单倍体相合异基因造血干细胞移植治疗白血病

背景：对于无HLA全相合同胞供者的患者,采用单倍体相合造血干细胞移植面临移植物抗宿主病重、移植相关死亡率高的风险,但通过不同的移植模式,将有可能获取相近的疗效。 目的：观察亲缘HLA单倍体相合异基因造血干细胞移植治疗白血病的疗效,并与亲缘HLA全相合异基因造血干细胞移植相比较。 方法：45例白血病患者分为2组。单倍体组移植方式为外周血或联合骨髓干细胞移植,预处理方案为改良白消安与环磷酰胺或加抗胸腺细胞球蛋白,移植物抗宿主病的预防采用环孢素A+甲氨蝶呤+霉酚酸脂;全相合组移植方式为外周血干细胞移植,预处理方案为BuCY,移植物抗宿主病的预防采用环孢素A+甲氨蝶呤。 结果与结论：两组均获得造血重建时间差异无显著性意义。单倍体及全相合组急性移植物抗宿主病的累积发病率分别为73%对52%(P > 0.05);慢性移植物抗宿主病的累积发病率分别为56%对45%(P > 0.05);移植相关死亡率分别为36%对17% (P > 0.05);单倍体组无复发,全相合组复发2例;两组的预计3年累积无病生存率分别为61%对60%(P > 0.05)。结果提示,亲缘单倍体异基因造血干细胞移植的总体疗效与亲缘全相合异基因造血干细胞移植相似,但中重度急性移植物抗宿主病的发生率较后者为高。     

亲缘间单倍体造血干细胞移植治疗白血病4例

背景：建立及维持非血缘供者库需要大量投资,而亲属部分相合的供者则不需要特殊费用,有更强的可操作性。 目的：评估亲缘间半相合造血干细胞移植治疗白血病的疗效。 方法：选取2002-11/2008-03中南大学湘雅医学院附属海口市人民医院血液科住院患者4例,均进行HLA单倍体相合亲缘供者造血干细胞移植。采用改良的Bu/CY预处理方案：阿糖胞苷2.0~3.0 g/(m2•d)×2 d,持续24 h静滴;马利兰4 mg/(kg•d)× 3 d;环磷酰胺50 mg/(kg•d)×2 d;甲基环已亚硝脲25 mg/(m2•d)×1 d;抗胸腺细胞球蛋白25 mg/(kg•d)×4 d。在改良方案的基础上加大阿糖胞苷剂量1倍,且改为持续24 h静滴,使预处理强度增加,促进造血干细胞持久植入。移植物抗宿主病预防：在经典的甲氨蝶呤方案基础上将环孢素A及霉酚酸酯提前至-7 d(回输干细胞前为-)使用。患者移植前后进行ABO血型及DNA检测。 结果与结论：①移植后造血重建检测：4例患者均获得造血重建,未发生预处理相关死亡。造血于细胞移植后-3~+7 d白细胞降为0,并持续2~14 d,+12~+20 d白细胞>1.0×109 L-1,+20~+51 d血小板>20×109 L-1。②移植物抗宿主病的发病情况：4例患者移植物抗宿主病 Ⅳ 级(肠道)1例,出现急性移植物抗宿主病Ⅱ级(肠道)1例,急性移植物抗宿主病Ⅱ级(皮肤)1例。提示随着预处理方案、移植物抗宿主病预防方案的优化,亲缘间单倍相合造血干细胞移植治疗白血病安全有效。     

多种来源造血干细胞移植治疗重型再生障碍性贫血

背景：造血干细胞移植是年轻重型再生障碍性贫血患者首选方法,但在中国多数重型再生障碍性贫血患者无合适的供者,单倍体相合或非血缘造血干细胞移植国内外目前还处于探索阶段,联合间充质干细胞移植报道少见。 目的：观察不同干细胞来源造血干细胞移植治疗重型再生障碍性贫血的疗效。 方法：10例(3~52岁)重型再生障碍性贫血患者,分别接受了亲缘HLA相合(2例),单倍体相合(5例),非血缘(3例)的外周血和/或骨髓造血干细胞移植,其中5例患者同时联合了间充质干细胞共移植。预处理方案主要为环磷酰胺、氟达拉滨和抗人胸腺球蛋白,以霉酚酸酯、环孢素A加短疗程的甲氨蝶呤预防移植物抗宿主病,单倍体相合移植的患者在此基础上加马利兰和CD25单克隆抗体;同基因的例5患者预处理方案为抗人胸腺球蛋白+甲基泼尼龙。输注间充质干细胞的量为(0.27~1.85)×106/kg。接受和未接受间充质干细胞组的患者回输的造血干细胞有核细胞分别为(7.4~17.38)×108/kg和(6.09~13.68)×108/kg。 结果与结论：除1例单倍体相合患者移植未成功,+36 d死于并发症外,余患者移植后染色体及DNA指纹检测等说明造血干细胞移植完全供者植入。移植后中性粒细胞达到0.5×109 L-1,血小板计数≥20×109 L-1中位时间分别为12 d和13 d;其中造血功能恢复快慢的趋势是同基因移植>外周血或/和骨髓+间充质干细胞移植>单纯外周血或/和骨髓干细胞移植,而亲缘HLA全相合的52岁患者造血恢复最慢。非血缘移植例1、6患者发生了Ⅰ度急性移植物抗宿主病,单倍体相合移植的例2和例10患者发生了Ⅱ度急性移植物抗宿主病后出现了局限性的慢性移植物抗宿主病,余下患者移植后生活质量良好,无慢性移植物抗宿主病;除未接受间充质干细胞的例3患者移植后出现严重感染外,其余患者移植后再未出现严重的感染和出血。结果提示造血干细胞是安全,高效治疗重型再生障碍性贫血的方法,联合应用间充质造血干细胞者患者造血恢复快,移植并发症少。     

单倍体外周血干细胞移植治疗急性白血病2例

摘要：异基因外周血造血干细胞移植是目前能够治愈急性白血病的最佳方法,随着国内独生子女家庭的日益增多,同胞供体减少,从中华骨髓库中检索配型全相合造血干细胞供者概率较低,耗时长,而单倍体造血干细胞移植如能成功开展将是解决供者来源困难的主要手段,但其面临植入困难和移植物抗宿主病发生率高且重这两大风险。通过改良预处理方案及在经典的环孢素Ａ+短程甲氨蝶呤的基础上,加用霉酚酸脂、白细胞介素11、抗人淋巴细胞免疫球蛋白及经重组人粒细胞集落刺激因子动员后的供体造血干细胞输注给受体联合预防移植物抗宿主病,成功的进行了2例单倍体外周血造血干细胞移植,2例患者均顺利植入,且无严重的移植物抗宿主病。     

异基因造血干细胞移植治疗白血病9例

摘要：重庆医科大学附属第一医院血液内科2007-01/2008-04应用异基因造血干细胞移植治疗白血病患者9例,6例急性髓细胞性白血病,3例慢性髓系白血病;供者中6例为HLA 完全相合的同胞,2例为HLA 9/10相合的无关供者,1例为半相合供者;预处理采用经典的BU/CY方案或GIAC方案;移植物抗宿主病的预防采用环孢菌素A+吗替麦考酚酯+甲氨喋呤方案或环孢菌素A+吗替麦考酚酯+甲氨喋呤+抗胸腺细胞球蛋白方案。结果全部患者均获得造血重建,中性粒细胞≥ 0. 5×109 L-1、血小板> 20×109 L-1 的中位时间分别是11,15 d;无急性移植物抗宿主病发生,1例发生慢性移植物抗宿主病;随访3~16个月无病生存率为77.8%。死亡2例。 关键词：异基因造血干细胞移植;移植物抗宿主病;白血病     

减低预处理剂量异基因造血干细胞移植后的白血病复发

目的：减低预处理剂量异基因造血干细胞移植预处理方案剂量强度弱于清髓性移植且又强于真正的非清髓移植，期望在降低毒副反应的同时能够减少复发。评价减低预处理剂量的异基因造血干细胞移植后白血病的复发情况及主要影响因素。 方法：①对象：选取2003-03/2005-06厦门大学附属中山医院血液科收治的23例白血病患者，急性粒细胞白血病6例，急性淋巴细胞白血病7例，慢性粒细胞白血病10例。供者同胞HLA全相合10例，同胞或亲缘供者不全相合12例，非血缘1例。供受者对治疗均签署知情同意书，实验经医院医学伦理委员会批准。②实验方法：23例白血病患者均采用减低预处理剂量方案，马利兰4 mg/（kg?d），2~3 d；环磷酰胺50 mg/（kg?d），2 d。其中19例患者在上述方案的基础上加用氟达拉滨30 mg/（m2?d），3~5 d；10例患者同时加用阿糖胞苷（1.0~2.0）g/（m2?d），1~3 d。供受者HLA位点不合时用兔抗胸腺细胞球蛋白（3.0~5.0）mg/（kg?d），3~5 d。异基因造血干细胞移植前行供者外周血干细胞动员，4~5 d后连续采集2次，23例白血病患者输入CD34+细胞中位数为4.02×106/kg。采用骁悉+环孢素+短程甲氨喋呤方案预防移植物抗宿主病。③实验评估：采用STR-PCR方法检测异基因造血干细胞植入证据。 结果：①造血功能重建检测：23例患者均顺利完成造血功能重建，无一例发生预处理相关死亡。经预处理后外周血白细胞最低值为(0.01~0.30)×109 L-1，血小板最低值为(5~20)×109 L-1；中性粒细胞恢复到0.5×109 L-1的中位时间为术后11 d，血小板恢复到30×109 L-1的中位时间为术后12 d。术后30 d经STR-PCR检测22例患者为完全供者型，骨髓象均完全缓解，剩余1例复发患者未行STR-PCR检测。②移植物抗宿主病发生情况：23例患者中，9例（39.1%）发生急性移植物抗宿主病，19例（82.6%）发生慢性移植物抗宿主病。③术后复发及生存情况：随访截止至2007-06-30，共5例患者复发，复发率21.7%，复发时间为移植后1~24个月；其中急性淋巴细胞白血病2例，急性粒细胞白血病2例，慢性粒细胞白血病1例，后3例移植前处于复发状态。移植前处于缓解期的患者其复发率为10%。 结论：①急、慢性粒细胞白血病缓解期患者采用减低预处理剂量的异基因造血干细胞移植方式，其术后复发率并未高于清髓性异基因造血干细胞移植，且预处理相关死亡率低。②疾病类型的选择、移植时的疾病状态、适当的预处理强度以及移植物抗宿主病是影响术后复发的重要因素。     

改良BU/CY预处理方案在外周血造血干细胞移植中的临床应用*

背景：在异基因造血干细胞移植中,预处理方案的选择是造血干细胞移植成败的重要关键环节之一,也是干细胞移植的重要研究方向。清髓性预处理方案毒性大,预处理相关死亡率高,从而探索理想的预处理方案,期望在降低不良反应的同时减少复发。 目的：观察用改良Bu/CY预处理方案治疗恶性血液病的疗效。 方法：选取2003-11/2008-03在中南大学湘雅医学院附属海口市人民医院血液科住院患者8例,均采用改良的Bu/CY预处理方案：阿糖胞苷2.0~3.0 g/(m2•d)×2 d,持续24 h静滴;马利兰4 mg/(kg•d)×3 d;环磷酰胺50 mg/(kg•d)× 2 d;甲基环已亚硝脲25 mg/(m2•d)×1 d;抗胸腺细胞球蛋白25 mg/(kg•d)×4 d。在改良方案的基础上加大阿糖胞苷剂量1倍,且改为持续24 h静滴,使预处理强度增加,促进造血干细胞持久植入。移植物抗宿主病预防：在经典的甲氨蝶呤方案基础上将环孢素A及霉酚酸酯提前至-7 d(回输干细胞前为-)使用。患者移植前后进行ABO血型及DNA检测。 结果与结论：①移植后造血重建检测：8例患者均获得造血重建,未发生预处理相关死亡。造血于细胞移植后-3~+7 d白细胞降为0,并持续3~22 d,+10~+21 d白细胞>1.0×109 L-1,+11~+51 d血小板>20×109 L-1。②移植物抗宿主病的发病情况：8例患者移植物抗宿主病Ⅳ级(肠道)1例,急性移植物抗宿主病Ⅰ~Ⅱ级3例。提示进一步改良BU/CTX方案其不良反应小,优于经典的全身照射/CY方案,且简便易行,抗白血病作用确实可靠,是治疗恶性血液病安全有效的方法。     

粒细胞集落刺激因子/粒-巨噬细胞集落刺激因子联合动员异基因造血干细胞移植

背景：目前FDA已批准应用于临床外周血造血干细胞移植的动员剂只有粒细胞集落刺激因子和粒-巨噬细胞集落刺激因子,其中粒细胞集落刺激因子单药应用是目前最主要的动员方案,但可引起供者骨骼肌肉酸痛、发热等不良反应。 目的：回顾性分析以粒细胞集落刺激因子/粒-巨噬细胞集落刺激因子联合应用为动员方案的异基因造血干细胞移植临床效果。 方法：选择2004-01/2009-10河南省人民医院血液科以粒细胞集落刺激因子与粒-巨噬细胞集落刺激因子联合应用为动员方案进行血缘全相合异基因造血干细胞移植51例,分析移植物成分、造血重建及移植物抗宿主病的发生率。 结果与结论：动员96 h后 CD34+细胞占单个核细胞的比例为(0.97±0.13)%,CD34+CD38-细胞占CD34+细胞的比例为(37.49±4.03)%;移植后的快速造血重建与 CD34+细胞、CD34+CD38-细胞输入量呈负相关。Ⅰ度、Ⅱ~Ⅳ度急性移植物抗宿主病的发生率分别为25.5%,15.7%;局限性、广泛性慢性移植物抗宿主病的发生率分别为39.2%,21.2%。提示在血缘全相合异基因造血干细胞移植中,粒细胞集落刺激因子/粒-巨噬细胞集落刺激因子联合可有效实现干细胞动员,所获CD34+细胞完全可以满足快速造血重建的需要;输入较多的CD34+细胞、CD34+CD38-细胞可能利于快速造血重建。     

HLA相合同胞异基因外周血造血干细胞移植治疗急性白血病

背景：HLA相合同胞间异基因外周血造血干细胞移植是治疗急性白血病的一种有效方法。 目的：评价HLA相合异基因外周血造血干细胞移植治疗急性白血病的临床疗效及并发症。 方法：25例急性白血病患者接受HLA相合同胞的异基因外周血造血干细胞移植,其中急性髓系白血病20例,急性淋巴细胞白血病5例。预处理方案为BU+CY方案或CY+TBI方案,移植物抗宿主病预防采用环孢素A+吗替麦考酚酯+短程甲氨蝶呤。 结果：最短随访2个月,最长随访80个月。患者均获造血重建,中性粒细胞≥0.5×109 L-1的时间为10~18 d,血小板≥20× 109 L-1的时间为10~37 d。主要并发症：感染败血症12例,巨细胞病毒感染9例,带状疱疹病毒感染3例,发生急性移植物抗宿主病10例,慢性移植物抗宿主病11例,出血性膀胱炎4例。至随访结束,17例无病生存,8例死亡。提示HLA相合同胞异基因外周血造血干细胞移植是治疗急性白血病安全有效的方法。     

非体外去T细胞单倍体外周血干细胞移植治疗恶性血液病

背景：应用亲属人类白细胞抗原单倍体相合供者进行造血干细胞移植,几乎可使所有需要移植治疗的患者都能在亲属间及时找到供者。但由于人类白细胞抗原不合的免疫学障碍,应用常规方式移植不但排斥率高而且重度移植物抗宿主病发病率显著增高。 目的：观察应用清髓性预处理联合多种免疫抑制方案进行非体外去T细胞的人类白细胞抗原单倍体相合外周血干细胞移植治疗恶性血液病的疗效。 设计、时间及地点：病例观察,于2002-07/2008-06在新疆医科大学第一附属医院血液科,血液病研究所完成。 对象：恶性血液病患者42例,年龄10~48岁。供受者人类白细胞抗原配型1个位点不合者7例,2~3个位点不合者35例。 方法：预处理方案为清髓性的,预防移植物抗宿主病均以环孢素加短程甲氨蝶呤为基础方案,人类白细胞抗原1个位点不合时加用霉酚酸酯,人类白细胞抗原2~3个位点不合时再加用抗胸腺细胞球蛋白及抗CD25单抗。移植物为经粒细胞集落刺激因子动员的未进行体外去除T细胞的外周血干细胞,移植的CD34+细胞11×106/kg。 主要观察指标：观察患者移植物抗宿主病发生情况及移植后1,3,6,12及18个月供、受者人类白细胞抗原相合及单倍体移植受者T、B亚群变化。 结果：42例患者均获得完全、持久供者干细胞植入,发生急性移植物抗宿主病19例,Ⅰ度16例,Ⅱ度3例,2年累积发病率为50.8%;在随访大于6个月的31例患者中发生 慢性移植物抗宿主病23例,局限型20例,广泛型3例,2年累积发病率为57.1%,无患者死于移植物抗宿主病。人类白细胞抗原单倍体非去T细胞外周血干细胞移植后T、B亚群下降及恢复与人类白细胞抗原相合移植无统计学差异。 结论：在小样本临床治疗中,应用清髓性预处理联合多种免疫抑制剂进行非体外去T细胞亲属间人类白细胞抗原单倍体相合外周血干细胞移植治疗恶性血液病安全有效, 今后需扩大样本量进一步证实其临床疗效。     

Epilepsy and anomalies of neuronal migration: MRI and clinical aspects

Neuronal migration disorders are the result of disturbed brain development. In such disorders, neurons are abnormally located. In diagnosing these conditions, magnetic resonance imaging is superior to any other imaging technique. This enables us to improve our knowledge of the clinical correlates of neuronal migration. With reference to migrational disorder, a retrospective study of all 303 patients with epileptic seizures referred for magnetic resonance imaging during a 3-year period was performed, 13 patients (aged 12-41, mean age 27) were identified. They represent 4.3% of the entire study group. Of the patients with known epilepsy, 6.7% and of the mentally retarded, 13.7% had migrational disorders. Four patients had schizencephaly as the dominant finding, one was classified as hemimegalencephaly, 2 had isolated heterotopias, and 6 had localized pachy- and/or poly-microgyria. The clinical pictures are complex. Ectopias of grey matter are recognised foci of epilepsy, but from an epileptological and a clinical viewpoint little attention has been given to these disorders. The present study shows that malmigration is not rare in epilepsy patients, especially not in the mentally retarded.     

Classification of methods in transcranial Electrical Stimulation (tES) and evolving strategy from historical approaches to contemporary innovations

Transcranial Electrical Stimulation (tES) encompasses all methods of non-invasive current application to the brain used in research and clinical practice. We present the first comprehensive and technical review, explaining the evolution of tES in both terminology and dosage over the past 100 years of research to present day. Current transcranial Pulsed Current Stimulation (tPCS) approaches such as Cranial Electrotherapy Stimulation (CES) descended from Electrosleep (ES) through Cranial Electro-stimulation Therapy (CET), Transcerebral Electrotherapy (TCET), and NeuroElectric Therapy (NET) while others like Transcutaneous Cranial Electrical Stimulation (TCES) descended from Electroanesthesia (EA) through Limoge, and Interferential Stimulation. Prior to a contemporary resurgence in interest, variations of transcranial Direct Current Stimulation were explored intermittently, including Polarizing current, Galvanic Vestibular Stimulation (GVS), and Transcranial Micropolarization. The development of these approaches alongside Electroconvulsive Therapy (ECT) and pharmacological developments are considered. Both the roots and unique features of contemporary approaches such as transcranial Alternating Current Stimulation (tACS) and transcranial Random Noise Stimulation (tRNS) are discussed. Trends and incremental developments in electrode montage and waveform spanning decades are presented leading to the present day. Commercial devices, seminal conferences, and regulatory decisions are noted. We conclude with six rules on how increasing medical and technological sophistication may now be leveraged for broader success and adoption of tES.     

Hepatic Considerations in the Use of Antiepileptic Drugs

Summary: Virtually all of the major antiepileptic drugs (AEDs) can cause hepatotoxicity, although fatal hepatic reactions are rare. The mechanisms, incidences, and risk profiles for such reactions differ from drug to drug. With carbamazepine and phenytoin, hepatotoxicity may be due to drug hypersensitivity. Although the profiles of patients at risk have not been well-defined for these two antiepileptic drugs, it would appear from reports in the literature that older adolescents and adults are at higher risk than children of developing serious or fatal hepatotoxicity. Once hepatotoxicity develops, mortality rates are 10–38% with phenytoin and 25% for carbamazepine. The risk profile for valproate fatal hepatotoxicity has been more clearly defined. Those at primary risk of fatal hepatic dysfunction are children under the age of 2 years who are receiving multiple anticonvulsants and also have significant medical problems in addition to severe epilepsy. The risk is considerably lower for patients over the age of 2 years on valproate monotherapy. In contrast to the risk profile with other AEDs, adults receiving valproate as monotherapy have the lowest risk of hepatotoxicity. Fatal hepatic dysfunction coincident with valproate may be the result of aberrant drug metabolism. Concomitant use of AEDs that induce microsomal P450 enzymes (e.g., phenytoin and phenobarbital) may enhance the production of a toxic metabolite, and hence the greater risk of hepatotoxicity with polypharmacy.     

Vascular Malformations and Epilepsy: Clinical Considerations and Basic Mechanisms

Summary: Vascular malformations (VMs) are associated with epilepsy. The natural history of the various VMs, clinical presentation, and tendency to provoke epilepsy determine treatment strategies. Investigations have probed the mechanisms of epileptogenesis associated with these lesions. Electrophysiologic changes are associated with epileptogenic cortex adjacent to VMs. Putative pathophysiologic mechanisms of epileptogenesis include neuronal cell loss, glial proliferation and abnormal glial physiology, altered neurotransmitter levels, free radical formation, and aberrant second messenger physiology.     

Neonatal Seizures: Problems in Diagnosis and Classification

Summary: The clinical identification of neonatal seizures is critical for the recognition of brain dysfunction; however, diagnosis is often difficult because of the poorly organized and varied nature of these behaviors. Current classification systems are limited in their ability to communicate motor, autonomic, and electroencephalo-graphic features of seizures precisely and to provide a basis for uniform effective diagnosis, therapy, and determination of prognosis. Recent investigations of neonates, utilizing bedside electroencephalographic/polygraphic/ video monitoring techniques, have provided the basis for improved diagnosis and classification of seizures in the newborn. These studies have demonstrated that not all clinical phenomena currently considered to be seizures require electrocortical epileptiform activity for their initiation or elaboration. In addition, the specific clinical character of the phenomena considered to be seizures, the clinical state of the infant, and the character of the EEG indicate the probable pathophysiological mechanisms involved and suggest probable etiologies, prognosis, and therapy. Similarities between animal models that demonstrate reflex physiology and neonates with motor automatisms and tonic posturing suggest that these clinical behaviors may not be epileptic in origin but, rather, primitive movements of progression and posture mediated by brainstem mechanisms. Although not all clinical behaviors currently considered to be neonatal seizures may have similar pathophysiological mechanisms, they are clinically significant because they all indicate brain dysfunction.     

Valproate Monotherapy in the Management of Generalized and Partial Seizures

Summary: For decades, therapeutic tradition has promoted the concept of polypharmacy in the management of epilepsy. In recent years, however, studies have shown that, for most patients, monotherapy can provide comparable or better seizure control than administration of multiple anticonvulsants, while diminishing the potential for adverse reactions, drug interactions, and poor compliance. Valproate is an important monotherapeutic agent that is highly effective in the control of idiopathic primary and secondarily generalized epilepsies, and partial seizures that do not generalize. Comparative studies have found that valproate is at least as effective as phenytoin and carbamazepine in the treatment of generalized and partial seizures. Given the similar efficacy, other factors such as pharmacokinetics and side effects may therefore determine anticonvulsant selection for monotherapy.     

Un nouveau cadre conceptuel de travail pour la psychiatrie

In an attempt to place psychiatric thinking and the training of future psychiatrists more centrally into the context of modern biology, the author outlines the beginnings of a new intellectual framework for psychiatry that derives from current biological thinking about the relationship of mind to brain. The purpose of this framework is twofold. First, it is designed to emphasize that the professional requirements for future psychiatrists will demand a greater knowledge of the structure and functioning of the brain than is currently available in most training programs. Second, it is designed to illustrate that the unique domain which psychiatry occupies within academic medicine, the analysis of the interaction between social and biological determinants of behavior, can best be studied by also having a full understanding of the biological components of behavior.     

Carbamazepine Efficacy and Utilization in Children

Summary: Carbamazepine is effective for preventing partial and generalized tonic-clonic seizures in children. Although absence epilepsies are more common in children than adults, an estimated 80% of children with epilepsy have seizure types or epilepsies that are potentially responsive to carbamazepine. The differential diagnosis of ictal staring is an especially important issue in children because absence and atypical absence seizures are more prevalent in children than adults. Age-related pharmacokinetic differences and drug interactions are major considerations in children. On average, children have higher clearance rates of carbamazepine, shorter half-lives, and higher ratios of carbamazepine-10, 11-epoxide to carbamazepine than adults. In addition, children with severe epilepsy are more likely to require multiple-drug therapy, which can lead to complex drug interactions. When carbamazepine is administered along with valproate, drug protein binding interactions can cause intermittent side effects.     

Special Pharmacokinetic Considerations in Children

Summary: Pediatric patients have greater degrees of pharmacokinetic variability and unpredictability than adults. This variability results from the effects of pharmacogenetics, age and growth, prior and current comedication, and disease. Newborns with seizures have the least predictable dosage requirements, and their needs change as drug-eliminating mechanisms mature in the neonatal period. Infants have the highest relative capacities to eliminate antiepileptics of any age group and require the largest relative doses. In addition to age-related trends, children demonstrate the same drug-specific, pharmacokinetic phenomena that adults do, including nonlinear phenytoin elimination, nonlinear valproate binding, and autoinduction of carbamazepine. Intercurrent illness and drug interactions further modify the age-related pharmacokinetic patterns in children and make dosage requirements even more unpredictable. Recent studies have shown that febrile illness can affect drug elimination, sometimes decreasing drug levels by 50% or more. Intermittent treatment with benzodiazepines administered either orally or rectally can be an important adjunct and help minimize this type of problem for children with marginally controlled epilepsy. Intermittent benzodiazepines are also helpful for children who have febrile seizures and who need only occasional antiepileptic protection.