Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023380 (lethargy)
 5,697 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Clonazepam, a new anticonvulsant, appears to be useful for childhood minor motor seizures and for petit mal refractory to Ethosuximide and Trimethadione. It appears less effective in infantile spasms though may be beneficial when there is no response to steroids. It is variably effective in partial complex and focal epilepsy and may exacerbate tonic seizures. A transient disadvantage is the high incidence of side effects, especially lethargy and ataxia, though these may be transitory. Aggressivity and hyperkinesis may necessitate medication withdrawal. Some children who initially respond to therapy and then relapse may respond again to a higher dosage.
 ...
PMID:The utility of clonazepam in epilepsy of various types. Observations with 22 childhood cases. 61 1

Fifty-two patients (age-range four months to 17 years) with drug-resistant convulsive disorders were treated for up to four years (average 15 months) with clonazepam, a benzodiazepine derivative. The types of seizures suffered by these patients were atypical petit mal, akinetic, massive infantile spasms, mixed minor motor seizures, myoclonic jerks, psychomotor, classic petit mal and grand mal. Evaluation of seizure control by clonazepam showed that the large majority of patients had improved--complete control of seizures was achieved in 27 per cent, and a greater than 50 per cent control was achieved in 61 per cent of the patients. Ten per cent of the patients showed no change and one patient worsened. Eight patients were successfully managed on clonazepam alone. Lethargy and ataxia were common side-effects but usually they were transient. No serious organic toxicity was noted.
 ...
PMID:Treatment of minor motor seizures with clonazepam. 120 84

Petit mal status is a heterogeneous clinical syndrome of nonconvulsive status epilepticus. The EEG accompaniment is likewise heterogeneous. Petit mal status occurs at all ages. The characteristics of this syndrome are quite nonspecific and consist of (a) behavioral changes, usually associated with lethargy, slowness, and decreased mental function, (b) abnormal generalized continuous or nearly continuous epileptiform EEG activity, and (c) absence of gross tonic-clonic activity or highly lateralized clonic activity. These criteria do not distinguish petit mal status from complex partial status. Clinical evidence for abruptness of recovery and EEG evidence for localization are required for this distinction, an important factor in therapeutic decisions.
 ...
PMID:Petit mal status. 682 61

To understand the cellular and molecular mechanisms that underlie generalized absence seizures sufficiently well to design rational, efficacious new therapies for patients, it is necessary to turn to animal models to gain insights into these mechanisms. The lethargic (lh/lh) mutant mouse expresses spontaneous absence seizures that share behavioral, electrographic, and anticonvulsant profiles with absence seizures in patients. This validates its use to study the mechanisms that underlie absence seizures. This chapter discusses two scientific approaches that involve the use of lh/lh mice. The first part of the chapter discusses neurobiologic approaches used to investigate critical mechanisms that regulate the synchronized burst firing within the thalamocortical network that generates absence seizures. Two of these critical mechanisms have been studied in detail with lh/lh mice. The first critical mechanism involves the required activation of gamma-aminobutyric acid B (GABAB) receptors to generate absence seizures. Because the numbers of GABAB receptors are increased in thalamocortical populations among lh/lh mice compared with littermates without epilepsy, these receptors appear to play a pathophysiologic role in the expression of absence seizures among lh/lh mice. Moreover, there may be a role for GABAB receptors in the generation of absence seizures among humans, because administration of compounds that activate GABAB receptors can produce absence seizures among humans. These findings suggest that GABAB receptor antagonists may represent a new class of antiabsence compounds that will be efficacious against absence seizures among patients. A second critical mechanism that regulates generation of absence seizures involves GABAA receptors in the nucleus reticularis thalami (NRT), a nucleus that sends GABA-ergic afferents to thalamic relay nuclei. Activation of GABAA receptors in the NRT appears to suppress the generation of absence seizures among lh/lh mice and in other models. Moreover, clonazepam may exert its antiabsence actions through this mechanism. Together, these findings suggest that compounds that selectively activate GABAA receptor isoforms expressed in NRT may represent a class of antiabsence drugs that could have fewer side effects than compounds currently used to treat patients. The second part of the chapter discusses a molecular genetic approach to delineation of the mechanisms that underlie absence seizures. Absence seizures among lh/lh mice are caused by a single-gene defect on chromosome 2. If positional cloning and gene isolation techniques are successful, it will be possible to identify the lh disease gene. Subsequent studies of the lh gene product should greatly increase not only our understanding of the pathophysiologic basis for absence seizures among lh/lh mice but also our ability to seek similar mutations in homologous genes in human families that express absence seizures. Accordingly, strategies and progress in cloning and identifying the lh disease gene are presented.
 ...
PMID:Studies of the lethargic (lh/lh) mouse model of absence seizures: regulatory mechanisms and identification of the lh gene. 1051 18

It is well established that impaired GABAergic inhibition within neuronal networks can lead to hypersynchronous firing patterns that are the typical cellular hallmark of convulsive epileptic seizures. However, recent findings have highlighted that a pathological enhancement of GABAergic signalling within thalamocortical circuits is a necessary and sufficient condition for nonconvulsive typical absence seizure genesis. In particular, increased activation of extrasynaptic GABA(A) receptors (eGABA(A)R) and augmented "tonic" GABA(A) inhibition in thalamocortical neurons have been demonstrated across a range of genetic and pharmacological models of absence epilepsy. Moreover, evidence from monogenic mouse models (stargazer/lethargic) and the polygenic Genetic Absence Epilepsy Rats from Strasbourg (GAERS) indicate that the mechanism underlying eGABA(A)R gain of function is nonneuronal in nature and results from a deficiency in astrocytic GABA uptake through the GAT-1 transporter. These results challenge the existing theory that typical absence seizures are underpinned by a widespread loss of GABAergic function in thalamocortical circuits and illustrate a vital role for astrocytes in the pathology of typical absence epilepsy. Moreover, they explain why pharmacological agents that enhance GABA receptor function can initiate or exacerbate absence seizures and suggest a potential therapeutic role for inverse agonists at eGABA(A)Rs in absence epilepsy.
 ...
PMID:Augmentation of Tonic GABA(A) Inhibition in Absence Epilepsy: Therapeutic Value of Inverse Agonists at Extrasynaptic GABA(A) Receptors. 2191 39