Infantile spasms and cytomegalovirus infection: antiviral and antiepileptic treatment

From 1 January 1995 to 31 December 2004, 22 patients (13 males, nine females; age range 2-12mo) with infantile spasms and cytomegalovirus (CMV) infection were treated with intravenous ganciclovir (GCV) and antiepileptic drugs. GCV was given for 3 to 12 weeks with a 1-month interval (one, two, or three courses). Epileptic spasms occurred before (group A: eight patients), simultaneously (group B: eight patients), and after (group C: six patients) a diagnosis of human CMV (HCMV) infection and antiviral treatment. In 11 patients, DNA CMV [corrected] was found in cerebrospinal fluid by nested-polymerase chain reaction method (neuroinfection). All infants excreted CMV in urine. DNA CMV [corrected] and specific immunoglobulin M and immunoglobulin G antibodies were present in blood. Ten patients, including four with neuroinfection, have been seizure-free for at least the past 18 months. In two patients with neuroinfection, vigabatrin monotherapy was withdrawn after a 2 year 6 month seizure-free period. Eighteen patients required antiepileptic drugs polytherapy, four of whom required additional adrenocorticotropic hormone (ACTH). Six patients on polytherapy were seizure-free on follow-up, two of whom were treated with ACTH, but one patient [corrected] who required ACTH [corrected] was seizure-free on follow-up. In five patients, psychomotor development was normal, 16 had tetraplegia (Gross Motor Function Classification System [GMFCS] Level V), and one had diplegia (GMFCS Level III). Early antiviral and antiepileptic therapy could result in the long-term cessation of seizures.     

The Complex Epilepsy Patient: Intricacies of Assessment and Treatment

Summary:  The aim of treatment of all patients with epilepsy is the same: a complete remission of seizures with minimal or no adverse events. However, the means to reach that common goal may differ among patients, not only because of differences in their epileptic syndrome or type of seizures within the same syndrome, but also because of a variety of comorbid pathologic entities that are commonly identified in patients with epilepsy. In this article, we discuss some of the complexities inherent in the planning of therapeutic regimens for epilepsy patients. Comorbid conditions, whether intrinsic or extrinsic to the epileptic disorder, must play a paramount role in the choice of the therapeutic regimen for seizure control. We review the impact of psychiatric comorbidities on the quality of life of patients with epilepsy, with special attention to the tight relationship between depression and epilepsy. Yet, despite this close relationship, comorbid depression is more often than not underrecognized and undertreated. Next, we review the impact of antiepileptic drugs (AEDs) on comorbid medical disorders and give clear examples of the potentially deleterious impact of several AEDs on the therapeutic effects of concomitant medications used for their treatment. Clearly, treating epilepsy is not only about controlling seizures.     

Efficacy of five days' barbiturate anesthesia in the treatment of intractable epilepsies in children

PURPOSE: To analyze the efficacy of barbiturate anesthesia in the treatment of intractable epilepsies in childhood. METHODS: Anesthesia for 4-5 days with thiopentone sodium was used to treat children with intractable epilepsy in the Department of Pediatrics, Oulu, Finland, from November 1980 through December 1995. The number of epileptic seizures, the number and dosage of antiepileptic drugs (AEDs), and psychomotor development before and after anesthesia were compared. RESULTS: Fifty-four children with intractable epilepsy were treated with barbiturate anesthesia. Twenty-four children had infantile spasms; 22, Lennox-Gastaut syndrome; seven, complex partial epilepsy; and one, myoclonic epilepsy. Twenty-four (44.4%) children had complications during the anesthesia. The seizures recurred in 53 of the 54 patients in a median time of 12 days after the anesthesia. In 42 (78%) children, the seizure frequency returned to a level equal to or higher than that before the anesthesia in a median time of 211 days. The number of AEDs was significantly greater after than before the anesthesia (6.33 vs. 4.8; p < 0.001). Seventeen (32.5%) children were treated surgically after the anesthesia. CONCLUSIONS: Although the seizures are eliminated or the seizure frequency decreases for a short period after the barbiturate anesthesia, the anesthesia does not change the long-term outcome and is therefore inefficient in the treatment of childhood intractable epilepsies.     

Introduction: Goals

Summary: Epilepsy is characterized by recurrent seizures. Many epilepsies with focal seizures as well as convulsive generalized seizures respond satisfactorily to antiepileptic drugs (AEDs) that reduce repetitive firing (e.g., phenytoin, carbamazepine, and valproate) or that augment GABA_A-mediated inhibition (e.g., phenobarbital and benzodiazepines). A number of drugs presently under development, such as NMDA receptor antagonists, loreclezole, losigamone, meth-ysticine, and dextromethorphan, are promising in acute animal models of otherwise drug-resistant convulsant activity. As a result of recent studies in both experimental models and surgically resected human epileptic brain, the prospects for development of AEDs have significantly improved. Several new AEDs recently have reached the commercial market or are in experimental or clinical trials. A comparative presentation of the standing of the new AEDs with respect to their efficacy and side effects is necessary, but still very difficult. Because initial experience with new AEDs is restricted to populations with severe drug-resistant epilepsy, the crucial question whether potential new AEDs can alter prognosis is not yet definitively answered. There is a clear need to compare the effects of standard AEDs and new AEDs in naive patients and over longer follow-up periods. Moreover, because of the strong desire to develop antiepileptic therapy that directly treats the primary etiology of a given epileptic syndrome , or modifies the neurobiological processes that cause recurrent seizures, better experimental epilepsy models for chronic epilepsy and further clinical studies are necessary to increase the knowledge on the pathophysiology of distinct epileptic syndromes. In this respect, studies on the differences between responders and nonresponders to a given AED treatment are extremely valuable.     

Seizures continue even after prompt anti-epileptic drug medication in Sturge–Weber syndrome—study from prolonged video electrocoticography, a case report

Introduction  The mechanism of epilepsy in Sturge–Weber syndrome (SWS) has not been elucidated, since it is difficult to detect epileptic discharges on scalp EEG records. To determine the electrophysiological characteristics of SWS, we evaluated epileptic discharges using intracranial electrocorticography (ECoG). Case summary  We report a 1-year and 3-month-old boy diagnosed with SWS whose psychomotor development was impaired despite good control of his seizures with several antiepileptic drugs (AEDs). Prolonged video ECoG monitoring was performed to determine whether subclinical seizures had induced his developmental delay. Discussion  Frequent seizures were detected as motionless staring and respiratory distress. His seizures originated from multiple areas along the Sylvian fissure, propagated very slowly, and lasted for 10 to 30 min. Left hemispherotomy was performed, and he was confirmed to be completely seizure-free after surgery. Our findings indicate that long-lasting and barely discernible seizures may continue in patients with SWS who appear to have good control of epilepsy with AEDs.     

Epilepsy and antiepileptic drug therapy in juvenile neuronal ceroid lipofuscinosis

PURPOSE: To survey the characteristics of epilepsy in patients with juvenile neuronal ceroid lipofuscinosis (JNCL) and determine the antiepileptic drug (AED) treatment most suitable for these patients. METHODS: The study included 60 patients with JNCL; their mean age was 16.5 years (range 5-33). The age at onset of epilepsy, type of seizures, effect of the first AED on seizures, and the current seizure frequency and AED therapy were studied. The side effects of the AEDs were also clarified. RESULTS: Fifty of the 60 patients had epilepsy. Patients' first epileptic seizure occurred at a mean age of 10.0 years (range 5-16), the most common type being generalized seizures. As the first AED tried, valproate (VPA) and lamotrigine (LTG) appeared equally effective, with 80% of the patients responding to these AEDs. During the study year, the median seizure frequency was four seizures a year (range 0-120), and 72% of the patients had good or satisfactory seizure control (0-6 seizures a year). In the different AED therapy groups, the proportion of patients with good or satisfactory seizure control ranged from 25% to 100%. LTG in monotherapy or in combination with clonazepam (CZP) was superior to other AEDs or combinations, but VPA also seemed effective. Adverse effects leading to the discontinuation of an AED were observed in 25% of the patients, most frequently in patients receiving phenobarbital (PB). No patient receiving LTG had to discontinue the drug due to adverse effects. CONCLUSION: Epilepsy in JNCL can usually be successfully treated with the current AEDs. In Finnish patients with JNCL, treatment is based on LTG, or, secondarily, VPA. In combination therapy, CZP seems a valuable add-on AED.     

Efficacy of current antiepileptics to prevent neurodegeneration in epilepsy models

Results of experiments performed in animal epilepsy models and human epilepsy during the past decade indicate that the epileptic brain is not a stable neuronal network, but undergoes modifications caused by the underlying etiology and/or recurrent seizures. In many forms of epilepsy, such as temporal lobe epilepsy, the underlying etiologic factor triggers a cascade of events (epileptogenesis) leading to spontaneous seizures and cognitive decline. In some patients, the condition progresses, due in part to recurrent seizures. The current treatment of epilepsy focuses exclusively on preventing or suppressing seizures, which are symptoms of the underlying disease. Now, however, we are beginning to understand the underlying neurobiology of the epileptic process, as well as factors that might predict the risk of progression in individual patients. Thus, there are new opportunities to develop neuroprotective and antiepileptogenic treatments for patients who, if untreated, would develop drug-refractory epilepsy associated with cognitive decline. These treatments might improve the long-term outcome and quality-of-life of patients with epilepsy. Here we review the available data regarding the neuroprotective effects of antiepileptic drugs (AEDs) at different phases of the epileptic process. Analysis of published data suggests that initial-insult modification and prevention of the progression of seizure-induced damage are candidate indications for treatment with AEDs. An understanding of the molecular mechanisms underlying the progression of epileptic process will eventually show what role AEDs have in the neuroprotective and antiepileptogenic treatment regimen.     

Classification of seizures and epilepsy

The management of seizures and epilepsy begins with forming a differential diagnosis, making the diagnosis, and then classifying seizure type and epileptic syndrome. Classification guides treatment, including ancillary testing, management, prognosis, and if needed, selection of the appropriate antiepileptic drug (AED). Many AEDs are available, and certain seizure types or epilepsy syndromes respond to specific AEDs. The identification of the genetics, molecular basis, and pathophysiologic mechanisms of epilepsy has resulted from classification of specific epileptic syndromes. The classification system used by the International League Against Epilepsy is periodically revised. The proposed revision changes the classification emphasis from the anatomic origin of seizures (focal vs generalized) to seizure semiology (ie, the signs or clinical manifestations). Modified systems have been developed for specific circumstances (eg, neonatal seizures, infantile seizures, status epilepticus, and epilepsy surgery). This article reviews seizure and epilepsy classification, emphasizing new data.     

Intractable epilepsy of childhood and its treatment

This paper discusses the concept of epilepsy intractability as the criterium qualifying for the administration of polytherapy, inclusion of new antiepileptic drugs /AEDs/ and application of neurosurgical treatment. There were also diagnostic criteria and complication discussed. To define the concept of epilepsy intractability correctly and to administer appropriate treatment, it is necessary to classify the kind of seizures and their possible reasons, to apply suitable AEDs, their doses and to treat patients with them for a suitable period of time. Intractable forms of epilepsy are diagnosed at about 20-30% of patients with suitable treatment. The disease prevalence is different at particular age groups and depends also on seizure type or epileptic syndrome. Therefore, Ohtahar syndrome, West, Lennox and Gastaut syndromes, epilepsia partialis continua belong to intractable epileptic syndromes at children. There is the biggest risk of psychic disorders appearance among patients resistant to antiepileptic treatment. Moreover, long-term application of AEDs may be associated with the induction of epileptic seizures, occurrence of side and toxic symptoms. Great interest in intractable epilepsy is connected with huge progress in treatment of this disease which has resulted in introduction of many new AEDs for the last few years. Its inclusion into treatment, first as add--on therapy, and then, due to clinical examinations, also as a monotherapy, enables the improvement in seizure control and in the quality of patients' life.     

短暂性癫痫性遗忘的临床和电生理研究(附6例报告)

目的探讨短暂性癫痫性遗忘(TEA)的临床和电生理特点。方法对本院脑电监测中心收治的6例TEA患者的临床和电生理特点进行研究。结果 6例患者,女性4例,男性2例,年龄34~74岁。除有癫痫性遗忘发作外,还伴有自动症、部分继发全面强直阵挛发作(s GTCS)、"愣神"等其他癫痫发作形式,5例患者的脑电图均为颞导(单侧或双侧)痫样放电,1例正常。其中5例均给予抗癫痫药物治疗,随访1 y,3例无临床发作,2例偶有发作。结论 TEA常常被误诊或漏诊,尽管大多数颞叶癫痫为难治性癫痫,我们的研究提示伴有TEA的颞叶癫痫对抗癫痫药物反应良好。     

Clinical characteristics and use of antiepileptic drugs among adolescents with uncomplicated epilepsy at a referral center in Novi Sad, Serbia

The study aimed to investigate the type and etiology of epileptic seizures and the use of antiepileptic drugs for the treatment of various forms of epileptic seizures among adolescents with active but uncomplicated epilepsy at a tertiary referral center in Novi Sad, Serbia. The study design was cross sectional. Data were obtained from patients and medical records. A total of 103 adolescents (39 males and 64 females) with active but uncomplicated epilepsy were included. Patients with primary generalized seizures had significantly better control of epilepsy than those with partial seizures with or without secondary generalization. A total of 80 (77.7%) adolescents had no known underlying etiology based on initial diagnosis and evaluation. All adolescents were classified into known idiopathic syndromes (54.4%), non-classifiable cryptogenic etiology (23.3%), and secondary epilepsy attributed to MRI-identified lesions (22.3%). Eighty-eight percent of adolescents were taking monotherapy and 64.8% of these were taking valproate. New antiepileptic drugs (AEDs), topiramate and lamotrigine, the only drugs available free of charge at the Serbian market, were used in 19.4% of patients. A total of 57.3% adolescents were seizure-free, 24.2% had occasional seizures, and 18.5% had seizures despite AED treatment.     

Long-term course of epilepsy in a large cohort of intellectually disabled patients.

This study was designed to describe the course of epilepsy (in terms of seizure frequency) and to assess the variables (antiepileptic therapy regimens and others) correlated to improvement. Seizure frequency (categories: seizure free, more than one seizure/year, monthly seizures, weekly seizures and daily seizures) and antiepileptic medication were retrospectively compared between 1992 and 2002 in a large cohort of 550 inpatients with chronic epilepsy and different degrees of intellectual disability or multiple handicaps. RESULTS: Seizure frequency decreased significantly (p<0.001). 218 of the 394 patients (55.3%) not seizure free in 1992 improved (changed into a better frequency category). The improvement rate was marginally higher in patients who had undergone a medication change (p=0.08). A high seizure frequency in 1992 (p=0.016) and older age (p=0.006), but not epilepsy syndrome or degree of intellectual disability, were predictors for improvement (stepwise logistic regression analysis). 56.4% of the improved patients were on combinations of two AEDs (17.4%, monotherapy; 20.2%, triple therapy). The most frequent therapy regimens in the improved patients were lamotrigine/valproate (48 patients), carbamazepine/phenobarbital (21) and carbamazepine only (19). Lamotrigine/valproate was effective in all kinds of epileptic syndromes. Most patients on lamotrigine had serum concentrations above 10microg/ml, approximately one half had dosages above 200mg/day. The rate of seizure freedom increased from 28.4 to 37.6%. The 84% of the patients seizure free in 1992 remained seizure free. Predictors for seizure freedom in 2002 were higher age (stepwise logistic regression, p<0.0005) and seizure freedom in 1992 (p<0.0005). CONCLUSIONS: Substantial improvement can be achieved even in intellectually disabled patients with chronic epilepsy. Although the rate of seizure freedom is reduced in comparison with a non-ID population, once seizure freedom has been achieved it is most likely to continue. For a majority of this patient population, monotherapy may not be sufficient. Lamotrigine/valproate appears to be a major therapeutic innovation.     

Acute encephalitis with refractory, repetitive partial seizures

BACKGROUND: Acute encephalitis with refractory, repetitive partial seizures (AERRPS) is a new epileptic syndrome described by Sakuma in Japan in 2001. The clinical manifestations, neuroimaging findings and outcome of AERRPS in Taiwan have not been reported. METHODS: From 2000 to 2006, we collected cases that fulfilled the diagnostic criteria of AERRPS and analyzed the clinical course, virology, medication, electroencephalographic findings, neuroimaging characters and prognosis retrospectively. RESULTS: Fourteen children aged from 1 year and 2 months to 15 years and 6 months were enrolled. They presented with prodromic symptoms including fever (n=13, 92.9%), upper respiratory tract infection symptoms (n=12, 85.7%) and gastrointestinal tract discomfort (n=6, 42.9%). Seizures occurred 3-14 days after antecedent symptoms with patterns of generalized tonic-clonic seizures, focal seizures or myoclonic seizures. The seizures were refractory to combinations of antiepileptic drugs (AEDs). Prolonged fever (n=14, 100.0%), hypersensitivity to AEDs (n=11, 78.6%) and liver function impairment (n=8, 57.1%) were noted during the period of hospitalization. The follow-up EEG findings were similar to those of initial findings including epileptiform discharges and/or generalized background slow waves. Initial brain MRI scans were normal but later showed focal or multifocal abnormal signal intensity followed by generalized brain atrophy in more than 50% of cases. The general prognosis was poor with variable psychomotor retardation and persistence of refractory epileptic seizures. CONCLUSIONS: The similarities of the clinical features support AERRPS as a new epileptic syndrome. More study is needed to specify the etiology of the syndrome as the first step for more effective treatment.     

神经外科患者癫痫反复发作处理分析

目的 探讨神经外科患者出现癫痫反复发作的临床特点、处理原则与方法.方法 回顾性分析沈阳军区总医院神经外科自2011年1月至6月收治的9例癫痫反复发作患者的临床资料,分析其加重的原因、发作特点及治疗方法和结果.结果 9例患者中3例合并胶质瘤、1例蛛网膜囊肿、1例海绵状血管瘤、1例脑软化灶;7例有癫痫病史,2例既往无癫痫病史;7例为额叶癫痫,2例颞叶癫痫.癫痫发作加重的原因:减药3例,新诊断的脑肿瘤2例,手术(颅内电极置入术)1例,原因不明3例.癫痫发作类型包括部分性发作与全面性发作,发作频率从间隔3min至间隔数小时发作一次.患者经给予多种抗癫痫药物联合用药治疗,包括口服与注射给药,癫痫得到控制,其中添加左乙拉西坦口服有较好的疗效.结论 神经外科患者出现癫痫反复发作多呈药物难治性,发作不易控制,其处理应使用对部分性癫痫发作有较好疗效的多种抗癫痫药物联合用药,剂量应高于常规初始剂量,包括静脉注射及肌注给药,以尽快控制癫痫发作.左乙拉西坦因口服吸收快、起效迅速及有较好的抗癫痫作用,对癫痫反复发作有较好的疗效.     

婴幼儿睡眠期Rolando区小棘波的临床特征和预后

目的：分析婴幼儿视频脑电图（V-EEG）中睡眠期罗朗多（Rolando）区小棘波的临床特征和预后,企为临床提供参考。方法：选择2012年4月～2013年5月潍坊医学院附属医院和临沂市人民医院儿科神经电生理室的31例睡眠期Rolando区小棘波的患儿的临床资料并随访治疗效果和预后。结果：31例中,男17例,女14例。起病年龄3～22个月,中位数12个月。其中良性婴儿癫痫9例（29％）,伴有轻度胃肠炎的良性婴儿惊厥6例（19％）,单纯热性惊厥9例（29％）,复杂热性惊厥3例（10％）,当天曾注射百白破及脊髓灰质炎疫苗引发高热惊厥1例（3％）;既往有重症小脑脑炎并发癫痫发作史1例（3％）,非癫痫发作2例（7％）。7例有惊厥家族史,其中1例有良性婴儿癫痫家族史,3例有热性惊厥家族史。21例未治疗,10例接受抗癫痫药物单药治疗,发作均被控制,其中1例已停服12个月,1例已停服6个月,随访均无复发。结论：婴幼儿期Rolando区小棘波对癫痫的诊断没有特异性,但与癫痫发作具有相关性,所有患儿短期预后良好。     

A new potential AED, carisbamate, substantially reduces spontaneous motor seizures in rats with kainate-induced epilepsy

Purpose: Animal models with spontaneous epileptic seizures may be useful in the discovery of new antiepileptic drugs (AEDs). The purpose of the present study was to evaluate the efficacy of carisbamate on spontaneous motor seizures in rats with kainate‐induced epilepsy. Methods: Repeated, low‐dose (5 mg/kg), intraperitoneal injections of kainate were administered every hour until each male Sprague‐Dawley rat had experienced convulsive status epilepticus for at least 3 h. Five 1‐month trials (n = 8–10 rats) assessed the effects of 0.3, 1, 3, 10, and 30 mg/kg carisbamate on spontaneous seizures. Each trial involved six AED‐versus‐vehicle tests comprised of carisbamate or 10% solutol‐HS‐15 treatments administered as intraperitoneal injections on alternate days with a recovery day between each treatment day. Results : Carisbamate significantly reduced motor seizure frequency at doses of 10 and 30 mg/kg, and caused complete seizure cessation during the 6‐h postdrug epoch in seven of the eight animals at 30 mg/kg. The effects of carisbamate (0.3–30 mg/kg) on spontaneous motor seizures appeared dose dependent. Conclusions: These data support the hypothesis that a repeated‐measures, crossover protocol in animal models with spontaneous seizures is an effective method for testing AEDs. Carisbamate reduced the frequency of spontaneous motor seizures in a dose‐dependent manner, and was more effective than topiramate at reducing seizures in rats with kainate‐induced epilepsy.     

Investigational Antiepileptic Drugs for the Treatment of Childhood Seizure Disorders: A Review of Efficacy and Safety

Summary: Pediatric epileptology is very different from adult epileptology. Although some epileptic disorders occur in both children and adults (e.g., localization-related epilepsy with complex partial seizures and primary generalized epilepsy with tonic-clonic seizures), other disorders can be called the catastrophic epilepsies of childhood (e.g., infantile spasms and the Lennox-Gastaut syndrome). They occur, or at least begin, exclusively in childhood and are often associated with mental retardation. Many of these pediatric disorders are notoriously unresponsive to currently available antiepileptic drugs (AEDs). Although there are undoubtedly many reasons for this, one possible explanation is that the methods used to screen potential AEDs use animal models of adult epilepsy. No screening program uses an animal model of seizures that begin during development and lead to functional decline.     

Aggravation of Generalized Epilepsies

Summary: Generalized epilepsies are treatable with a number of antiepileptic drugs (AEDs) that are effective in different seizure types and epilepsy syndromes. The mechanisms of action of these AEDs are incompletely understood but include inhibition of low-threshold calcium currents and of voltage-gated sodium channels and facilitation of GABA_A receptor currents. The mechanisms of aggravation are also unknown but could include elevation of brain GABA, blockade of voltage-gated sodium channels, and idiosyncratic toxicity reactions. Anecdotal reports suggest that aggravation of generalized epilepsy can occur with virtually all AEDs. The best-documented examples are aggravation of absences by carbamazepine and aggravation of symptomatic generalized epilepsies by vigaba-trin. Therefore, the physician must be constantly aware of the problem of aggravation of seizures by AEDs. With careful diagnosis of the epileptic syndrome and an awareness of the problem, aggravation of seizures can be minimized.     

Epilepsy Education in Medical Schools: Report of the American Epilepsy Society Committee on Medical Student Education

The education of medical students about epilepsy is often fragmentary and incomplete. Basic information regarding the classification of epileptic seizures, epilepsy syndromes, first aid for seizures, and practical use of antiepileptic drugs (AEDs) may not be covered in medical school curricula. In this report we describe reasons why the study of epilepsy provides a relatively unique opportunity to integrate concepts related to basic neuroscience and clinical neurology. Furthermore, we present a curricular framework that may prove useful for the education of medical students about epilepsy.     

Long-Term Course of Childhood Epilepsy with Intractable Grand Mal Seizures

Abstract: Twenty-nine children with childhood epilepsy characterized by frequent grand mal (generalized tonic-clonic) seizures in spite of maximal doses of antiepileptic drugs and by an early onset of seizures (before 1 :year of age) were followed up for more than 5 :years. The children were divided into 3 :groups: severe myoclonic epilepsy in infancy (SME), no SME, and intractable childhood epilepsy with generalized tonic-clonic seizures (GTC). In all the 3 :groups, the grand mal seizures persisted, whereas the other types of seizures tended to disappear as the patients aged, and the prognosis for mental development was poor. In the majority of cases in all the 3 :groups, the waking grand mal seizures altered to sleep grand mal seizures with aging. Two pairs of monozygotic twins with SME suggested that genetic factors play a role in this epileptic syndrome. Intractable childhood epilepsy with GTC is distinguished by the absence of other types of generalized seizures. It cannot be regarded as an epileptic syndrome, but its pathogenesis and treatment require further studies.