Childhood absence epilepsy

Childhood absence epilepsy is a seizure disorder consists of comprehensive seizures, the onset of which are sudden and which end with altered awareness.[1] Childhood absence epilepsy (CAE) is a well-known and common pediatric epilepsy syndrome afecting 10–17% of all children with epilepsy.[2] It is also known as pyknolepsy, and is an idiopathic generalized epilepsy that occurs in otherwise normal children. The word pyknolepsy originates from the Greek piknoz (picnós), which means recurrent or grouped.[3] Absence seizures can be divided into two forms: childhood absence epilepsy and juvenile absence epilepsy. The usual age of onset of childhood absence epilepsy is between 4 and 10 years, with peak between 5 and 7 years; the average age of onset for juvenile absence epilepsy is around 12 years.[1] 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. Prognosis is excellent in well-defined cases of childhood absence epileps, with most patients eventually "growing out" of their seizures.[4]

Signs and symptoms

Childhood absence epilepsy is categorized by the sudden onset of seizures and disruption of ongoing activities. The seizures typically last from several seconds to half a minute. They are characterized by blank stares and brief upward rotating of the eyes.[1] 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”.[3] 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.[3] Though the seizure of the children CAE has been control antiepileptics but they had the risk of academic failure and high rates of attention deficits.[3]

Causes

Childhood absence epilepsy is a complex polygenic disorder. Particularly in the Han Chinese population, there is association between mutations in the calcium channel, voltage-dependent, T type, alpha 1H subunit (CACNA1H) and childhood absence epilepsy. These mutations cause increased channel activity and associated increased neuronal excitability. 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.

Pathophysiology

There are currently 20 mutations in CACNA1H associated with childhood absence epilepsy. These mutations are likely not wholly causative and should instead be thought of as giving susceptibility. This is particularly true since some groups have found no connection between childhood absence epilepsy and CACNA1H mutations.[5] Many of the CACNA1H mutations have a measurable effect on channel kinetics, including activation time constant and voltage dependence, deactivation time constant, and inactivation time constant and voltage dependence (summarized in Table 1). Many of these mutations should lead to neuronal excitability, though others may lead to hypoexcitability. These predictions are from mathematical modeling and may differ from what occurs in neurons where other proteins, some of which may interact with CACNA1H, are present.

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 childhood absence epilepsy-like phenotype that also overlaps with generalized epilepsy with febrile seizures plus type-3. The first of these, R43Q, abolishes benzodiazepine potentiation of gamma-aminobutyric acid induced currents.[6][7] The second associated mutation, C588T, has not been further characterized.


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 [8],[9],[10]
E282K D1S5-6 Hyperpolarized Unchanged Unchanged Unchanged Unchanged Hypoexcitable [8],[9],[10]
P314S D1-2  ?  ?  ?  ?  ?  ? [11]
C456S D1-2 Hyperpolarized Accelerated Unchanged Unchanged Unchanged Hyperexcitable [8],[9],[10]
A480T D1-2  ? Unchanged  ?  ? Unchanged  ? [12],[13]
P492S D1-2  ?  ?  ?  ?  ?  ? [11],[11]
G499S D1-2 Unchanged Unchanged Unchanged Unchanged Unchanged Unchanged [8],[10]
P618L D1-2  ? Accelerated  ?  ? Accelerated  ? [12],[13]
V621fsX654 D1-2  ?  ?  ?  ?  ?  ? [12]
P648L D1-2 Unchanged Unchanged Unchanged Depolarized Slowed Hyperexcitable [8],[10]
R744Q D1-2 Unchanged Unchanged Unchanged Unchanged Unchanged Unchanged [8],[10]
A748V D1-2 Unchanged Accelerated Unchanged Unchanged Unchanged Unchanged [8],[10]
G755D D1-2  ? Unchanged  ?  ? Accelerated  ? [12],[13]
G773D D1-2 Depolarized Slowed Slowed Depolarized Slowed Hyperexcitable [8],[10]
G784S D1-2 Unchanged Slowed Unchanged Unchanged Unchanged Unchanged [8],[10]
R788C D1-2 Depolarized Slowed Slowed Unchanged Slowed Hyperexcitable [10],[11]
G773D + R788C D1-2 Unchanged Unchanged Slowed Unchanged Unchanged Hyperexcitable [10]
V831M D2S2 Unchanged Hyperpolarized Slowed Depolarized Slowed Hypoexcitable [8],[9],[10]
G848S D2S2 Unchanged Unchanged Slowed Unchanged Unchanged Unchanged [8],[10]
D1463N D2S5-6 Unchanged Accelerated Unchanged Unchanged Unchanged Unchanged [8],[9],[10]
*
 Depending on experimental paradigm

Diagnosis

Childhood absence epilepsy can be diagnosed during an outpatient clinic visit with a careful history, physical exam including hyperventilation, and a routine electroencephalogram.[2] 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.[3]

Management
Main articles: Epilepsy and Absence seizure

The syndromic approach very important for conducting the treatment.[3] There are three antiepileptic drugs which has been used for the first line of treatment there are ethosuximide (ETX), valproic acid (VPA), and lamotrigine (LTG). [2]

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.[3] Few of these children will have mutations in CACNA1H or GABRG2, as the prevalence of those in the studies presented is 10% or less.

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. 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.
  2. 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.
  3. 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.
  4. Hirsch E, Thomas P, Panayiotopoulos C (2007). "Childhood and absence epilepsies". Epilepsy: A Comprehensive Textbook: 2397–2411.
  5. 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 A, Nabbout R, Olsson I, Sander T, Sirén A, Robinson R, Rees M, Gardiner R (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.
  6. Wallace R, Marini C, Petrou S, Harkin L, Bowser D, Panchal R, Williams D, Sutherland G, Mulley J, Scheffer I, Berkovic S (2001). "Mutant GABA(A) receptor gamma2-subunit in childhood absence epilepsy and febrile seizures". Nature Genetics. 28 (1): 49–52. doi:10.1038/88259. PMID 11326275.
  7. Marini C, Harkin L, Wallace R, Mulley J, Scheffer I, Berkovic S (2003). "Childhood absence epilepsy and febrile seizures: a family with a GABA(A) receptor mutation". Brain. 126 (Pt 1): 230–40. doi:10.1093/brain/awg018. PMID 12477709.
  8. 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.
  9. 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.
  10. 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.
  11. 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.
  12. 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.
  13. 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.


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