Myoclonic Status in Nonprogressive Encephalopathies: Study of 29 Cases

Transcription

1 Epilepsia, 48(1): , 2007 Blackwell Publishing, Inc. C 2007 International League Against Epilepsy Myoclonic Status in Nonprogressive Encephalopathies: Study of 29 Cases Roberto Horacio Caraballo, Ricardo Oscar Cersósimo, Alberto Espeche, Hugo Antonio Arroyo, and Natalio Fejerman Department of Neurology, Hospital de Pediatría Prof Dr. Juan P. Garrahan, Buenos Aires, Argentina Summary: Purpose: Myoclonic status in nonprogressive encephalopaties (MSNE) is characterized by recurrence of longlasting myoclonic status appearing in infants and young children with nonprogressive encephalopathy. Here, we describe the electroclinical features and evolution of MSNE. Methods: Between February 1, 1990 and July 31, 2005, 29 patients who met diagnostic criteria of MSNE were enrolled in the study at our department and have been followed up to the present time. Results: Three main subgroups could be identified. The first subgroup of 18 patients presented myoclonic absences and rhythmic myoclonias. These were followed by a brief silent period related to a subcontinuous delta-theta activity involving the central areas, and rhythmic delta waves with superimposed spikes mainly involving the parietooccipital regions and often activated by eye closure. It was found in all children with a genetic etiology. The second subgroup included five patients showing a pattern characterized by inhibitory phenomena associated with a dystonic component and sudden irregular rapid lightning-like jerks. The EEG showed subcontinuous multifocal slow spikewaves, predominating in frontocentral regions. These patients are affected by a cortical malformation or the etiology is unknown. The third subgroup included six children who initially suffered from myoclonic absences. The status was initially characterized by subcontinuous generalized spike-wave-type paroxysms related to rhythmic myoclonia of face and limbs. After 1 3 weeks, the EEG showed sharp theta waves with very slow pseudorhythmic continuous spikes in the central regions and vertex. The etiology was found to be perinatal anoxic injury. Conclusion: MSNE should be considered as a new epileptic syndrome in the group of epileptic encephalopathy. Key Words: Angelman syndrome Epileptic encephalopathy Myoclonic seizures Negative myoclonia Nonprogressive encephalopaty Refractory epilepsy. In 1980, Dalla Bernardina et al. (1980) described a peculiar form of myoclonic epilepsy in children with nonprogressive encephalopathy. He named the entity myoclonic status in nonprogressive encephalopathies (MSNE). MNSE is characterized by recurrence of longlasting myoclonic status appearing in infants and young children with nonprogressive encephalopathy and has a poor prognosis (Dalla Bernardina et al., 2002). Several authors have described a quite similar electroclinical picture in children with nonprogressive encephalopathy, Angelman syndrome and in some children with 4p-syndrome (Chiron et al., 1988; Matsumoto et al., 1992; Sugimoto et al., 1992; Casara et al., 1995; Viani et al., 1995; Engel, 2001), but few of them have stressed how, in some of these cases, the electroclinical picture was typically that of a myoclonic status in nonprogressive Accepted July 16, Address correspondence and reprint requests to Roberto H. Caraballo at Department of Neurology, Hospital de Pediatría, Prof Dr. Juan P. Garrahan, Combate de los Pozos 1881, CP 1245, Buenos Aires, Argentina. rhcaraballo@arnet.com.ar doi: /j x encephalopathy (Sgró et al., 1995; Guerrini et al., 1996; Cersósimo et al., 2003). Recently, this form of epileptic encephalopathy has been proposed in the scheme of the ILAE Task Force on Classification and Terminology under the heading syndromes in development (Engel, 2001). In the present study, we describe the electroclinical features and evolution of 29 cases with this peculiar type of epileptic encephalopathy. MATERIAL AND METHODS Between February 1, 1990 and July 31, 2005, 29 patients who met diagnostic criteria of MSNE were enrolled in a study at our department and have been followed up to the present time. We analyzed gender, age at onset, personal and family history of epilepsy and febrile seizures, duration, manifestation, circadian distribution, and frequency of seizures, response to therapy and final outcome. EEGs were performed while the patients were awake and asleep. Electrodes were placed according to the 107

2 108 R. H. CARABALLO ET AL. international system. In 10 patients, polygraphic EEG recordings were done. The morphology, topography, and reactivity of interictal paroxysms to eye closing and opening and under intermittent light stimulation (ILS) were studied. Clinical and neurological examinations and etiologies were also analyzed. All patients underwent brain CT scans and MRI. Other studies, such as neurometabolic investigations and genetic studies were performed as well. Clinical and EEG details of all patients were reviewed and unanimously agreed upon by all authors. RESULTS Of the 29 patients in this study, 18 were females and 11 males with a male female ratio of 1:1.5. Their current ages range between 4 and 15 yr (mean age 6 yr). The mean time of follow-up was 7 yr (range 2 13 yr). Familial antecedents of epilepsy were reported in four (13%) and febrile seizures in two patients (6.5%). The etiology was genetic in 18 patients: deficit in chromosome 15q 11-q13 (Angelman syndrome) in 15 patients, deletion of the short arm of chromosome 4 (Wolf- Hirschhorn syndrome or 4p-syndrome) in two cases, and Rett syndrome in the remaining one. Prenatal or perinatal anoxic insults were found in five cases and the etiology was unknown in six patients. In the patients with a genetic etiology, the neuroradiologic findings were normal, in those with an etiology secondary to anoxic injury, the brain CT scan and MRI imaging showed cerebral atrophy. In those with unknown etiology the neuroradiological imaging showed developmental cortical malformations in four patients, bilateral polymicrogyria in three and partial callosum agenesia, vermis hypoplasia and microcephalia in one. These four patients could be genetically determined as sporadic cases and the epilepsy was secondary to developmental cortical malformations. Neurological examination showed axial hypotonia and severe mental retardation in 23 patients (79%), and ataxic cerebral palsy with a dystonic-dyskinetic syndrome was found in six cases (11%). Dysmorphisms evoking a genetic etiology with microcephalia were present in 18 patients. Age at first seizure ranged from 1 month to 4 yr, with a mean age of 15 months and median age of 9 months. The onset of epilepsy was constituted of a myoclonic status characterized by very frequent or subcontinuous absences during the day accompanied by periorbital and perioral myoclonias and rhythmic and arrhythmic jerks of distal muscles in fifteen patients. Myoclonic absences and massive myoclonias were present in seven patients, focal motor seizures were found in five and generalized tonic or clonic seizures in two patients. The mean and median ages when myoclonic status was recognized were 16 and 14 months, respectively (range: 4 months 4 yr) Based on the classification according to the electroclinical features by Dalla Bernardina et al., three main subgroups could be identified. The electroclinical features of the first subgroup of 18 patients were characterized by brief myoclonic absences and rhythmic myoclonias. These were eventually followed by a brief silent period related to a subcontinuous delta-theta activity involving the central areas, and brief sequences of rhythmic delta waves with superimposed spikes mainly involving the parietooccipital regions and often activated by eye closure. In this first group the status occurred during the first year of life (Fig. 1). The duration of the status was variable, recurring sporadically in about one-half of the cases, whereas they were more chronic (lasting for years) in about onefourth of the cases. Rare unilateral or generalized seizures occurring occasionally during a febrile illness were also observed. This latter electroclinical picture was found in all children with Angelman syndrome, 4p-syndrome and Rett syndrome. In all cases the status proved to be refractory to different AEDs including ACTH. In six cases ESM associated with VPA induced an improvement. When the myoclonic status improved significantly or disappeared, the clinical picture improved dramatically. The behavioral disturbances improved and some children became ambulatory. In four cases (22%) of these patients the myoclonic status disappeared entirely during evolution of the disease. In this subgroup the mean time of follow-up was 6 yr (range 2 11 yr). The mean and median ages when myoclonic status was recognized were 10 and 13 months, respectively (range: 4 months 3 yr). The mean age when myoclonic status stopped was 4 yr (range: 2 6 yr). The second subgroup included five patients showing a pattern characterized by the marked predominance of inhibitory phenomena associated with dystonic movements and bilateral positive myoclonias and long-lasting negative myoclonias. At onset, the status was often difficult to recognize because of severe mental impairment and abundance of continuous polymorphous and rough abnormal movements. The mostly erratic jerks were therefore difficult to distinguish from the violent dyskinetic movements (Fig. 2A). Moreover, subcontinuous multifocal slow spike-waves, predominating in posterior regions, but fluctuating in amplitude and diffusion, were very difficult to correlate with the positive and negative myoclonias on the EEG (Fig. 2B). Sometimes a long-lasting status appeared characterized by the recurrence of very ample and diffuse rhythmic slow spike-waves associated with rhythmic and generalized myoclonias followed by an inhibitory phenomenon. The patients were often resistant to intravenous benzodiazepine and required intensive care therapy. Three children died during this status, two females and one male,

3 MYOCLONIC STATUS IN NONPROGRESSIVE ENCEPHALOPATHIES 109 FIG. 1. The EEG recording of an 11- month-old girl with Angelman syndrome shows diffuse high amplitude slow waves with notched delta appearance. The EMG recording shows frequent erratic, sometimes rhythmic myoclonias with related EEG paroxysms. aged 3, 5, and 7 yr, respectively. Brief generalized tonic clonic seizures, sometimes clusters, occurred in one case. In this subgroup, the status was always refractory to AEDs and permanent throughout the evolution with definitive aposturality and severe mental deficit. Patients who show this particular electroclinical picture are females affected by a nonprogressive encephalopathy of unknown etiology or sustained by a cortical malformation. In this subgroup the mean time of follow-up was 5 yr (range 3 10 yr). The mean and median ages when myoclonic status was recognized were 4 and 13 months, respectively (range: 4 months 6 yr). The mean age when myoclonic status stopped was 5 yr (range: 2 6 yr). The third subgroup included six children showing only mild neurological impairment at onset, who initially suffered from partial motor seizures localized in the face followed by conciousness impairment. The myoclonic status began progressively, more rapidly in four and more subtly in two. The status was initially characterized by a subcontinuous sequence of generalized spike-wave-type paroxysms or bilateral continuous slow wave with notched delta appearance related to rhythmic myoclonia of face and limbs (Fig. 3 A and B). After 1 3 weeks, we could observe a progressive deterioration of the morphology and paroxysms on the EEG were modified and became sharp theta waves with very slow pseudorhythmic continuous spikes in the central regions and vertex. At the same time, the clinical motor picture was progressively compromised, and pyramidal signs and intentional tremors appeared. Furthermore, continuous myoclonic inhibitory phenomena appeared. These phenomena were only clinically and polygraphically recognized when the patient presented increased postural tone during muscle contraction. The patients presented severe neuropsychological impairment that was equally progressive, and in six of the cases a discrete cortico-subcortical and cerebellar atrophy was visible on MRI. However, progressive pathology did not appear in any of these patients and, in the long term, the picture instituted remained unchanged. In these patients the pyramidal signs were transitory and probably secondary to this particular epileptic syndrome. According to these findings, the electroclinical picture seemed

4 110 R. H. CARABALLO ET AL. FIG. 2. (A) A 4-yr-old girl with bilateral frontal polymicrogyria showing myoclonic status as shown on the EMG recording, associated with diffuse slow wave discharges. (B) One year later, showing long-lasting myoclonic status with subcontinuous negative myoclonias mixed with dyskinetic movements as shown on the EMG recording, associated with irregular and subcontinuous slow spike-wave discharges.

5 MYOCLONIC STATUS IN NONPROGRESSIVE ENCEPHALOPATHIES 111 FIG. 3. (A) 1-yr-5-month-old girl with severe neuropsychological impairment, who suffered from neonatal anoxia and had repeated status epileptic lasting several days from the age of 7 months. The EEG recording shows bilateral continuous slow waves with superimposed spikes accompanied by rhythmic bilateral positive myoclonias. (B) At 6 yr of age the EEG recording shows rhythmic bilateral slow spike-wave paroxysms associated with bilateral positive myoclonias.

6 112 R. H. CARABALLO ET AL. to be one of a pharmacoresistent epilepsy that was not sustained by a progressive disease. Partial motor seizures, predominantly tonic and only sometimes followed by generalization, were frequent, while other types of seizures were absent. In this last subgroup, the etiology was found to be perinatal anoxic injury. In this subgroup the mean time of follow-up was 4 yr (range 3 9 yr). The mean and median ages when myoclonic status was recognized were 8 and 15 months, respectively (range: 7 months 5 yr). The mean age when myoclonic status stopped was 3 yr (range: 2 6 yr). DISCUSSION The present study describes a particular type of epileptic encephalopathy with myoclonic epileptic seizures characterized by the recurrence of long-lasting atypical status associated with an impairment of attention and continuous polymorphous jerks, mixed with other complex abnormal movements, in infants suffering from a nonprogressive encephalopathy, which could constitute a new and unusual epileptic syndrome. Through an accurate electroclinical analysis three particular subsets may be distinguished that have an important diagnostic and prognostic significance. The first is characterized by the association of absences, subcontinuous jerks, at times rhythmic or arrhythmic, and mainly positive brief myoclonic absences. A diagnosis of Angelman syndrome or another syndromic entity sustained by a chromosomal abnormality must be considered when such a picture presents. The second subset is characterized by the association of absence status and a mainly negative, continuous rhythmic myoclonus, mixed with sudden uncontrolled continuous dyskinetic movements. This condition predominantly affects females and is probably secondary to developmental cortical malformations. The third is characterized by continuous spike activity in rolandic regions, persisting throughout life, and accompanied by bilateral rhythmic myoclonias followed by an inhibitory phenomenon. This picture leads to progressive neuromotor deterioration corresponding to a form of epileptic encephalopathy in the absence of progressive disease. These three subgroups present electroclinical features that are similar to the series of patients with MSNE described by Dalla Bernardina et al. (2004). Reports in the literature describing this particular electroclinical picture are rare (Chiron et al., 1988; Dulac et al., 1998; Dalla Bernardina et al., 2002) and certainly do not reflect its real incidence. The main reasons for this underestimate are the severe mental retardation and continuous abnormal movements. Both the absences and the myoclonias could remain hidden for several months in many cases. The diagnosis may also be missed as polygraphic EEG recordings are not often performed in infants with epilepsy. On the other hand, considering the insidious appearance and probably the age at onset of myoclonias, the status may be unrecognized in many cases (Boyd et al., 1988; Ganji and Duncan, 1989; Van Lierde et al., 1990; Laan et al., 1997; Rubin et al., 1997). It is also probable that similar electroclinical pictures have been included by some authors in other diagnostic settings such as minor motor status, the myoclonic variant of Lennox- Gastaut syndrome or myoclonic status in symptomatic cases of myoclonic-astatic epilepsy (Brett, 1966; Gastaut, 1981; Doose, 1992). As far as differential diagnoses are concerned, two different conditions can present a more or less intriguing problem. Because of the significant progressive increase of neuropsychologic impairment and paroxysmal abnormalities on the EEG and the polymorphous myoclonic manifestations, the first and often most complex step is to rule out a progressive disease. In cases, presenting frequent atypical absences with concomitant myoclonic-atonic phenomena, the electroclinical picture can be quite similar to the late infantile form of neuronal ceroid-lipofuscinosis (Binelli et al., 2000; Veneselli et al., 2001; Caraballo et al., 2005). The absence of progressive visual impairment, the presence of normal visual-evoked potentials, even when the somatosensory evoked potentials are roughly abnormal as frequently observed, the absence of a paroxysmal response to ILS, the persistence of recognizable sleep spindles, and the more or less significant improvement of the clinical picture concomitant with a satisfactory, even if transitory improvement of the status can be helpful in making a correct diagnosis. Neuropathologic and genetic molecular analyzes are necessary to rule out neuronal ceroid-lipofuscinosis. The differential diagnosis can be somewhat difficult with some of the cases reported in the literature as suffering from a newborn continuous focal epilepsy, early onset progressive encephalopathy with migrant continuous myoclonus or migrating partial seizures of early infancy (Dalla Bernardina et al., 1987; Coppola et al., 1995; Gaggero et al., 1996). In fact, many of these cases may present a long-lasting status characterized by continuous discharges of diffuse spikes and waves accompanied by bilateral asynchronous myoclonias with obtundation and drooling. CONCLUSION In the present study, we describe a peculiar epileptic entity characterized by the recurrence of long-lasting status associated with absences and continuous polymorphous myoclonias, mixed with other complex abnormal movements in infants suffering from a nonprogressive encephalopathy, independently of the etiology. This condition may be difficult to recognize clinically because of previous intellectual deficit and continuous

7 MYOCLONIC STATUS IN NONPROGRESSIVE ENCEPHALOPATHIES 113 abnormal movements. However, it can be easily identified on polygraphic recordings. The etiology can be various, but is mainly genetic and developmental cortical malformative. An early recognition allows adequate treatment avoiding or diminishing neuropsychological impairment. Finally, MSNE should be considered as a new epileptic syndrome in the group of epileptic encephalopathy. REFERENCES Binelli S, Canafoglia L, Panzica F, Pozzi A, Franceschetti S. (2000) Electroencephalographic features in a series of patients with neuronal ceroid lipofuscinosis. Neurological Sciences 21(3 suppl):s83 S87. Boyd SG, Harden A, Patton MA. (1988) The EEG in early diagnosis of the Angelman (Happy Puppet) syndrome. European Journal of Pediatrics 147:508. Brett EM. (1966) Minor epileptic status. Journal of the Neurological Sciences 3: Caraballo R, Sologuestua A, Ruggieri VL, Monges S, Cersosimo R, Taratuto AL, Medina C, Fejerman N. (2005) Clinical and Electroencephalographic aspects of late infantile neuronal ceroid lipofuscinosis. Revistade Neurologia 40(3): Casara GL, Vecchi M, Boniver C, Drigo P, Baccichetti C, Artifoni L, Franzoni E, Marchiani V. (1995) Electroclinical diagnosis of Angelman syndrome: a study of 7 cases. Brain & Development 17: Cersosimo R, Caraballo R, Espeche A, Cassar L, Torrado MV, Chertcoff L, Baialardo E, Arroyo HA, Fejerman N. (2003) Angelman syndrome: the electroclinical characteristics in 35 patients. Revista de Neurologia 37(1): Coppola G, Plouin P, Chiron C, Robain O, Dulac O. (1995) Migrating partial seizures in infancy: a malignant disorder with developmental arrest. Epilepsia 36(10): Chiron C, Plouin P, Dulac O, Mayer M, Pavset G. (1988) Epilepsies myocloniques des encephalopathies non progressives avec etats de mal myoclonique. Neurophysiologie Clinique 18: Dalla Bernardina B, Trevisan C, Bondavalli S. (1980) Une forme pareticuliére d épilepsies myoclonique chez des enfants porteurs d encéphalopathie fixée. Boll Lega It Epil 29 30: Dalla Bernardina B, Colamaria V, Capovilla V, Fontana E, Di Roma N, Salerno M. (1987) Epilessia parziale continua del lattante. Boll Lega It Epil 58/59: Dalla Bernardina B, Fontana E, Darra F. (2002) Myoclonic status in nonprogressive encephalopathies. In Roger J, Bureau M, Dravet C, Genton P, Tassinati CA, Wolf P (Eds) Epilpeptic syndromes in infancy, childhood and adolescence. 3 rd ed. John Libbey, London, pp Dalla Bernardina B, Fontana E, Darra F. (2004) Myoclonic status in nonprogressive encephalopathies. In Delgado-Escueta AV, Guerrini R, Medina MT, Genton P, Bureau M, DravetCh (Eds) Myoclonic epilepsies, advances in neurology series. Lippincott Williams & Wilkins, Philadelphia, pp Doose H. (1992) Myoclonic astatic epilepsy of early childhood. In Roger J, Bureau M, Dravet C, Dreifuss FE, Perret A, Wolf P (Eds) Epileptic syndromes in infancy, childhood and adolescence, John Libbey, London, pp Dulac O, Plouin P, Shewmon A. (1998) Contributors to the Royaumont Workshop, Myoclonus and epilepsy in childhood, 1996 Royaumont meeting. Epilepsy Research 30: Engel J. (2001) A proposed diagnostic scheme for people with epileptic seizures and with epilepsy: report of the ILAE Task Force on Classification and Terminology. Epilepsia 42(6): Gaggero R, Baglietto MP, Curia R, De Negri M. (1996) Early-onset progressive encephalopathy with migrant, continuous myclonus. Child s Nervous System 12(5): Ganji S, Duncan MC. (1989) Angelman s (Happy Puppet) syndrome: clinical, CT scan and serial electroencephalography study. Clinical EEG 20: Gastaut H. (1981) Individualisation des épilepsies dites bénignes ou fonctionnelles aux différentes ages de la vie. Appréciation des variations correspondantes de la prédisposition épileptique á ces ages. Revue d elect encephalographic et de neurophysiologie clinique 11: Guerrini R, De Lorey TM, Bonanni P. (1996) Cortical myoclonus in Angelman syndrome. Annals of Neurology 40: Laan LA, Renier WO, Arts WF, Buntinx IM, vd Burgt IJ, Stroink H, Beuten J, Zwinderman KH, van Dij K JG, Brouwer OF. (1997) Evolution of epilepsy and EEG findings in Angelman syndrome. Epilepsia 38(2): Matsumoto A, Kumagai T, Miura K. (1992) Epilepsy in Angelman syndrome associated with chromosome 15q deletion. Epilepsia 33:1083. Rubin DI, Patterson MC, Westmoreland BF, Klass DW. (1997) Angelman s syndrome: clinical and electroencephalographic findings. Electroencephalography and Clinical Neurophysiology 102: Sgró V, Riva E, Canevini MP, Colamaria V, Rottoli A, Minotti L, Canger R, Dalla Bernardina B. (1995) 4p-syndrome: chromosomal disorder associated with a particular EEG pattern. Epilepsia 36(12): Sugimoto T, Yasubara A, Ohta T, Nishida N, Saitoh S, Hamabe J, Niikawa N. (1992) Angelman syndrome in three siblings: characteristic epileptic seizures and EEG abnormalities. Epilepsia 33: Van Lierde A, Atza MG, Giardino D, Viani F. (1990) Angelman s syndrome in the first year of life. Developmental Medicine and Child Neurology 32: Veneselli H, Biancheri R, Buoni S, Fois A. (2001) Clinical and EEG findings in 18 cases of late infantile neuronal ceroid lipofuscinosis. Brain & Development 23(5): Viani F, Romeo A, Viri M, Mastrangelo M, Lalatta F, Selicorni A, Gobbi G, Lanzi G, Bettio D, Briscioli V. (1995) Seizures and EEG patterns in Angelman s syndrome. Journal of Child Neurology 10(6):