Myoclonus epilepsy with ragged-red fibers
Jun. 10, 2021
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Self-limited epilepsy with centrotemporal spikes (SLECTS) is the new name for the previous epilepsy syndrome of benign childhood epilepsy with centrotemporal spikes (BECTS). It was first reported in the 1950s and is now recognized as the most frequent epilepsy syndrome in children between the ages of 4 and 13 years. The term “benign” was applied to this syndrome to differentiate from other sinister causes for focal epilepsies. However, it was noted subsequently that cognitive and language problems and atypical evolutions with a not-so-benign course were seen in this syndrome. As per the recent epilepsy classification, the new term “self-limited” has replaced the term “benign”. The common idiopathic focal epilepsies of childhood are increasingly being termed “self-limited focal epilepsies of childhood” (SFEC) and at times, the word “benign” is completely omitted to name the syndrome as “childhood epilepsy with centrotemporal spikes” (CECTS). For the purpose of this review, we are using the term self-limited epilepsy with centrotemporal spikes (SLECTS) for the typical cases to maintain uniformity. Atypical varieties of the syndrome and atypical evolutions after a seemingly classical onset are also discussed separately. Emerging data about the academic performance and attention impairment in children with this syndrome are also discussed.
• Typical seizures seen in SLECTS may occur without centrotemporal spikes. Conversely, centrotemporal spikes may occur in children without seizures, in children with other epilepsy syndromes, and in children with structural lesions in the rolandic area.
• An increasing frequency of specific cognitive, language, memory, and attention-related disorders are being reported in children with SLECTS.
• Atypical features in clinical and electroencephalographic manifestations seem to correlate with transitory cognitive and language disorders.
• Very rarely SLECTS may evolve into Landau-Kleffner syndrome and continuous spike-and-waves during slow sleep syndrome with potential for persistent neuropsychological impairments.
• In cases presenting with the atypical features, especially early onset of the disease and frequent discharges in electroencephalogram (EEG) during sleep, initial treatment with benzodiazepines or sulthiame is recommended.
Rolandic (centrotemporal) region is named after Luigi Rolando (1773-1831), an Italian anatomist known for his pioneer research into the localization of function in the human brain. A particular EEG pattern with migratory spikes originating over the rolandic region was first reported in the 1950s (79; 83). In 1958, the first clinical description associated with EEG features was published (147). The same EEG pattern was later correlated with a common form of focal childhood epilepsy, then called "midtemporal epilepsy," characterized by hemifacial and oropharyngeal ictal symptoms and a favorable prognosis (82). Because of the localization of the ictal events, Lombroso proposed the term "sylvian seizures" (135). In the same year, Loiseau and colleagues presented an electroclinical series of 122 children with what they called “a particular form of epilepsy in childhood,” stressing its benign character. Several long-term follow-up studies confirmed the good prognosis (13; 121; 134). This form of epilepsy was called “benign childhood epilepsy with centrotemporal spikes” and was placed in the group of idiopathic localization-related (focal, local, partial) epilepsies in the International Classification of Epilepsies and Epileptic Syndromes (36; 61). As new syndromes were recognized within the spectrum of benign childhood focal epilepsies (159), the term “benign” was considered initially acceptable for this syndrome but was considered inappropriate for some of the other idiopathic focal epilepsies (87).
However, the new ILAE Classification of the Epilepsies proposed the term “self-limited” for “benign” course of epilepsies to reflect a “likely spontaneous resolution of a syndrome” (187). Hence, a new term “self-limited epilepsy with centrotemporal spike” (SLECTS) has been proposed for BCECTS (187). The common idiopathic focal epilepsies of childhood are increasingly being termed “self-limited focal epilepsies of childhood” (SFEC) and at times, the word “benign” is completely omitted to name the syndrome as “childhood epilepsy with centrotemporal spikes” (CECTS) (204).
Loiseau and Duche had provided 5 criteria for the diagnosis of this syndrome: (1) onset between the ages of 2 and 13 years; (2) absence of neurologic or intellectual deficit before the onset; (3) partial seizures with motor signs, frequently associated with somatosensory symptoms or precipitated by sleep; (4) a spike focus located in the centrotemporal (rolandic) area with normal background activity on the interictal EEG; and (5) spontaneous remission during adolescence (Loiseau and Duche 1988).
The key features of this syndrome are:
Age. SLECTS begins between 2 and 13 years of age. In 80% of patients, seizures appear between 5 and 10 years of age. Patients usually recover before 16 years of age (13). The age at seizure onset has been proposed as the most important predictor of early remission, irrespective of the initial EEG findings, antiepileptic drug (AED) treatment, or seizure frequency (119).
Oropharyngeal and facial manifestations include drooling from hypersalivation and swallowing disturbance; guttural sounds; involuntary movements or tonic contractions of the tongue or jaw; unilateral numbness or paresthesia of the tongue, lips, gums, and cheek; speech arrest (a form of anarthria); and myoclonic contraction of 1 side of the face.
Sensorimotor phenomena may involve a leg or one half of the body. Miscellaneous symptoms such as abdominal pain can also occur rarely (Loiseau and 13). Among 230 children with SLECTS, 6 presented with sensory motor seizures in the leg as the main ictal manifestation (76).
Seizures. Most of the seizures reflect discharges in the precentral and postcentral gyri in the suprasylvian region with motor, sensory, and autonomic manifestations in the face, mouth, and throat (Loiseau and 13). This is associated independently with bilateral, repetitive, broad, centrotemporal interictal EEG spikes displaying a characteristic tangential dipolar pattern (86). The ictal manifestations are not indicative of temporal lobe involvement and the term “centro-temporal” refers only to the spike topography. Seizures are typically brief, lasting for 1 to 3 minutes. More than half of the patients retain consciousness and may recollect the sensations. Although focal seizures are characteristic of this disorder, generalized seizures may also be observed infrequently, particularly in younger children. The initial event is often a nocturnal hemifacial convulsion, which may spread to the arm and the leg, or may become secondarily generalized. The ictal patterns may vary from child to child and from seizure to seizure. Each individual patient usually has a single type of seizure, but 20% to 25% of children experience more than 1 type.
Relation to sleep. More than one half of patients with SLECTS have seizures only during sleep, whether during the day or the night. Seizures during waking hours are more likely to occur shortly after awakening. Seizure frequency is usually low and around 10% of cases present only 1 seizure. However, in about 20% of children, seizures are frequent and may even occur several times per day (46). An onset before 3 years of age has been stated as the single most important predictor for multiple seizures (115; 234). In studies neither clinical features, seizure characteristics, nor routine EEG findings were found to be useful in predicting the likelihood of a second seizure in SLECTS (226). However, in a longer follow-up study of 52 children, the presence of a frontal focus and bilateral asynchrony were found to be correlated with the recurrence of seizures in the serial EEGs (200).
Behavioral problems. In a study of 40 children with centrotemporal spikes with and without seizures compared with 40 healthy controls, patients were significantly impaired in intelligent quotient (IQ), visual perception, short-term memory, and psychiatric status. The deficits in IQ correlated more with the frequency of spikes in the EEG than with the frequency of seizures (227). Similar findings were reported in 19 children with this syndrome (53). An increased frequency of centrotemporal spikes was found in children with attention deficit hyperactivity disorder (94). A systematic review on attention impairment in SLECTS suggested that various attention systems are impaired in children with active centrotemporal spikes, implying a more widespread functional cortical disturbance (106). More specifically, in a comparative study of children with SLECTS, Panayiotopoulos syndrome, and no epilepsy (healthy controls), disengagement and inhibition of visual-spatial attention seemed to correlate more with right-sided spikes (14). A longitudinal study of 1 boy with acquired epileptic dysgraphia was reported. Most probably, in this case, the acquired regression of graphomotor skills was associated with an increase in spike frequency as happens in the cases with atypical evolutions of this syndrome (59). Sleep behavior disturbances seem to be frequent in children with epilepsy. Parents of children with SLECTS reported a significantly shorter sleep duration, more frequent parasomnias, and increased daytime sleepiness (201).
Cognitive problems and low academic achievement in children with SLECTS have been emphasized in several reports on this syndrome. A study of 50 children identified educational problems in 54%, developmental learning disability in 38%, expressive language impairment in 18%, and attention disorders in 18% of the cases. The educational problems correlated significantly with the absence of a fronto-central dipole in the EEG (p < 0.001) whereas the abnormal language functions correlated significantly with atypical seizure semiology (p = 0.02) (222). Eighteen children were studied in terms of neuropsychological and learning abilities. IQ and verbal functions were normal, but reading, numerical and/or spelling abilities were significantly delayed by 1 academic year or more in 10 children (168). Neuropsychological functioning and mathematics achievement were compared in 30 affected children with 30 healthy controls. Results suggested guarded academic prognosis in children with this syndrome (185). In a series of 22 children with SLECTS compared with controls, a comprehensive battery of neuropsychological tests demonstrated significant deficits in higher functions of spatial perception, including spatial orientation in the patients (223). A study on school abilities evaluated 20 affected children and 21 healthy controls and found that 9 children with SLECTS presented specific difficulties in reading, writing and calculation (167). In a study of 25 children between 4 and 7 years of age with SLECTS or centrotemporal spikes, compared with controls, the results showed an association of SLECTS with language and memory deficits (49). Deficits in speech-related abilities were detected in a series of 25 patients with this syndrome, although these functions showed to be reversible after remission of epilepsy (220). In some patients, language impairment was considered as a probable precursor of this epileptic syndrome (155). Again, the impact of SLECTS on school performance was demonstrated in a study of 40 cases and controls. The patients showed lower scores in academic performance, digits and similarities subtests of WISC, and auditory processing subtests, probably due to executive dysfunction (144).
Language, memory, and other problems. In a study of 48 children, problems in motor development and its relation to language impairment were detected (154). Impaired social behavior (especially on “theory of mind tasks”) was also found in 15 children (81).
Existence of a neurocognitive endophenotype associated with SLECTS was suggested after a complete neurocognitive evaluation of 13 probands and 11 epilepsy-free siblings (195).
A metaanalysis of 22 studies on literacy and/or language skills in children with this epileptic syndrome showed the presence of reading and phonological processing deficits highlighting the need for early literacy and language assessment (194; 41). The atypical evolution of the seizures and a longer duration of epilepsy may influence the language skills of these patients. Thirty-one patients with clinical and electroencephalographic diagnosis of SLECTS and 31 paired normal children underwent a language and neuropsychological assessment performed with several standardized protocols. Findings showed significant dyslexia in patients with SLECTS (151). Risk factors for reading and phonological disorders were evaluated in an observational study of 108 probands with this epileptic syndrome and their 159 siblings: reading disorder was reported in 42% of probands and 22% of siblings (216). Seizure or treatment variables did not appear to be important risk factors for reading disorder. Memory consolidation processes were found impaired in 15 children with idiopathic focal epilepsies. The association between higher spike-wave index during NREM sleep and poorer nonverbal declarative memory consolidation supported the hypothesis that interictal epileptic activity could disrupt sleep memory consolidation (77). A systematic review of studies published between 2005 and 2016 on language skills in children with SLECTS concluded that children had language skill disorders in the receptive and productive domains of semantics, morphosyntax, imitations in the intrasyllabic, syllabic, and phonemic levels, and deficits in verbal fluency (semantic and phonemic) and in verbal memory (203).
A study comparing the functional integrity of verbal working memory neural networks in SLECTS with healthy controls using functional magnetic resonance imaging (fMRI) showed that the behavioral performances during working memory tasks, in particular accuracy and response time, were poorer in children with SLECTS than in controls (32) and an increased working memory load was associated with reduced activation and behavioral performances.
Central auditory processing disorder was noted in 46% of patients with SLECTS and without intellectual disability, dyslexia, and attention-deficit hyperactivity disorders (138) due to the common neurologic pathways and topographic distribution of spikes in the temporal regions.
Atypical features. Wirrell and colleagues published a retrospective case series of 42 children diagnosed with SLECTS in whom atypical features were found in 50% of the patients (229). Since then, more comprehensive and prospective studies have focused on the correlation between EEG abnormalities and neuropsychological impairments in children with this syndrome. Atypical features can be seen on clinical grounds (daytime-only seizures, postictal Todd paresis, prolonged seizures, or even status epilepticus) or in EEG features (atypical spike morphology, unusual location, or abnormal background) (01). In a study, 11% of 70 patients with this syndrome presented with postictal paresis (42). Several cases of focal status epilepticus in this condition have been reported. The manifestations include hemifacial seizures, dysarthria or anarthria, and persistent drooling (72; 179; 35; 68; 113; 85; 182; 70).
Early age of onset of seizures seems to be one of the most important items among atypical features (115; 234; 70).
Opercular status epilepticus usually occurs in children with atypical evolution or may be induced by carbamazepine or lamotrigine (68; 163) and are often associated with continuous spike and waves in the sleep EEG. The terms “typical” and “atypical” were used in a follow-up study of 74 children with typical features and 11 with atypical features. The authors reported a significantly higher percentage of learning and behavioral disabilities in the second group (218). In a prospective study of 44 children, 16 children with atypical features were seen in the early EEGs such as slow spike-wave focus, synchronous foci, or generalized 3 Hz spike-wave discharges. This atypical group had significantly lower full scale IQ and verbal IQ, and impairments in certain tasks of the performance scale (139). Atypical features were found in almost half of the 126 patients with this epilepsy (50). The frequency of atypical presentations and comorbidities of SLECTS was comprehensively described in 196 patients, highlighting the prevalence of ADHD (31%), behavioral abnormalities (1.7%), and specific cognitive deficits (22%) (24; 206).
• Overall, the data regarding the prevalence of atypical SLECTS is variable but it is commonly agreed that the atypical forms are characterized by atypical clinical features: earlier age of onset of seizures, day-time only seizures, postictal Todd’s paresis, prolonged seizures or status epilepticus, and poor neuropsychological outcomes
• Atypical EEG findings include atypical spike morphology and distribution, absence-like spike-and-wave discharges, and abnormal background.
Atypical evolution. It is important to discriminate between “atypical features in children with SLECTS” and “atypical evolutions of benign focal epilepsies” (65; 66). The latter refers to children with benign focal epilepsies, including those centrotemporal spikes who present disorders related to continuous spike-and-waves during slow sleep. These disorders are associated with severe language and cognitive or behavioral impairments that may be persistent. Qualitative interictal-EEG patterns have been suggested that predict an atypical evolution (137).
Early onset of SLECTS, appearance of new seizures such as atypical absences or negative myoclonus, increased frequency of frontocentrotemporal EEG focus in both sleep and wakefulness, and presence of more than 5 ripples on the centrotemporal spikes are predictive of atypical development (214; 161). A study proposed a novel prediction model for early identification of patients with SLECTS at risk for continuous spike-and-waves during slow sleep syndrome or Landau-Kleffner syndrome and identified 3 notable risk factors: fronto-temporal and temporo-parietal localization of epileptic foci, semiology of seizures involving dysarthria, and somatosensory auras in the early presentation of the disease (169). However, the patients with atypical evolutions with continuous spike-and-wave activities and severe language or behavior impairments account for only around 5% of patients with SLECTS in most of the tertiary epilepsy centers for children. Even when a significant number of children with SLECTS show some learning difficulties, the vast majority of them are able to attend normal schools. Also, in most of the mentioned studies, the types of antiepileptic drugs and their blood levels are not reported, and neither are they considered as eventual cause of the neuropsychological findings (02; 70). Interestingly, in a study of 30 children with SLECTS, parental emotional impact was the major independent predictor of quality of life (37).
In general, SLECTS is associated with an excellent prognosis. Seizures are difficult to control in only a small number of cases. The prognosis is favorable even for those whose seizures are difficult to control, and seizures almost always remit spontaneously in late adolescence. In their investigation of 168 patients 7 to 30 years after cessation of epilepsy with centrotemporal spikes, Loiseau and colleagues reported that seizures occurred in only 3 cases after adulthood (134). The seizure types were all generalized tonic-clonic seizures. Two of the 3 cases had isolated incidences. This incidence of generalized seizures in adults with a history SLECTS in childhood is nevertheless higher than that of seizures in the general population (134). Cognitive functions were evaluated in 23 adolescents and young adults in complete remission showing no significant differences with controls. However, qualitative analysis suggested a different organizational pattern for cerebral language in adolescents and young adults in remission from this syndrome (95). An important proportion of children present with moderate to severe language impairment. The most affected domains were expressive grammar and literacy skills. Persistent deficits in children in remission after this syndrome suggested possible long-term consequences (146). A comprehensive study of neuropsychological and language profiles of 42 children showed that the patients have normal intelligence and language ability although a specific pattern of difficulties in memory and phonologic awareness was found. No correlation between EEG features and the mentioned impairments was demonstrated (150). Written language skills were also evaluated in 32 children with severe, but not atypical, SLECTS compared with 36 controls. Epilepsy and educational outcome were recorded for a period of 1 to 5 years after diagnosis. As a group, the patients performed significantly worse than controls in spelling, reading aloud, and reading comprehension, and they presented dyslexic-type errors (160). In a study, 20 patients and 20 controls were assessed for language performance using standard neuropsychological measures and for patterns of language lateralization using fMRI (125). The study revealed that language-related activation was less lateralized to the left hemisphere in anterior brain regions in the patients. This finding was consistent with decreased performance in the neuropsychological tests, which are most dependent on the integrity of anterior aspects of the language axis, namely, sentence production.
Children with typical SLECTS may have symptoms of autism spectrum disorder and ADHD, especially with late onset of seizures (15). The prevalence of ADHD may be up to 65% and patients perform poorer on executive and attentional tasks (126; 48). SLECTS patients with ADHD have significantly thinner superior-inferior frontal cortex, superior temporal cortex, left pericalcarine, and lingual and fusiform cortex compared to healthy controls and a thinner left fusiform cortex compared to SLECTS without ADHD (105).
Alterations in white matter microstructures, predominantly in the left hemisphere, were noted in 19 children with SLECTS and cognitive abnormalities (108). Cognition, cortical thickness, and subcortical volumes were studied in 24 children with SLECTS and compared with centrotemporal spikes and 41 controls (78). Atypical maturation of cortical thickness antecedent to the epilepsy syndrome resulted in early identified abnormalities that continued to develop abnormally over time.
Thirty-three children with a diagnosis of SLECTS were monitored for at least 2 years showed a higher risk for residual verbal difficulties. Abnormal neuropsychological development was significantly correlated with greater frequency of NREM sleep discharges, school-age epilepsy onset, and a higher number of antiepileptic drugs (73).
The presence of atypical interictal epileptiform EEG patterns does not appear to alter prognosis (17). A meta-analysis of 794 patients in 13 cohorts, concluded that the early prediction of seizure outcome in the new patient cannot be made with certainty in SLECTS (21). In a small group of patients with status epilepticus in this epilepsy syndrome, the finding of independent right and left seizures was considered a risk factor (85).
As stated before (115), early onset of SLECTS is associated with poor response to initial treatment (234). Outcome of this condition was compared for 126 children with typical and atypical features. Group A comprised 66 children with typical features, and group B comprised 60 children with atypical features that included onset before 4 years of age, developmental delay or learning difficulties, and EEG abnormalities beyond those seen in typical cases. Both groups had similar long-term outcome (50).
However, atypical evolutions may cause doubt about prognosis. For example, in the cases of benign atypical partial epilepsy described by Aicardi and Chevrie (03), the children showed focal or generalized atonic fits leading to multiple daily falls. These inhibitory attacks appear in clusters that last for weeks, and the EEG shows continuous spikes-and-waves during slow sleep. The term “pseudo Lennox syndrome” was suggested for this syndrome (89). Status lasting days or weeks including motor facial seizures and anarthria with persistent drooling constitute another complication of this syndrome (72; 68). Both complications have shown an ultimate good prognosis. However, acquired epileptic aphasia and the syndrome of continuous spikes-and-waves during slow sleep have also been associated with this syndrome, with the risk for permanent language dysfunction or neuropsychologic involvement (63; 68; 69). It is not completely clear from the currently available data whether we can consider atypical benign focal epilepsies of childhood, status epilepticus of SLECTS, Landau-Kleffner syndrome, and continuous spike-and-wave slow sleep syndrome as independent electroclinical syndromes, syndromes related to SLECTS as part of a continuum, or atypical evolutions appearing in a minority of patients.
EEG activity in this atypical evolution seems to be a kind of secondary bilateral synchrony, but the reasons why some children develop this EEG pattern are yet not understood. In some cases, certain antiepileptic drugs seemed to be responsible (192; 27; 170).
A Dutch study of epilepsy in childhood included a long-term follow up (12 to 17 years) in 29 children with SLECTS. The authors concluded that both typical and atypical cases had very good prognosis and high remission rates (24). Transition issues were considered in children with SLECTS and other idiopathic epilepsies. The authors concluded that this epilepsy syndrome always enters terminal remission before the general age of a planned transition of adolescents (25).
Genetic etiology. The characteristic centrotemporal EEG spike pattern in SLECTS is inherited as an autosomal dominant trait with variable penetrance (93). This type of inheritance was also suggested by studies of monozygotic twins with these discharges (101), and HLA antigens and their haplotypes (60). However, in another study of clinical and genetic aspects in children with benign focal sharp waves, including 134 probands with seizures (24% of which had typical seizures), the findings were in agreement with a multifactorial pathogenesis of epilepsies with focal epileptiform sharp waves (56). Epileptic seizures appear in only 25% or less of individuals with this EEG trait. Expression of the gene may be influenced by other genetic and environmental factors.
A family with 9 affected individuals in 3 generations was reported with oral and speech dyspraxia and cognitive impairment in this syndrome (188). A 3-generation pedigree with 11 of 22 children affected with a variant form of SLECTS, a speech impairment, oromotor apraxia, and cognitive deficit was reported (116).
Linkage to chromosome 15q14 was found in 54 patients of 22 families (149). However, in a study of 70 families with the same syndrome in Italy, the mentioned linkage could not be found (171). Seizures and EEG phenotype of SLECTS were found in 3 children with “de novo” terminal deletions of the long arm of chromosome 1q and the authors suggested that it could be a potential site for a candidate gene (215). In a multicenter twin collaboration study analysis of etiology of SLECTS, no concordant twin pairs with the classic form of this syndrome were found in the 18 pairs identified, suggesting that noninherited factors are of major importance in etiology (212).
Thirty siblings from 23 affected families were studied and the conclusion was that the segregation ratio of centrotemporal spikes in families with SLECTS is consistent with a highly penetrant autosomal dominant inheritance, with equal sex ratio (10).
A genome-wide linkage of centrotemporal spikes to 11.p13 was reported (197). Pure likelihood statistical analysis allowed fine mapping of centrotemporal spikes to variants in Elongator Protein Complex 4 (ELP4) in 2 independent data sets. This is the first human disease association of ELP4, which is related to genes implicated in cell motility and migration. Other advances in genetic studies have also been reported (181). Three patients with intellectual disability, various dysmorphic features, and epilepsies involving the rolandic region were reported carrying deletions in 16p13, including GRIN2A (175). A girl with a mutation of KCNQ2, presenting benign familial neonatal convulsions and childhood epilepsy with centrotemporal spikes in childhood, was also reported (99).
Several reports have been published regarding mutations in GRIN2A associated with SLECTS. Lemke and colleagues detected new heterozygous mutations in GRIN2A in 27 of 359 affected individuals from 2 independent cohorts (120). Mutations occurred significantly more frequently in the more severe phenotypes. GRIN2A was identified as the major gene for epileptic encephalopathies within the spectrum of epileptic aphasia (29; 124). A clinical genetic study of 31 probands with continuous spike-and-wave during sleep syndrome, Landau-Kleffner syndrome, atypical benign partial epilepsy, and other epileptic disorders with aphasia, showed higher frequencies of seizures in relatives of these probands pointing towards a complex inheritance of these conditions (208).
In a study, array comparative genomic hybridization (aCGH) and quantitative polymerase chain reaction were used to analyze the genomic status of a series of 47 unrelated SLECTS patients who displayed various types of electroclinical manifestations. Thirty rare copy number variations (CNVs) were detected in 21 patients. The CNVs of highest interest comprised or disrupted strong candidate or confirmed known genes for epilepsy, including GRIN2A and PRRT2 (54). Association of brain-derived neurotrophic factor (BDNF) and elongator protein complex 4 (ELP4) polymorphisms with SLECTS has been questioned in a study on 60 patients (84).
With the objective to test whether mutations in γ-aminobutyric acidtype A receptor (GABAA-R) subunit genes contribute to the etiology of SLECTS or its atypical variants, exome sequencing was performed in 204 European patients. The statistical association and the functional evidence suggested that mutations of the GABRG2 gene may increase the risk of this syndrome or its atypical variants (174).
To date, fewer than 10 genes have been associated with SLECTS (GRIN2A, ELP4, BDNF, KCNQ2/3, DEPDC5, RBFOX1/3, and GABRG2) (58). A nonsynonymous heterozygous CHRNA4 pathogenic variant has been described in 3 patients with SLECTS in a pedigree from China who responded to the CHRNA4-targeted drug CBZ (148). A heterozygous frameshift variant causing loss of function of NR4A2 has been noted in this type of epilepsy associated with intellectual deficiency and language impairment (172).
A study of rare gene deletions affecting protein coding regions in 194 patients with SLECTS (100) found that 43 patients (22%) carried rare gene deletions in chromosomes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 15, 16, 17, 18, 19, and 20 that overlapped with the known autism- and epilepsy-associated candidate genes. A study on exome sequencing in 57 patients with self-limited focal epilepsies of childhood with typical or atypical presentations and negative status for GRIN2A pathogenic variants identified rare candidate variants in 20 patients that were most commonly associated with atypical SLECTS (180). Pathogenic variants in GRIN2B and CAMK2A and a likely pathogenic variant in CACNG2 were identified. The rest of the variants were considered of unknown significance.
A genome-wide association study investigating the role of common genetic variants in 1800 Chinese Han SLECTS patients and 7090 healthy controls showed strong associations of multiple SNPs in regions on chromosome 3, 15, and 10 located in or nearby the genes KALRN, CHRNB4, and PTCHD3/RAB18, respectively (191). The authors demonstrate that the SNP rs1948 (through effects on expression of CHRNA5 in brain tissue) and maternal smoking around birth are significantly associated with increased risk of SLECTS (odds ratio = 3.9). The study highlights the role of common variant heritability and environmental risk factors in pathogenesis of SLECTS (191).
Pathophysiology. The typical focal, ictal clinical behavior and EEG discharge indicate a disturbance in the sylvian and rolandic areas. SLECTS, Landau-Kleffner syndrome, and continuous spike-and-waves during slow sleep syndrome are often considered as a spectrum of disorders with a common transient, age-dependent, nonlesional, genetically based epileptogenic abnormality, implying the role of a perisylvian epileptic network where the cognitive impairment is caused by epileptic discharges interfering with cognitive development (92). Electrophysiologic studies, however, fail to demonstrate a discrete generator, and a large, shifting area of dysfunction may be present. In some patients SLECTS, the occurrence of generalized spike-wave EEG discharges, as well as focal spikes in other areas, suggests a relationship between this disorder and the idiopathic generalized epilepsies, as well as with other idiopathic focal epilepsies (122). Around 20% of patients with centrotemporal spikes may also have sharp slow wave complexes in other cortical locations (158). A delayed cortical maturation at the centrotemporal brain regions has been proposed based on the comparison of resting-state brain activities by quantitative electroencephalography in 16 SLECTS patients with clinical seizure remission stage in comparison with healthy controls (193). The study revealed a significantly higher absolute power of the theta and alpha waves in SLECTS patients with clinical seizure remission mainly over the centrotemporal electrodes as opposed to the expected age-related decrease with brain maturation.
Because SLECTS presents during a specific age group when significant diffuse white matter maturation in the brain is going on and has a dramatic activation with non-REM sleep, a role of aberrant thalamo-cortical circuits has been postulated (118). Patients with atypical evolution of SLECTS show a symmetric hypoperfusion at the level of thalamus in interictal SPECT without structural abnormalities on MRI and increased risk of cognitive deficits (07). A study compared the EEG sleep findings in 30 children with SLECTS with 20 age-matched healthy controls and found significantly lower mean values of the amplitude, duration, and density of the spindle activity in patients with SLECTS (183). Additionally, the risk of epilepsy was found to increase by 1.9 % by the decrease of the mean amplitude of the spindles by 1 mV when compared to control group. Overall, these findings suggested an underlying pathophysiologic mechanism for thalamocortical oscillations in SLECTS.
A comparative brain tractography study of 23 children with SLECTS aged 8 to 15 years and age-matched controls showed that children with SLECTS had aberrant development of thalamocortical connectivity to the rolandic cortex, absence of an expected increase in connectivity with age, and persistence of abnormalities over time when observed longitudinally (204).
SLECTS accounts for about 24% of all epileptic seizures in children between 5 and 14 years of age (30). Its annual incidence has been reported to be between 7.1 and 21 per 100,000 in children under 15 years of age, with a male preponderance (93). Because nocturnal seizures can be easily missed in diagnosis, this disorder may be even more common than generally suspected. There is a slight male predominance.
The prevalence of epilepsy is much higher among close relatives of children with SLECTS than in a matched control group (23). In 1 study, 15% of siblings had seizures and centrotemporal spikes, 19% of siblings had centrotemporal spikes without clinical events, and 11% of the parents had childhood seizures that had disappeared by adulthood (93).
In an epidemiological study of epilepsy in childhood with a cohort of 440 consecutive patients, excluding only neonatal seizures from the analysis, SLECTS accounted for 8% of patients (114). An epidemiological study of childhood epilepsy in a Swedish county identified 205 children with epilepsy. The total prevalence rate was 3.4 per 1000 with a peak prevalence in the age group 8 to 11 years. Among the epilepsy syndromes recognized, SLECTS was the most common (117). SLECTS has been recognized all over the world. In a retrospective study in China, 276 patients were enrolled and electroclinical features showed to be quite characteristic (236).
A retrospective cohort study of 379 children aged 0 to 16 years born between 1994 and 2012 in the UK and followed from birth until September 2017 reported that the contemporary UK incidence of this epilepsy is 5/100,000/year and has remained virtually unchanged between 1997 and 2014; males and children aged 6 to 11 years have the highest incidence. Comorbidities, particularly pervasive developmental disorders, were noted in 12% of children (196).
The presence of the characteristic centrotemporal spikes alone is not diagnostic of epilepsy. Within the susceptible age range, more children will exhibit the characteristic EEG spike pattern without seizures than with seizures. Furthermore, centrotemporal spikes with other morphologic features can be seen in nonepileptic children with diffuse brain disturbances such as cerebral palsy (166) and Rett syndrome (177). SLECTS is the most common epilepsy syndrome, seen in patients with fragile X syndrome, and centro-temporal spikes may be present as an asymptomatic finding (107).
Distinction between SLECTS and structural focal epilepsies, such as mesial temporal lobe epilepsy, can usually be made easily on the basis of history and the unique dipole pattern of the centrotemporal spike. The EEG alone is sufficient to make the diagnosis of SLECTS when nocturnal convulsions are the presenting complaint and a generalized epileptic syndrome is initially suspected.
Because of their prevalence, fortuitous associations may be found between SLECTS and static brain lesions with epilepsy (184). Isolated cases of children with this epileptic syndrome and unilateral opercular neuronal migration disorders have been published (05; 63; 189). Cerebral tumors were reported in 5 patients (190). Five children with neuronal migration disorders and gliosis were reported as presenting similar to clinical and EEG features of SLECTS. The authors emphasized the role of magnetoencephalography in the differential diagnosis (153). Characteristic spikes of SLECTS were found in 2 of 17 preadolescent children who eventually underwent anteromesial temporal resection for refractory temporal lobe epilepsy due to hippocampal sclerosis and the authors suggested that it might not have been an incidental finding (156).
The pathophysiologic relationships that may exist between SLECTS and other self-limited focal nonrolandic epilepsies can make differential diagnosis difficult. The coexistence of 2 types of self-limited focal epilepsies in children has been reported, either presenting in sequence one after the other or at the same time (157; 27; 39; 28; 31). The coexistence of childhood absence epilepsy and SLECTS was detected in 11 patients through a systematic record review from 8 epilepsy centers (217). A comparison of 17 patients with absence epilepsy and centrotemporal spikes with age-matched 90 children with absence epilepsy showed significantly more global developmental (5 [29%] vs. 5 [6%], P < .009) and expressive language (4 [24%] vs. 5 [6%], P < .034) delay, and more difficulties with school performance (11 [65%] vs. 32 [36%], P < .025), especially with language-related tasks (6 [35%] vs. 5 [6%], P < .001) in children with absence epilepsy and centrotemporal spikes (51). The latter may be a marker of additional cognitive challenges for the physicians.
Finally, another interesting association to consider is with migraine in patients with SLECTS (18). In a comparative cohort of children with SLECTS, with cryptogenic/symptomatic partial epilepsy and with no history of seizures (n = 53 each), a higher rate of migraine was identified in focal epilepsy, regardless of the etiology (230). Another study of 72 children with SLECTS and their siblings showed that prevalence of migraine was 15% in epilepsy probands versus 7% in nonepileptic controls (33). Prevalence of migraine was 14% in siblings of SLECTS and 4% in siblings of controls.
When the clinical and EEG features are typical, the diagnosis is certain. The diagnostic tests and their relevance are discussed below:
EEG. The cornerstone of the diagnosis of SLECTS lies in the characteristic interictal EEG pattern: centrotemporal spikes on normal background activity. The centrotemporal spikes are typically seen independently on both sides of the head. They are broad, diphasic, high-voltage (100 to 300 microvolts) spikes, with a transverse dipole, and they are often followed by a slow wave. The spikes may occur isolated or in clusters, with a rhythm of about 1.5 to 3 Hz. Focal rhythmic slow activity is occasionally observed in the region where the spikes are seen (143). Generalized 3 Hz spike-and-waves and focal spikes in other brain areas may also be seen in a minority of children (17). In a study on hemispheric lateralization in 114 children with SLECTS, the lateralization of interictal spikes was not consistent, but there was a slight left hemispheric predominance in boys and a right hemispheric predominance in girls (145).
The centrotemporal spikes are not enhanced by eye opening or closure, by hyperventilation, or by photic stimulation. Even more, it has been reported that hyperventilation reduces the frequency of rolandic spikes (225). The discharge rate is increased in drowsiness and in all stages of sleep, and in about one third of children, the spikes appear only in sleep (135). The sleep EEG organization is preserved (45). In spite of their increasing frequency during sleep, the centrotemporal spikes show the same morphology as during wakefulness. A change in morphology, particularly the appearance of fast spikes or polyspikes, or a marked increase in the slow component, or a brief depression of voltage evoke an organic etiology even when the ictal features are suggestive of SLECTS (47). There is no correlation between the burden of spike discharges in the EEG and frequency, length, or duration of clinical seizures (121). In fact, extreme discrepancies between the rarity of seizures and the activity of the EEG foci are not uncommon, and clinical experience indicates that the EEG is often relatively unchanged, even with effective treatment (08).
The ictal EEG discharge usually begins focally in the centrotemporal area and then spreads to adjacent areas or generalizes. Ictal onset may shift from side to side (83; 44).
Several authors emphasized the characteristic dipolar pattern in the EEG (86; 130; 209). Two groups of patients have been noted according to EEG findings (maximal negativity was registered in high- and low-central regions, but never in midtemporal regions), a high-central region group with more frequent hand involvement and the low-central group with common orofacial symptoms. Electroencephalographic spike source dipoles of centrotemporal spikes were analyzed in 37 patients (109). Differences in spike source dipole were found in patients showing atypical outcomes. An algorithm for automatic classification of centrotemporal spikes in the interictal EEG according to the epilepsy type has been proposed that may distinguish benign from symptomatic causes (141).
Spike ripples have been identified as a promising new biomarker of epilepsy in noninvasive EEG studies (74). Ripples on centrotemporal spikes are considered to indicate epilepsy severity. The absence of ripples predicts a relatively benign clinical entity (214). A study proposed that spike ripples (ripples cooccurring with epileptiform discharges) have a comparable sensitivity and negative predictive value but greater specificity and positive predictive value as compared to spikes alone in predicting seizure risk in children with SLECTS (112).
In a comparative study between 7 patients with atypical SLECTS and 18 patients with typical SLECTS in the secondary bilateral synchrony and nonsecondary bilateral synchrony periods, it was found that ripples were enhanced when interictal epileptiform discharges were bilaterally synchronized in patients with atypical SLECTS (97). The study highlighted the distinction between atypical from typical SLECTS with ripple distribution in the nonsecondary bilateral synchrony period.
A study of 21 children with SLECTS compared to controls showed that the patients have mild language defects, revealed by tests measuring phonemic fluency, verbal re-elaboration of semantic knowledge, and lexical comprehension. Interictal EEG discharges demonstrated that a high rate of occurrence while awake, multifocal location, and temporal prominence (176).
Twenty-six children with this syndrome were compared with healthy controls. The absolute and relative powers in the delta, theta, alpha, and beta bands of the quantitative EEG and their relation to IQ measurements were evaluated. In children with SLECTS, a negative correlation between the absolute delta and theta powers and the performance IQ was observed (202).
Combined recording of interictal spikes and somatosensory evoked potentials concluded that in some patients multiple simultaneous neuronal populations are active within the central region (12). Verrotti and colleagues stated that in SLECTS, NREM sleep interictal epileptiform discharges (IED) may interfere in the dialogue between temporal and frontal cortex, causing declarative memory deficits (221).
Intrahemispheric cortico-cortical EEG functional connectivity (EEGfC) was explored in 17 non-medicated children with SLECTS and 19 controls, and the areas of increased EEGfC corresponded to cortical areas related to speech and attention deficits (34).
A nonlinear analysis, including measures such as multiscale entropy and recurrence quantitative analysis, of visually normal EEGs has been used to differentiate between patients with and without SLECTS (186). Magnetoencephalographic analysis of generator and propagation of centrotemporal spikes in SLECTS with neuromagnetic 3-dimensional dipole localization suggested that these discharges are generated through a mechanism similar to that of somatosensory evoked responses (140). A localization analysis of spontaneous magnetic brain activities also suggested the value of magnetoencephalography for pathophysiological elucidation (102). Six children with bilateral centrotemporal synchronous discharges were studied using magnetoencephalography and EEG with equivalent current dipole modelling. Results implied cortical epileptogenicity in bilateral perirolandic areas (127). Interictal spikes were recorded during fMRI acquisition in a MR-compatible digital EEG system in 7 children, and the spike-related activation in the perisylvian central region was found in 3 of them (19). Using high resolution EEG and MEG and a realistic volume conductor model, spatiotemporal aspect of the sources of spikes in children with SLECTS were investigated. Results for the EEG and MEG were different. Both high resolution EEG and MEG revealed that in some cases sources well separated in space and time exist, whereas in other cases, only single source activity can be resolved (96). In a study of 20 children examined by combined EEG, magnetoencephalography and MRI, location of spikes was determined by dipole source estimates. A correlation was shown between location of spikes and selective cognitive deficits, with left perisylvian spikes associated with lower language test in 11 cases, whereas 6 children with right perisylvian location performed within normal ranges in all parts of the tests (231). Serial changes in regional cerebral volumes were measured using 3-dimensional magnetic resonance imaging in 2 children with SLECTS presenting cognitive impairments, compared with 5 children without deficits. Frontal and prefrontal volumes revealed growth disturbances in the patients with cognitive impairments (103).
In a study of 10 children combining MEG and EEG to elucidate the oscillatory dynamics with respect to interictal spike occurrence in this epilepsy syndrome, bilateral increase of 0.5 to 25 Hz oscillations during unilateral spike formation was found, suggesting that by using wavelet transform analysis, one could be able to detect irritative features not detected in visual analysis (128). In a study of 9 children using comprehensive neuropsychological testing, the authors reaffirmed that magnetoencephalography is a valuable diagnostic tool in the examination of children with SLECTS (165).
MRI brain. A few cases have been noted to have focal cortical dysplasia and even tumors after presenting with the clinical and EEG phenotype of SLECTS (05; 63; 190; 189). In 171 consecutive patients with this syndrome studied with CT or MRI, 10 children were noted to have neuroimaging abnormalities (80).
Positron emission tomography (PET) is not routinely performed in these children. PET might be helpful to distinguish SLECTS from symptomatic cases of focal epilepsy in children because regional glucose metabolism is normal in patients with the former (213). Focal cortical hypermetabolism in the central cortex was noted in 3 children with atypical SLECTS during the seizure-free period (40), suggesting a localized, increased cortical activity, likely due to either subclinical seizure activity or “active” inhibitory (GABAergic) processes. Functional MRI, especially in the resting state, is being increasingly used to identify the epileptogenic focus as well as the propagation of the spike activation. Amplitude of low-frequency fluctuation and regional homogeneity are 2 of the most widely used neuroimaging methods to localize the regional brain activity (235). A “granger causality density” method has been proposed as an effective and reliable neuroimaging biomarker to localize the interictal focus of SLECTS and make an early diagnosis (43). Another pilot study proposed the use of transcranial magnetic stimulation paired with EMG and EEG to measure the trajectory of cortical excitability in children with SLECTS and to assess whether motor cortex plasticity correlates with learning ability (11). Resting state functional MRI analysis has shown an association between centro-temporal spikes and earlier hemodynamic activations in epileptogenic regions in SLECTS that were counteracted by levetiracetam treatment (233). These investigational techniques may improve the overall management of SLECTS in future.
Functional MRI volumetric differences and shape deformities of caudate, putamen, pallidum, and thalamus were studied in a group of 13 children with recent-onset SLECTS and 54 healthy controls (129). Children with SLECTS demonstrated significantly hypertrophied putamen, and the larger putamen volumes were linked to better cognitive performances. Aberrant functional connectivity between motor and language networks were found in 23 children with rolandic epilepsy studied with fMRI (16).
SLECTS is an age-related syndrome that almost always disappears by adulthood regardless of age at onset; therefore, excessive restriction of activities and overprotection of affected children are not advised. Drug therapy is necessary only in about 30% of patients. Monotherapy should be used whenever possible. Carbamazepine and valproic acid were always the drugs of choice. More recently, levetiracetam monotherapy has gained attention as a probable alternative.
Levetiracetam has been shown to be efficacious and well tolerated in this syndrome. In a comparative trial on 56 patients with SLECTS, 33 children received levetiracetam and 23 received valproic acid as initial monotherapy (232). The seizure-freedom rates were not significantly different between the 2 groups. A greater number of the children taking valproic acid achieved EEG normalization compared to those taking levetiracetam (95% vs. 72% at 18 months). The authors concluded that low-dosage valproic acid and levetiracetam monotherapy are equally effective in controlling seizures but valproic acid exhibited better efficacy than levetiracetam in improving the electrophysiological abnormalities. In a comparative study, 89 patients were treated with carbamazepine, 73 patients with valproic acid, and 35 patients with levetiracetam (104). Responders comprised 11.2% of the patients treated with carbamazepine, 56.2% of the patients with valproic acid, and 71.4% of the patients with levetiracetam.
A study demonstrated that levetiracetam inhibits centro-temporal spikes-associated activation intensity and alters its temporal pattern (235). Levetiracetam also affects the brain deactivation related to higher cognition networks. Forty patients with SLECTS, including levetiracetam-medicated patients (n = 20) and drug-naive patients (n = 20), were studied. Both the groups showed centro-temporal spikes-associated activation in the rolandic cortex whereas activation strength, time-to-peak delay, and overall activation were diminished in the levetiracetam-medicated group. A study compared the changes in the cognitive profile of 20 children with SLECTS on levetiracetam monotherapy (dose range 500-1750 mg/d) and 10 children with specific learning disabilities. Children administered levetiracetam showed a mild but statistically significant improvement in overall cognitive abilities. Verbal skills, visual-perceptual reasoning, working memory, and processing speed showed slight but significant improvement as compared to the control group at 2-year follow-up (152). A German study of 43 children with SLECTS suggested that antiepileptic drug treatment with either sulthiame or levetiracetam does not affect cognitive performance (199).
Seventy newly diagnosed patients with SLECTS were treated with oxcarbazepine monotherapy and followed with clinical EEG and cognitive evaluations. The results suggested that oxcarbazepine is effective in preventing seizures and normalizing EEGs and seems to preserve cognitive functions and behavioral abilities as long-term monotherapy in children with typical forms of this condition (210). Children with bilateral findings on EEG showed a similar good response to treatment with either sodium valproate or carbamazepine or oxcarbazepine. Children with unilateral findings on EEG were found to respond better to carbamazepine or oxcarbazepine (164).
In a comparative study between levetiracetam and oxcarbazepine, 39 children with SLECTS were randomly assigned to one of these drugs. Preliminary findings suggested that both drugs where effective (38). A monotherapy noncontrolled study with levetiracetam in 21 children with the disorder showed that it is effective and well tolerated in children using doses ranging from 1000 to 2500 mg per day (219). An add-on levetiracetam study in 32 children showed that 62.5% of the patients did benefit and that levetiracetam tended to be more helpful in atypical SLECTS (224). Results from a pilot study transitioning children with onto levetiracetam monotherapy showed a beneficial effect on language skills (111).
Benzodiazepine treatment for several weeks was also recommended (52). In comparison with valproate and carbamazepine, clonazepam showed to be more efficient in making rolandic discharges disappear after 4 weeks of treatment (142). The use of clobazam at night may be considered in those children who only have seizures during sleep (64). A prospective controlled study of clobazam versus carbamazepine in patients with frequent seizure episodes showed that clobazam in monotherapy was as effective as carbamazepine and better tolerated (06).
Sulthiame was recommended in several reports (55; 123). In a double-blind, placebo-controlled study of 66 children, sulthiame was found to be remarkably effective in preventing seizures and was well tolerated (173). Another report also shows the benefits of sulthiame (62). It has been considered as the drug of choice in patients presenting atypical evolutions associated to secondary bilateral synchronies in the EEG (68; 64). A series of 28 patients with symptomatic and 25 cases with idiopathic encephalopathy related to electrical status epilepticus during slow sleep treated with add-on sulthiame was presented (67). Twenty-one of the 25 patients in the idiopathic group, most having SLECTS in the past became seizure free and without ESES in less than 3 months after the add-on therapy with sulthiame. A noninferiority study comparing levetiracetam to sulthiame performed in 43 patients with SLECTS showed that the rates of seizure free patients were relatively high in both groups, although the results indicated that termination of drug treatment due to seizure recurrence or adverse events occurred more frequently in the levetiracetam group compared to sulthiame group (20). Another randomized controlled trial to compare the effects of levetiracetam and sulthiame on EEG in 43 children with SLECTS showed similar reductions in the spike-wave-index with both the drugs. Persistent EEG abnormalities in both the groups were associated with treatment failures (198). A multicentric study of 1817 Chinese children demonstrated that oxcarbazepine, levetiracetam, and valproic acid could be used as the first-line drugs and the efficacy of oxcarbazepine and levetiracetam was higher than that of valproic acid (132). A metaanalysis of 49 studies from 2000 to 2018 suggested that levetiracetam, as an initial antiepileptic drug, was superior to carbamazepine for cognitive protection (09).
In a retrospective study of 430 patients with centrotemporal spikes, the comparative efficacy of levetiracetam, oxcarbazepine, and valproate was evaluated over a 2-year follow-up (88). There was no significant difference in EEG results, number of status epilepticus, atypical features, or recurrence rate. The authors noted that the failure rate of levetiracetam as initial therapy was significantly higher than those of oxcarbazepine and valproic acid.
In a monotherapy trial of topiramate (131), the drug was orally administrated once a night (2 mg/kg/day) and twice a day (4 mg/kg/day) in 85 patients with SLECTS. There was no significant difference in overall efficacy rate or changes in EEG activity between the 2 groups but the rate of adverse reactions for night dose was significantly lower than day-time dosing group, suggesting the former as a feasible strategy for the treatment of SLECTS. In a retrospective study of 120 patients who were randomly treated with lamotrigine, oxcarbazepine, or topiramate monotherapy and underwent EEG and standardized language tests, it was noted that the seizure recurrence rates were 19.4% with lamotrigine, 21.7% with topiramate, and 11.4% with oxcarbazepine. Overall, the improvements in language and problem-solving performance in children with SLECTS were greater for lamotrigine and oxcarbazepine than for topiramate (91).
The initiation of antiepileptic treatment may be deferred until the occurrence of a second seizure occurs. Focal seizures, a short interval between the first and second attack, and an early onset, usually indicate the necessity of treatment. A subset of patients requiring more than 1 medication for seizure control showed more seizures prior to initiation of treatment and tended to have a higher frequency of tics, attention deficit hyper activity disorder, and learning disabilities (04). Because the seizures will almost invariably disappear in adolescence, therapy beyond that period is of little value. Relapse of seizures, however, may occur after premature antiepileptic drug withdrawal. Studies suggest that the antiepileptic drugs can control the seizures but they neither improve the interictal EEG significantly nor shorten the years of spike persistence (110). Young age of seizure onset correlated with longer duration of EEG abnormalities (119). Pattern of spike disappearance did not significantly differ between the medication naïve group and antiepileptic drug-treated group (90). In a prospective study of treatment in childhood epilepsy, it was concluded that 1 year of treatment may be recommended in children with SLECTS (22).
In a retrospective analysis of initial antiepileptic drug treatment in 84 children with this epilepsy syndrome, it was shown that 14% of the children continued to have seizures after initial AED treatment (98). Multivariate analysis suggested that younger age of seizure onset was the independent risk factor, predicting a poor response to initial AED treatment. In a retrospective study to identify risk factors associated with poor response to initial AED therapy in 57 with SLECTS, 28% experienced poor responses, and predicting factors included onset of seizures prior to the age of 5 years and history of febrile seizures (162). A retrospective study of 17 patients with SLECTS plus electric status epilepticus during sleep, many of them presenting with different comorbidities (ADHD and behavioral disturbances), showed that after treatment with an average of 3 antiepileptic medications during a mean follow-up of 5.5 years, the patients did not present cognitive or behavioral deterioration (211). The author suggested that steroid usage is usually necessitated by the occurrence of cognitive decline.
The following recommendations may be worthwhile to prevent atypical evolutions:
(a) Avoid the use of classic antiepileptic drugs (phenobarbital, paraldehyde, carbamazepine, valproate) and some of the new antiepileptic drugs (lamotrigine, oxcarbazepine, gabapentin) in children with atypical clinical features and/or excessive EEG abnormalities.
(b) When these risks are evident, initiate treatment with sulthiame or benzodiazepines.
(c) In patients presenting with seizures only during night sleep without the abovementioned atypical features single nocturnal doses of clobazam may be recommended.
(d) Finally, if the interval between the events is very long, the risks and benefits of maintaining the child only with lifestyle modification without the initiation of antiepileptic drugs may be discussed with the parents.
Treatment strategies in children with electrical status epilepticus during slow sleep. Because these children are usually receiving more than one antiepileptic drug, first discontinue the antiepileptic drug that has already been demonstrated as capable of inducing the electrical status and then add sulthiame or a benzodiazepine. In cases with negative myoclonus, ethosuximide may also be a choice. Good results are usually seen with sulthiame in doses up to 15 mg/kg/day (71). In general, patients were kept either on sulthiame alone or in combination with levetiracetam or clobazam.
The prognosis is excellent, and with less than 2% of cases developing absence seizures or generalized tonic-clonic seizures in adult life. Adults who had recovered from SLECTS did not have general negative outcomes in the field of development, education, employment, and social adaptation (26).
A systematic review and metaanalysis of 42 published studies on cognitive functioning in children with SLECTS until 2016 (comprising a total of 1237 children with SLECTS and 1137 healthy control children) concluded that children with SLECTS demonstrated significantly lower scores on neuropsychological tests across all cognitive factors compared to healthy controls (228). The observed effects ranged from 0.42 to 0.81 pooled standard deviation units, with the largest effect for long-term storage and retrieval and the smallest effect for visual processing. Overall, children with SLECTS display a profile of variable diffuse cognitive deficits consistent with a model of widespread cortical dysfunction. The adverse cognitive outcome may not be affected by the number of interictal epileptiform discharges in patients with SLECTS (207).
In a comparative study, children with SLECTS showed thinner cortex at the origin of centro-temporal spikes whereas the typically developing children with faster processing speed had thicker cortices in the regions supporting visuo-motor integration and motor and executive function (75)
A natural history study of children with SLECTS from a large, prospective, longitudinal cohort reported a high incidence of ADD/ADHD symptoms (18.3%) or learning difficulties (21.7%) before the diagnosis (178). New or persistent ADHD (20%), mood disorders (23.6%), learning difficulties (14.5%), and behavioral disorders (7.3%) were common after the diagnosis. At 9-year follow-up, performance on formal neuropsychological testing was comparable to population statistics and sibling controls. Most children (61.7%) had entered terminal resolution after 12-minute seizure-free period. The presence of a premorbid neurodevelopmental concern predicted a longer epilepsy duration (p = 0.02), higher seizure count (p =0.02), and a postmorbid psychiatric or neurodevelopmental diagnosis (p = 0.002).
A small Swedish study indicated residual deficits in dichotic listening (verbal perception) and oromotor performance in young adults with SLECTS when followed up for 10 years (205).
Sudden unexpected death in epilepsy is a very rare outcome in SLECTS and has been reported in 3 children with this syndrome among 189 decedents enrolled in the North American Sudden Unexpected Death in Epilepsy Registry (57). This seems to be an intriguing observation that needs further validation.
A 16-year-old Chinese girl who was diagnosed with SLECTS at the age of 2 years developed refractory status epilepticus induced by propofol anesthesia during a blepharoplasty procedure after being seizure-free for 3 years (136). Caution and monitoring during surgical procedures may be advised.
Arushi Gahlot Saini MD DM MNAMS
Dr. Saini of Postgraduate Institute of Medical Education and Research, Chandigarh, India has no relevant financial relationships to disclose.See Profile
K P Vinayan MD
Dr. Vinayan of the Amrita Institute of Medical Sciences has no relevant financial relationships to disclose.See Profile
Solomon L Moshé MD
Dr. Moshé of Albert Einstein College of Medicine has no relevant financial relationships to disclose.See Profile
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