In 1981, Dravet and Bureau (1981) first described seven infants with myoclonic seizures and named the syndrome myoclonic epilepsy in infants. The syndrome was included in the International Classification of Epilepsies and Epileptic Syndromes (Commission, 1989) in the group of idiopathic generalized epilepsies and syndromes with age-related onset. Subsequently, reports by other authors were reviewed by Dravet and Bureau (2005) and Guerrini et al. (2012).
Several authors have reported infants with reflex myoclonic seizures triggered by noise or touch using the name reflex myoclonic epilepsy in infancy as a distinctive epileptic syndrome (Ricci et al., 1995); however, this entity has also been considered a variant of benign myoclonic epilepsy of infancy (Caraballo et al., 2003). Reports of other children with reflex myoclonic seizures have been published, including in patients with photosensitive seizures (Zafeiriou et al., 2003; Capovilla et al., 2007).
The benignity of the syndrome has been questioned, as the term benign should be limited to those forms of epilepsy for which the good prognosis can be predicted from onset (Engel, 2006). Because that is not the rule in all cases with an idiopathic form of myoclonic epilepsy in infancy (Zuberi & O'Regan, 2006), the term was changed to myoclonic epilepsy in infancy (MEI) (Engel, 2006). The question is whether infants with MEI with a benign course and those with not such a benign course have the same epileptic syndrome. Because this latter term did not allow one to accurately define a specific type of MEI, the new name proposed was idiopathic myoclonic epilepsy in infancy. Nevertheless, because the entity is of unknown etiology but likely to be genetic, we prefer to use the term myoclonic epilepsy in infancy (MEI) in this report.
MEI is characterized by brief generalized myoclonic seizures associated with generalized spike-wave paroxysms without other seizure types occurring in the first 3 years of live in developmentally normal children.
In the long-term follow-up, some patients with MEI have been reported to develop other idiopathic epileptic syndromes after a seizure-free period following remission of the myoclonic seizures (Prats-Vinas et al., 2002; Auvin et al., 2006; Darra et al., 2006; Capovilla et al., 2007; Moutaouakil et al., 2010). Cognitive outcome was variable (Prats-Vinas et al., 2002; Auvin et al., 2006; Darra et al., 2006; Capovilla et al., 2007).
Herein we analyze the electroclinical features, treatment, and outcome of 38 consecutive patients with MEI with long-term follow-up.
Material and Methods
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- Material and Methods
A retrospective chart review was conducted in 38 patients with MEI seen at the Neurology department of the Pediatric Hospital Juan P Garrahan, Buenos Aires, Argentina, between 1990 and 2012. During the same period, 8,561 patients with epilepsy were seen at the department. The patients were found in an electronic epilepsy database at this neurology department, a tertiary referral center for inpatients and outpatients. The study was approved by the hospital ethics committee. Eight patients with reflex myoclonic seizures were previously published by our group (Caraballo et al., 2003). All patients met the following inclusion criteria: (1) normal development until seizure onset; (2) no organic or other obvious cause for the seizures; (3) seizure onset between 2 months and 4 years of life; (4) type of seizure: myoclonic, including reflex myoclonic seizures; and (5) generalized paroxysms of polyspike or spike-and-wave complexes. Patients with structural or metabolic etiologies were excluded.
In this study all 38 patients underwent sleep and awake electroencephalography (EEG) recordings, and 15 additionally underwent a video-EEG recording. Seizure onset, semiologic features, frequency, distribution, duration of the seizures, and interictal and ictal EEG recordings were analyzed. A polygraphic-EEG recording was obtained in two. Computed tomography (CT) scan was obtained in 30 patients, and brain magnetic resonance imaging (MRI) in nine patients. Neurometabolic studies were done in two cases, and karyotyping was performed in two. Lumbar puncture was performed in two patients to rule out glucose transporter type 1 (Glut-1) deficiency syndrome. Data on school achievements and neuropsychological evaluations (Stanford-Binet Intelligence Scale and Wechsler Intelligence Scale for Children 3rd or 4th edition) were repeatedly obtained during the follow-up of 3–22 years. Mean follow-up was 13.5 years. In the absence of formal neuropsychological tests, cognitive changes were evaluated according to clinical judgment.
Biochemical controls included periodic blood analysis (complete blood cell count) and liver function test; they did not show abnormalities. Antiepileptic drug (AED) treatment was analyzed. Treatment was not based on a protocol, but had been indicated by each physician independently. Plasma levels of classic AEDs were determined. In children who received prolonged topiramate treatment, urine analysis was done to check kidney function and renal ultrasound was performed to rule out renal calculi.
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- Material and Methods
This retrospective study based on the electroclinical features and outcome observed in our series of patients with MEI clearly shows a well-defined epileptic syndrome with spontaneous and/or reflex myoclonic seizures and a good outcome in terms of seizure control and neuropsychological profile. MEI was classified as idiopathic, generalized epilepsy with an as-yet-unknown etiology, but likely of genetic cause considering the high prevalence of epilepsy and febrile seizures both in family members and patients with MEI and the possibility of the latter to develop another type of idiopathic or genetic epileptic syndrome. A family history and the association of MEI with other types of idiopathic epileptic syndrome have been reported by several authors (Arzimanoglou et al., 1996; Prats-Vinas et al., 2002; Auvin et al., 2006; Darra et al., 2006; Moutaouakil et al., 2010; Mangano et al., 2011). In addition, patients with focal electroclinical features of idiopathic benign focal epilepsy of childhood with rolandic spikes associated with MEI have been described (Darra et al., 2006; Korff et al., 2009).
Our series of patients is similar to the cases published previously (Dravet & Bureau, 2005; Auvin et al., 2006; Darra et al., 2006; Hirano et al., 2009) not only from the electroclinical, but also from the therapeutic and prognostic point of view. However, data obtained in an important electroclinical study showed that the myoclonic seizures may have electroclinical features of focal manifestations (Darra et al., 2006), as has been documented in patients with juvenile myoclonic epilepsy (Thomas et al., 2005). Focal paroxysms have also been reported in other series of patients with MEI (Lin et al., 1998; Dravet & Bureau, 2005), and the focal, asymmetric, or asynchronic component of the myoclonic seizures may represent a manifestation of a particular age-dependent genetic hyperexcitability of the motor cortex (Darra et al., 2006). In our current series of patients and in patients reported previously (Caraballo et al., 2011a) we describe particular myoclonic seizures associated with absences. These seizures were discussed by Guerrini et al. (2012), who argued that they actually may not be absence seizures. Recently, in a large series of children with early onset absence epilepsy, no significant differences in demographic and electroclinical aspects were observed between children with early onset absence epilepsy who responded well to AED monotherapy and those who became seizure-free with add-on treatment of a second AED (Agostinelli et al., 2012).
Assessing the reflex myoclonic seizures registered in our group of patients and the other cases that have been reported in the literature confirming their presence in patients with MEI, they should probably be considered as a variant of this syndrome rather than a different epileptic syndrome (Ricci et al., 1995; Caraballo et al., 2003; Zafeiriou et al., 2003; Auvin et al., 2006; Darra et al., 2006; Capovilla et al., 2007). This group of infants with reflex seizures had an excellent outcome, and some of them, similar to our patients described earlier, did not receive any AEDs.
According to our series of patients and other patients reported (Auvin et al., 2006; Darra et al., 2006; Guerrini et al., 2012), there is a group of infants who present with subtle and isolated myoclonic seizures associated with normal interictal EEG recordings or bilateral spikes in central or vertex regions, which may be difficult to recognize as being of epileptic origin. In these cases, an ictal EEG is mandatory for defining the electroclinical features to start early and adequate AED treatment.
As to neuropsychological manifestations, several authors reporting series of patients with MEI have pointed out that cognitive dysfunction was observed (Giovanardi Rossi et al., 1997; Lin et al., 1998; Dravet & Bureau, 2005; Mangano et al., 2005; Auvin et al., 2006; Darra et al., 2006; Guerrini et al., 2012) as in our series of patients. Most of our patients (32 of 38) had a normal neuropsychological performance. Two patients presented with mental retardation and four other cases had cognitive alterations. In the former two patients as in the latter four, the neuropsychological profile previous to seizure onset was difficult to assess, and thus progressive cognitive impairment was also difficult to demonstrate. Some of the patients may have cognitive involvement previous to seizure onset possibly depending on environmental factors, and/or the possible genetic cause may also play an important role. The neuropsychological impairment should be evaluated accurately to define the relationship of epileptogenic mechanisms and cognitive impact. Similar findings were shown in a single study analyzing the neuropsychological and behavioral outcome in seven patients with an average follow-up of 6 years, 9 months (Mangano et al., 2005). As in our study, the authors did not find any significant electroclinical and therapeutic differences between patients with a normal neuropsychological profile and those with cognitive disturbances (Mangano et al., 2005). Our results corroborate a good prognosis not only in terms of seizure control, but also regarding neuropsychological performance in most of the patients in our series. However, we believe that delay of the diagnosis should be avoided so as to start early treatment to stop the high frequency of the seizures.
The majority of patients with MEI have been treated with valproic acid as monotherapy (Dravet & Bureau, 2005; Auvin et al., 2006; Darra et al., 2006; Guerrini et al., 2012). It was used as the first choice AED in most of our patients as well. Levetiracetam may also be considered (Gentile et al., 2010). A possible paradoxical worsening of myoclonic seizures has been reported (Thomas et al., 2006). One of our patients with refractory seizures was referred to our service with a misdiagnosis of West syndrome, and with vigabatrin the electroclinical manifestations significantly worsened adding reflex myoclonic seizures. When vigabatrin was withdrawn, the seizures disappeared and the EEG became normal.
In the long-term follow-up of patients with MEI, generalized tonic–clonic or clonic seizures have been reported after a myoclonic-free interval; however, seizures were isolated or easily controlled by a short treatment. Less frequently, absence seizures with or without eyelid myoclonia, juvenile myoclonic epilepsy, and photic-induced myoclonic seizures have also been published (Prats-Vinas et al., 2002; Auvin et al., 2006; Darra et al., 2006; Guerrini et al., 2012). The EEG abnormalities may persist for many years, usually without myoclonic seizures. As to neuropsychological outcome, slight and severe mental retardation have been reported, and cases with dyslexia, attention deficit disorders, and language and motor delay have also been described (Mangano et al., 2005; Guerrini et al., 2012). When compared to patients with normal cognitive outcome, patients with an abnormal neuropsychological profile had no apparent differences in age at onset, EEG abnormalities, other types of seizure, and response to treatment (Guerrini et al., 2012).
In the differential diagnosis, syndromes with myoclonic seizures in infancy or early childhood should be taken into account (Guerrini et al., 1994; Dravet et al., 2005; Crespel et al., 2012; Caraballo et al., 2013). In addition, MEI should be differentiated from West syndrome and epileptic spasms in clusters without hypsarrhythmia in infancy and early childhood (Caraballo et al., 2011b). Patients with electroclinical features similar to those of MEI associated with Glut-1 deficiency have been described (Oguni, 2005; Roullet-Perez et al., 2008; Gaspard et al., 2011). The autosomal recessive benign myoclonic epilepsy in infancy reported in one family linked to chromosome 16p 13 had similarities with that of patients with MEI, but in the former the myoclonic jerks may be grouped in long clusters for many hours, were always associated with generalized tonic–clonic seizures, and persisted into adulthood (Zara & De Falco, 2005).
Considering the differential diagnosis with nonepileptic conditions, in infants with episodes resembling myoclonic seizures with normal psychomotor development and normal EEG recordings performed while awake and during sleep, benign nonepileptic myoclonus or Fejerman syndrome should be taken into account (Caraballo et al., 2009).
The shortcoming of our study is the lack of polygraphic-EEG recordings to define the features of the myoclonic seizures. Registration of the seizures is crucial mainly in those cases with subtle electroclinical manifestations to diagnose this syndrome. However, in almost half of our patients a video-EEG allowed the recognition of myoclonic seizures.
According to the last proposal of the International League Against Epilepsy (ILAE) Task Force (Berg et al., 2010) MEI should be considered among the epilepsies of unknown etiology; however, we believe that genetic factors are evident in this syndrome. With respect to replacement of the term “benign” by “self-limited,” the group of reflex MEI without AED treatment may be considered self-limited, since the myoclonic seizures disappeared spontaneously. The infants with a good response to AEDs may be named “pharmacosensitive.”
Prospective studies considering polygraphic-EEG recordings and genetic studies should be conducted to delineate the nosology of infants with myoclonic seizures meeting the diagnostic criteria of MEI.