颅脑创伤患者颅内生化代谢的动态监测-临床颅内微透析技术的研究

目的应用微透析技术研究了7例颅脑创伤患者脑细胞间液中葡萄糖(G1u)、乳酸(Lac)、丙酮酸(Pyru)、甘油(Gly)、乳酸/葡萄糖比值(L/G)和乳酸/丙酮酸比值(L/P)的变化规律以及亚低温治疗对其影响.方法将微透析导管分别捅人患者脑创伤病灶半暗带区、相对正常脑组织区和腹部皮下组织,收集微透析液,灌流速度为0 3μl/min.每1 h收集1管透析液.7例患者的平均收集时间为65.00±18.45 h;收集的透析液用生化分析仪测定Glu、Lac、Pyru和G1y.结果患者大脑创伤病灶组织的Glu、Lac、Pyru、Gly、L/G、L/P与相对正常脑组织中均无显著性差异;而脑细胞间液的Glu、Gly含量均明显低于腹腔皮下组织的相应值;而Lac含量高于皮下组织的含量.结论微透析技术提供了一种实时监测颅脑创伤患者脑和皮下组织细胞间液生化指标的手段.     

颅脑损伤患者脑细胞间液代谢物含量的变化及其临床意义

目的探讨颅脑损伤患者脑细胞间液中葡萄糖（Glu）、乳酸（Lac）、丙酮酸（Pyru）、甘油（Gly）、一氧化氮（NO）含量的变化及其临床意义。方法将微透析导管分别插入患者病灶半暗带区、相对正常脑组织区和腹部皮下组织收集微透析液，用生化分析仪测定Glu、Lac、Pyru、Gly、NO的变化，并计算Lac与Glu（UG）及Lac与Pyru（L／P）之比值。结果病灶半暗带区脑组织中Glu、Pyru、Gly的含量及L/G、L/P比值与相对正常脑组织中的相应值无显著性差异（P〉0.05），Glu的含量和坍比值均明显低于腹腔皮下组织的相应值（P〈0．01），Lac和NO浓度则明显高于正常脑组织和腹部皮下组织（P〈0．01）。结论微透析技术提供了一种实时监测颅脑损伤患者脑细胞间液生化指标的手段。患者脑组织间液中的生化指标和NO的含量变化可能与其预后密切相关。     

亚低温对颅脑创伤大鼠脑血流量及组织间液乳酸水平的影响

目的 利用微透析技术观察颅脑创伤大鼠伤后2.5h内邻近受伤区侧脑室透析液中乳酸、脑血流量的变化及亚低温治疗效果。方法 28只Wistar雌性大鼠随机分为正常对照组、常温创伤组和亚低温治疗组。亚低温组动物于创伤后用冰袋进行全身降温,在脑温降至30℃并保持1h后,加热复温至37℃。将透析管插入邻近受伤区的侧脑室区,位于前囱后1.5mm,中线旁2.5mm,深度3.5mm;灌流速度为4μl/min,每30min采1管样本,后两组均于收集第2管样本后制作颅脑创伤动物模型,继续透析至2.5h。应用激光多普勒血流仪监测脑血流量的变化。结果 (1)对照组大鼠透析液中乳酸水平在各时限内差异无显著性意义(P>0.05);常温创伤组于伤后1.5h内乳酸水平明显升高,与对照组比较差异有显著性意义(P<0.01);亚低温组经低温治疗后,乳酸水平降低,与其余两组相比差异有显著性意义(均P<0.01)。(2)常温创伤组大鼠,仅在伤后20min时出现脑血流量减少,与对照组比较差异有显著性意义(P<0.05);而其余各时限与对照组比较差异均无显著性意义(P>0.05)。亚低温组经治疗后2h内脑血流量持续降低,与常温创伤组比较差异有显著性意义(P<0.05)。结论 亚低温治疗可降低损伤区周围脑组织血流量,加速大鼠神经细胞对乳酸的代谢,从而起到神经细胞保护作用。     

脑损伤后脑细胞外液中糖代谢变化的微透析研究

目的探讨微透析技术监测脑损伤局部细胞外液(ECF)中糖代谢指标变化的意义。方法应用微透析技术动态收集大鼠轻、重度脑损伤局部的ECF透析液,观察其葡萄糖含量([Glu]d)和乳酸含量([Lac]d)的变化。结果透析管插入引起[Glu]d和[Lac]d的变化很小(P>0.05)。脑损伤后[Glu]d下降,与对照组及损伤前相比,相差显著(P<0.05),且损伤越重其变化越显著(P<0.05)。而脑损伤后[Lac]d则上升,与对照组及损伤前相比,相差显著(P<0.05),且损伤越重,其变化亦越显著(P<0.05)。脑损伤后[Glu]d和[Lac]d的变化分别与脑组织含水量呈显著负相关(P<0.05)和显著正相关性(P<0.05)。结论微透析技术是一种理想的动态监测脑损伤局部生化改变的方法;利用该技术监测损伤区ECF中糖代谢指标的异常变化,可以作为判定脑损伤程度的重要依据。     

亚低温对颅脑创伤大鼠脑血流量及组织间液乳酸水平的影响

目的：利用微透析技术观察颅脑创伤大鼠伤后2．5h内邻近受伤区侧脑室透析液中乳酸、脑血液量的变化及亚低温治疗效果。方法：28只Wistar雌性大鼠随机分为正常对照组，常温创伤线和亚低温治疗组，亚低温组动物于创伤后用冰袋进行全身降温，在脑温降至30℃并保持1h后，加热复温至37℃，将透析管插入邻近受伤区的侧脑室区，位于前囟后1.5mm，中线旁2.5mm，深度3.5mm，灌流速度为4μl/min，每30min采1管样本，后两组均于收集第2管样本后制作颅脑创伤动物模型，继续透析至2.5h，应用激多普勒血流仪监测脑血流量的变化。结果：（1）对照组大鼠透析液中乳酸水平在各时限内差异无显著性意义（P＞0．05）；常温创伤后1.5h内乳酸水平明显升高，与对照组比较差异有显著性意义（P＜0．01）亚低温组经低温治疗后，乳酸水平降低，与其余两组相比差异有显著性意义（均P＜0．01）。（2）常温创伤组大鼠，仅在伤后20min时出现脑血流量减少，与对照组比较差异有显著性意义（P＜0．05）；而其余各时限与对照组比较差异均无显著性意义（P＞0．05）。亚低温经治疗后2h内脑血流量持续降低，与常温创伤组比较差异有显著性意义（P＜0．05）。结论：亚低温治疗可降低损伤区周围脑组织血流量，加速大量神经细胞对乳酸的代谢，从而起到神经细胞保护作用。     

轻型及特重型颅脑创伤患者脑细胞间液生化指标对比研究

应用微透析技术检测10例颅脑创伤患者的脑细胞间液(ECF)中乳酸／丙酮酸(L／P)、乳酸／葡萄糖(L／G)及甘泔(Gly)的浓度并探讨其意义。现将结果报告如下。     

脑动脉瘤术中临时阻断载瘤动脉前后脑生化代谢的微透析研究

目的应用微透析技术研究15例动脉瘤显微手术中临时阻断载瘤动脉前后患者脑细胞间液中葡萄糖、乳酸及乳酸/葡萄糖比值的变化规律。方法在开颅动脉瘤夹闭手术过程中,将微透析导管插入相应的脑皮质中,收集微透析液,灌流速度0.3μl/min,15例患者平均收集时间(2.56±0.32)h,收集的微透析液应用生化分析仪及相应试剂盒测定乳酸、葡萄糖含量。结果在动脉瘤临时阻断及夹闭之前乳酸、葡萄糖含量变化不明显,临时阻断后乳酸含量明显升高,而葡萄糖含量下降。结论应用微透析技术进行术中监测发现载瘤动脉临时阻断后对患者脑细胞间液物质生化代谢有影响,术中应尽量减少临时阻断并缩短阻断时间。     

大鼠脑损伤局部谷氨酸的异常释放对乳酸含量变化的影响

目的探讨谷氨酸(Glu)在大鼠脑损伤局部的异常释放以及其对乳酸(Lac)含量变化的影响。方法采用大鼠局部脑损伤动物模型,分为对照组、损伤组、干预组。伤前15min干预组注射Riluzole(一种Glu突触前释放抑制剂),损伤组注射等容量的生理盐水,对照组仅开骨窗不损伤脑。应用微透析技术检测各组伤后不同时间透析液中Glu含量([Glu]d)及Lac含量([Lac]d)变化。结果[Glu]d及[Lac]d在伤后15min、30min和45min干预组明显低于损伤组(P<0.05),而明显高于对照组(P<0.05);在伤后60min,损伤组仍明显高于对照组(P<0.05)。伤后不同时间[Glu]d和[Lac]d变化呈显著正相关(P<0.01)。结论脑损伤后受损脑组织细胞液中Glu水平的升高是Glu神经元末梢大量释放Glu所致,并继而引起了Lac的含量升高。     

亚低温持续不同时间对缺血脑组织中氨基酸和单胺类递质含量的影响

目的观察脑缺血后即时亚低温并维持不同时间对脑缺血损伤的影响,探讨亚低温脑保护作用的生物学机制. 方法脑缺血动物模型采用改良的Pulsinelli四动脉阻断法.采用氨基酸分析仪测定脑组织中谷氨酸(Glu)、天门冬氨酸(Asp)、甘氨酸(Gly)和γ-氨基丁酸(GABA)含量;采用荧光分光光度法测定多巴胺(DA)、去甲肾上腺素(NE)、5-羟色胺(5-HT)及其代谢产物5-羟吲哚乙酸(5-HIAA). 结果常温脑缺血组织中Glu、Asp、Gly和GABA的含量明显低于假手术组(P<0.01),亚低温持续30～240 min脑组织中Glu、Asp、Gly和GABA 含量明显高于常温脑缺血组(P<0.05 或P<0.01).常温脑缺血后组织中DA、NE和5-HT的含量明显低于假手术组(P<0.01),5-HIAA含量高于假手术组(P<0.01);亚低温持续30 min脑组织中5-HT含量明显高于常温脑缺血组(P<0.01),5-HIAA的含量低于常温脑缺血组(P<0.05);亚低温持续60～240 min脑组织中DA、NE和5-HT含量明显高于常温脑缺血组(P<0.05或P<0.01),5-HIAA含量低于常温脑缺血组(P<0.01). 结论脑缺血后即时亚低温明显减轻常温脑缺血时组织中氨基酸和单胺类神经递质的代谢紊乱,提示亚低温减轻脑缺血损伤作用最好是在脑缺血后立即实施,并持续达1 h以上效果更明显.     

不同脑温状态地西泮对大鼠脑缺血组织氨基酸含量的影响

目的 探讨不同脑温状态下,地西泮对大鼠脑缺血组织谷氨酸(Glu)、天门冬氨酸(Asp)、甘氨酸(Gly)及γ-氨基丁酸(GABA)含量的影响.方法建立大鼠大脑中动脉缺血再灌注模型,诱导目标脑温,用HPLC荧光法检测轻度高温、常温、亚低温各组脑缺血组织Glu、Asp、Gly及GABA含量.结果 (1)与常温假手术组比较,常温脑缺血对照组及常温地西泮组Glu、Asp、Gly显著增高(P均<0.001),GABA在常温脑缺血对照组差异无统计学意义(P>0.05),在常温地西泮组则显著增高(P<0.01).(2)与常温脑缺血对照组比较,常温地西泮组Glu、Asp、Gly稍降低,GABA稍增高,但差异均无统计学意义(P均>0.05).(3)与常温地西泮组比较,轻度高温地西泮组Glu、Asp、Gly显著增高(P均<0.001),GABA差异无统计学意义(P>0.05);亚低温地西泮组Glu、Asp、Gly显著降低(P均<0.01),GABA显著增高(P<0.001).结论亚低温状态下,地西泮显著上调GABA水平,从而有利于地西泮"抑制性保护"机制的建立,可能使地西泮的神经保护作用得到增强.     

Diagnostic Difficulties and Treatment Implications

Summary: Differentiation between types of epileptic seizures has been aided in recent years by the introduction of intensive neurodiagnostic techniques and the development of increasingly detailed classification systems. Paradoxically, these developments have not simplified the task of matching the appropriate antiepileptic drug to a particular seizure type. It is reasonable to assume that anticonvulsant drugs will have different effects on different types of seizures, but faulty, circular reasoning can enter the picture if one also assumes that responses of seizures to different drugs signify different seizure types. There are several examples of differential diagnoses that can fall prey to this problem, including the diagnosis between partial seizures with secondary generalization and generalized tonic-clonic seizures, and the diagnosis between complex partial seizures and absence seizures with automatisms, among others. Considerations of etiology in future classification systems can further complicate the problem: should one then choose an anticonvulsant drug on the basis of individual seizure type or on the basis of the type of epilepsy? Ramifications of this issue extend even to the drug approval process. Official sanction is not given for use of a drug for a seizure type not included in the original efficacy studies, even if later scientific evidence shows that seizure type to be related to a type that is included. New trials must be undertaken. These problems arise from how we choose to classify seizures.     

Cognitive Dysfunction Associated with Antiepileptic Drug Therapy

Summary: Epilepsy is frequently associated with cognitive dysfunction. However, the reasons for this correlation are unclear. Possible influential factors include patient age; duration, frequency, etiology, and type of seizures; hereditary factors; psychosocial issues; and antiepileptic drug (AED) therapy. Whereas many of these factors are beyond the physician's control, AED therapy is one element that can be addressed in treatment decisions by recognizing the potential cognitive effects of particular AEDs. For example, phenobarbital impairs memory and concentration; phenytoin affects attention, problem solving ability, and performance of visuomotor tasks. In contrast, carbamazepine may affect concentration, while valproate would appear to have minimal effects on cognition. Moreover, cognitive effects of AEDs are amplified with coadministration of multiple anticonvulsants (polytherapy). A review of studies on the cognitive effects of monotherapy with AEDs, as opposed to those of polytherapy, provides evidence that drug-related cognitive dysfunction can be reversed if patients are switched to a simpler therapeutic regimen. Future research should be directed toward developing reliable measures for assessing and monitoring cognition, and understanding the particular cognitive side effects of each AED. Physicians also need to revise their opinions about which side effects are "tolerable" for epileptic patients.     

Carbamazepine Efficacy in Adults With Partial and Generalized Tonic-Clonic Seizures

Summary: Carbamazepine and phenytoin are drugs of choice in initial monotherapy for adult partial and secondarily generalized tonic-clonic seizures. These designations reflect the results of the Veterans Administration Epilepsy Cooperative Study Group of 1985. An earlier comparative study of carbamazepine and phenytoin by Ramsay and associates found both drugs equally effective in controlling new-onset seizures. Among the advantages of carbamazepine is that it causes relatively few cognitive and dysmorphic side effects. Its disadvantages are its unavailability in parenteral formulation and its metabolic autoinduction. The latter must be compensated for by planned dosage increases to maintain therapeutic plasma steady-state levels during the first 2 or 3 months of treatment. Carbamazepine is judged a drug of choice in the treatment of these secondarily generalized tonic-clonic seizures, and the drug of choice in children, adolescents, and women susceptible to the dysmorphic side effects associated with other anticonvulsant agents.     

Etiologic and Preventive Aspects of Epilepsy in the Child–Bridging the Gap Between Laboratory and Clinic

Summary: Four broad categories of basic phenomena are pertinent to developing ways to prevent epilepsy. These include mechanisms of epileptogenesis, ictal initiation and temporary entrainment by the seizure discharge of normally functioning brain, seizure propagation, and control mechanisms that function both to restrain the cascade of epileptic events culminating in a seizure and to arrest the epileptic event and restore the interictal state. In newborns and children, hypoxia-ischemia is a major factor leading to epileptogenesis, and several schemes are proposed to classify, quantify, and prevent hypoxic-ischemic encephalopathy. Control mechanisms must be better understood in order to develop prophylactic recommendations for epilepsy, and an experimental model of "kindling antagonism" may increase our understanding of these. Programs of prevention of seizures in children will evolve only if basic researchers and clinicians work productively together to develop an adequate understanding of factors important in epileptogenesis and antiepileptogenic control mechanisms.     

Treatment Considerations in Anticonvulsant Monotherapy

Summary: The long-standing practice of polypharmacy in treating epilepsy is giving way to use of monotherapy. Monotherapy can improve seizure control as well as reduce the risk of serious idiosyncratic reactions, dose-related side effects, and complex drug interactions. Monotherapy also offers improved compliance and cost-effectiveness. The basis of monotherapy is accurate diagnosis and assessment of the patient's seizure type(s), followed by selection of a single appropriate anticonvulsant drug. Many patients currently treated with multiple anticonvulsants can be successfully converted to monotherapy with a carefully monitored program in which troublesome and redundant drugs are gradually withdrawn from the therapeutic regimen.     

Predisposing and Causative Factors in Childhood Epilepsy

Summary: We review information from large studies of defined populations, examining the role of known factors and especially of prenatal and perinatal factors in contributing to nonfebrile seizure disorders of early childhood. We depend especially, but not exclusively, on the recently completed analyses from the Collaborative Perinatal Project of the National Institute of Neurological and Communicative Disorders and Stroke, the NCPP. About 4% of children in the NCPP who had at least one non-febrile nonsymptomatic seizure by the age of 7 years had a previous seizure during acute neurologic illness, such as meningitis or during the acute illness after trauma. Many such seizures should potentially be preventable. Of children with seizures, 10% had had a neonatal seizure and 13% had had a febrile seizure. Among the hundreds of prenatal and perinatal factors explored as predictors of childhood seizure disorders, the principal predictors identified were congenital malformations of the fetus, cerebral and noncerebral; family history of certain neurologic disorders; and neonatal seizures. In agreement with the British National Child Development Study, labor and delivery factors in the NCPP appeared to contribute very little to childhood seizure disorders. Maldevelopment, rather than damage at birth to an initially intact nervous system, appeared to be the more common mechanism. Most seizure disorders of early childhood remained unexplained by the large set of prenatal and perinatal characteristics examined.     

Dextromethorphan: Cellular Effects Reducing Neuronal Hyperactivity

Summary: Dextromethorphan is a dextrorotary morphinan without affinity for opioid receptors, commonly used as an antitussive medication. During the past 5 years, interest in the compound and its demethylated derivative, dextrorphan, has been revived because additional neuroprotective and an-tiepileptic properties were found in in vitro studies, animal experiments, and a few clinical cases. Both morphinans are able to inhibit N -methyl-D-aspartate (NMDA) receptor channels and voltage-operated calcium and sodium channels with different potencies. The inhibition of the NMDA receptor is believed to be the predominant mechanism of action responsible for the anticonvulsant and neuroprotective properties of the compounds.     

Anticonvulsant Drugs and Cognitive Function: A Review of the Literature

Summary: Alterations of cognitive function are separate from disturbances of behavior seen in association with epilepsy. The nature of the cognitive disability may to a certain extent depend on the seizure type. Partial seizures, mainly derived from a temporal lobe focus, impair memory tasks, while generalized seizures seem to have more effect on attentional abilities. A number of studies, reviewed in this paper, suggest that anticonvulsant drugs further impair cognitive function. Maximal impairments are seen in patients receiving polytherapy: rationalization of polytherapy improves cognitive abilities. Studies in children and adults have allowed differentiation of the effects of various commonly used antiepileptic agents. Maximal cognitive deficits are seen with. phenytoin, while phenobarbital and sodium valproate induce moderate disturbances, and carbamazepine seems relatively free from such toxicity. Further research is needed on the interrelationship between types of seizure disorders, types of anticonvulsant medications, and cognitive function.     

Effects of NMD A- and AMPA-Receptor Antagonists on Different Forms of Epileptiform Activity in Rat Temporal Cortex Slices

Summary: Lowering extracellular magnesium induces different patterns of epileptiform activity in rat hippocampus and entorhinal cortex. Short recurrent epileptiform discharges in the hippocampus are stable over time, whereas seizurelike events (SLEs) in the entorhinal cortex, the subiculum, and the neighboring neocortex develop into late recurrent discharges which are not blocked by clinically employed antiepileptic drugs. We tested the sensitivity of the different epileptiform discharge patterns to. /V-methyl-D-aspartate (NMDA)- and non-NMDA-receptor antagonists. As NMDA-receptor antagonist we used dextrorphan, ket-amine, and 2-aminophosphonovalerate (2APV); as α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA)-receptor antagonist we employed the quinoxaline derivative glutamate 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX). The findings show that the different patterns of epileptiform activity, including the late recurrent discharges, are sensitive to all NMDA-receptor antagonists. However, when dextrorphan was employed to suppress seizure-like events, later recurrent discharges did not develop during the remaining time course of the experiment. CNQX reversibly suppressed recurrent discharges in the hippocampus and SLEs in the entorhinal cortex. However, late recurrent discharges become insensitive to CNQX, even at a high concentration of 60 μM m. This finding suggests a prominent role for NMDA receptors in the generation of late recurrent discharges.     

Pediatric Epilepsy Surgery

Summary: The use of implantable arrays of epidural electrodes has made it possible to carry out extraoperative electrocorticography (ECoG) and functional localization in the awake child. This has permitted cortical excisions that are determined by criteria similar to those obtained during surgical procedures performed under local anesthesia in adults. In addition, the method also permits simultaneous ECoG and video monitoring during the child's symptomatic seizures, providing additional important localizing information that is impractical to obtain in operations under local anesthesia. We report our experience with 75 children, ages 5 months to 15 years, whom we have managed with epidural electrode arrays. The method of extraoperative ECoG is described and illustrative cases are presented to demonstrate its feasibility and utility in children. In addition, we call attention to gliomas as a common cause of chronic focal seizures in children. Of 49 children undergoing resection and followed for from 1 to 14 years (mean of 5.8 years), 32 (65%) are either seizure free or have had a significant reduction in seizure frequency that has unambiguously improved their quality of life. The results are analyzed further by relating the surgical outcome to each of the pathologic entities that caused the seizures. This analysis reveals the variety of neurological conditions that commonly cause intractable focal seizure disorder in children and distinguishes those pathologic entities in which the seizure disorder is apt to respond to surgical intervention from those that will not.