoid, PNO: pneumogram. Short-lasting TS detected during the first stage of non-REM sleep, characterized by mild abduction of arms, head flexion, apnoea. Ictal EEG showed diffuse polyspikes gradually increasing in amplitude and frequency. Note the mild bilateral muscular contraction recorded over EMG 1 and 2, and apnoea over PNO. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of the article.)
for several years. Finally, multiple spike-and-wave complexes during sleep were seen before the disappearance of all epileptic EEG discharges in patients in whom seizures improved. In a 10-year follow-up study on 38 LGS patients, Ogawa et al. (2001) found that frequent epileptiform discharges persisted in 39% of patients, correlating with a poor
seizure outcome. Hughes and Patil (2002) evaluated the EEG evolution in 64 LGS patients with a follow-up >16 years. The disappearance of DSSW usually occurred after the age of 16 years, while in 95% of patients BA gradually slowed and focal discharges remained the only interictal epileptic EEG abnormalities.
276
E. Ferlazzo et al.
Graphic 1 Evolution of tonic seizures during wakefulness and sleep in our LGS patients.
Graphic 2
Evolution of other seizure types.
In our patients, the evolution of EEG findings was characterized by the normalization of BA in 44% as well as a clear reduction of epileptiform discharges during wakefulness in 74% over the years. Conversely, DFR during sleep, usually associated with TS, were retained in all patients in adulthood. This aspect is crucial when evaluating adult LGS patients. Indeed, a standard EEG may be normal and thus, not significant of the real evolution of patients’ seizure disorder. Hence, only polysomnography, including EEG, EMG and pneumogram (PNG) (essential to detect TS, at times manifesting only with apnoea) must be considered the main neurophysiologic investigation to correctly assess adult LGS patients (see Fig. 1). The cognitive outcome of LGS is generally poor (Genton and Dravet, 2007). Literature data report that severe men-
Graphic 3
Evolution of EEG epileptiform abnormalities.
tal retardation occurs in 43% of patients with cryptogenic LGS and in 76% with symptomatic LGS (Oguni et al., 1996). Nevertheless, excluding patients already presenting mental retardation at the onset of LGS, only 8% of 107 LGS subjects did not display mental retardation after a ≥3 years FU (Goldsmith et al., 2000). The presence of AA at the onset of the disease and the persistence of frequent epileptiform discharges at follow-up, were reported to represent strong predictors of both poor cognitive and seizure outcome (Ogawa et al., 2001). Among the102 patients with LGS followed by Yagi (1996), 12 worked normally, 36 had part-time or sheltered job, while 54 were under home care or institutionalized at the end of follow-up. In our series, 26/27 patients at the end of follow-up had moderate to severe cognitive impairment, and 52% (14/27) behaviour disorder. Since we performed a retrospective study and neuropsychological evaluation was not performed periodically, we could not evaluate how cognitive impairment progressed over the years. Moreover, we did not find any correlation between seizure and cognitive outcome and LGS aetiology. To explain the poor cognitive outcome of LGS subjects, Filippini et al. (2006) hypothesized that a genetic predisposition causes both the clinical manifestations and the mental retardation. Alternatively, prolonged exposure to potentially harmful abnormal electroclinical activity before the appearance of clinical seizures could interfere with normal development during a critical period of cerebral development; subsequent AED treatment, although effective, is unable to modify an already established cerebral damage. A more favourable cognitive outcome is more likely to occur in patients with the later age at LGS onset, probably because the brain has already progressed beyond certain critical developmental stages such as synaptogenesis and apoptosis, and seizures have a less detrimental impact on intellectual development (Goldsmith et al., 2000).
Limits of the study The main limits are constituted by the small size of the sample, the retrospective design of the study and the selection bias. Indeed, we only included subjects who retained all clinical and EEG features of LGS over the years, whereas subjects evolving towards different forms of epilepsy were not evaluated. Moreover, it is not possible to exclude that subjects with a mild form of LGS (i.e., seizure-free patients or those with rare or subtle seizures) were lost at followup. Hence, our results may not be generalizable to all LGS patients. In conclusion, in adult LGS patients: • TS, especially during sleep, remain the major seizure type; • a gradual normalization of BA and reduction of epileptiform abnormalities during wakefulness can be observed over time, while DFR always persist during sleep; • since the awake EEG may be normal, polysomnography (EEG, EMG, PNG) is mandatory for the detection of DFR and subtle TS; • EEG and seizure improvement do not correlate with cognitive outcome, which remains poor in most patients.
Lennox–Gastaut syndrome in adulthood
Acknowledgement We are grateful to Antonina Donato, IRCCS Centro Neurolesi ‘‘Bonino-Pulejo’’, Messina, Italy, for editing the manuscript.
References Arzimanoglou, A., French, J., Blume, W.T., et al., 2009. Lennox—Gastaut syndrome: a consensus approach on diagnosis, assessment, management, and trial methodology. Lancet Neurol. 8, 82—93. Beaumanoir, A., Blume, W., 2005. The Lennox—Gastaut syndrome. In: Roger, J., Bureau, M., Dravet, C., et, al. (Eds.), Epileptic Syndromes in Infancy, Childhood and Adolescence, 4th ed. John Libbey, London, pp. 25—148. Dulac, O., NGuyen, T., 1993. The Lennox—Gastaut syndrome. Epilepsia 34 (Suppl. 47), S7—S17. Filippini, M., Boni, A., Dazzani, G., et al., 2006. Neuropsychological findings: myoclonic astatic epilepsy (MAE) and Lennox—Gastaut syndrome (LGS). Epilepsia 47 (Suppl. 2), S56—S59. Genton, P., Dravet, C., 2007. Lennox—Gastaut syndrome. In: Engel, J.R., Pedley, T.A. (Eds.), Epilepsy. A Comprehensive Textbook. Wolters Kluver, Lippincott Williams and Wilkins, Philadelphia, pp. 2417—2427. Goldsmith, I.L., Zupanc, M.L., Buchhalter, J.R., 2000. Long-term seizure outcome in 74 patients with Lennox—Gastaut syndrome: effects of incorporating MRI head imaging in defining the cryptogenic subgroup. Epilepsia 41, 395—399.
277 Heiskala, H., 1997. Community-based study of Lennox—Gastaut syndrome. Epilepsia 38, 526—531. Hughes, J.R., Patil, V.K., 2002. Long-term electro-clinical changes in the Lennox—Gastaut syndrome before, during, and after the slow spike-wave pattern. Clin. Electroencephalogr. 33, 1—7. Ignatowicz, R., Michalowicz, R., Ignatowiczowa, L., et al., 1994. Lennox—Gastaut syndrome-clinical course and therapy. Polski Tygoclnik Lekarski 49, 96—98. Ogawa, K., Kanemoto, K., Ishii, Y., et al., 2001. Long-term followup study of Lennox—Gastaut syndrome in patients with severe motor and intellectual disabilities: with special reference to the problem of dysphagia. Seizure 10, 197—202. Oguni, H., Hayashi, K., Osawa, M., 1996. Long-term prognosis of Lennox—Gastaut syndrome. Epilepsia 37 (Suppl. 3), S44—S47. Ohtsuka, Y., Amano, R., Mizukawa, M., et al., 1990. Long-term prognosis of the Lennox—Gastaut syndrome. Jpn. J. Psychiatry Neurol. 44, 257—264. Oller-Daurella, L., 1973. Evolution et prognostic du syndrome de Lennox—Gastaut syndrome. In: Lugaresi, E., Pazzaglia, P., Tassinari, C. (Eds.), Evolution and Prognosis of Epilepsies. Aulo Gaggi, Bologna, pp. 155—164. Rantala, H., Putkonen, T., 1999. Occurrence, outcome and prognostic factors of infantile spasms and Lennox—Gastaut syndrome. Epilepsia 40, 286—289. Roger, J., Rémy, C., Bureau, M., et al., 1987. Le syndrome de Lennox—Gastaut de l’adulte. Rev. Neurol. 143, 401—405. Yagi, K., 1996. Evolution of Lennox—Gastaut syndrome: a long-term longitudinal study. Epilepsia 37 (Suppl. 3), S48—S51.
journal homepage: www.elsevier.com/locate/epilepsyres
Lennox—Gastaut syndrome in adulthood: Clinical and EEG features Edoardo Ferlazzo a,∗, Marina Nikaronova b, Domenico Italiano a, Michelle Bureau c, Charlotte Dravet c,d, Tiziana Calarese c,e, Danielle Viallat c, Margarethe Kölmel b, Placido Bramanti a, Lorenzo De Santi a, Pierre Genton c a
IRCCS Centro Neurolesi ‘‘Bonino-Pulejo’’, Via Palermo, SS 113, C.da Casazza, 98124 Messina, Italy Danish Epilepsy Centre, Dianalund, Denmark c Centre Saint-Paul, Hôpital Henri Gastaut, Marseille, France d Division of Child Neurology and Psychiatry, Policlinco A. Gemelli, Rome, Italy e Division of Child Neurology and Psychiatry, University of Messina, Messina, Italy b
Received 26 November 2009; received in revised form 12 January 2010; accepted 18 January 2010 Available online 10 February 2010
KEYWORDS Lennox—Gastaut syndrome; Adults; Seizures; EEG
∗
Summary Purpose: We performed a retrospective study to investigate seizure, EEG, social and cognitive outcome in adult LGS subjects. Methods: We retrospectively evaluated 27 LGS patients aged 40—59 years. We assessed in particular the evolution of different seizure types and EEG findings, as well as cognitive and social outcome. Results: During the early stages of the disease, all patients presented tonic seizures (TS) during wakefulness and sleep, 20/27 had atypical absences (AA), more rarely other seizure types. EEG showed slow background activity in 21/27 patients, diffuse slow spike-wave discharges (DSSW) during wakefulness in 22/27, and bursts of diffuse fast rhythms (DFR) in sleep in all patients. At last observation, 11 patients only had TS during wakefulness, but all still presented TS during sleep; AA persisted in 6 patients. EEG showed normal BA in 12/27 patients; only 7/27 still presented DSSW. On the contrary, sleep EEG showed the persistence of DFR in all. A moderate to severe cognitive impairment was observed in 26/27 patients. Conclusions: In adult LGS patients TS during sleep remain the major seizure type; moreover, a standard waking EEG may be normal. Thus, polysomnography represents the most important mean of investigation also in adult LGS patients. © 2010 Elsevier B.V. All rights reserved.
Corresponding author. Tel.: +39 090 3656748; fax: +39 090 3656749. E-mail address: [email protected] (E. Ferlazzo).
0920-1211/$ — see front matter © 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.eplepsyres.2010.01.012
272
Introduction Lennox—Gastaut syndrome (LGS) is a severe epileptic encephalopathy beginning between 1 and 8 years of age, with a peak between 3 and 5 years. It represents from 3 to 10% of all childhood epilepsies (Genton and Dravet, 2007). The prevalence of LGS is estimated between 1 and 2% of all epileptic patients (Heiskala, 1997). This clinical entity has classically been defined by the triad of multiple, drug-resistant seizure types, mainly tonic, atonic, and atypical absences (AA), with tonic seizures (TS) during sleep as a constant feature; diffuse slow spike-wave discharges (DSSW) during wakefulness and bursts of diffuse fast rhythms (DFR) at 10—20 Hz during sleep on the EEG; progressive mental deterioration and behaviour disorder, occurring after seizure onset (Genton and Dravet, 2007; Arzimanoglou et al., 2009). LGS can evolve from West syndrome or from unspecified epilepsies, or it may represent the first seizure disorder. LGS usually occurs in patients with various preexisting types of brain damage, including perinatal hypoxic ischemia, antenatal or perinatal vascular accidents, cerebromeningeal infections, brain malformations and migration disorders (most of symptomatic forms), but it may also occur in patients without pre-existing history or signs of brain lesion (Dulac and NGuyen, 1993; Beaumanoir and Blume, 2005; Arzimanoglou et al., 2009). Despite the well-defined clinical and neurophysiologic characteristics of LGS in childhood, longitudinal studies evaluating the electroclinical features in adulthood are still lacking. Authors investigating the long-term (>10 years follow-up) LGS outcome (OllerDaurella, 1973; Roger et al., 1987; Beaumanoir and Blume, 2005), showed that ∼50% of patients retain all typical clinical and EEG features. Both cryptogenic and symptomatic LGS subjects may on the contrary evolve toward symptomatic generalized epilepsies, severe epilepsy with multiple independent spike foci, or localization-related epilepsies (Oguni et al., 1996). The aim of our study is to evaluate the clinical and EEG characteristics of adult subjects with typical LGS. We then tried to retrospectively assess how seizures and EEG features evolved as compared to the early stages of disease.
Methods Patients The population study was composed of consecutive adult patients with typical LGS, followed at the Hôpital Henri Gastaut (Centre Saint-Paul), Marseille, France, and at the Danish Epilepsy Centre, Dianalund, Denmark. All subjects came at our observation from the early stages of disease (first 5—10 years of disease), between 1960 and 1976. The diagnosis of LGS was based on the following criteria: multiple generalized seizure types including TS; DSSW or DFR on the EEG; mental deterioration associated with the onset of epilepsy. All patients were retrospectively evaluated with special regard to the evolution of different seizure types and EEG findings, as well as cognitive and social outcome. Data from each patient were collected with full details of seizure types and frequency, antiepileptic treatment and response to therapy, neuropsychological assessment, ictal and interictal EEG findings during wakefulness and sleep, neuroradiological findings. Information about seizure types and frequency were obtained from epilepsy diaries, relatives’ descriptions and EEG and video-EEG analysis. Additional clinical data collected
E. Ferlazzo et al. included gender, personal antecedents including perinatal asphyxia, head injury, encephalitis and meningitis, age at seizure onset, delay between seizure onset and diagnosis of epilepsy, follow-up duration. Seven clinicians (C.D., P.G., M.B., D.V., E.F., M.N., M.K.), conducted personal interviews with patients (when possible) or their relatives. All patients had undergone several EEG examinations during wakefulness and sleep over the years, with no less than one polysomnography recording including at least surface EMG of deltoid muscles. Neuropsychological evaluation was based on assessment of verbal and performance intelligence by means of Wechsler Intelligence Scale for Children or Wechsler Adult Intelligence Scale, although in most patients cognitive impairment was too severe to allow formal testing.
Statistical analysis Statistical analysis, comparing the presence of TS and other seizure types, as well as EEG features (i.e., DSSW and DFR during wakefulness and sleep), in the early stages of the disease and at last follow-up, was performed by Fisher’s exact test and SPSS version 13.0 running on Mac OSX. Differences were considered statistically significant at p < 0.05.
Results Patients We collected 27 patients (12 M and 15 F) aged from 40 to 59 years (average 45.2 years). Clinical and neuroradiological data are summarized in the Table 1 . Epilepsy aetiology was clearly symptomatic in 8 cases and cryptogenic in 19. Five patients with symptomatic LGS had a previous West syndrome (#7, 10, 13, 18, 25). No patient evolved from Ohtahara syndrome. Age at LGS onset varied between 1.5 and 8 years (mean 3.6 years). The mean age at first evaluation was 9.5 years (range 2—18 years), the mean duration of follow-up was 35.7 years (range 22—47 years).
Seizure evolution During the early stages of disease, all patients had TS during both wakefulness and sleep, 20/27 had AA, 12/27 atonic seizures (AS), 9/27 generalized tonic-clonic seizures (GTCS), 7/27 myoclonic and 3/27 also focal seizures. Moreover, 15 patients experienced episodes of tonic or absence status epilepticus (Graphic 2). At the end of follow-up, TS during wakefulness were present only in 11/27 patients (p < 0.0001), whereas all subjects still had TS during sleep (Graphic 1). AA persisted only in 6/27 patients (p < 0.0001), AS in 4 (p = 0.035). The remaining seizure types were not significantly reduced at last follow-up (Graphic 2). One patient (#22) also had psychogenic seizures. Absence or tonic status epilepticus were not reported to occur in any patient at last follow-up (p < 0.0001) (Graphic 2).
EEG evolution At disease onset, EEG showed slow background activity (BA) in 21/27 subjects, and DSSW during wakefulness in 22/27 patients (Graphic 3). Bursts of DFR during sleep were observed in all patients who underwent sleep EEG (24/27)
Clinical and neuroradiological findings in our LGS series.
Patients (sex) Age at onset (years)
Age at first observ.
Age at last f-up
Neuroimaging
Actual situation
AED in early stages
AED at last f-up
1 (M)
8
18
47
MRI: diffuse cortical atrophy
VPA, CLB, ESM
VPA, FLB
2 (F)
2
10
44
MRI: diffuse cortical atrophy
VPA, PB
VPA, LTG, LEV
3 (F) 4 (F)
3 1,5
9 8
48 40
CT: normal MRI: diffuse cortical atrophy
VPA, CBZ, PB VPA, ESM, CLB
VPA, LEV, CLB LTG, TPM, CLB
5 (F)
4
11
57
CT: normal
VPA, CBZ, CLB
LTG, LEV
6 (F)
1.5
5
47
MRI: cerebellar atrophy
PB, PTH
VPA, LTG, CLB
7 (M)
3
40
MRI: cortical atrophy
VPA, ESM, CZP
VPA, LEV, ESM
8 (M)
7 months West syndrome, LGS age 3 1.5
Severe MR, aggressiveness, institutionalized Severe MR, institutionalized, aggressiveness Moderate MR, lives at home Severe MR, aggressiveness, hyperactivity, institutionalized Severe MR, somnolence, institutionalized Severe MR, ataxia, institutionalized Severe MR, institutionalized
11
41
MRI: normal
VPA, PB
CBZ, TPM, GVG
9 (F)
4
6
40
MRI: left hemisphere atrophy
VPA, CZP
LEV, VPA, OXC
10 (F)
5 months West syndrome, LGS age 4 7 2
15
41
MRI: left occipital polymicrogyria
Severe MR, hyperactivity, institutionalized Severe MR, hyperactivity, aggressiveness, institutionalized Severe MR, hyperactivity, lives at home
VPA, CLB
CBZ, LEV, CLB
17 17
59 45
CT: normal CT: diffuse cortical atrophy
PB, PTH, ESM VPA, ESM
VPA, LTG VPA, LTG, LEV
2
40
MRI: diffuse cortical atrophy
Moderate MR, lives at home Severe MR, aggressiveness; institutionalized Severe MR, autism, institutionalized
VPA, ESM, CLB
LEV, TPM
8 13 12 7
42 42 49 40
MRI: MRI: MRI: MRI:
VPA, CBZ, CZP VPA ETS, VPA, PRM, CBZ VPA, NTZ
LTG, TPM PHT, CZP, PB LTG, PB, VPA, CZP LTG, TPM, CLB
2
46
MRI: normal
Severe MR, lives at home Severe MR, lives at home Severe MR, lives at home Severe MR, aggressiveness, somnolence, lives with parents Severe MR, ataxia, institutionalized
PB, CBZ, CLN, NTZ,
PHT, LTG, PB, CLB
9
47
CT: diffuse atrophy
40 51
MRI: normal CT: posterior cranial fossa cyst
PB, ETS, CBZ, PHT, CLN VPA, CLB, PB ACTH, PB, PHT, ETS, CBZ, VPA
FLB, LTG, VPA, CLB, PB
12 12
Severe MR, aggressiveness, institutionalized Mild MR, married with a son Moderate MR, ataxia, lives in family
11 (M) 12 (M) 13 (F)
14 15 16 17
(M) (M) (F) (M)
18 (F)
4 months West syndrome, LGS age 4 1.5 4 2 4
19 (F)
14 months West Syndrome; LGS age 2 5
20 (F) 21 (M)
6 2
normal normal moderate diffuse atrophy right frontal lesion
Lennox–Gastaut syndrome in adulthood
Table 1
CBZ, LTG VPA, LTG, FLB
273
57 27 (M)
10 5
26 (M)
CBZ: carbamazepine, CLB: clobazam, CZP: clonazepam, ESM: ethosuximide, FLB: felbamate, GVG: vigabatrin, LEV: levetiracetam, LTG: lamotrigine, MR: mental retardation, NZP: nitrazepam, OXZ: oxcarbazepine, PB: phenobarbital, PHT: phenitoin, PRM: primidone, TPM: topiramate, VPA: valproate.
PHT, PB, LTG
LEV, LTG, NZP, PRM
PHT, CBZ, VPA, CLB, NTZ PB, PHT, CBZ Moderate MR, somnolence, institutionalized Moderate MR, lives with parents, sheltered employment MRI: left parietal vascular malformation MRI: cortical diffuse atrophy with ventricular expansion 45
ACTH, PB, PHT, CBZ, VPA CT: normal 43
5 months West Syndrome; LGS age 4 6 25 (F)
2
40 2 24 (F)
8
49 5 1.5 23 (M)
6
CBZ, CLB, VPA VPA, PHT, ACTH, PB
LTG, VPA, CBZ
LTG, CBZ, ESM FB, PHT
VPA, PHT, CLB, PB
Moderate MR, aggressiveness, lives in family Deaf and dumb, right hemiparesis, severe MR, institutionalized Severe MR, aggressiveness, lives in family Severe MR, aggressiveness, somnolence, institutionalized 8 22 (F)
18
40
MRI: corpus callosus agenesis, diffuse cortical atrophy. MRI: left hemisphere atrophy (post meningo-encephalitis) MRI: diffuse cortical atrophy
AED in early stages Actual situation Neuroimaging Age at last f-up Age at first observ. Age at onset (years) Patients (sex)
Table 1 (Continued )
PHT, PB, CLB
E. Ferlazzo et al.
AED at last f-up
274
(Graphic 3 and Fig. 1). Only 8 patients, mostly symptomatic, presented focal epileptic abnormalities. At last observation, BA was slow only in 15/27 patients while it was normal in 12 (p = 0.014) (see Fig. 1). Moreover, only 7/27 patients still presented DSSW during wakefulness (p < 0.0001) whereas all patients still presented DFR during sleep (Graphic 3 and Fig. 1).
Cognitive outcome As to mental status, 26/27 patients presented moderate to severe cognitive impairment at last observation; 12 patients also presented behaviour disorders (mostly hyperactivity and aggressiveness). Fifteen patients were institutionalized, while 12 lived with their family. One patient only (#20) had mild cognitive impairment and was married with a child; she only presented rare TS during sleep.
Discussion In this study we evaluated the electroclinical features of adult patients with typical LGS, who had been followed in our epilepsy centres for an average period of 35 years. Previous reports evaluating seizure outcome in LGS are difficult to compare since inclusion criteria were often different. Longitudinal studies (Ohtsuka et al., 1990; Ignatowicz et al., 1994; Oguni et al., 1996) showed that ∼2/3 of LGS subjects have an unfavourable outcome with seizure persistence over the years. In a >10-year follow-up study on 102 LGS patients, Yagi (1996) found that TS, especially during sleep, were the most resistant seizure type and persisted in nearly all patients; in addition, 20% of his patients also had AA or astatic seizures and only 8% were seizure-free. Our data furthermore confirm the evolution pattern of seizures in LGS patients during a longer follow-up. Indeed, in our series, daytime seizures (TS, AA and AS) significantly reduced over the years, while TS persisted mainly during sleep. Our findings have relevant clinical significance. Since daytime TS and AS may disappear over the years, adult LGS subjects may not retain the same tendency to fall as compared to child or youth, thus making heavy or specific (i.e., rufinamide, callosotomy, etc.) treatments to prevent drop attacks, questionable or unnecessary in some patients. Several studies (Ohtsuka et al., 1990; Yagi, 1996; Oguni et al., 1996; Rantala and Putkonen, 1999; Goldsmith et al., 2000) showed no significant difference between cryptogenic and symptomatic cases in terms of evolution of seizure types or frequency, EEG findings, or response to treatment. Symptomatic LGS patients tend to have more seizure types, but cryptogenic aetiology did not decrease the risk of poor outcome (Rantala and Putkonen, 1999; Goldsmith et al., 2000). Our results are in accordance with those findings. Indeed, no prognostic difference among symptomatic or cryptogenic LGS patients was present in our series. Furthermore, 3/8 symptomatic patients presented focal seizures or EEG abnormalities. Previous reports have attempted to analyze the evolution of EEG abnormalities in LGS over time. In Yagi’s LGS series (1996), DSSW during waking disappeared first, but multiple spike-and-wave complexes or DFR during sleep remained
Lennox–Gastaut syndrome in adulthood
275
Figure 1 Patient 5, standard EEG and polysomnographic recordings performed at the age of 48 years. Clinically, she presented only TS during sleep. In the early stages of the disease she experienced diurnal and nocturnal TS, GTCS, atonic seizures, rare tonic status epilepitcus with waking EEG showing slow background activity at 7 Hz along with frequent DSSW. (A) Standard waking EEG was normal [background activity in the alpha range, bilateral, symmetric, predominant over the posterior head regions, well reacting to eye opening (blue line)]. (B) Polysomnographic recordings including EEG, EMG 1: right deltoid, EMG 2: left deltoid, PNO: pneumogram. Short-lasting TS detected during the first stage of non-REM sleep, characterized by mild abduction of arms, head flexion, apnoea. Ictal EEG showed diffuse polyspikes gradually increasing in amplitude and frequency. Note the mild bilateral muscular contraction recorded over EMG 1 and 2, and apnoea over PNO. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of the article.)
for several years. Finally, multiple spike-and-wave complexes during sleep were seen before the disappearance of all epileptic EEG discharges in patients in whom seizures improved. In a 10-year follow-up study on 38 LGS patients, Ogawa et al. (2001) found that frequent epileptiform discharges persisted in 39% of patients, correlating with a poor
seizure outcome. Hughes and Patil (2002) evaluated the EEG evolution in 64 LGS patients with a follow-up >16 years. The disappearance of DSSW usually occurred after the age of 16 years, while in 95% of patients BA gradually slowed and focal discharges remained the only interictal epileptic EEG abnormalities.
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E. Ferlazzo et al.
Graphic 1 Evolution of tonic seizures during wakefulness and sleep in our LGS patients.
Graphic 2
Evolution of other seizure types.
In our patients, the evolution of EEG findings was characterized by the normalization of BA in 44% as well as a clear reduction of epileptiform discharges during wakefulness in 74% over the years. Conversely, DFR during sleep, usually associated with TS, were retained in all patients in adulthood. This aspect is crucial when evaluating adult LGS patients. Indeed, a standard EEG may be normal and thus, not significant of the real evolution of patients’ seizure disorder. Hence, only polysomnography, including EEG, EMG and pneumogram (PNG) (essential to detect TS, at times manifesting only with apnoea) must be considered the main neurophysiologic investigation to correctly assess adult LGS patients (see Fig. 1). The cognitive outcome of LGS is generally poor (Genton and Dravet, 2007). Literature data report that severe men-
Graphic 3
Evolution of EEG epileptiform abnormalities.
tal retardation occurs in 43% of patients with cryptogenic LGS and in 76% with symptomatic LGS (Oguni et al., 1996). Nevertheless, excluding patients already presenting mental retardation at the onset of LGS, only 8% of 107 LGS subjects did not display mental retardation after a ≥3 years FU (Goldsmith et al., 2000). The presence of AA at the onset of the disease and the persistence of frequent epileptiform discharges at follow-up, were reported to represent strong predictors of both poor cognitive and seizure outcome (Ogawa et al., 2001). Among the102 patients with LGS followed by Yagi (1996), 12 worked normally, 36 had part-time or sheltered job, while 54 were under home care or institutionalized at the end of follow-up. In our series, 26/27 patients at the end of follow-up had moderate to severe cognitive impairment, and 52% (14/27) behaviour disorder. Since we performed a retrospective study and neuropsychological evaluation was not performed periodically, we could not evaluate how cognitive impairment progressed over the years. Moreover, we did not find any correlation between seizure and cognitive outcome and LGS aetiology. To explain the poor cognitive outcome of LGS subjects, Filippini et al. (2006) hypothesized that a genetic predisposition causes both the clinical manifestations and the mental retardation. Alternatively, prolonged exposure to potentially harmful abnormal electroclinical activity before the appearance of clinical seizures could interfere with normal development during a critical period of cerebral development; subsequent AED treatment, although effective, is unable to modify an already established cerebral damage. A more favourable cognitive outcome is more likely to occur in patients with the later age at LGS onset, probably because the brain has already progressed beyond certain critical developmental stages such as synaptogenesis and apoptosis, and seizures have a less detrimental impact on intellectual development (Goldsmith et al., 2000).
Limits of the study The main limits are constituted by the small size of the sample, the retrospective design of the study and the selection bias. Indeed, we only included subjects who retained all clinical and EEG features of LGS over the years, whereas subjects evolving towards different forms of epilepsy were not evaluated. Moreover, it is not possible to exclude that subjects with a mild form of LGS (i.e., seizure-free patients or those with rare or subtle seizures) were lost at followup. Hence, our results may not be generalizable to all LGS patients. In conclusion, in adult LGS patients: • TS, especially during sleep, remain the major seizure type; • a gradual normalization of BA and reduction of epileptiform abnormalities during wakefulness can be observed over time, while DFR always persist during sleep; • since the awake EEG may be normal, polysomnography (EEG, EMG, PNG) is mandatory for the detection of DFR and subtle TS; • EEG and seizure improvement do not correlate with cognitive outcome, which remains poor in most patients.
Lennox–Gastaut syndrome in adulthood
Acknowledgement We are grateful to Antonina Donato, IRCCS Centro Neurolesi ‘‘Bonino-Pulejo’’, Messina, Italy, for editing the manuscript.
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