Epilepsy absence

Absence Epilepsies are a group of epileptic syndromes typically starting in childhood or adolescence and characterized by a sudden lack of attention and mild automatic movements for some seconds to minutes. Absence epilepsies are generalized, i.e. the whole neocortex shifts into a state of sleep-like oscillations. 

Primary generalized seizures are also heterogeneous with respect to their clinical features. Such seizures can impose as absence epilepsy, which is characterized by a brief interruption of consciousness due to highly synchronized neuronal activity involving thalamocortical networks without increases in neuronal firing rate. On the other hand, tonic-clonic convulsions with loss of consciousness are often also primarily generalized. 

Deletion of the Cav3.1 channel in thalamocortical relay neurons prevents absence epilepsy. Block of the neuronal LVA channels alleviates certain forms of epilepsy. Deletion of Cav3.2 leads to coronary artery constriction and focal myocardial fibrosis. 

Gabapentin and pregabalin are prescribed in certain epileptic diseases such as absence epilepsy and in neuropathic pain. Their therapeutic target for pain suppression is the a2S-l subunit. 

Godschalk M, Dzoljic M, Bonta I Slow wave sleep and a state resembling absence epilepsy induced in the rat by gamma-hydroxybutyrate. Eur J Pharmacol 44 103-111, 1977... 

Fletcher, CF, Lutz, CM, O Sullivan, TN, Shaughnessy Jr, JD, Hawkes, R, Frankel, WN, Copeland, NG and Jenkins, NA (1996) Absence epilepsy in tottering mutant mice is associated with calcium channel defects. Cell 87 607-617. 

Juvenile absence epilepsy with generalized tonic-clonic seizure on awakening... 

Calcium channels have been shown to play a role in epilepsy as well [23]. Currently used antiepileptic drugs exhibit a wide spectrum of activity, including modulation of voltage-gated sodium and calcium channels. T-type calcium channels have been demonstrated to play an important role in absence epilepsy, a specific form of epilepsy characterized by brief lapses in consciousness correlated with spike-and-wave discharges in the electroencephalogram [14,24-28]. Ethosuximide 1 has been shown to block T-type calcium channels and is used clinically to treat absence epilepsy [25]. Several selective small-molecule T-type calcium channel antagonists have demonstrated efficacy in rodent epilepsy models (vide infra). 

FIGURE 37-4 Antiseizure mediated reduction of IT. Certain antiseizure drugs reduce the flow of calcium through T-type Ca2+ channels (ethosuximide, valproate), thereby reducing the pacemaker current that underlies spike-wave discharges of generalized absence epilepsy. 

AKAP protein kinase A anchoring protein CAE childhood absence epilepsy... 

Sander, T., Berlin, W., Gscheidel, N., Wendel, B., Janz, D., and Hoehe, M. R. (2000) Genetic variation of the human mu-opioid receptor and susceptibility to idiopathic absence epilepsy. Epilepsy Res. 39, 57-61. 

N. G. GABA release and uptake measured in crude synaptosomes from genetic absence epilepsy rats from Strasbourg (GAERS). 

A splice-site mutation in GABRG2 associated with childhood absence epilepsy and febrile convulsions. Arch Neurol 59 1137-1141... 

Carbamazepine is an effective agent for the treatment of partial seizures and generalized tonic-clonic seizures its use is contraindicated in absence epilepsy. Carbamazepine is also useful in the treatment of trigeminal neuralgia and is an effective agent for the treatment of bipolar disorders (see Chapter 33). 

At present, the primary indication for vigabatrin is in the treatment of patients with partial seizures, but it appears to be an effective and generally well tolerated antiepileptic medication for other seizure types as well. It should not be used in patients with absence epilepsy or with myoclonic seizures. Vigabatrin is not approved as an AED in the United States, although it is approved in many other countries. 

It is now generally accepted that the specific antiepileptic action of ethosuximide (and the older agent tri-methadione, no longer employed) against absence epilepsy is its ability to reduce the low-threshold calcium current (LTCC) or T (transient) current. These currents underlie the 3-Hz spike wave discharges that are characteristic of absence epilepsy. A blockade of... 

The only clinical use for ethosuximide (Zarontin) is in the treatment of absence epilepsy. If absence attacks are the only seizure disorder present, ethosuximide alone is effective. If other types of epilepsy are present, ethosuximide can be readily combined with other agents. 

A 14-year-old patient is diagnosed with absence epilepsy. Any of the following drugs could be considered a reasonable choice to prescribe EXCEPT... 

Figure 5. Mutations in the human Cav3.2 (T-type) voltage-gated calcium channel associated with Childhood Absence Epilepsy (CAE), Idiopathic Generalized Epilepsy (IGE) and Autism Spectrum Disorder (ASD)...

Table 7. CACNA1H (Cav3.2, ct1H) Functional results for mutations associated with CAE = childhood absence epilepsy, IGE = Idiopathic generalized epilepsy and ASD = Autism Spectrum Disorder (only those mutations with functional data are listed)...

Imbrici P, Jaffe SL, Eunson LH, Davies NP, Herd C, Robertson R, Kullmann DM, Hanna MG (2004) Dysfunction of the brain calcium channel CaV2.1 in absence epilepsy and episodic ataxia. Brain... 

Khosravani H, Altier C, Simms B, Hamming KS, Snutch TP, Mezeyova J, McRory JE, Zamponi GW (2004) Gating effects of mutations in the Cav3.2 T-type calcium channel associated with childhood absence epilepsy. J Biol Chem 279 9681-9684. 

Peloquin JB, Khosravani H, Barr W, Bladen C, Evans R, Mezeyova J, Parker D, Snutch TP, McRory JE, Zamponi GW (2006) Functional analysis of Ca3.2 T-type calcium channel mutations linked to childhood absence epilepsy. Epilepsia 47 655-658. 

Tsakiridou E, Bertolhni L, de Curtis M, Avanzini G, Pape HC (1995) Selective increase in T-type calcium conductance of reticular thalamic neurons in a rat model of absence epilepsy. J Neurosci 15 3110-3117. 

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