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[Functional imaging in idiopathic generalized epilepsy].

Positron emission tomography has offered the possibility to investigate the pathophysiology of idiopathic generalized epilepsies. Absence epilepsies demonstrate normal cerebral glucose metabolism and benzodiazepine receptor density. Conversely, juvenile myoclonic epilepsies are associated with frontal hypometabolism, which aggravates during a working memory task. Typical 3 Hz spike and wave discharges lead to a diffuse hypermetabolism. The latter resembles that observed during GAERS rats absences, and clearly differs from the hypometabolism encountered in partial epilepsies associated with generalized spike and wave discharges. Overall, functional imaging data provide further evidence of syndromic specificities in idiopathic generalized epilepsies.

Animals↗

A novel SCN1A mutation associated with generalized epilepsy with febrile seizures plus--and prevalence of variants in patients with epilepsy.

We recently described mutations of the neuronal sodium-channel alpha-subunit gene, SCN1A, on chromosome 2q24 in two families with generalized epilepsy with febrile seizures plus (GEFS+) type 2. To assess the contribution that SCN1A makes to other types of epilepsy, 226 patients with either juvenile myoclonic epilepsy, absence epilepsy, or febrile convulsions were screened by conformation-sensitive gel electrophoresis and manual sequencing of variants; the sample included 165 probands from multiplex families and 61 sporadic cases. The novel mutation W1204R was identified in a family with GEFS+. Seven other coding changes were observed; three of these are potential disease-causing mutations. Two common haplotypes, with frequencies of .67 and .33, were defined by five single-nucleotide polymorphisms (SNPs) spanning a 14-kb region of linkage disequilibrium. An SNP located 18 bp upstream of the splice-acceptor site for exon 3 was observed in 7 of the 226 patients but was not present in 185 controls, suggesting possible association with a disease mutation. This work has confirmed the role of SCN1A in GEFS+, by identification of a novel mutation in a previously undescribed family. Although a few candidate disease alleles were identified, the patient survey suggests that SCN1A is not a major contributor to idiopathic generalized epilepsy. The SCN1A haplotypes and SNPs identified here will be useful in future association and linkage studies.

Amino Acid Sequence↗

[Eponyms and epilepsy (history of Eastern civilizations)].

The history of eponyms for epilepsy in the lands of the Eastern globe present the portrait of the attitudes of both the laymen and skilled people towards the disease and patient, as well as to the Nature itself. As opposed to the West which during the Middle ages changed its concepts of epilepsy as the organic brain disease for the sublime 'alchemic' position, the people of the East were more prone to consider from the beginning of their civilization till the XIX century that epilepsy is the consequence of the evanescent spiritual and extracorporal forces which by themselves were out of their reach. As compared to the western civilization, the historical resources are, often as a consequence of a linguistic barriers, more scarce-as consequently is the number of eponyms, but are nevertheless picturesque. The medical science from Babylonian period presumed that epileptic manifestations are the consequence of the demonic or ill spiritual actions. There existed an attitude that at the beginning of an epileptic attack the patient was possessed by a demon (the Akkadic, i.e., Babylonian verb "sibtu" denoting epilepsy, had the meaning "to seize" or "to be obsessed"); at the end of the clonic phase the demon departed from the body. Different demons were responsible for different forms of epilepsy such as nocturnal and children epilepsy, absence epilepsy and pure convulsions, simple and complex automatisms, and gelastic epilepsy. Thus, the doctors from the period of Babylon aside from making primordial classification of epilepsies, knew about their clinical picture (prodromal symptoms and aura, Jackson's epilepsy. Todd's paralysis), postictal phenomena and intericatl emotional instability; provocative factors were also known (sleep deprivation, emotions, as well as alcohol, albeit in a negative sense-as a cure for epilepsy). There is no doubt than in the period of Babylon the clinical picture of serial fits and its progress to status epilepticus were clearly recognized and considered as life threatening events. Persian history of epilepsy, except from the 6th century Zoroastrian "Avesta" document, lacks the written or spoken medical heritage untill the 7th century A.D. and the Arabic conquest of the entire Moslem world. On the other hand, Islamic medicine should be freed from the simple prejudice that the Moslem authors were only the translators of Greek medicine; contrary to such a view, their work contains a high degree of individuality. Although Mohammed introduced a lot of novelty into medicine, Khoran and the Sayings do not explicitly refer to epilepsy. Of importance is to notice that Moslem medicine did not have demons in the "repertoire" of direct causes of epilepsy. The causes and the cures of epilepsy were more magic-mystical and occult in nature, which is reminiscent of the European, as well as Serbian Middle age attitudes. Avicenna recognized difference between children and adult epilepsy. He considered insomnia and afternoon siesta as well as intensive sounds and light to be a provocative factors, whereby we see that at least empirically he knew of sleep (deprivation), startle and reflex epilepsy. The XIII century invasion of Mongols brought about the recession in Moslem Medicine; it recovered only in the XVIII century under the strong influence of European medicine handed over to us through Jewish doctors of various nationalities. The story of the China history of epilepsy has its debut approximately in the 8th century B. C. Medical texts from this period name epilepsy "Dian" and "Xian" which meant "the falling sickness" and "convulsions", respectively. Chinese medical terminology often interchangeably used the words "mania", "madness" and "psychosis" for "epilepsy" which, aside from a prominent language barrier, brings additional confusion. Although Chinese documents gave the first description of the grand mal epileptic attack already in the 8th century B. C. (ABSTRACT TRUNCATED)

China↗

Exclusion of linkage between idiopathic generalized epilepsies and the GABAA receptor alpha 1 and gamma 2 subunit gene cluster on chromosome 5.

Hereditary factors play a major role in the etiology of idiopathic generalized epilepsies (IGEs). The pivotal function of ionotropic gamma-aminobutyric acid type A receptors (GABRs) in inhibitory neurotransmission in the mammalian central nervous system suggests that they may be involved in epileptogenesis and genetic predisposition to IGEs. Dinucleotide repeat polymorphisms associated with the human GABAA receptor alpha 1 (GABRA1) and gamma 2 subunit (GABRG2) gene cluster on chromosome 5q32-q35 offer the opportunity to test whether these candidate genes confer susceptibility to IGEs. Our linkage analyses in 63 families ascertained through IGE patients with either juvenile myoclonic epilepsy, juvenile absence epilepsy or childhood absence epilepsy do not support the hypothesis that variants within the GABRA1 and GABRG2 gene cluster contribute a frequent major gene effect to the expression of the common familial IGEs.

Base Sequence↗

Epilepsy with typical absence seizures with onset during the first year of life.

Absence epilepsy with multiple daily seizures and onset at the age of 6 and 1/2 months in a healthy female child with normal development is described. EEG-video recording revealed typical absence seizures (vacant staring and interruption of motor activity) and complex absences (as above, plus raising of the eyeballs, slight beatings of the eyebrows, and forward propulsion of head and shoulders). The absences were accompanied by bilateral symmetrical 3-Hz spike-wave discharges preceded, and at times followed, by bilateral frontoparietal theta activity coinciding with onset and termination of the absence seizures. The seizures regressed with nitrazepam therapy. At age 3-years, the child is seizure-free and shows normal neurologic development.

Electroencephalography↗

Common subtypes of idiopathic generalized epilepsies: lack of linkage to D20S19 close to candidate loci (EBN1, EEGV1) on chromosome 20.

Hereditary factors play a major role in the etiology of idiopathic generalized epilepsies (IGEs). A trait locus (EBN1) for a rare subtype of IGEs, the benign neonatal familial convulsions, and a susceptibility gene (EEGV1) for the common human low-voltage electroencephalogram have been mapped close together with D20S19 to the chromosomal region 20q13.2. Both loci are potential candidates for the susceptibility to IGE spectra with age-related onset beyond the neonatal period. The present study tested the hypothesis that a putative susceptibility locus linked to D20S19 predisposes to spectra of IGEs with age-related onset from childhood to adolescence. Linkage analyses were conducted in 60 families ascertained through IGE patients with juvenile myoclonic epilepsy, juvenile absence epilepsy or childhood absence epilepsy. Our results provide evidence against linkage of a putative susceptibility gene for four hierarchically broadened IGE spectra with D20S19 assuming tentative single-locus genetic models. The extent of an "exclusion region" (lod scores below-2) varied from 0.5 cM up to 22 cM on either side of D20S19 depending on the trait assumed. These results are contrary to the expectation that a susceptibility gene in vicinity to D20S19 confers a common major gene effect to the expression of IGE spectra with age-related onset from childhood to adolescence.

Chromosome Mapping↗

[Severity and epidemiology of myoclonic epilepsy].

The author first reviews the definition of myoclonia as an epileptic crisis differentiated from tonic crises and infantile spasms. He reviews the prevalence and incidence found in bibliographic data, under the following headings 1. Early myoclonic encephalopathy or neonatal myoclonic encephalopathy 2. Early epileptic syndrome with bursts of suppression or Otahara's syndrome. 3. West's syndrome. 4. The benign myoclonic epilepsy syndrome of children. 6. Syndrome of myoclonic epilepsy in non-progressive encephalopathy. 7. Early myoclonic epilepsy of children or Dose's syndrome. 8. Lennox-Gastaut syndrome. 9. Syndrome of epilepsy with absences in children. 10. Myoclonic absence epilepsy syndrome. 11. Landau-Kleffner syndrome and the syndrome of continuous slow spike-and-wave epilepsy during slow sleep. 12. Photosensitive epilepsy. 13. Absence epilepsy in young patients. 14. Juvenile myoclonic epilepsy. 15. Syndrome of gran mal epilepsy on waking. 16. Progressive myoclonic epilepsies. The author reviews 6,450 cases, 408 patients who had myoclonic crises, that is 6.3%. The differences seen in this total group of patients were: the myoclonic crises which presented alone, myoclonic crises accompanied by simple typical absences, those initially accompanied by generalized tonic-clonic crises and those presenting typical absences, tonic-clonic generalized crises and myoclonus simultaneously. The course of the different groups is analyzed.

Epilepsies, Myoclonic↗

Clinical experience with levetiracetam in idiopathic generalized epilepsy according to different syndrome subtypes.

Clinical experience in open-label studies and anectodal reports suggest that levetiracetam is effective in generalized epilepsy. In this open-label prospective study, 19 patients (3 men, 16 women) affected by idiopathic generalized epilepsy were followed for at least 6 months following the introduction of levetiracetam. Patients were categorized according to syndrome subtype: juvenile myoclonic epilepsy (8), juvenile absence epilepsy (5), childhood absence epilepsy (4), and eyelid myoclonia with absences (2). Eleven patients received levetiracetam as monotherapy, eight as add-on therapy. Effectiveness was demonstrated in 18 patients: 13 became seizure-free (five juvenile myoclonic epilepsy, five juvenile absence epilepsy, three childhood absence epilepsy), and five achieved significant reductions in seizure frequency (three juvenile myoclonic epilepsy, one childhood absence epilepsy, one eyelid myoclonia with absences). Only one patient experienced no change in seizure frequency (eyelid myoclonia with absences). Clinical improvement was accompanied by EEG abnormality suppression or reduction. Levetiracetam was well tolerated; no patient reported side-effects.

Anticonvulsants↗

Relations between cortical and thalamic cellular activities during absence seizures in rats.

In a rat model of generalized absence epilepsies (Genetic Absence Epilepsy Rats from Strasbourg, GAERS), multiunit activity was recorded simultaneously at different sites of the thalamocortical system under neurolept anaesthesia (fentanyl-droperidol). Under these conditions, bilaterally synchronized spike-and-wave-discharges (SWDs) occurred spontaneously on the electroencephalogram (EEG) that were in principle identical to those reported earlier from unanaesthetized preparations. The generation of SWDs on the EEG was associated with spike-concurrent, rhythmic burst-like activity in (mono-)synaptically connected regions of specific (somatosensory) thalamic regions and layers IVN of the somatosensory cortex, and the reticular thalamic nucleus. Precursor activity was typically recorded in cortical units, concomitant with 'embryonic' SW seizures on the EEG, before the paroxysm was evident on the gross EEG and in the thalamus. On average, SWD-correlated activity in layers IVN of the somatosensory cortex started significantly earlier than correlated burst-like firing in reticular and in ventrobasal thalamic neurons. Cellular peak firing in thalamus and cortex during bilaterally synchronized SWDs was related to the spike component on the gross EEG with the temporal rank order ventroposteromedial > ventrolateral > or = ventroposterolateral thalamic > > rostral reticular thalamic nuclei > or = cortex (layers IVN) = caudal reticular thalamic nucleus. A spike-related depression and wave-related increase in firing was recorded in anteroventral ventrolateral thalamic areas, presumably reflecting their peculiar anatomical arrangement within the thalamus. These results from an in vivo preparation with intact synaptic connections that spontaneously produces SWDs indicate that SWDs spread within the thalamocortical network, involving short and long delays. The order of concurrent rhythmic firing observed in thalamocortical circuits during SW seizures are supportive of the hypothesis that the processes of rhythmogenesis recruit local thalamic networks, while cortical mechanisms appear to synchronize rhythmic activities on a larger spatiotemporal scale, thereby providing an important contribution to the generalization of epileptiform activity and expression of SWDs on the EEG.

Animals↗

Differentiation of typical absence seizures in epileptic syndromes. A video EEG study of 224 seizures in 20 patients.

This is a comparative video-electroencephalographic (EEG) study of typical absence seizures in 4 epileptic syndromes. In 20 patients, 224 absences were recorded and analysed. Significant clinical and EEG differences were found in the seizure patterns of childhood absence epilepsy (CAE), juvenile absence epilepsy (JAE), juvenile myoclonic epilepsy with absences (JMEA) and myoclonic absence epilepsy (MAE). Clinically, CAE demonstrated more severe impairment of consciousness than JAE while, in JMEA, ictal manifestations were frequently mild and difficult to detect. In the latter, the adolescent patient usually continued his activity, was able to perform even mathematical calculations and often his speech was not disturbed. In children with JMEA, impairment of consciousness was more apparent and sometimes severe. Automatisms occurred in all 4 epileptic syndromes and were proportional to the severity of the demonstrated impairment of consciousness, being rare in JMEA but frequent in CAE and JAE. Expressive speech and overbreathing usually persisted for 1-2 s after the onset of the EEG ictal discharge in CAE. It was less disturbed in JAE where in some absence seizures, interrupted speech and overbreathing were restored during the ictus. A characteristic clinical manifestation of CAE was opening of the eyes in all absence seizures within 1.8 +/- 0.6 s (max. 2.5 s) from the onset of the EEG paroxysms. This early eye-opening behaviour was not observed in JMEA. In MAE, rhythmical myoclonic jerks at 3 Hz make the diagnosis unmistakable. Myoclonic jerks were extremely rare in the absences of JMEA, although all patients had independent myoclonic jerks on awakening. The ictal EEG discharge was longer in JAE (mean 16.3 +/- 7.1 s) than in CAE (12.4 +/- 2.1 s) or JMEA (6.6 +/- 4.2 s). The opening phase of the EEG paroxysms did not show significant differences in CAE, JAE and JMEA but significant changes were found in their initial and terminal ictal phases. In JMEA, the spike-multiple spike-slow wave complexes were not rhythmic and frequently demonstrated variable spike-slow wave relationships. Ictal discharge fragmentations and spike-wave discharges looking like compressed capital Ws were often seen and are characteristic of JMEA. seen and are characteristic of JMEA. Absence seizures demonstrated a more severe impairment of expressive rather than receptive speech, irrespective of differences between syndromes. Evoked as well as spontaneous automatisms occurred in the same patients.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗

Susceptibility to focal and generalized seizures in Wistar rats with genetic absence-like epilepsy.

The susceptibility to develop cortically induced focal and generalized seizures was examined in Genetic Absence Epilepsy Rats from Strasbourg (GAERS), an inbred strain of Wistar rats with absence epilepsy. A GABA-withdrawal syndrome induced after suppression of a 2-h intracortical GABA infusion was used as a model of focal epileptogenesis: localized cortical discharges appear at the infusion site within 1 h. GAERS were more prone to develop a GABA-withdrawal syndrome than non-epileptic inbred controls and non-selected Wistar rats. After a transient suppression of absence seizures following GABA infusion in GAERS, generalized spike-and-wave discharges and focal spikes were recorded simultaneously in the cortex. GAERS also showed a higher incidence of systemic pentylenetetrazol-induced convulsions at the dose of 25 mg/kg. Higher doses had similar convulsant effects in all groups. In conclusion, the results confirm a genetic susceptibility in GAERS and/or resistance in inbred non-epileptic rats to focal and generalized seizures involving the cortex. Rats with absence epilepsy appear to be more prone to seizures elicited by cortical GABA deficiency.

Animals↗

Refinement of map position of the human GluR6 kainate receptor gene (GRIK2) and lack of association and linkage with idiopathic generalized epilepsies.

Hereditary factors play a major role in the etiology of idiopathic generalized epilepsies (IGEs). The pivotal function of glutamate receptors (GluRs) in excitatory neurotransmission implicates their involvement in epileptogenesis and genetic susceptibility to IGEs. A trinucleotide repeat polymorphism detected in the 3' untranslated region of the kainate-selective GluR6 receptor gene (GRIK2) on chromosome 6 makes it possible to perform linkage and association studies with this high-ranking candidate gene. The present study tested the hypothesis that allelic variants of GRIK2 contribute to the genetic susceptibility to the common IGEs. Linkage and association analyses were conducted in 63 families ascertained through IGE patients with juvenile myoclonic epilepsy, juvenile absence epilepsy, or childhood absence epilepsy. Our linkage and association results suggest that allelic variants of GRIK2 are not involved in the expression of the common familial IGEs, and radiation hybrid mapping assigns GRIK2 to the chromosomal region 6q16.3-q21. This localization excludes GRIK2 as a candidate for the putative IGE susceptibility locus "EJM1" on the short arm of chromosome 6.

Chromosome Mapping↗

Idiopathic generalized epilepsies with typical absences.

Idiopathic generalized epilepsy (IGE) comprises several subsyndromes. These are principally: benign neonatal familial convulsions, benign neonatal convulsions, benign myoclonic epilepsy in infancy, childhood absence epilepsy, juvenile absence epilepsy, juvenile myoclonic epilepsy, epilepsy with generalised tonic-clonic seizures on awakening. In addition, there are less well-recognized syndromes, such as eyelid myoclonia with absences. The pathophysiology of the IGE syndromes is not fully understood; it is evident that typical absences are the result of abnormal oscillations between the thalamus and cerebral cortex. Genetic studies are in progress to elucidate the biochemical defects underlying the conditions. The clinical and electroencephalographic features of the individual subsyndromes are distinct, but some patients may be difficult to classify into a particular subgroup. A correct syndromic diagnosis is important, as treatment strategies differ for patients with the different forms of IGE, and it is necessary for genetic research.

Adolescent↗

Aggravation of absence seizures by carbamazepine in a genetic rat model does not induce neuronal c-Fos activation.

The mechanisms underlying carbamazepine aggravation of absence seizures are uncertain but are thought to involve enhancement of neuronal activity within the thalamocortical circuitry. We used c-Fos immunohistochemistry (cFos-ir) to examine patterns of neuronal activation and the relationship to seizure expression following administration of carbamazepine in a rat model of absence epilepsy (Genetic Absence Epilepsy Rats of Strasbourg, GAERS). Female ovariectomized GAERS implanted with extradural EEG electrodes received either 20 mg/kg carbamazepine or vehicle IP. Seizure expression was quantified by measuring the total number and duration of spike-wave discharges (SWD) and with the individual burst discharge lengths over a 90-minute EEG. This was correlated with cFos-ir in thalamocortical slices from rats killed 180 minutes after carbamazepine administration. Carbamazepine-treated rats (n = 5) had a significantly greater total duration of SWD than vehicle-treated rats (17.9% versus 8.8%, P = 0.04). Despite this aggravation of seizures, the level of cFos-ir did not differ between the treatment groups. A positive correlation was found between cFos-ir in the reticularis thalami (Rt) and the total seizure duration (R = 0.66, P = 0.04) and mean burst length (R = 0.68, P = 0.03) but not total number of seizures. The lack of difference in cFos activation patterns between carbamazepine and vehicle-treated animals suggests that the mechanism for carbamazepine aggravation of absence seizures may not involve neuronal activation but rather enhanced neuronal synchronization. The association between increased neuronal activation in the Rt and seizure burden in GAERS provides further support for the critical role of this structure in the maintenance, but not initiation, of absence seizure activity.

Animals↗

Migraine in patients with history of centro-temporal epilepsy in childhood: a Hm-PAO SPECT study.

The authors report the results of a retrospective controlled study on the incidence of migraine in centro-temporal epilepsy compared to absence epilepsy, partial epilepsy and a group of patients with cranial trauma without epilepsy. The following observations from this series of 129 patients were made. Migraine was present in 63% of the patients with centro-temporal epilepsy (rolandic epilepsy), in 33% with absence epilepsy, in 7% with partial epilepsy and in 9% of the cranial trauma group. These results suggest that the association of centro-temporal epilepsy and migraine is non-fortuitous and also to a lesser degree in absence epilepsy. The role of neurotransmitters in this association is discussed. No decrease in cerebral blood flow was observed in 12 patients with rolandic epilepsy on a Hm-PAO SPECT study.

Adolescent↗

Idiopathic generalized epilepsy of adolescence: are the syndromes clinically distinct?

Juvenile myoclonic epilepsy, juvenile absence epilepsy, and epilepsy with generalized tonic-clonic seizures (GTCS) on awakening are the three syndromes of idiopathic generalized epilepsy of adolescent onset currently included in the classification of epilepsy syndromes of the International League Against Epilepsy (ILAE). Although they differ in their predominant seizure types, the syndromes share several clinical features, thus giving rise to questions of phenotypic overlap and purity. We studied the clinical features of 101 patients with idiopathic generalized epilepsy beginning in adolescence. A standardized interview was used to elucidate seizure phenomenology, precipitants, frequency, and response to treatment. Groups defined by seizure type were compared and their similarities examined. The group with myoclonic but not absence seizures (21 patients) corresponded to the ILAE syndrome of juvenile myoclonic epilepsy, whereas those with absences but not myoclonus (37 patients) resembled juvenile absence epilepsy. Twenty-six patients shared the features of juvenile myoclonic epilepsy and juvenile absence epilepsy. Epilepsy with GTCS on awakening was not a specific syndromic entity; 10 patients had this seizure type alone. Seven patients were without a syndromic diagnosis. In these patients only GTCS occurred, but neither on awakening nor in the evening period of relaxation. We conclude that whilst syndromes of idiopathic generalized epilepsy of adolescence can be recognized, the current classification does not include all patients. In addition, the boundaries between the syndromes are indistinct, suggesting underlying neurobiological, possibly genetic, relationships.

Adolescent↗

Idiopathic generalized epilepsies recognized by the International League Against Epilepsy.

There are eight syndromes currently recognized by the International League Against Epilepsy (ILAE) that would fit the original operational definition of idiopathic generalized epilepsy (IGE) syndromes, including benign myoclonic epilepsy in infancy; generalized epilepsy with febrile seizures plus, an entity in evolution; epilepsy with myoclonic absences; epilepsy with myoclonic-astatic seizures; childhood absence epilepsy; juvenile absence epilepsy; juvenile myoclonic epilepsy; and epilepsy with generalized tonic-clonic seizures only. All of these syndromes can be easily diagnosed when distinctive features are present. In some cases, such features are not present or only appear later in the course of the disease, making it challenging to distinguish the various syndromes. Electroencephalogram (EEG) is the most helpful laboratory test and often will strongly support the diagnosis of IGE, but may not be very helpful in discriminating between several of the syndromes with overlapping features. The same applies for genetic testing, although it is expected that further research exploring the genotype-phenotype relationships will enhance our abilities to make definitive diagnoses. At the current time, clinical features are still the cornerstone of accurate classification, and accurate classification, in turn, is the best predictor of outcome.

Child↗

[Are idiopathic generalized epilepsies of childhood really benign?].

Most of the idiopathic generalized epilepsies are considered as benign in childhood. Using literature data and some personal investigations, we screened the cognitive impairment and school difficulties observed in children with idiopathic generalized epilepsies, especially absence epilepsies, myoclonic epilepsies considered as non-severe, and generalized epilepsies with tonico-clonic seizures. In a controlled study concerning typical absence epilepsy, we have shown a lack of high or moderately elevated level of non-verbal and total IQ scores on Wechsler's tests (WISC III); we also observed a significant impairment of memory, a lengthening of school realisations, concerning motor skills and alertness and also hyperactivity and/or attention disorders, concerning 35 to 50% of cases. Most of these children present with school difficulties, of variable degree. These results show that the term "benign" is not appropriate in many cases of so-called benign idiopathic generalized epilepsies.

Adolescent↗