Epilepsy & Seizures
Genetic epilepsy with febrile seizures plus
May. 02, 2022
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Self-limited epilepsy with centrotemporal spikes (SLECTS) is the new name for the previous epilepsy syndrome of benign 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 it from other sinister causes for focal epilepsies. However, it was subsequently noted that dysfunctions in cognitive and language domains as well as atypical evolutions with a not-so-benign course are seen in this syndrome. As per the current 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 purposes of this review, we are using the term self-limited epilepsy with centrotemporal spikes (SLECTS) for the typical cases to maintain uniformity. Atypical evolutions after a seemingly classical onset as well as clinical variants are discussed separately. Emerging data on cognitive impairment in children with SLECTS have also been described.
• The defining feature of SLECTS is the presence of classical centrotemporal spikes on interictal EEG. However, these are not specific to this syndrome. Centrotemporal spikes may be seen in children without seizures, with other epilepsy syndromes, and with structural lesions in the rolandic area. Moreover, the typical seizures in SLECTS may be seen without the classical spikes on the interictal record.
• An increasing frequency of specific cognitive, language, memory, and attention-related disorders are being reported in children with SLECTS.
• Atypical clinical and EEG features are usually seen with transitory cognitive and language impairments.
• Very rarely, SLECTS may evolve into Landau-Kleffner syndrome and continuous spike-and-waves during slow sleep syndrome with potential for persistent neuropsychological impairments.
Rolandic (centrotemporal) region is named after Luigi Rolando (1773-1831), an Italian anatomist known for his pioneer research in 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 (63; 68). In 1958, the first clinical description associated with EEG features was published (125). 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 (67). Because of the localization of the ictal events, Lombroso proposed the term "sylvian seizures" (114). 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 at that time confirmed the good prognosis (10; 98; 113). 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 (28; 47). As new syndromes were recognized within the spectrum of benign childhood focal epilepsies (136), the term “benign” was considered initially acceptable for this syndrome but was considered inappropriate for some of the other idiopathic focal epilepsies (71).
However, the new ILAE Classification of the Epilepsies proposed the term “self-limited” for the “benign” course of epilepsies to reflect a “likely spontaneous resolution of a syndrome” (151). Hence, a new term “self-limited epilepsy with centrotemporal spike” (SLECTS) has been proposed for BCECTS (151). 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) (167).
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 (10). The age at seizure onset has been proposed as the most important predictor of early remission, irrespective of the initial EEG findings, antiseizure medication treatment, or seizure frequency (96).
Ictal phenomenon. 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 10). This is associated independently with bilateral, repetitive, broad, centrotemporal interictal EEG spikes displaying a characteristic tangential bipolar pattern (70). The ictal manifestations are not indicative of temporal lobe involvement and the term “centro-temporal” refers only to the spike topography.
Seizures. 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 one type.
Oropharyngeal and facial manifestations. are the classical and initial manifestations of the seizures in most children. These include drooling from hypersalivation, 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 one side of the face.
Sensorimotor phenomena. may involve a leg or one half of the body. Miscellaneous symptoms such as abdominal pain may also occur rarely (Loiseau and 10). Among 230 children with SLECTS, six presented with sensory motor seizures in the leg as the main ictal manifestation (59).
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 one seizure. However, in about 20% of children, seizures are frequent and may even occur several times per day (34). Onset before 3 years of age has been stated as the single most important predictor for multiple seizures (93; 192). Neither clinical features, seizure characteristics, nor routine EEG findings were found to be useful in predicting the likelihood of a second seizure in SLECTS (182). 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 (163).
Behavioral problems. Behavioral disorders may be present in approximately one third of patients with SLECTS, including ADHD and oppositional defiant disorder (132). Early onset of seizures and the presence of bilateral interictal epileptiform discharges may suggest an increased risk for behavioral disorders in these children.
Sleep disturbances. Parents of children with SLECTS report a significantly shorter sleep duration, more frequent parasomnias, and increased daytime sleepiness (164).
Cognitive problems. Cognitive problems and low academic achievement might be seen in children with SLECTS. 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 (183).
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 frontocentral dipole in the EEG (p < 0.001) whereas the abnormal language functions correlated significantly with atypical seizure semiology (p = 0.02) (178). The impact of SLECTS on school performance was demonstrated in another study of 40 cases and controls (123). The patients showed lower scores in academic performance, digits and similarities subtests of WISC, and auditory processing subtests, probably due to executive dysfunction. Impaired social behavior (especially on “theory of mind tasks”) was found in 15 children (65).
Children and adolescents with SLECTS had worse performance on social cognition compared to healthy children as evaluated by Faux-Pas Child Task, which evaluates the recognition and comprehension of other people’s mental state (106).
Language skills. A meta-analysis of 22 studies on literacy and language skills in children with SLECT showed the presence of reading and phonological processing deficits highlighting the need for early literacy and language assessment (157). 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 (129). 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 (176). Seizure or treatment variables did not appear to be important risk factors for the reading disorder. 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 (60).
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 (165). Another systematic review of 43 studies (1179 patients and 1086 healthy controls) on executive functioning in children with SLECTS concluded that children with SLECTS show weaker performances in inhibitory control, cognitive flexibility, and verbal fluency when compared with a control group (142). However, because the quality of evidence was classified as very low, caution is needed when interpreting the strength of the results.
Other problems. Spectral resolution is the ability needed for complex listening tasks, such as understanding speech in the presence of background noise, and has a significant role in children, particularly in classroom learning. A study on the auditory spectral resolution abilities of children with SLECTS using the spectral temporally modulated Ripple test showed that the auditory spectral resolution threshold measured was significantly lower when compared to controls (159).
A study of 74 children with SLECTS showed significant oral dyspraxia in these children as compared to children without epilepsy, particularly in simple and sequenced movements (11). This was attributable to the genetically determined immaturity of cortical structures related to motor planning in children with SLECTS.
A neuropsychological comparative study in 33 recently diagnosed patients with SLECTS and 33 patients with SLECTS after complete remission showed that the newly diagnosed patients with SLECTS exhibited emotion discrimination dysfunction, mainly related to sadness, fear, and disgust, using the Eye Basic Emotion Discrimination Task and the Eye Complex Emotion Discrimination Task (188). This dysfunction was more severe in children with an earlier onset of seizures. However, after epilepsy remission, the ability to discriminate emotions returned to normal.
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 (25).
Central auditory processing disorder was noted in 46% of patients with SLECTS and without intellectual disability, dyslexia, and attention-deficit hyperactivity disorders (117).
Atypical features. The data regarding the prevalence of atypical SLECTS are variable. The atypical clinical features include earlier age of onset of seizures, daytime-only seizures, postictal Todd paresis, prolonged seizures or status epilepticus, focal or opercular status epilepticus, and poor neuropsychological outcomes. Reported atypical EEG findings are unusual spike morphology and distribution, absence-like spike-and-wave discharges, and abnormal background. Atypical features have been noted in up to 50% of the patients with SLECTS (185; 37). 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 (118). In a retrospective, multicenter study of 46 patients with atypical features in SLECTS, the predominant manifestations were seizures with affective symptoms (28.2%); seizures with unilateral facial sensorimotor symptoms; oropharyngolaryngeal manifestations; speech arrest with sialorrhea only when awake (24.8%); opercular epileptic status with unilateral or bilateral clonic seizures of the mouth, with speech arrest and sialorrhea when awake and during sleep (15.3%); postictal Todd paralysis after unilateral clonic seizures (15.3%); negative myoclonus (13%); focal sensorimotor seizures characterized by unilateral numbness in the cheeks and one upper limb, additional to unilateral facial clonic seizures, speech arrest, and sialorrhea (2.1%); and sporadic focal tonic-dystonic seizures in the left upper limb only during sleep (2.1%) (61).
Atypical evolution. It is important to discriminate between “atypical features” in children with SLECTS and “atypical evolutions” of SFEC (51; 52). An atypical evolution refers to children with SFEC, including those with centrotemporal spikes, who present with disorders related to continuous spikes and waves during sleep or Landau-Kleffner syndrome. These are associated with severe language and cognitive or behavioral impairments that may be persistent.
The following have been proposed to identify or quantify atypical evolutions:
(1) 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 five ripples on the centrotemporal spikes are predictive of atypical development (174; 137).
(2) Atypical SLECTS showed more widespread and severe hypometabolism than typical SLECTS, mainly located in the fronto-temporo-parietal cortex (102).
(3) Notable risk factors proposed to predict atypical evolutions are frontotemporal and temporo-parietal localization of epileptic foci, semiology of seizures involving dysarthria, and somatosensory auras in the early presentation of the disease (140).
However, the patients with atypical evolutions account for only around 5% of patients with SLECTS in most of the tertiary epilepsy centers for children.
In general, SLECTS is associated with an excellent prognosis.
Seizures. The majority of the children will have only very infrequent seizures, which are well controlled with the initial antiseizure medication. The prognosis is favorable even for those whose seizures are difficult to control, and seizures almost always remit spontaneously in late adolescence.
Cognitive functions. Most of the children will have normal cognitive functions during the period of active epilepsy and after remission (77). Microstructural changes in cortex and white matter were described in some previous studies, the clinical significance of which is not clear (87; 62).
Moderate to severe language impairment. Moderate to severe language impairment has been reported in some children. The most affected domains were expressive grammar and literacy skills. Persistent deficits in children after the seizure remission suggested possible long-term consequences (124). 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 (127).
When monitored for at least 2 years, 33 children with a diagnosis of SLECTS showed a higher risk for residual verbal difficulties. Abnormal neuropsychological development was significantly correlated with a greater frequency of NREM sleep discharges, school-aged epilepsy onset, and a higher number of antiepileptic drugs (56).
Attention deficit hyperactivity disorder (ADHD). The prevalence of ADHD may be up to 65%, and patients perform poorer on executive and attentional tasks (105; 36). SLECTS patients with ADHD were found to 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 (85). A study of 42 patients with newly diagnosed SLECT evaluated the long-term prognosis of attention deficit in children (over a period of 7 years) and showed that the newly diagnosed patients with SLECTS had an impaired attention network, mainly in the alerting and orienting domains (187). Age of onset, number of seizures, and time of antiepileptic treatment may affect the attention networks. The dysfunction in the attention network was reversed with the remission of SLECTS.
EEG patterns. The presence of atypical interictal epileptiform EEG patterns does not appear to alter prognosis (13). 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 (16).
Atypical evolutions. Most of the children with atypical evolutions will also have a good long-term prognosis (Aicardi and Chevrie 1982; 55; 53). However, acquired epileptic aphasia and the syndrome of continuous spikes-and-waves during slow sleep have also rarely been associated with SLECTS, along with the risk for permanent language dysfunction or neuropsychologic involvement (49; 53; 54).
EEG activity in this atypical evolution seems to be a kind of secondary bilateral synchrony. In some cases, certain antiepileptic drugs do seem to be associated with this evolution (155; 21; 141).
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 (18).
Antiseizure medication therapy. Antiseizure medication therapy does not necessarily improve and may actually decrease health-related quality-of-life in SLECTS children with low seizure frequency (02).
Transition. SLECTS almost always enters terminal remission before the general age of a planned transition of adolescents (19).
Over the years, our understanding of the genetic basis of SLECTS has significantly evolved. The characteristic centrotemporal pattern in SLECTS was initially considered an autosomal dominant trait with variable penetrance based on monozygotic twin studies (76; 46; 08). Later, a multifactorial pathogenesis of epilepsies with focal epileptiform sharp waves was considered (42). In a multicenter twin collaboration study analysis of the 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 the etiology (172). The atypical evolution of SLECTS may have a more complex inheritance than a simple monogenic pattern (170).
SLECTS has subsequently been linked to chromosome 15q14, terminal deletions of the long arm of chromosome 1q, chromosome 11.p13, polymorphisms in elongator protein complex 4 (ELP4) and brain-derived neurotrophic factor (BDNF), deletions in 16p13, and mutations in GRIN2A, PRRT2, KCNQ2/3, DEPDC5, NR4A2, CHRNA4, ZMYND11RBFOX1/3, and GABRG2) (97; 40; 69; 145; 44; 143; 126; 45; 78; 128).
GRIN2A has been identified as the major gene in epileptic encephalopathies. The role of GRIN2A mutations in SLECTS, especially in severe phenotypes, has been highlighted in recent studies. With the advent of advanced genetic techniques, genome-wide studies are highlighting rare associations of SLECTS with deletions in chromosomes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 15, 16, 17, 18, 19, and 20 that overlap with the known autism- and epilepsy-associated candidate genes (82). Similar associations have been seen with multiple single nucleotide polymorphisms in regions on chromosomes 3, 15, and 10 located in or nearby the genes KALRN, CHRNB4, and PTCHD3/RAB18, respectively (154). Environmental risk factors, such as maternal smoking around birth, have also been implicated in the pathogenesis of SLECTS (154). A trios-based whole-exome sequencing study in 28 Chinese patients with typical and atypical SLECTS showed an association with the genes ADGRV1, GRIN2B, and RyR2 (111). As these genes are all calcium homeostasis–associated genes, they suggest a potential effect of calcium homeostasis in the epilepsy.
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 (75).
Electrophysiologic studies, however, fail to demonstrate a discrete generator, and a large, shifting area of dysfunction may be present. In some SLECTS patients, 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 (99). Around 20% of patients with centrotemporal spikes may also have sharp slow wave complexes in other cortical locations (135). 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 (156). 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 (95). Children with SLECTS have been shown to have delayed brain development, with increased gray matter volume and decreased white matter volume in the rolandic regions, and a 0.45-year delay in brain age in contrast to children with typical development. Delayed brain age has been associated with neuroanatomic changes in the rolandic regions as well as cognitive dysfunction of attention (193). It has been demonstrated that the epileptiform spikes can be triggered and promoted by either a reduced NMDA current or h-type current, and changes in inhibitory transmission in the thalamic reticular nucleus mediate an antagonistic dynamic between epileptiform spikes and spindles in patients with SLECTS (101). A neurodevelopmental origin of SLECTS has been proposed based on a systematic review of MR imaging studies, suggesting that the development of regions of the cortex in children with this epilepsy is abnormal, more widespread, and due to neurodevelopmental delay rather than apparent "damage" from the epilepsy (158).
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 (04). 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 (148). 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 (167).
A study based on cortical morphometry with surface-based morphometry in 25 patients with SLECTS showed that there is aberrant cortical thickness, cortical gyrification, and sulcal depth in areas related to cognitive functions, including language, attention, and memory (104). There was negative correlation between age of onset and cortical thickness and cortical gyrification, as well as between verbal IQ and cortical gyrification in these areas. This correlation between some brain regions and verbal IQ and age of onset provides a potential marker of early neurodevelopmental disturbance and cognitive dysfunction in SLECTS.
A protocol has been proposed for an ongoing multicentric study on the connectome-based predictive modeling for predicting brain age in patients with SLECTS (179). This is a machine-learning approach that uses whole-brain connectivity measured with neuroimaging data ("neural fingerprints") to predict brain-behavior relationships.
SLECTS accounts for about 24% of all epileptic seizures in children between 5 and 14 years of age (23). 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 (76). 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 (17). In a 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 (76).
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 (92). 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 (94). 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 (195).
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 (160).
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 (139) and Rett syndrome (146). SLECTS is the most common epilepsy syndrome, seen in patients with fragile X syndrome, and centrotemporal spikes may be present as an asymptomatic finding (86).
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 (149). Isolated cases of children with this epileptic syndrome and unilateral opercular neuronal migration disorders have been published (01; 49; 152). Cerebral tumors were reported in five patients (153). 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 (131). 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 (133).
The pathophysiologic relationships that may exist between SLECTS and other self-limited focal nonrolandic epilepsies can make differential diagnosis difficult. The coexistence of two types of self-limited focal epilepsies in children has been reported, either presenting in sequence one after the other or at the same time (134; 21; 29; 22; 24). The coexistence of childhood absence epilepsy and SLECTS was detected in 11 patients through a systematic record review from eight epilepsy centers (177). 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 (38). 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 (14). 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 (186). 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 (26). Prevalence of migraine was 14% in siblings of SLECTS and 4% in siblings of controls.
EEG. The defining feature of the syndrome of SLECTS is the presence of centrotemporal spikes on interictal EEG. EEG background will be normal for the age.
Characteristics of EEG spikes in SLECTS
• 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 (122).
• Generalized 3 Hz spike-and-waves and focal spikes in other brain areas may also be seen in a minority of children (13).
• The centrotemporal spikes are not enhanced by eye opening or closure, by hyperventilation, or by photic stimulation. Hyperventilation may even reduce the frequency of rolandic spikes (181).
• The spike rate is increased in drowsiness and in all stages of sleep, and in about one third of children, the spikes appear only in sleep (114).
• The sleep EEG organization is preserved (33). 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 focal fast spikes or polyspikes, or a marked increase in the slow component, or a brief depression of voltage may suggest the possibility of a focal lesion (35).
• There is no correlation between the burden of spike discharges in the EEG and frequency, length, or duration of clinical seizures (98). 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 (06).
Dipolar pattern in SLECTS
• Several authors emphasized the characteristic dipolar pattern in the EEG (70; 108; 171).
• According to EEG findings, two groups of patients have been noted (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 (88). Differences in spike source dipole were found in patients showing atypical outcomes.
Newer techniques for EEG analysis
• 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 (120).
• Spike ripples have been identified as a promising new biomarker of epilepsy in noninvasive EEG studies (57). Ripples on centrotemporal spikes are considered to indicate epilepsy severity. The absence of ripples predicts a relatively benign clinical entity (174). 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 (91). In a comparative study between seven 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 (80). The study highlighted the distinction between atypical from typical SLECTS with ripple distribution in the nonsecondary bilateral synchrony period.
• 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 (27).
• 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 (150).
• A novel machine-learning model that efficiently distinguished rolandic seizures from normal EEG signals has been proposed, with an accuracy exceeding 97.6% (116). This proposed machine-learning model processes the identification procedure in the following order: (1) creating preliminary EEG features using signal empirical mode decomposition, (2) applying weighted overlook graph, and (3) classifying the results through a 2-dimensional convolutional neural network.
• A novel SLECTS spike detection algorithm based on time domain EEG sequence features and the long short-term memory neural network has been proposed to aid in the automated detection of rolandic spikes, with a sensitivity of 92.04% and precision of 85.75% (191).
Spike clearance velocity. Spike clearance velocity (defined as a decrease in the spike-wave rate over time in 4-year sequential follow-up EEGs) has also been suggested as an EEG marker to guide antiseizure medications in children with SLECTS (166). The study assessed the spike characteristics and temporal spike evolution on serial EEGs of children with SLECTS treated with antiseizure medications. The study cohort consisted of 127 children with SLECTS divided into three groups based on antiseizure medication responsiveness: group I was seizure-free with monotherapy (n: 61, 48%); group II was seizure-controlled with monotherapy (n: 52, 41%); and group III was seizure-controlled with dual therapy (n: 14, 11%). The clinical profiles and sequential 4-year follow-up visual EEG recordings of the children were evaluated. Each EEG was reanalyzed with three spike characteristics on the epochs: (1) spike-wave rate, (2) spike topography, and (3) spike localization. The spike clearance velocity, defined as a decrease in the spike-wave rate over time in 4-year sequential follow-up EEGs, was calculated. The authors found no statistical significance across the study groups with respect to initial EEG spike characteristics (spike-wave rate, spike localization, and spike topography). However, the spike clearance velocity was significantly slower in group III than in group I in 4-year sequential follow-up EEGs. Further, the spike clearance velocity was not different across the antiseizure medication groups (oxcarbazepine, valproic acid, and levetiracetam).
Magnetoencephalographic analysis. Magnetoencephalography 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 (119). An MEG-based study of 33 children with SLECTS and 18 healthy children to explore the pathophysiological mechanism of cognitive function changes in early untreated children showed magnetic source inactivation of the medial frontal cortex and posterior cingulate cortex regions during the interictal time, possibly accounting for the cognitive decline in early untreated children with SLECTS (103). The magnetic source localization in the 4 to 8 Hz frequency band may be a new imaging marker for the diagnosis of new SLECTS.
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 (01; 49; 153; 152). In 171 consecutive patients with this syndrome studied with CT or MRI, 10 children were noted to have neuroimaging abnormalities (64). Frontal and prefrontal volumes revealed growth disturbances in the patients with cognitive impairments (180).
Positron emission tomography. Positron emission tomography is not routinely performed in these children. PET might be helpful to distinguish SLECTS from symptomatic cases of focal epilepsy in children (173). Focal cortical hypermetabolism in the central cortex was noted in three children with atypical SLECTS during the seizure-free period (30), suggesting a localized, increased cortical activity, likely due to either subclinical seizure activity or “active” inhibitory (GABAergic) processes.
Functional MRI (fMRI). Several fMRI studies have been reported in SLECTS. 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 (107). Aberrant functional connectivity between motor and language networks were found in 23 children with rolandic epilepsy studied with fMRI (12). 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 (32). Resting state fMRI studies in a smaller number of patients with SLECT (n=12) show normal cortical-subcortical functional connectivity with compensatory hyperconnectivity between cortical networks caused by widespread cortical abnormal discharges and might account for the self-limited clinical outcome in SLECTS (58). Another fMRI study of 26 children with SLECTS to measure intrinsic brain activity showed aberrant dynamic regional coherence in sensorimotor, linguistic, and lateral temporal regions, suggesting that there is an intrinsic dynamic mechanism or interplay that underlies cognitive performance in these children (83).
Transcranial magnetic stimulation. A 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 (09). Resting state functional MRI analysis has shown an association between centrotemporal spikes and earlier hemodynamic activations in epileptogenic regions in SLECTS that were counteracted by levetiracetam treatment (190).
Other investigational techniques. Seizure occurs when the balance between excitatory and inhibitory inputs to neurons is perturbed, resulting in abnormal electrical activity. Based on this, a study showed that an existing excitatory and inhibitory imbalance in neural networks is a useful diagnostic biomarker for SLECTS using a resting-state dynamic causal modeling-based support vector machine (rs-DCM-SVM) algorithm, with an accuracy of 81% to 88% (31). This multicenter study enrolled a discovery cohort (76 children with rolandic epilepsy and 76 normal controls) and a replication cohort (59 children with rolandic epilepsy and 60 normal controls). Spatial independent component analysis was used in seven canonical neural networks, and a total of 25 regions of interest were selected from these networks. The rs-DCM-SVM classifier was used for individual classification, consensus feature selection, and feature ranking.
• 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 if there are very frequent seizures.
• Monotherapy should be used whenever possible.
• Focal motor seizures, a short interval between the first and second attack, and an early onset usually indicate the necessity of treatment.
• Carbamazepine and valproic acid were traditionally the drugs of choice for this syndrome. Levetiracetam monotherapy has gained attention as a probable alternative. A systematic review of seizure-freedom rates in patients with SLECTS receiving antiepileptic drugs suggested the use of sulthiame, levetiracetam, or clobazam as first-line agents for the treatment of SLECTS in children (66).
• Current data are insufficient to make firm recommendations as most of the studies include a very small number of patients, with limited head-to-head comparisons.
In a comparative trial on 56 patients with SLECTS, 33 children received levetiracetam and 23 received valproic acid as initial monotherapy (189). The seizure-freedom rates were not significantly different between the two 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 another study, 89 patients were treated with carbamazepine, 73 patients with valproic acid, and 35 patients with levetiracetam (84). 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 meta-analysis of 49 studies from 2000 to 2018 suggested that levetiracetam, as an initial antiepileptic drug, was superior to carbamazepine for cognitive protection (07). Levetiracetam inhibited centrotemporal spikes-associated activation intensity and altered its temporal pattern. It also affected the brain deactivation related to higher cognition networks (194). Another 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 (130). 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.
Oxcarbazepine monotherapy was found to be more effective and associated with higher improvements in intelligence and cognitive function than levetiracetam monotherapy in children with SLECTS (161). A multicentric study of 1817 Chinese children demonstrated that oxcarbazepine, levetiracetam, and valproic acid could be used as first-line drugs, and the efficacy of oxcarbazepine and levetiracetam was higher than that of valproic acid (110). In a retrospective study of 430 patients with centrotemporal spikes, the comparative efficacy of levetiracetam, oxcarbazepine, and valproic acid was evaluated over a 2-year follow-up (72). There was no significant difference in EEG results, number of status epilepticus events, atypical features, or recurrence rates.
Benzodiazepine treatment for several weeks was also recommended (39). In comparison with valproate and carbamazepine, clonazepam showed to be more efficient in making rolandic discharges disappear after 4 weeks of treatment (121). The use of clobazam at night may be considered in those children who only have seizures during sleep (50). 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 (03).
Sulthiame was recommended in several reports (41; 100). In a double-blind, placebo-controlled study of 66 children, sulthiame was found to be remarkably effective in preventing seizures and was well tolerated (144). It has been considered as the drug of choice in patients presenting with atypical evolutions associated to secondary bilateral synchronies in the EEG (53; 50). 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 (15). 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 (162).
In a monotherapy trial of topiramate (109), 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 two groups but the rate of adverse reactions for night dose was significantly lower than daytime 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 (74).
As 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 (89). Young age of seizure onset correlated with longer duration of EEG abnormalities (96). Pattern of spike disappearance did not significantly differ between the medication naïve group and antiepileptic drug-treated group (73).
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 antiseizure medication treatment (81). Multivariate analysis suggested that younger age of seizure onset was the independent risk factor, predicting a poor response to initial antiseizure medication treatment. In a retrospective study to identify risk factors associated with poor response to initial antiseizure medication 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 (138).
Auditory stimulation during non-REM sleep suppresses spike activity and has been proposed as a nonpharmacological treatment of SLECTS (90). Further studies are needed before this technique can be implemented in clinical practice.
Overall, the long-term seizure outcome seems to be excellent, with less than 2% of cases developing absence seizures or generalized tonic-clonic seizures in adult life. Adults who had recovered from SLECTS were also not found to have negative outcomes in the fields of development, education, employment, and social adaptation (20).
However, children with SLECTS display variable diffuse cognitive deficits consistent with widespread cortical dysfunction.
A systematic review and meta-analysis of 42 studies published prior to 2016 on cognitive functioning in children with SLECTS concluded that children with SLECTS demonstrated significantly lower scores on neuropsychological tests across all cognitive factors compared to healthy controls (184). However, the possibility of a publication bias cannot be ruled out. The adverse cognitive outcome may not be affected by the number of interictal epileptiform discharges in patients with SLECTS (169). An observational cross-sectional study showed that the mean cognitive and neuropsychological performances were adequate overall 5 years after seizure remission, except for the dictation (175).
A natural history study of children with SLECTS from a large, prospective, longitudinal cohort reported a high incidence of ADHD symptoms (18.3%) or learning difficulties (21.7%) before the diagnosis. 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 (147). A systematic review of nine case-control and cohort studies on ADHD and ADHD-related neural networks in SLECTS showed that the reported prevalence of ADHD in patients with SLECTS was around 60% (05). Early age of seizure onset, long course of disease, and low intelligence scores were found in a cohort of SLECTS with comorbid ADHD (79). Comorbid ADHD has been associated with a higher degree of impairment in some domains of intellect (48).
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 (168).
Sudden unexpected death in epilepsy is a very rare outcome in SLECTS and has been reported in three children with this syndrome among 189 decedents enrolled in the North American Sudden Unexpected Death in Epilepsy Registry (43). 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 (115). Caution and monitoring during surgical procedures may be advised.
K P Vinayan MD DM
Dr. Vinayan of the Amrita Institute of Medical Sciences has no relevant financial relationships to disclose.See Profile
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
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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