Efficacy of hippocampal transection for left temporal lobe epilepsy without hippocampal atrophy

We describe a case of left temporal lobe epilepsy without hippocampal atrophy. A 31-year-old woman presented with typical symptoms of complex partial seizures. Magnetic resonance imaging demonstrated slightly obscure internal structures in the left hippocampus. Scalp electroencephalography revealed interictal epileptiform discharges in the left temporal lobe. A Wada test with propofol determined the language-dominant hemisphere to be the left. Intraoperative electrocorticography revealed active epileptic discharges in the hippocampus and the anterior temporal basal area. The hippocampal epileptic area was treated with multiple transection, which led to the complete cessation of epileptic discharges. After surgery, the Rey Auditory Verbal Learning Test score decreased from 12 to 9. However, it returned to the preoperative level 6months after surgery. We describe this case as a typical example demonstrating the efficacy of hippocampal transection for seizure control and the preservation of verbal memory.     

Hippocampal synaptic pathology in patients with temporal lobe epilepsy

Immunostaining of synaptic terminals was studied in the hippocampus of 26 patients who had surgical resections for intractable temporal lobe epilepsy. Two monoclonal antibodies (EP10 and SP12) reactive with distinct synaptic antigens were used on paraffinembedded tissues. The results indicated qualitative reductions on synaptic terminals in CA4 and other regions where cell loss is reported. The inner molecular layer of the dentate gyrus was observed to have increased synaptic immunostaining. Synaptic terminal loss in CA4 and redistribution in the molecular layer were most frequent in cases with hippocampal sclerosis. However, both forms of synaptic pathology were also noted in most cases where the pathological findings were classified as indefinite, and in some cases associated with mass lesions of the temporal lobe. These results support the importance of neuronal loss and synaptic reorganization as possible mechanisms of illness in epilepsy. They also indicate that synaptic immunostaining may be a useful adjunct to routine neuropathological diagnostic techniques.Supported by the British Columbia Health Research Foundation and the Theodore and Vada Stanley Foundation     

Temporal lobe volumetric cell densities in temporal lobe epilepsy

Volumetric cell densities in 13 different subfields of the temporal lobe were calculated to test various hypotheses about mesial and lateral temporal lobe sclerosis in patients with complex partial epilepsy. In patients benefitting (primary group) from anterior temporal lobectomy (ATL), sclerosis was greater (fewer cells) in anterior than in posterior hippocampus. By contrast, the patients lacking full benefit (nonprimary group) from ATL had decreased numbers of neurons equally distributed from anterior to posterior hippocampus, indicating that zones of mesial temporal cell loss are linked to zones of epileptogenicity. These data support a model of focal hippocampal epilepsy originating from zones of cell loss and synaptic reorganization that is epileptic. There were no differences in cell densities in gyrus hippocampi or in lateral temporal gyri when patients with temporal lobe epilepsy and controls were compared. Hippocampal cell densities in mesial temporal lobe were not reduced in psychomotor epileptic patients with extrahippocampal foci consisting of foreign tissue. Variables in seizure histories were not correlated with Ammon's horn cell densities, indicating that most of the sclerosis preceded the seizures, which did virtually no significant further damage to hippocampus with repeated partial or generalized seizures.     

Neuropathological findings in 224 patients with temporal lobe epilepsy

During the period between 1976 and 1990, 247 patients with pharmaco-resistant complex partial seizures and a documented unilateral epileptogenic area in the mediobasal temporal lobe underwent a selective amygdalo-hippocampectomy procedure at our institution. Biopsy specimens from 224 patients (91% of the total) were available for a retrospective histopathological and immunohistochemical review. The tissue specimens of 23 patients without evidence for a macroscopic lesion have been used for neurochemical studies and could not be evaluated histopathologically. The most common temporal lobe pathology were neoplasms in 126 patients, i.e. 56%. Tumor entities observed included 23 astrocytomas (18% of all tumors), 17 gangliogliomas (13%), 15 oligodendrogliomas (12%), 15 cases of glioblastoma multiforme (12%), 13 pilocytic astrocytomas (10%), 12 oligo-astrocytomas (10%), 11 anaplastic astrocytomas (9%) and 20 tumors of various other histologies. In 23 specimens (10%), small foci of oligodendroglia-like clear cells were found. The frequent association of these foci with low-grade gliomas or neural hamartomas raises the possibility that these structures may serve as precursor lesion for neuroepithelial tumors of the temporal lobe. In 98 cases, pathological changes of non-neoplastic origin were encountered. The most common diagnoses in this group included hippocampal gliosis/sclerosis (49 cases, 22%) and vascular malformations (20 cases, 9%). Hamartomas, i.e. focal accumulations of dysplastic neuro-glial cells were diagnosed in 14 patients (6%). In only four cases have we not been able to detect any microscopic pathology. These results indicate that a high proportion of pharmaco-therapy-resistent complex-partial seizures are caused by neoplasms of the temporal lobe, some of which appear to the strikingly overrepresented in this group of patients.     

伴海马硬化的颞叶癫痫患者的临床特点及手术治疗

目的探讨颞叶癫痫海马硬化的临床特点及手术治疗的效果。方法伴海马硬化的颞叶癫痫患者18例,其中男10例,女8例;年龄12~37岁,病程3~10年。癫痫复杂部分性发作10例,部分性发作继发全身性发作2例,全身强直-痉挛性发作6例。结合患者的临床表现、MRI检查和视频脑电图(V-EEG)监测结果,对这18例患者行前颞叶切除术(包括大部分海马和杏仁核)。结果所有患者术中皮层和深部电极脑电图均发现颞叶皮层海马、杏仁核有异常放电,术后病理检查均证实海马硬化的诊断。术后18例患者均出现发热,但经过抗炎、腰椎穿刺及支持治疗后渐好转。术后1年以上的随访发现16例癫痫发作完全消失,2例术后较术前显著改善,仅偶有癫痫发作,但均长期服用抗癫痫药物。结论对于颞叶癫痫伴有海马硬化的患者,如果同时脑电图又发现有同侧颞叶痫样放电,则可以考虑行该侧前颞叶切除术(包括大部分海马和杏仁核),若手术切除彻底,其术后疗效也较满意。     

Surgical outcome of patients with mesial temporal lobe epilepsy related to hippocampal sclerosis

Seizure outcome in mesial temporal lobe epilepsy related to hippocampal sclerosis (MTLE-HS) that was evaluated according to a noninvasive protocol was assessed in 165 patients and reported using both Engel's and ILAE classifications. The mean postoperative follow-up was 5.0 +/- 2.7 years. At the end of first year, 77.1% of patients were in Engel-I, and 52.7% were in ILAE-I. Antiepileptic drugs (AEDs) were discontinued in 41 patients (42.7%), all remained seizure-free for >or= 2 years that could be accepted as "cure." Thirty-six patients had recurrences, 19 had running-down phenomena. Anterior temporal lobectomy (ATL) was performed in 27 patients with a better outcome when compared to patients operated by selective anterior hippocampectomy. Clinical risk factors for better and worse outcome, which show some similarity in different reports, seem to veil the main reason, which is the accurate delineation of epileptogenic zone considering the presence of different subgroups and underlying developmental pathologies.     

Accelerated long-term forgetting after amygdalohippocampectomy in temporal lobe epilepsy

Aim of the studyTemporal lobe epilepsy (TLE) has been associated with the phenomenon of accelerated long-term forgetting (ALF). In this study, we aimed to demonstrate the effect of surgery on the ALF phenomena thus contributing to potential explanation of the causal mechanism.Materials and methodsWe evaluated 51 patients with TLE related to hippocampal sclerosis who had amygdalohippocampectomy and had remained seizure-free after surgery. A control group consisted of 24 healthy individuals. All were given a verbal learning test assessing recall after 30 min, 1 week and 6 weeks.ResultsIn our study, the Left-TLE (L-TLE) group showed a statistically significant reduction in the performance at all assessment intervals from 30 min to 1 week compared to the Right-TLE and control groups regarding verbal learning memory test (VLMT) as well as for logical memory. The forgetting rates in the VLMT from 30 min to 1 week were not statistically significantly different between all 3 groups. The logical memory test results equally showed no statistically significant difference in the forgetting rates for the 3 groups between 30 min and 1 week.Conclusions and clinical implicationsThese results may support ongoing debates assuming the initial low performance in the memory of L-TLE patients to be directly related with left hippocampal-temporal tissue loss irrespective of epileptic activity. The discovery of the ALF phenomenon explains that standard memory tests are unable to detect memory loss in some patients who are experiencing a significant level of problems with forgetfulness in their daily lives.     

ApoE epsilon4 allele and disease duration affect verbal learning in mild temporal lobe epilepsy

PURPOSE: To clarify the possible role of other factors including the ApoE epsilon4 allele for memory decline in temporal lobe epilepsy (TLE). METHODS: We conducted a neuropsychological and molecular study in 138 consecutive patients (78 female patients; mean age, 50.2 years, SD +/- 17.9; range, 14 to 87 years) with mild nonlesional TLE, who rarely or never had seizures at long-term follow-up. The mean age at seizure onset was 33.0 years (SD, +/-21.7), and the mean duration of epilepsy was 17.1 years (SD, +/-15.7). RESULTS: Thirty-four (25%) of 138 patients had test scores indicating verbal learning deficit (VLD). The presence of an ApoE epsilon4 allele was associated with an increased risk of VLD (OR, 4.18; 95% CI, 1.66-10.55). The effect of the ApoE genotype was independent of both the age at epilepsy onset and disease duration as well as of a low educational level, which were separately associated with VLD (p values = 0.045, 0.001, and 0.001, respectively). A significant linear trend (p = 0.005) was seen in the relation between disease duration and cognitive impairment, with the highest risk being in patients with an epilepsy duration > or =25.5 years (OR, 7.06; 95% CI, 1.67-29.85), especially if they carried the epsilon4 allele (OR, 32.29; 95% CI, 5.23-195.72). CONCLUSIONS: These results provide evidence for an alteration in cognitive performance as a function of the presence of the ApoE epsilon4 allele and point to the critical role of disease duration itself for cognitive impairment in TLE.     

伴海马硬化的颞叶癫痫患者的临床特点分析

目的通过比较伴和不伴海马硬化的颞叶癫痫患者的临床特点,为临床诊治提供依据。方法收集2009年6月至2012年6月期间南京军区南京总医院颞叶癫痫患者144例,通过头颅MRI或颞叶癫痫手术病理分类,对每位患者发作时临床表现、发作间期、起病年龄及脑电图等进行分析。结果伴海马硬化的颞叶癫痫患者起病年龄较不伴海马硬化的颞叶癫痫患者更小,同时更易出现发作前先兆和意识障碍。伴或不伴海马硬化的颞叶癫痫患者的脑电图异常率相似,大多数患者脑电图可发现癫痫样异常改变。海马硬化患者有高热惊厥史的更常见。结论伴有海马硬化的颞叶癫痫患者有一些特殊的临床表现,深入了解伴海马硬化的颞叶癫痫患者的临床特点将利于更好更快地选择颞叶癫痫患者的合理治疗方案。     

Efficacy of temporal lobe surgery for epilepsy in patients with negative MRI for mesial temporal lobe sclerosis

Epilepsy surgery is a successful treatment for refractory temporal lobe epilepsy (TLE). Reports suggest fewer seizure-free outcomes for patients with TLE and who have a negative brain MRI (nMRI) for mesial temporal sclerosis. Data were collected prospectively from patients with nMRI who underwent temporal lobe surgery for TLE characterized by unilateral ictal temporal lobe seizure onset based on a scalp video electroencephalogram or invasive subdural electrode recordings. A total of 86 patients were followed for at least 24 months after surgery. Outcome was evaluated using the Engel classification. Seizure control was obtained by 55% (47/86) of patients (Class [CL]-I), 27% (23/86) showed significant improvement (CL-II) and 19% (16/86) were deemed surgical failures. Shorter duration of epilepsy, later onset of seizures, and ictal theta rhythm (5-7 Hz) were the most significant predictors of postoperative seizure control. Although hypometabolism on positron emission tomography scan and significant memory disparity (>2.5/8) were not significant prognosticators independently, cumulatively they were predictors for favorable outcome.     

Accelerated long-term forgetting in temporal lobe but not idiopathic generalised epilepsy

Temporal lobe epilepsy (TLE) has been associated with the phenomenon of accelerated long-term forgetting (ALF), in which memories are retained normally over short delays but are then lost at an accelerated rate over days or weeks. The causes of ALF, and whether it represents a consolidation deficit distinct from the one associated with forgetting over short delays, remain unclear. In addition, methodological issues have made results of some previous studies difficult to interpret. This study used improved methodology to investigate the role of seizure activity in ALF. Forgetting was assessed in participants with TLE (who have involvement of temporal lobe structures) and idiopathic generalised epilepsy (IGE; in which seizures occur in the absence of identified structural pathology in the temporal lobes). Learning of novel stimuli was matched between patients with TLE, patients with IGE and healthy controls matched for age and IQ. Results indicated that the TLE group showed accelerated forgetting between 30-min and three-weeks, but not between 40-s and 30-min. In contrast, rates of forgetting did not differ between patients with IGE and controls. We conclude that (1) ALF can be demonstrated in TLE in the absence of methodological confounds; (2) ALF is unlikely to be related to the experience of epilepsy that does not involve the temporal lobes; (3) neither seizures during the three-week delay nor polytherapy was associated with ALF.     

Verbal retention lateralizes patients with unilateral temporal lobe epilepsy and bilateral hippocampal atrophy

PURPOSE: To examine the lateralization utility of preoperative verbal retention in patients with and without bilateral hippocampal atrophy. METHODS: The sample consisted of 74 patients with EEG-defined unilateral temporal lobe epilepsy (TLE) who had also undergone volumetric magnetic resonance imaging (MRI). Verbal retention was operationalized by the Logical Memory percentage retention subtest (LM%) of the Wechsler Memory Scale. Patients were divided into groups with (a) bilaterally normal hippocampal volumes, (b) unilateral atrophy, or (c) bilateral atrophy. Two different thresholds (empirically derived vs. normative) were used to lateralize on the basis of LM%. LM% lateralization was then examined by group using chi2, sensitivity, positive predictive values, and odds ratios. Analyses were also conducted separately in the subset of patients who were seizure free after surgery. RESULTS: Mean LM% performance was significantly lower in patients with left versus right TLE in the subset with bilateral hippocampal atrophy (p = 0.018), but not in patients with a normal MRI (p = 0.918) or unilateral atrophy (p = 0.087). The odds of a correct lateralization by LM% increased from 1.67 in patients with normal MRI to 36.11 in patients with bilateral hippocampal atrophy. The power of a right and left lateralization prediction by LM% was 100% and 75%, respectively, in patients with bilateral hippocampal atrophy. Similar results were obtained when analysis was restricted to patients who were seizure free after surgery. CONCLUSIONS: Preoperative verbal retention as measured by LM% may provide meaningful lateralization information in patients who are difficult to lateralize via MRI.     

Hippocampal formation involvement in a language-activation task in patients with mesial temporal lobe epilepsy

PURPOSE: The study aims to explore the contribution of the hippocampal formation to the retained language-comprehension network in patients with unilateral mesial temporal lobe epilepsy (TLE). METHODS: We performed a functional magnetic resonance (MRI) study based on a language comprehension paradigm in 45 right-handed patients with unilateral mesial TLE and 35 healthy control subjects. Activations in the hippocampal formations in both hemispheres were analyzed for each subject as well as for groups of left TLE, right TLE, and controls. RESULTS: In sum, 82% of TLE patients displayed hippocampal activations. A significant difference in hippocampal activation between left and right TLE was found: Right TLE patients showed increased activity in the left hippocampal formation compared with left TLE patients. In contrast, patients with left TLE did not show increased activity in the right hippocampal formation compared with right TLE patients. In comparison with a healthy control group, right TLE patients activated the left hippocampal formation to a greater extent, whereas patients with left TLE did not activate the right hippocampal formation to a greater degree. These findings point to an increased involvement of the left hippocampal formation during a language-comprehension task in right TLE patients. In contrast, left TLE in right-handed patients seems not associated with an enhanced involvement of the right hippocampal formation in retained language comprehension. CONCLUSIONS: These findings suggest that effective language comprehension in right-handed subjects with TLE depends on the involvement of the left hippocampal formation and underline the risks of postoperative language decline in patients with left TLE.     

Hippocampal neuronal density in temporal lobe epilepsy with and without gliomas

Summary The majority of patients with temporal lobe epilepsy show hippocampal sclerosis, which pathologically represents neuronal loss and gliosis. We studied volumetric neuronal density on a representative mid to mid-posterior level slice of hippocampi surgically removed from intractable temporal lobe epilepsy cases, and compared the results between 25 non-tumor epilepsy (NTE) cases and 5 tumor-associated epilepsy (TAE) cases. Eleven age-matched non-epileptic autopsy cases were studied as controls. Cells were counted in the CA1 through CA4 fields and the stratum granulosum of the dentate fascia. In NTE every hippocampal field showed statistically significant loss of neurons, the neuronal density in each field ranging from 35% to 50% of that of control. The mean neuronal density between the TAE and NTE groups also showed statistically significant differences in all hippocampal fields. The neuronal density of hippocampal fields of NTE ranged from 43% to 58% of that of TAE. Tumor-associated epilepsy cases, however, failed to show any statistically significant deviation from the control in their neuronal density. The etiology of the difference in neuronal density between the TAE and NTE groups is discussed.Supported by NIH grant NS06208     

Depression in temporal lobe epilepsy surgery patients: an FDG-PET study

PURPOSE: Depression is common in temporal lobe epilepsy (TLE) and after temporal lobectomy, and its etiology is obscure. In nonepileptic depression (including depression associated with other neurologic disorders), a consistent PET imaging finding is frontal lobe hypometabolism. Many TLE patients have hypometabolism involving frontal regions. Thus in data available from routine clinical assessments in an epilepsy surgery unit, we tested the hypothesis that the pattern of hypometabolism, particularly in the frontal lobe, may be associated with the depression seen in patients with TLE and TLE surgery. METHODS: We studied 23 medically refractory TLE patients who underwent anterior temporal lobectomy and who had preoperative FDG-PET scanning. All patients had pre- and postoperative psychiatric assessment. By using statistical parametric mapping (SPM-99), patterns of hypometabolism were compared between patients who had a preoperative history of depression (n=9) versus those who did not (n=14) and between those in whom postoperative depression developed (n=13) versus those in whom it did not (n=10). A significant region of hypometabolism was set at p<0.001 for a cluster of >or=20 contiguous voxels. RESULTS: Patients with a history of depression at any time preoperatively showed focal hypometabolism in ipsilateral orbitofrontal cortex compared with those who did not (t=4.64; p<0.001). Patients in whom depression developed postoperatively also showed hypometabolism in the ipsilateral orbitofrontal region (t=5.10; p<0.001). CONCLUSIONS: Although this study is methodologically limited, and other explanations merit consideration, orbitofrontal cortex dysfunction, already implicated in the pathophysiology of nonepileptic depression, may also be relevant to the depression of TLE and temporal lobectomy.     

Olfactory auras in patients with temporal lobe epilepsy

PURPOSE: To investigate olfactory auras in patients with temporal lobe epilepsy (TLE). METHODS: We reviewed medical records of 217 Chinese patients who underwent temporal lobectomy for medically intractable TLE between 1987 and 1998 in Taiwan. Patients with olfactory auras asked for detailed characteristics of their auras. RESULTS: In all, 12 (5.5%) patients had olfactory auras, seven men and five women. All patients except one described and characterized the unpleasant olfactory auras. Olfactory auras were usually combined with other auras, most frequently sensations of epigastric rising, nausea, and fear. Association with gustatory hallucination was uncommon, in only one patient. On neuroimaging study, 11 patients had structural lesions involving the mesial temporal structures, two exclusively involving the amygdala. Histologic diagnosis included gliosis of the mesial temporal regions in seven (58.3%) patients, neoplasm in four (33.3%) patients, and arteriovenous malformation in one patient. Postoperatively, eight patients were seizure free. Three patients had rare seizures; however, none reported residual olfactory auras. CONCLUSIONS: Olfactory auras are infrequent in TLE. In this study, mesial temporal sclerosis is the most common etiology rather than tumors. Mesial temporal structures, especially the amygdala, may play important roles in the genesis of olfactory auras.     

Immunohistochemical study of Metallothionein in patients with temporal lobe epilepsy

Epilepsy is characterized by spontaneous recurrent seizures and temporal lobe epilepsy (TLE) is the most common serious neurological example of acquired and frequent epilepsy. Oxidative stress is recognized as playing a contributing role in several neurological disorders, and most recently have been implicated in acquired epilepsies. The MTs occur in several brain regions and may serve as neuroprotective proteins against reactive oxygen species causing oxidative damage and stress. The main aim of this work was to describe the immunohistochemical localization of MT in the specimens derived from the patients affected by TLE. Histopathological examination showed NeuN, GFAP and MT immunopositive cells that were analyzed for determinate in hippocampal and parietal cortex samples. An increase in the reactive gliosis associated with increased MT expression was observed in patients with TLE.     

Quantitative neuropathology of the entorhinal cortex region in patients with hippocampal sclerosis and temporal lobe epilepsy

PURPOSE: Clinical, radiologic, and experimental evidence indicates that the entorhinal cortex (EC) region may be linked to the pathophysiology of hippocampal sclerosis (HS) in patients with temporal lobe epilepsy. Few neuropathologic studies of this region have been undertaken in patients with HS undergoing surgery, some suggesting preferential loss of layer III neurones. METHODS: We carried out a quantitative analysis in 26 patients with HS, nine patients with lesional temporal lobe epilepsy (LTLE), and eight postmortem controls. We measured neuronal densities in EC by using a three-dimensional cell-counting technique on NeuN immunostained and Nissl-stained sections. We also quantified the density of calretinin-positive interneurones in this region and the density of neurones in adjacent subiculum and CA1 subfields. We also assessed the patterns of gliosis in the EC in the patient groups and the presence of any neocortical neurone loss. RESULTS: No significant difference was found in the mean neuronal densities in the EC region between HS and LTLE groups or postmortem controls. Laminar gliosis in midcortical layers was seen in a proportion of HS cases but also in the LTLE group. No significant difference was seen in the density of calretinin interneurones and no correlation between the presence of neocortical neuronal loss and EC neuronal densities. CONCLUSIONS: A stereotypical pattern of neuronal loss and gliosis in the EC region in patients with HS is not confirmed that distinguishes this pathologic process from that in patients with lesional TLE.     

颞叶癫痫患者认知功能及相关因素的分析

目的分析颞叶癫痫患者认知功能的状况,并进一步探讨性别、病程、临床发作、神经电生理及药物等因素对患者认知功能的影响。方法从我院2002～2010年住院部中抽出符合入选标准的55例颞叶癫痫患者及随机抽取的同期48例健康对照者的韦氏成人智力量表、韦氏成人记忆量表、H.R.成人神经心理成套测验记录测验值进行回顾性分析。结果颞叶癫痫患者全量表智商(full intelligence quotient,FIQ)、记忆商(memory quo-tient,MQ)均明显低于健康对照者(P<0.001),脑病损程度(disease quotient,DQ)明显高于健康对照者(P<0.001)。不同文化程度的颞叶癫痫患者IQ、MQ、DQ有显著性差异,文化程度越高,其IQ及MQ越高(P<0.01),DQ越小(P<0.01);不同发作频率的颞叶癫痫患者IQ、MQ及DQ有显著性差异,发作越频繁,其IQ及MQ越低(P<0.01),DQ越高(P<0.01);不同脑电图异常改变的颞叶癫痫患者IQ、MQ和DQ有显著性差异,癫痫样放电越明显,其IQ及MQ越低(P<0.01),DQ越高(P<0.01)。多元逐步回归分析显示,影响患者IQ、MQ及DQ的因素依次为发作频率和脑电图癫痫样放电。结论颞叶癫痫患者存在不同程度的认知功能障碍。关注颞叶癫痫患者认知功能状况,尽早采取有效的治疗方法控制癫痫发作是避免和减少患者认知功能障碍,提高生活质量的重要前提。     

影响颞叶癫痫预后相关因素分析

目的研究颞叶癫痫患者病史、脑电图、头颅影像学资料等与其预后的关系。方法回顾分析我院确诊的99例颞叶癫痫患者病史、头颅影像学资料、发作间期脑电图资料、药物疗效,依据药物疗效分为难治性癫痫组46例,非难治性癫痫组53例,比较两组间差异。结果比较两组间差异发现:头颅MRI异常(χ2=7.55,P<0.01)、发作间期脑电图(electroencephalogram,EEG)反复异常(χ2=8.21,P<0.01)、初发年龄小(Z=-3.81,P<0.01)、病程长(Z=-4.41,P<0.01)与难治性颞叶癫痫有关。结论头颅MRI异常、发作间期EEG反复异常、初发年龄小、病程长为颞叶癫痫预后的不良因素。