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. 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.[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. CAE is a well-known and common pediatric epilepsy syndrome affecting 10–17% of all children with epilepsy.[2] It was previously known as pyknolepsy. The word pyknolepsy originates from the Greek piknoz (picnós), which means recurrent or grouped.[3] The usual age of onset of CAE is between 4 and 10 years, with peak between 5 and 7 years.[1] Prognosis is generally good with most patients eventually "growing out" of their seizures.[4]

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 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]

Neuropsychological impairment

There are few a 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.[5] Intelligence tests are measured the first-line tool for evaluating cognitive deficits in children. from intelligence quotient (IQ) tests result help guide diagnosis, treatment, and educational planning.[5] Many existing statistics illustrate that child with CAE presenting an average IQ. [5] Instead of having average IQ children with CAE have subtle cognitive difficulties.[5] Significant social difficulties often can be seen in CAE children with lower IQ.[5] Occurrence of behavioral issues might be associated with significantly worse cognitive development.[5] Some evidence depicted that there are impairment in verbal rather than nonverbal aspects in CAE children.[5] Few authors described that the deficits only limited to the few areas of language like verbal fluency, particularly phonological and category fluency.[5] Attention deficit and learning disability are frequently found in the CAE.[5]It can inhibit the academic performance as well as day to day activities of the children.[5]

Causes

CAE 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 CAE. 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 CAE and CACNA1H mutations.[6] 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 CAE-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.[7][8] 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 [9],[10],[11]
E282K D1S5-6 Hyperpolarized Unchanged Unchanged Unchanged Unchanged Hypoexcitable [9],[10],[11]
P314S D1-2  ?  ?  ?  ?  ?  ? [12]
C456S D1-2 Hyperpolarized Accelerated Unchanged Unchanged Unchanged Hyperexcitable [9],[10],[11]
A480T D1-2  ? Unchanged  ?  ? Unchanged  ? [13],[14]
P492S D1-2  ?  ?  ?  ?  ?  ? [12],[12]
G499S D1-2 Unchanged Unchanged Unchanged Unchanged Unchanged Unchanged [9],[11]
P618L D1-2  ? Accelerated  ?  ? Accelerated  ? [13],[14]
V621fsX654 D1-2  ?  ?  ?  ?  ?  ? [13]
P648L D1-2 Unchanged Unchanged Unchanged Depolarized Slowed Hyperexcitable [9],[11]
R744Q D1-2 Unchanged Unchanged Unchanged Unchanged Unchanged Unchanged [9],[11]
A748V D1-2 Unchanged Accelerated Unchanged Unchanged Unchanged Unchanged [9],[11]
G755D D1-2  ? Unchanged  ?  ? Accelerated  ? [13],[14]
G773D D1-2 Depolarized Slowed Slowed Depolarized Slowed Hyperexcitable [9],[11]
G784S D1-2 Unchanged Slowed Unchanged Unchanged Unchanged Unchanged [9],[11]
R788C D1-2 Depolarized Slowed Slowed Unchanged Slowed Hyperexcitable [11],[12]
G773D + R788C D1-2 Unchanged Unchanged Slowed Unchanged Unchanged Hyperexcitable [11]
V831M D2S2 Unchanged Hyperpolarized Slowed Depolarized Slowed Hypoexcitable [9],[10],[11]
G848S D2S2 Unchanged Unchanged Slowed Unchanged Unchanged Unchanged [9],[11]
D1463N D2S5-6 Unchanged Accelerated Unchanged Unchanged Unchanged Unchanged [9],[10],[11]
*
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.[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

The syndromic approach is very important for conducting treatment.[3] There are three antiepileptic drugs which have been used for the first-line treatment; there are ethosuximide (ETX), valproic acid (VPA), and lamotrigine (LTG). [2] ETX has very limited clinical range; it suppresses absence seizures but not generalized tonic–clonic seizures or focal onset seizures.[2] The mechanism of ETX can be described as the barrier of fleeting low-threshold calcium currents formed by the T-type calcium channels in thalamic neurons, in that way preventing the corresponding firing of corticothalamic neurons that produce the spike wave discharges of absence seizures.[2] The peak level occurs after 3-5 hours of intake; it is advisable for 7-10 days of daily dose to be in steady level.[2] There are a few gastrointestinal side effects, such as hiccups, vomiting, abdominal discomfort, and diarrhoea.[2] There are some adverse reactions and neurologic side effects associated with ETX, like fatigue, insomnia, ataxia, which may lead to discontinuation of ETX.[2] ETX can be given as a syrup (250mg/mL) or a capsule (250 mg); the primary dosage is 20-30 mg/kg/day, usually divided into two doses around 10 mg/kg/day.[2] Valproate (VPA) is also used as monotherapy in CAE if there is occurrence of generalized tonic–clonic seizure, as ETX is not effective.[2] There are several mechanisms related to VPA, including raising the level of gamma-aminobutyric acid (GABA), calcium-dependent potassium activating, and blocking of voltage-sensitive sodium channels, but there is evidence for the mechanism by which VPA controls absence seizures.[2] VPA also have some probable side effects related to either dose or distinctive (few are idiosyncratic). The side effects include high-frequency tremor, altered mental status, increased appetite and weight gain.[2] Lamotrigine (LTG) can be used as first-line treatment for CAE along with VPA and ETX.[2] It was though less frequently used rather than VPA and ETX.[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. There are some evidence shows that CAE girls are more frequently effected than boys. [5]

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. 1 2 3 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.
  2. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 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. 1 2 3 4 5 6 7 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.
  4. ↑ Hirsch E, Thomas P, Panayiotopoulos C (2007). "Childhood and absence epilepsies". Epilepsy: A Comprehensive Textbook: 2397–2411.
  5. 1 2 3 4 5 6 7 8 9 10 11 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.
  6. ↑ 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. S2CID 40437686.
  7. ↑ 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.
  8. ↑ 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.
  9. 1 2 3 4 5 6 7 8 9 10 11 12 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.
  10. 1 2 3 4 5 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.
  11. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 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.
  12. 1 2 3 4 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.
  13. 1 2 3 4 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.
  14. 1 2 3 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.


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