Childhood absence epilepsy

Childhood absence epilepsy (CAE) is one of the most frequent pediatrcic epilepsy syndrome. CAE is an idiopathic generalized epilepsy that occurs in otherwise normal children, it is also known as genetic epilepsy.[1] The only seizure type at the time of diagnosis is the typical absence seizure that can occur up to hundred time a day. The typical absence seizure has a sudden onset of altered awareness and ends also abruptly.[2] The absence seizures are brief (about 4 to 20 seconds) but occur frequently, sometimes hundreds of times per day, and involve abrupt and severe impairment of consciousness. Mild automatisms are frequent, but major motor involvement early in the course excludes this diagnosis. Electroencephalographs demonstrate characteristic "typical 3Hz spike-wave" discharges. CAE is a well-known and common pediatric epilepsy syndrome affecting 10–17% of all children with epilepsy.[3] It was previously known as pyknolepsy. The word pyknolepsy originates from the Greek piknoz (picnós), which means recurrent or grouped.[4] The usual age of onset of CAE is between 4 and 10 years, with peak between 5 and 7 years.[2] The typical absence seizure has a sudden onset of altered awareness and ends also abruptly.[5] Electroencephalograms demonstrate characteristic "typical 3Hz spike-wave" generalized rythmic discharges that begin and end abruptly.[5] Prognosis is generally good with fair rates of response to treatment and with most patients « growing out » of their absences.[5] However, learning difficulites and seizure occurrence rates remain higher than the general population even after several years.[5]

When typical absence seizures start at the age of 8 years or older, when the absence seizures are infrequent or when the absence seizures are observed in a patient that had experienced a generalized tonic-clonic seizure, a diagnosis of juvenile absence epilepsy should be considered.

Signs and symptoms

CAE is characterized by the presence of absence seizures.[2] The absence seizures are usually brief (about 4 to 30 seconds) but occur frequently, usually around a dozen per day but sometimes even hundreds of times per day.[5] They involve abrupt impairment of consciousness with loss of awareness and responsiveness, behavioral arrest, and arrest of the activity that may vary from complete arrest to continuing the activity with an altered status.[5]Other seizure features include starring, eyelid movement or eye-opening and pallor.[5] Mild automatisms and mild movements at the beginning of the seizures are frequent, but major motor involvement, as atonic falls, early in the course of the disease exclude this diagnosis. [5] The International League Against Epilepsy commission defined absence seizure as “of sudden onset, interruption of ongoing activities, staring, possible upwards version of eyes with few seconds duration, associated with symmetrical 2–4 Hz, mainly 3 Hz spike-wave complexes, normal background activity”.[4] Absence seizure was divided into two subgroups (Penry et al. 1975), first with consciousness impairment, and others were associated with the other clinical component, namely clonic, atonic, tonic, autonomic, and with automatisms.[4] Though CAE usually occur in children with normal neurodevelopment and are sensitive to antiepileptic treatment, children with CAE have a risk of academic failure and high rates of attention deficits.[4]

Neuropsychological impairment

There are few neuropsychological symptoms found in children with CAE. These are executive dysfunction, attention problem, learning disabilities, and language problems. These problems even persist after seizures are treated.[6] Many existing statistics illustrate that children with CAE present an average IQ. [6] Instead of having average IQ children with CAE have subtle cognitive difficulties.[6] Significant social difficulties often can be seen in CAE children with lower IQ.[6] Occurrence of behavioral issues might be associated with significantly worse cognitive development.[6] Some evidence depicted that there is impairment in verbal rather than nonverbal aspects in CAE children.[6] Few authors described that the deficits were limited to the few areas of language like verbal fluency, particularly phonological and category fluency.[6] Attention deficit and learning disability are frequently found in the CAE.[6]It can inhibit academic performance as well as day-to-day activities of the children.[6]

Causes

CAE is considered a complex polygenic disorder. This fact is supported by the high occurrence (up to 20%) of generalized epilepsies or febrile seizures in family members of children with CAE.[7] In cases with early-onset or accompanying features, Glut-1 deficiency (a metabolic disorder responding well to ketogenic diet) could be the cause of the absence seizures.[7] Genetic mutations have been identified in recent years involving mainly GABAreceptors and calcium channel modulator genes.[7]

Pathophysiology

Pathophysiology of absence seizures has been widely studied in animal models but is not fully decoded to date.[5] There is however solid evidence for the involvement of bilateral cortical and subcortical networks which are part of the default state system.[5] Pathophysiology when genetic mutations are present is further discussed below.[5] Particularly in the Han Chinese population, there is an association between mutations in the calcium channel, voltage-dependent, T type, alpha 1H subunit (CACNA1H), and childhood absence epilepsy.[5] These mutations cause increased channel activity and associated with increased neuronal excitability.[5] Seizures are believed to originate in the thalamus, where there is an abundance of T-type calcium channels such as those encoded by the CACNA1H gene (12).[5] In a European study for CACNA1H associated with CAE, 20 mutations have been identified.[5] These mutations are likely not wholly causative and should instead be thought of as giving susceptibility.[5] This is particularly true since some groups have found no connection between CAE and CACNA1H mutations.[8] Many of the CACNA1H mutations have a measurable effect on channel kinetics and especially on activation time constant and voltage dependence, on deactivation time constant, and on inactivation time constant and voltage dependence (summarized in Table 1) leading either to neuronal excitability or hyperexcitability.[8] However, these predictions result from mathematical modeling and may differ from what occurs in neurons (in vivo) where other proteins, some of which may interact with CACNA1H, are present.[8]

Along with mutations in the CACNA1H gene, two mutations in gamma-aminobutyric acid receptor subunit gamma-2 (GABRG2), the gene encoding a GABAA receptor gamma subunit, are also associated with a CAE-like phenotype that also overlaps with generalized epilepsy with febrile seizures plus type-3.[9] The first of these, R43Q, abolishes benzodiazepine potentiation of gamma-aminobutyric acid induced currents.[10][9]The second associated mutation, C588T, has not been further characterized.[9][10]


Table 1. Summary of mutations in CACNA1H associated with childhood absence epilepsy
Mutation Region Activation Deactivation Inactivation Excitability Prediction References
V50 Tau V50 Tau
F161L D1S2-3 Unchanged* Unchanged Depolarized Accelerated Unchanged Hypoexcitable [11],[12],[13]
E282K D1S5-6 Hyperpolarized Unchanged Unchanged Unchanged Unchanged Hypoexcitable [11],[12],[13]
P314S D1-2  ?  ?  ?  ?  ?  ? [14]
C456S D1-2 Hyperpolarized Accelerated Unchanged Unchanged Unchanged Hyperexcitable [11],[12],[13]
A480T D1-2  ? Unchanged  ?  ? Unchanged  ? [15],[16]
P492S D1-2  ?  ?  ?  ?  ?  ? [14],[14]
G499S D1-2 Unchanged Unchanged Unchanged Unchanged Unchanged Unchanged [11],[13]
P618L D1-2  ? Accelerated  ?  ? Accelerated  ? [15],[16]
V621fsX654 D1-2  ?  ?  ?  ?  ?  ? [15]
P648L D1-2 Unchanged Unchanged Unchanged Depolarized Slowed Hyperexcitable [11],[13]
R744Q D1-2 Unchanged Unchanged Unchanged Unchanged Unchanged Unchanged [11],[13]
A748V D1-2 Unchanged Accelerated Unchanged Unchanged Unchanged Unchanged [11],[13]
G755D D1-2  ? Unchanged  ?  ? Accelerated  ? [15],[16]
G773D D1-2 Depolarized Slowed Slowed Depolarized Slowed Hyperexcitable [11],[13]
G784S D1-2 Unchanged Slowed Unchanged Unchanged Unchanged Unchanged [11],[13]
R788C D1-2 Depolarized Slowed Slowed Unchanged Slowed Hyperexcitable [13],[14]
G773D + R788C D1-2 Unchanged Unchanged Slowed Unchanged Unchanged Hyperexcitable [13]
V831M D2S2 Unchanged Hyperpolarized Slowed Depolarized Slowed Hypoexcitable [11],[12],[13]
G848S D2S2 Unchanged Unchanged Slowed Unchanged Unchanged Unchanged [11],[13]
D1463N D2S5-6 Unchanged Accelerated Unchanged Unchanged Unchanged Unchanged [11],[12],[13]
*
Depending on experimental paradigm

Diagnosis

CAE can be diagnosed during an outpatient clinic visit with a careful history, physical exam including hyperventilation, and a routine electroencephalogram.[3] The diagnosis is made upon history of absence seizures during early childhood and the observation of 3 Hz generalized spike waves paroxysms, bilateral centrotemporal spikes, and frontal or temporal bilateral interictal discharges on the EEG.[4] In children with CAE without atypical features electroclinical features, no neuroimaging is needed.[7]

Management
Main articles: Epilepsy and Absence seizure

There are three antiepileptic drugs that have been used for the first-line treatment of CAE; these are ethosuximide (ETX), valproic acid (VPA), and lamotrigine (LTG).[3] ETX is an effective first-line treatment for the absence seizures only by blocking the low-threshold calcium currents produced by T-type calcium channels in the thalamus.[3] The peak level occurs after 3-5 hours of intake; steady levels of the drug in the blood are achieved after 7-10 days of the same daily dose.[3] The usual dosage is 20-30 mg/kg/day divided into two doses.[3] Common side effects include gastrointestinal disturbances such as hiccups, vomiting, abdominal discomfort, diarrhea, and exceptionally other symptoms like fatigue, insomnia, dizziness, or ataxia.[3] Valproate (VPA) has also been proven effective as a monotherapy in CAE although ETX is usually preferred as it has a lower impact on attention according to the Childhood Epilepsy study.[17] There are several mechanisms related to VPA’s antiepileptic action, including raising the level of gamma-aminobutyric acid (GABA), calcium-dependent potassium activating and blocking of voltage-sensitive sodium channels, but there is no specific evidence for the mechanism by which VPA controls the absence seizures.[3] VPA has a wide range of side effects (high-frequency tremor, altered mental status, increased appetite and weight gain, pancreatitis, hepatic failure, thrombocytopenia, teratogenesis during pregnancy) although serious side effects are rare and usually dose-dependent.[3] Usual maintenance dose in children is 20–30 mg/kg/day.[3] Lamotrigine (LTG) could be used as alternative/ add-on treatment for CAE along with VPA and ETX.[3] Other possible treatments in the rare cases of pharmacoresistant include levetiracetam, clobazam, topiramate, zonisamide.[3]

Epidemiology

The occurrence of absence seizures varies from 0.7 to 4.6/100,000 in the overall population and from 6 to 8/100,000 in children up to 15 years-old.[4] There are some evidence shows that CAE girls are more frequently effected than boys. [6]

See also

References
  • Perez-Reyes E (2006). "Molecular characterization of T-type calcium channels". Cell Calcium. 40 (2): 89–96. doi:10.1016/j.ceca.2006.04.012. PMID 16759699.

Footnotes
  1. Bloch, J; Miranda, MJ (27 March 2017). "[Scientific evidence on treatment and prognosis of childhood absence epilepsy]". Ugeskrift for Laeger. 179 (13). PMID 28397652.
  2. Verrotti, A; D'Alonzo, R; Rinaldi, VE; Casciato, S; D'Aniello, A; Di Gennaro, G (April 2017). "Childhood absence epilepsy and benign epilepsy with centro-temporal spikes: a narrative review analysis". World Journal of Pediatrics : WJP. 13 (2): 106–111. doi:10.1007/s12519-017-0006-9. PMID 28101769. S2CID 1149138.
  3. Kessler, SK; McGinnis, E (February 2019). "A Practical Guide to Treatment of Childhood Absence Epilepsy". Paediatric Drugs. 21 (1): 15–24. doi:10.1007/s40272-019-00325-x. PMC 6394437. PMID 30734897.
  4. Guilhoto, LM (January 2017). "Absence epilepsy: Continuum of clinical presentation and epigenetics?". Seizure. 44: 53–57. doi:10.1016/j.seizure.2016.11.031. PMID 27986418. S2CID 205140359.
  5. Matricardi, S; Verrotti, A; Chiarelli, F; Cerminara, C; Curatolo, P (March 2014). "Current advances in childhood absence epilepsy". Pediatric Neurology. 50 (3): 205–12. doi:10.1016/j.pediatrneurol.2013.10.009. PMID 24530152.
  6. Verrotti, A; Matricardi, S; Rinaldi, VE; Prezioso, G; Coppola, G (15 December 2015). "Neuropsychological impairment in childhood absence epilepsy: Review of the literature". Journal of the Neurological Sciences. 359 (1–2): 59–66. doi:10.1016/j.jns.2015.10.035. PMID 26671087. S2CID 22332751.
  7. "CHILDHOOD ABSENCE EPILEPSY". www.epilepsydiagnosis.org.
  8. Chioza, B; Everett, K; Aschauer, H; Brouwer, O; Callenbach, P; Covanis, A; Dulac, O; Durner, M; Eeg-Olofsson, O; Feucht, M; Friis, M; Heils, A; Kjeldsen, M; Larsson, K; Lehesjoki, AE; Nabbout, R; Olsson, I; Sander, T; Sirén, A; Robinson, R; Rees, M; Gardiner, RM (May 2006). "Evaluation of CACNA1H in European patients with childhood absence epilepsy". Epilepsy Research. 69 (2): 177–81. doi:10.1016/j.eplepsyres.2006.01.009. PMID 16504478. S2CID 40437686.
  9. Wallace, RH; Marini, C; Petrou, S; Harkin, LA; Bowser, DN; Panchal, RG; Williams, DA; Sutherland, GR; Mulley, JC; Scheffer, IE; Berkovic, SF (May 2001). "Mutant GABA(A) receptor gamma2-subunit in childhood absence epilepsy and febrile seizures". Nature Genetics. 28 (1): 49–52. doi:10.1038/ng0501-49. PMID 11326275. S2CID 33795196.
  10. Marini, C; Harkin, LA; Wallace, RH; Mulley, JC; Scheffer, IE; Berkovic, SF (January 2003). "Childhood absence epilepsy and febrile seizures: a family with a GABA(A) receptor mutation". Brain : A Journal of Neurology. 126 (Pt 1): 230–40. doi:10.1093/brain/awg018. PMID 12477709.
  11. Chen Y, Lu J, Pan H, Zhang Y, Wu H, Xu K, Liu X, Jiang Y, Bao X, Yao Z, Ding K, Lo W, Qiang B, Chan P, Shen Y, Wu X (2003). "Association between genetic variation of CACNA1H and childhood absence epilepsy". Ann Neurol. 54 (2): 239–43. doi:10.1002/ana.10607. PMID 12891677. S2CID 33233159.
  12. Khosravani H, Altier C, Simms B, Hamming K, Snutch T, Mezeyova J, McRory J, Zamponi G (2004). "Gating effects of mutations in the Cav3.2 T-type calcium channel associated with childhood absence epilepsy". J Biol Chem. 279 (11): 9681–4. doi:10.1074/jbc.C400006200. PMID 14729682.
  13. Vitko I, Chen Y, Arias J, Shen Y, Wu X, Perez-Reyes E (2005). "Functional characterization and neuronal modeling of the effects of childhood absence epilepsy variants of CACNA1H, a T-type calcium channel". J Neurosci. 25 (19): 4844–55. doi:10.1523/JNEUROSCI.0847-05.2005. PMC 6724770. PMID 15888660.
  14. Liang J, Zhang Y, Wang J, Pan H, Wu H, Xu K, Liu X, Jiang Y, Shen Y, Wu X (2006). "New variants in the CACNA1H gene identified in childhood absence epilepsy". Neurosci Lett. 406 (1–2): 27–32. doi:10.1016/j.neulet.2006.06.073. PMID 16905256. S2CID 24772193.
  15. Heron S, Phillips H, Mulley J, Mazarib A, Neufeld M, Berkovic S, Scheffer I (2004). "Genetic variation of CACNA1H in idiopathic generalized epilepsy". Ann Neurol. 55 (4): 595–6. doi:10.1002/ana.20028. PMID 15048902. S2CID 46369511.
  16. Khosravani H, Bladen C, Parker D, Snutch T, McRory J, Zamponi G (2005). "Effects of Cav3.2 channel mutations linked to idiopathic generalized epilepsy". Ann Neurol. 57 (5): 745–9. doi:10.1002/ana.20458. PMID 15852375. S2CID 28752058.
  17. Glauser, TA; Cnaan, A; Shinnar, S; Hirtz, DG; Dlugos, D; Masur, D; Clark, PO; Capparelli, EV; Adamson, PC; Childhood Absence Epilepsy Study, Group. (4 March 2010). "Ethosuximide, valproic acid, and lamotrigine in childhood absence epilepsy". The New England Journal of Medicine. 362 (9): 790–9. doi:10.1056/NEJMoa0902014. PMC 2924476. PMID 20200383.


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