Myoclonus epilepsy with ragged-red fibers
Nov. 06, 2023
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Self-limited epilepsy with centrotemporal spikes (SeLECTS) is the new name for the previous epilepsy syndrome of benign epilepsy with centrotemporal spikes. 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, cognitive dysfunction, language impairment, and atypical evolutions with adverse seizure and neurodevelopmental outcomes were rarely seen in this syndrome.
The ILAE Task Force report on the nosology and definitions of childhood-onset epilepsy syndromes proposes the terms “self-limited focal epilepsies” of childhood (SeLFE) for focal epilepsies with onset in childhood and “self-limited epilepsy with centrotemporal spikes” (SeLECTS) for Rolandic epilepsy (168). SeLECTS is the most frequent SeLFE and accounts for 6% to 7% of all childhood epilepsies (196). Its incidence is estimated to be 6.1 per 100,000 children below 16 years of age per year (193).
• presents with focal seizures with dysarthria, sialorrhea, dysphasia, and unilateral clonic or tonic–clonic movement of the mouth, or nocturnal focal to bilateral tonic-clonic seizures.
• Seizures commonly occur within 1 hour of falling asleep or 1 to 2 hours prior to awakening.
• There are high-amplitude, centrotemporal, biphasic epileptiform abnormalities on EEG.
• There is no developmental regression.
• Remission occurs by mid- to late adolescence.
• Specific cognitive, language, memory, and attention-related disorders are increasingly being reported.
• SeLECTS may atypically evolve into Landau-Kleffner syndrome and epileptic encephalopathy with continuous spike-and-wave activation in sleep (EE-SWAS) with potential for persistent neuropsychological impairments.
The 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 (65; 70). In 1958, the first clinical description associated with EEG features was published (132). 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 (69). Because of the localization of the ictal events, Lombroso proposed the term "sylvian seizures" (121). 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 in the past had confirmed the relatively good prognosis (12; 104; 120). 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 (31; 51).
As new syndromes were recognized within the spectrum of benign childhood focal epilepsies (145), the term “benign” was considered initially acceptable for this syndrome (73). However, the 2017 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” (160). Thus, the new term “self-limited epilepsy with centrotemporal spikes” (SeLECTS) was proposed for this epilepsy syndrome. The word “benign” is sometimes completely omitted to name the syndrome as “childhood epilepsy with centrotemporal spikes” (CECTS) (178). However, the ILAE Task Force on Nosology and Definitions affirms the term SeLECTS for this epilepsy syndrome (168).
Age, sex, and course of illness. The age at onset is typically between 4 and 10 years (range 3 to 14 years) in 90% of patients, with a peak at approximately 7 years. Both sexes are affected, with a slight male predominance (60%). Seizures usually resolve by puberty but can occasionally continue until 18 years of age (18). During the active phase of epilepsy, behavioral and neuropsychological deficits may emerge or worsen, particularly in language and executive functioning, and later improve or resolve. The prognosis for seizure remission is excellent, even for those whose seizures are initially difficult to control (21). 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 (102). Antecedent, birth, and neonatal history; development; cognition; neurologic examination; and head size prior to seizure onset are typically normal. A history of febrile seizures may be seen in 5% to 15% of cases. Preexisting attention-deficit/hyperactivity disorder and specific cognitive function deficits may occur (140). SeLECTS may be seen in children with a history of prior neurologic injury or intellectual disability, but these features are considered coincidental and not causal.
Ictal phenomenon. Focal seizures with characteristic frontoparietal opercular features or nocturnal bilateral tonic-clonic seizures are mandatory for diagnosis.
The characteristic semiology of the focal seizures includes the following (168):
(1) somatosensory symptoms, with unilateral numbness or paresthesia of the tongue, lips, gums, and inner cheek.
(2) orofacial motor signs, specifically tonic or clonic contraction of one side of the face, mouth, and tongue, then involving one side of the face. In nocturnal seizures, the initial focal component may often not be witnessed.
(3) speech arrest; children have difficulty or are unable to speak (dysarthria or anarthria) but can understand language.
(4) sialorrhea, a characteristic ictal symptom. It is unclear whether this is due to increased salivation, swallowing disturbance, or both.
(5) In seizures associated with SeLECTS, cognitive (eg, gustatory hallucinations), emotional (eg, fear), and autonomic features are not seen.
The initial event is often a nocturnal hemifacial convulsion, which may rapidly evolve to tonic-clonic activity of the ipsilateral upper limb, to an ipsilateral hemiclonic seizure, or to a focal to bilateral tonic-clonic seizure. Seizures are typically brief, lasting for 1 to 3 minutes. More than half of the patients retain consciousness and may recollect the sensations. Seizures occur in sleep in the great majority (80% to 90%) of patients, and only while awake in up to 20% of children (36). Todd paresis may occur postictally. Miscellaneous symptoms, such as abdominal pain, may rarely occur (12). Among 230 children with SeLECTS, six presented with sensory motor seizures in the leg as the main ictal manifestation (61). Generalized tonic-clonic seizures during wakefulness are exclusionary and should prompt one to review the diagnosis.
This is associated independently with bilateral, repetitive, broad, centrotemporal interictal EEG spikes displaying a characteristic tangential bipolar pattern (72). The ictal manifestations are not indicative of temporal lobe involvement and the term “centro-temporal” refers only to the spike topography.
Recurrence of seizures. Onset before 3 years of age has been stated as the single most important predictor for multiple seizures (98; 205). Neither clinical features, seizure characteristics, nor routine EEG findings were found to be useful in predicting the likelihood of a second seizure in SLECTS (191). 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 (175). The occurrence of atypical absence seizures, focal atonic seizures, and focal motor seizures with negative myoclonus with loss of balance and falls should suggest evolution to EE-SWAS, and evidence of cognitive impairment or regression should be sought.
Behavioral problems. Behavioral disorders may be present in approximately one third of patients with SeLECTS, including ADHD and oppositional defiant disorder (141). Early onset of seizures and the presence of bilateral interictal epileptiform discharges may suggest an increased risk for behavioral disorders in these children.
Cognitive problems. Cognitive problems and low academic achievement might be seen in children with SeLECTS. 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 (192).
Another 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) (187). The impact of SeLECTS on school performance was demonstrated in another study of 40 cases and controls (130). 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 (67).
Children and adolescents with SeLECTS 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 (114). Patients with SeLECTS also demonstrate processing speed dysfunction (111).
Language skills. A meta-analysis of 22 studies on literacy and language skills in children with SeLECTS showed the presence of reading and phonological processing deficits highlighting the need for early literacy and language assessment (166). 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 SeLECTS and 31 paired normal children underwent a language and neuropsychological assessment performed with several standardized protocols. Findings showed significant dyslexia in patients with SLECTS (137). 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 (185). 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 (62).
A systematic review of studies published between 2005 and 2016 on language skills in children with SeLECTS 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 (176). Another systematic review of 43 studies (1179 patients and 1086 healthy controls) on executive functioning in children with SeLECTS concluded that children with SeLECTS show weaker performances in inhibitory control, cognitive flexibility, and verbal fluency when compared with a control group (150). 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 SeLECTS using the spectral temporally modulated Ripple test showed that the auditory spectral resolution threshold measured was significantly lower when compared to controls (170).
Children with SeLECTS show altered functional connectivity associated with speech production between the left precuneus and the right cerebellum, between the right precuneus and the bilateral thalamus and the left superior temporal gyrus, between the right cuneus and the right postcentral gyrus and the right inferior parietal lobule, and between the right cerebellum and the right middle frontal gyrus, suggesting an abnormal functional connectivity basis of speech production (200).
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 (13). 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 (199). 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 SeLECTS than in controls (28).
Central auditory processing disorder was noted in 46% of patients with SeLECTS and without intellectual disability, dyslexia, and attention-deficit hyperactivity disorders (124).
Atypical features have been noted in up to 50% of the patients with SeLECTS (195; 39):
• Earlier age of onset of seizures (< 3 years and more than 14 years of age)
• Daytime seizures only
• Usual seizure frequency more than daily
• Focal motor or generalized convulsive status epilepticus >30 min
• Moderate to profound intellectual disability
• Poor neuropsychological outcomes
• Hemiparesis or focal neurologic findings, other than Todd paresis
• Causal lesion on brain MRI
• Lack of sleep activation of centrotemporal abnormalities
• Persistently unilateral centrotemporal abnormalities on serial EEGs
• Unusual spike morphology and distribution or sustained focal slowing without centrotemporal spikes or diffuse slowing on EEG
• Absence-like spike-and-wave discharges
In children with SeLECTS, presence of atypical features in the early EEGs, such as slow spike-wave focus, synchronous foci, or generalized 3 Hz spike-wave discharges, predicted lower full-scale IQ and verbal IQ and impairments in some tasks of the performance scale (125).
In a retrospective, multicenter study of 46 patients with atypical features in SeLECTS, 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%) (63).
Atypical evolution accounts for around 5% of patients with SeLECTS in most of the tertiary epilepsy centers for children. Early onset of SeLECTS, neurocognitive regression with a continuous spike-and-wave pattern in sleep (suggests EE-SWAS), appearance of new seizures such as atypical absences or negative myoclonus, increased frequency of fronto-centro-temporal EEG focus in both sleep and wakefulness, and presence of more than five ripples on the centrotemporal spikes are predictive of atypical development (184; 146).
Atypical SeLECTS showed more widespread and severe hypometabolism than typical SeLECTS, mainly located in the fronto-temporo-parietal cortex (109).
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 (149).
In general, SeLECTS is associated with an excellent prognosis.
Seizures. The majority of children have 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 have normal cognitive functions during the period of active epilepsy and after remission (80). Microstructural changes in cortex and white matter were described in some previous studies, the clinical significance of which is not clear (92; 64).
Language impairment. Moderate to severe language impairment has been reported in some children, especially in expressive grammar, phonologic awareness, and literacy skills (134). Persistent deficits in children after seizure remission suggested possible long-term consequences (131). Abnormal neuropsychological development significantly correlated with a greater frequency of NREM sleep discharges, epilepsy onset at school age, and a higher number of antiepileptic drugs (58).
Attention deficit hyperactivity disorder (ADHD). The prevalence of ADHD may be up to 65%, and patients perform poorer on executive and attentional tasks (113; 38). This has been related to thinner superior-inferior frontal cortex, superior temporal cortex, left pericalcarine, and lingual and fusiform cortex compared to healthy controls (90). A study of 42 patients with newly diagnosed SeLECTS evaluated the long-term prognosis of attention deficit in children (over a period of 7 years) and showed impaired attention network, mainly in the alerting and orienting domains (198).
Atypical evolutions. Most of the children with atypical evolutions will also have a good long-term prognosis (Aicardi and Chevrie 1982; 57; 55; 20). However, Landau-Kleffner syndrome and EE-SWAS may portend permanent language dysfunction or neuropsychologic involvement (53; 55; 56).
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 (04).
Transition. SLECTS almost always enters terminal remission before the general age of a planned transition of adolescents (21).
Over the years, our understanding of the genetic basis of SeLECTS has significantly evolved. The characteristic centrotemporal pattern in SeLECTS was initially considered an autosomal dominant trait with variable penetrance based on monozygotic twin studies (78; 50; 10). Later, a multifactorial pathogenesis of epilepsies with focal epileptiform sharp waves was considered (46). In a multicenter twin collaboration study analysis of the etiology of SeLECTS, 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 (182). The atypical evolution of SeLECTS may have a more complex inheritance than a simple monogenic pattern (180).
SeLECTS 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) (103; 44; 71; 153; 48; 151; 133; 49; 81; 135).
GRIN2A has been identified as the major gene in epileptic encephalopathies. The role of GRIN2A mutations in SeLECTS, 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 (86). 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 (164). Environmental risk factors, such as maternal smoking around birth, have also been implicated in the pathogenesis of SLECTS (164). 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 (118). As these genes are all calcium homeostasis–associated genes, they suggest a potential effect of calcium homeostasis in the epilepsy.
Several neurobiological hypotheses have been put forward in SeLECTS Sylvian and rolandic areas. The typical focal, ictal clinical behavior and EEG discharge indicate a disturbance in the sylvian and rolandic areas. SeLECTS, 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 (77).
Involvement of larger brain areas. Electrophysiologic studies fail to demonstrate a discrete generator, and it is suggested that a large, shifting area of dysfunction may be present, including the deep brain structures, such as the cingulate gyrus, basal ganglia, and thalamus, based on hemodynamic responses in these areas with centrotemporal spikes (85). In some SeLECTS 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 (105). Around 20% of patients with centrotemporal spikes may also have sharp slow wave complexes in other cortical locations (144).
Thalamocortical circuitry. Because SeLECTS 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 (101). 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 (107).
Patients with atypical evolution of SeLECTS show a symmetric hypoperfusion at the level of thalamus in interictal SPECT without structural abnormalities on MRI and increased risk of cognitive deficits (06). A study compared the EEG sleep findings in 30 children with SeLECTS 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 SeLECTS (157). 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. Paucity of sleep spindles in the Rolandic cortex and adjacent areas has been noted during the active phase of epilepsy. Because spindles are generated in the thalamus and amplified through regional thalamocortical circuits, it has been hypothesized that regional spindle deficits predict cognitive function (169). These findings suggest an underlying pathophysiologic mechanism for thalamocortical oscillations and functional and structural thalamocortical circuit disruption in SeLECTS (99). A comparative brain tractography study of 23 children with SeLECTS aged 8 to 15 years and age-matched controls showed that children with SeLECTS 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 (178).
Neurodevelopmental origin. A neurodevelopmental origin of SeLECTS 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 (167). Children with SeLECTS have been shown to have delayed brain development, with alteration in gray matter and white matter volumes in the brain, specifically in the rolandic regions, and a 0.45-year delay in brain age in contrast to children with typical development (156). A delayed cortical maturation at the centrotemporal brain regions has been proposed based on the comparison of resting-state brain activities by quantitative EEG in 16 SeLECTS patients with clinical seizure remission stage in comparison with healthy controls (165). According to a brain age prediction model (BAE NET) based on structural MRI brain data from normal children with typical development, children with SeLECTS showed imaging phenotypes of delayed brain development, with increased grey matter volume and decreased white matter volume in the rolandic regions. The children with SeLECTS also had a 0.45-year delay of brain-predicted age compared to normal children. Delayed brain age was associated with morphometric changes in the rolandic regions as well as deficits in attention on formal testing (207). A study based on cortical surface-based morphometry in 25 patients with SeLECTS showed that there is aberrant cortical thickness, cortical gyrification, and sulcal depth in areas related to cognitive functions, including language, attention, and memory (112). There was a negative correlation between age of onset of seizures 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 may suggest 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 SeLECTS (188). This is a machine-learning approach that uses whole-brain connectivity measured with neuroimaging data ("neural fingerprints") to predict brain-behavior relationships.
SeLECTS accounts for about 24% of all epileptic seizures in children between 5 and 14 years of age (25). 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 (78). In an epidemiological study of epilepsy in childhood in a cohort of 440 consecutive patients, SeLECTS accounted for 8% of patients (97). In an epidemiological study of 205 cases of childhood epilepsy in a Swedish county, SeLECTS was the most common epilepsy syndrome (100). 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 SeLECTS than in a matched control group (19). 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 (78). 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 (171).
The presence of the characteristic centrotemporal spikes alone is not diagnostic of SeLECTS. These may be seen in children without seizures as well as in nonepileptic children with diffuse brain disturbances, such as cerebral palsy (148) and Rett syndrome (154).
SeLECTS is the most common epilepsy syndrome, seen in patients with fragile X syndrome, and centrotemporal spikes may be present as an asymptomatic finding (91).
DEE-SWAS or EE-SWAS. Patients with DEE-SWAS may present with similar seizures but can be distinguished by cognitive and language regression. Children with SeLECTS may rarely evolve to this syndrome.
Focal seizures due to structural brain abnormality. Distinction between SeLECTS 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 SeLECTS when nocturnal convulsions are the presenting complaint, and a generalized epileptic syndrome is initially suspected.
Other self-limited focal epilepsies. The morphology of the EEG abnormalities in the various self-limited focal epilepsies may overlap, and their seizure localization may change with age. If patients present with prolonged focal nonmotor seizures with prominent autonomic features, especially ictal vomiting, self-limited epilepsies with autonomic seizures should be considered.
Fortuitous associations may be found between SeLECTS and static brain lesions with epilepsy (158). Reported examples are unilateral opercular neuronal migration disorders (03; 53; 162), cerebral tumors (163), neuronal migration disorders and gliosis (139), and hippocampal sclerosis (142).
Pathophysiologic relationships may exist between SeLECTS and SeLFEs, which can make differential diagnosis difficult. The coexistence of two types of SeLFEs in children has been reported, either presenting in sequence one after the other or at the same time (143; 23; 32; 24; 26). The coexistence of childhood absence epilepsy and SeLECTS was detected in 11 patients through a systematic record review from eight epilepsy centers (186). 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 (40).
An interesting association with migraine has been proposed in patients with SeLECTS (16). In a comparative cohort of children with SeLECTS, 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 (197). Another study of 72 children with SeLECTS and their siblings showed that prevalence of migraine was 15% in epilepsy probands versus 7% in nonepileptic controls (29). Prevalence of migraine was 14% in siblings of SLECTS and 4% in siblings of controls.
Characteristics of EEG spikes in SeLECTS
• Background activity is typically normal, with normal sleep architecture. If sustained focal slowing without centrotemporal spikes or diffuse slowing is recorded, another epilepsy syndrome or a structural lesion should be considered, and brain imaging is recommended. 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 (37).
• High-amplitude (> 200 μV, peak to trough) centrotemporal sharp-and-slow-wave complexes that activate in drowsiness and sleep are mandatory for diagnosis (79). They are triphasic, high-voltage (100–300 µV) sharp waves (initial low-amplitude positivity, then high-amplitude negativity, followed again by low-amplitude positivity), with a transverse dipole (frontal positivity, temporoparietal negativity), often followed by a high-voltage slow wave.
• The abnormalities may be isolated or occur in trains of doublets and triplets, and focal, rhythmic, slow activity is occasionally observed in the same region as the spikes (129).
• Spikes may be unilateral or bilateral and independent or synchronous and may be seen outside the centrotemporal region (midline, parietal, frontal, occipital). Generalized 3 Hz spike-and-waves and focal spikes in other brain areas may also be seen in a minority of children (15).
• 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 (190). They may be activated by sensory stimulation of the fingers or toes in 10% to 20% cases (42).
• Ictal recordings are rare and may be accompanied by a brief decrease in amplitude of the background EEG, followed by diffuse sharp wave abnormalities of increasing amplitude, predominantly in one centrotemporal region, followed by high-amplitude slowing and then a return to the usual interictal EEG (161).
• With focal to bilateral tonic-clonic seizures, ictal rhythms may become bilaterally synchronous (as opposed to generalized) sharp wave or spike-and-wave activity (02).
There is no correlation between the burden of spike discharges on EEG and frequency, length, or duration of clinical seizures (104). 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).
Dipolar pattern in SeLECTS. Several authors emphasized the characteristic dipolar pattern in EEG (72; 115; 181). According to EEG findings, two groups of patients have been noted: (1) a high-central region group with more frequent hand involvement and (2) a low-central group with common orofacial symptoms. Electroencephalographic spike source dipoles of centrotemporal spikes were analyzed in 37 patients (93). 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 and may distinguish benign from symptomatic causes (127). A novel machine-learning model that efficiently distinguished rolandic seizures from normal EEG signals has been proposed, with an accuracy exceeding 97.6% (123). 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 SeLECTS 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% (203).
Spike ripples have been identified as a promising new biomarker of epilepsy in noninvasive EEG studies (59). Ripples on centrotemporal spikes are considered to indicate epilepsy severity. The absence of ripples predicts a relatively benign clinical entity (184). 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 SeLECTS (96). A comparative study of seven patients with atypical SeLECTS and 18 patients with typical SeLECTS in the secondary bilateral synchrony and non-secondary bilateral synchrony periods found that ripples were enhanced when interictal epileptiform discharges were bilaterally synchronized in patients with atypical SeLECTS (83). The study highlighted the distinction between atypical and typical SeLECTS with ripple distribution in the non-secondary bilateral synchrony period.
Intrahemispheric cortico-cortical EEG functional connectivity (EEGfC) was explored in 17 nonmedicated children with SeLECTS and 19 controls, and the areas of increased EEGfC corresponded to cortical areas related to speech and attention deficits (30).
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 SeLECTS (159).
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 SeLECTS (177). The study cohort consisted of 127 children with SeLECTS 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 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. MEG-based studies in patients with centrotemporal spikes in SeLECTS suggest that these discharges are generated through a mechanism similar to that of somatosensory evoked responses (126). An MEG-based study of 33 children with SeLECTS and 18 healthy 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 SeLECTS (110). The magnetic source localization in the 4 to 8 Hz frequency band may be a new imaging marker for the diagnosis of new SeLECTS and cognitive impairment via identification of disordered networks (108).
Structural abnormality. Typically, MRI is normal and is not required for the electroclinical diagnosis of the syndrome. Nonspecific MRI findings, such as hippocampal asymmetry, white matter abnormalities, and enlargement of the lateral ventricles, should not exclude a diagnosis of SeLECTS. Focal cortical dysplasia and tumors have presented with the clinical and EEG phenotype of SeLECTS (03; 53; 163; 162). Patients with focal epilepsy due to structural abnormalities, such as focal cortical dysplasia, heterotopia, or low-grade brain tumors, may mimic SeLECTS but usually show atypical features, such as unilateral EEG abnormality or drug resistance (168). In 171 consecutive patients with this syndrome studied with CT or MRI, 10 children were noted to have neuroimaging abnormalities (66).
Volumetric changes. Frontal and prefrontal volumes revealed growth disturbances in patients with cognitive impairments (189). Thickness of the corpus callosum has been suggested as a new radiologic biomarker for predicting first antiseizure medication response and seizure recurrence in SeLECTS patients (43). Thicknesses of genu and isthmus were significantly reduced in the SeLECTS group compared to healthy controls, and the total number of seizures negatively correlated with the thickness of the body, isthmus, and splenium (p < 0.001), thus, working as a protective mechanism to prevent seizure spread to other brain regions.
Positron emission tomography is not routinely performed in these children. It may be helpful to distinguish SeLECTS from symptomatic cases of focal epilepsy in children (183). Focal cortical hypermetabolism in the central cortex was noted in three children with atypical SeLECTS during the seizure-free period (33), suggesting a localized, increased cortical activity, likely due to either subclinical seizure activity or “active” inhibitory (GABAergic) processes.
Several fMRI studies have been reported in SeLECTS. It is increasingly being used to study the dynamic alternations in networks in SeLECTS (206). Aberrant functional connectivity between motor and language networks, abnormal intrahemispheric segregation, and interhemispheric integration has been seen in these children (14; 204). Another fMRI study of 26 children with SeLECTS showed aberrant dynamic regional interplay in sensorimotor, linguistic, and lateral temporal regions, which may affect cognitive performance in these children (87). Resting state fMRI studies in a smaller number of patients with SeLECTS (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 SeLECTS (60). A “granger causality density” method has been proposed as an effective and reliable neuroimaging biomarker to localize the interictal focus of SeLECTS and make an early diagnosis (35).
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 SeLECTS and to assess whether motor cortex plasticity correlates with learning ability (11). Resting state functional MRI analysis has shown an association between centrotemporal spikes and earlier hemodynamic activations in epileptogenic regions in SeLECTS that were counteracted by levetiracetam treatment (202). A small open pilot study of four SeLECTS patients who had frequent seizures (at least three seizures during the 3-month baseline) found a beneficial role of low-frequency repetitive transcranial magnetic stimulation (1 Hz with 500 pulses at 90% of resting motor threshold for 10 weekdays) in reducing clinical seizures after localizing sources of interictal epileptiform discharges with magnetoencephalography (88).
An excitatory and inhibitory imbalance in neural networks has been suggested as a useful diagnostic biomarker for SeLECTS using a resting-state dynamic causal modeling-based support vector machine (rs-DCM-SVM) algorithm, with an accuracy of 81% to 88% (34).
SeLECTS is an age-related syndrome that almost always disappears by adolescence, 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. Focal motor seizures, a short interval between the first and second attack, and an early onset usually indicate the necessity of treatment.
Monotherapy should be used whenever possible. In a Cochrane systematic review, the seizure-free rates were 64% for carbamazepine, 67% to 70% for clobazam, 67% to 89% for oxcarbazepine, 86% to 100% for levetiracetam, 69% for topiramate, and 68% to 90% for sulthiame (174). A systematic review of seizure-freedom rates in patients with SeLECTS receiving antiseizure medication suggested the use of sulthiame, levetiracetam, or clobazam as first-line agents for the treatment of SeLECTS in children (68). Another systematic review of randomized controlled studies between 1990 and 2021 indicated some discrepancies in efficacy and tolerability among antiseizure medications used in patients with SeLECTS. More randomized controlled trials comparing antiseizure medications with larger populations are required to ascertain the optimum antiepileptic drug treatment to guide clinicians.
Carbamazepine and valproic acid were traditionally the drugs of choice for this syndrome. Levetiracetam monotherapy has gained attention as a probable alternative. In a comparative study of carbamazepine, valproic acid, and levetiracetam in 89 patients, the maximum response rates were with levetiracetam (71%), followed by valproic acid (56%) and carbamazepine (11.2%) (89). However, better response rates have been noted for carbamazepine—up to 64% during the first year of treatment in a Cochrane meta-analysis (174). The results of the pooled analysis in a systematic review indicated that levetiracetam did not demonstrate a higher probability of seizure freedom than carbamazepine [RR = 1.25, 95% CI (0.52, 2.99)] (27). In a comparative trial of 56 patients with SeLECTS, the seizure-freedom rates were similar between levetiracetam and valproic acid monotherapy groups, but a greater number of the children taking valproic acid achieved EEG normalization (95% vs. 72% with levetiracetam at 18 months) (201). However, valproic acid use in adolescent females is of concern due to hormone abnormalities, obesity, and polycystic ovarian syndrome. A meta-analysis of 49 studies from 2000 to 2018 suggested that levetiracetam, as an initial antiseizure medication, was superior to carbamazepine for cognitive protection (09). Levetiracetam inhibited centrotemporal spikes-associated activation intensity and altered its temporal pattern. It also affected the brain deactivation related to higher cognition networks (208). Children administered levetiracetam showed a mild but statistically significant improvement in overall cognitive abilities, verbal skills, visual-perceptual reasoning, working memory, and processing speed as compared to the control group (children with specific learning disabilities) at 2-year follow-up (138).
Oxcarbazepine monotherapy was found to be more effective and associated with higher improvements in intelligence and cognitive function than levetiracetam monotherapy in children with SeLECTS (172). 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 (117). In a retrospective study of 430 patients with centrotemporal spikes, the comparative efficacy of levetiracetam, oxcarbazepine, and valproic acid evaluated over a 2-year follow-up was similar (74). On meta-analysis of published randomized studies, no significant difference between levetiracetam, oxcarbazepine, and valproic acid was noted for seizure freedom rates (27).
Benzodiazepine treatment for several weeks was also recommended (41). In comparison with valproate and carbamazepine, clonazepam showed to be more efficient in making rolandic discharges disappear after 4 weeks of treatment (128). The use of clobazam at night may be considered in those children who only have seizures during sleep (54). 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 (05); however, the quality of evidence was low.
Sulthiame was recommended in several reports (45; 106). In a double-blind, placebo-controlled study of 66 children, sulthiame was found to be remarkably effective in preventing seizures and was well tolerated (152). It has been considered as the drug of choice in patients presenting with atypical evolutions associated to secondary bilateral synchronies in the EEG (55; 54). A noninferiority study comparing levetiracetam to sulthiame in 43 patients with SeLECTS showed that the rates of seizure-free patients were relatively high in both groups, although termination of drug treatment due to seizure recurrence or adverse events occurred more frequently in the levetiracetam group compared to sulthiame group (17). Another randomized controlled trial to compare the effects of levetiracetam and sulthiame on EEG in 43 children with SeLECTS showed similar reductions in the spike-wave-index with both the drugs (173).
In a monotherapy trial of topiramate (116), the drug was orally administrated once a night (2 mg/kg/day) and twice a day (4 mg/kg/day) in 85 patients with SeLECTS. 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 SeLECTS.
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 SeLECTS were greater for lamotrigine and oxcarbazepine than for topiramate (76).
A retrospective study evaluating the efficacy of lacosamide monotherapy in 18 children with SeLECTS showed that 39%, 67%, and 72% were seizure-free at 0 to 3, 4 to 6, and 7 to 12 months from treatment initiation, respectively (136).
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 or poor response in 14% to 28% cases (84; 147). 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 (94). Young age of seizure onset correlated with longer duration of EEG abnormalities (102). Pattern of spike disappearance did not significantly differ between the medication naïve group and antiepileptic drug-treated group (75). Predictors of poor response to initial antiseizure medications include younger age of seizure onset and history of febrile seizures (147).
Auditory stimulation during non-REM sleep suppresses spike activity and has been proposed as a nonpharmacological treatment of SeLECTS (95). Further studies are needed before this technique can be implemented in clinical practice.
Because sleep and epilepsy have an established bidirectional relationship, especially in SeLECTS, a UK-based, multicenter, open-label, randomized trial is currently underway to assess the effectiveness of behavioral sleep intervention in children with SeLECTS (01). The Changing Agendas on Sleep, Treatment and Learning in Epilepsy (CASTLE) Sleep-E trial compares clinical and cost effectiveness between standard care and standard care augmented with a novel, tailored, parent-led CASTLE Online Sleep Intervention. The latter consists of a self-paced, e-learning module for parents that supports parents in implementing general prevention techniques (eg, good sleep hygiene) and specific behavioral change techniques (eg, bedtime fading) relevant to their child’s sleep problems.
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 SeLECTS were not found to have negative outcomes in the fields of development, education, employment, and social adaptation (22). However, smaller studies report selective impairment, such as deficits in verbal perception and oromotor performance, in young adults with SeLECTS when followed for 10 years (179).
The data in children during the active years of epilepsy are variable and largely indicate the presence of cognitive and behavioral impairment. A systematic review and meta-analysis of 42 studies published prior to 2016 on cognitive functioning in children with SeLECTS concluded that they demonstrated significantly lower scores on neuropsychological tests across all cognitive factors compared to healthy controls (194). However, the possibility of a publication bias cannot be ruled out.
A natural history study of children with SeLECTS from a large, prospective, longitudinal cohort reported a high incidence of ADHD symptoms (18.3%) or learning difficulties (21.7%) before the diagnosis (155). 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 (155). A systematic review of nine case-control and cohort studies on ADHD and ADHD-related neural networks in SeLECTS showed that the reported prevalence of ADHD in patients with SeLECTS was around 60% (07). The predictors of ADHD in SeLECTS were early age of seizure onset, long course of disease, and low intelligence scores (82). Comorbid ADHD has been associated with a higher degree of impairment in some domains of intellect (52).
Sudden unexpected death in epilepsy is a very rare outcome in SeLECTS and has been reported in three children with this syndrome among 189 decedents enrolled in the North American Sudden Unexpected Death in Epilepsy Registry (47). This seems to be an intriguing observation that needs further validation.
A 16-year-old Chinese girl who was diagnosed with SeLECTS 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 (122). Caution and monitoring during surgical procedures may be advised.
All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.
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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