Inappropriate requests for serum anti-epileptic drug levels in hospital practice

BACKGROUND: Serum anti-epileptic drug (AED) levels are indicated to assess AED adherence or toxicity, and are applicable to only a few AEDs. Expert consensus views on the clinical role of serum AED levels are summarized in the evidence-based guidelines published by the Scottish Intercollegiate Guidelines Network. AIM: To examine local compliance with these guidelines. DESIGN: Retrospective case-note audit. METHODS: We included all serum AED level measurements requested from our hospital over two months. Our audit standards were first, that serum AED levels should be requested only for suspicion of poor AED adherence or toxicity ('indication-compliant'), and secondly, for 'full compliance', that 'indication-compliant' requests should be made only for AEDs with established dose-response and dose-toxicity relationships (phenytoin, carbamazepine, phenobarbitone). RESULTS: There were 114 measurements in 102 patients. Serum AED level requests were for phenytoin (n = 50), valproate (n = 27), carbamazepine (n = 22), lamotrigine (n = 8), phenobarbitone (n = 7), and were made by physicians (n = 46), paediatricians (n = 30), neurologists (n = 15), neurosurgeons (n = 14), psychiatrists (n = 7), and intensivists (n = 2). AED toxicity was queried in 29 requests (25%), and adherence in 10 (9%); thus 34% of requests were 'indication-compliant'. However, 16 of these were for valproate or lamotrigine; thus only 23 requests (20%) were 'fully compliant'. Clinical management changed in only 17 of the 47 patients whose levels fell outside target ranges, and only two of these followed indication-compliant AED measurement. DISCUSSION: The audit identified a failure locally to comply with standard evidence-based guidelines. If, as is likely, this reflects practice elsewhere in the UK, there are potentially major clinical management and resource implications.     

Predictability of individualized dosage regimens of carbamazepine and valproate mono- and combination therapy

What is known and Objective: Many investigators agree that appropriate rational utilization of therapeutic drug monitoring (TDM) with Bayesian feedback dosage adjustment facilitates epilepsy treatment with carbamazepine (CBZ) and/or valproate (VPA) by increasing the seizure control and safety, as well as by reducing treatment costs. In previous works we have developed and used in clinical practice population pharmacokinetic (PK) models of different dosage forms for VPA and post‐induction CBZ behaviour, as well as for combined therapy with CBZ plus another ‘old’ antiepileptic drug (AED). An important step of external validation is to evaluate how well a procedure of Bayesian individualizing AED dosage regimens based on a proposed population PK model and sparse TDM data ‘works’, and how helpful it is in real practical clinical settings. The aim of this study was to evaluate the predictability of individualized dosage regimens for monotherapy with CBZ in the post‐induction period or with VPA, as well as for CBZ and VPA given as combination therapy based on TDM data of epileptic patients and the earlier developed population models. Methods: Four groups of TDM data were analysed using the USC*PACK software for PK/PD analysis: 556 predictions for adult epileptic patients on CBZ monotherapy, 662 predictions for VPA monotherapy, 402 predictions of CBZ serum levels and 430 predictions of VPA serum levels for adult epileptic patients on CBZ+VPA combination therapy. Statistical characteristics of the prediction errors (PE) and weighted PE were used to estimate bias and precision of predictions. Intraindividual and interoccasional variability of predictions were also estimated. Results and Discussion: This study demonstrated that in most cases of CBZ and VPA monotherapy and combination therapy, predictions of future AED concentrations based on the earlier developed population PK models, TDM data and patient‐specific maximum a posteriori probability Bayesian posterior parameter values provided clinically acceptable estimates. Statistical analysis of the residuals demonstrated that the distributions of residual and weighted residual were close to the normal distribution (Kolmogorov–Smirnov test, P > 0·05) and their mean values did not differ statistically significant from zero (no statistically significant bias, P > 0·05) for all groups of predictions. The observed decreased quality of predictions of VPA concentrations during VPA+CBZ combination therapy, especially when CBZ dosages were changed, might well be explained by their PK interactions. For all groups, in linear regression analysis, the observed trend of decreasing of the prediction quality over various future prediction time horizons was considered statistically significant (P < 0·05). Prediction of serum levels further in future was less precise than those closer to the present for a 1·5‐ to 3·5‐year observation period. No bias in predictions was associated with the time horizons. What is new and Conclusion: Our validation results suggest good predictive performance of the population models developed earlier, and quite acceptable predictions of future AED serum levels for individualized dosage regimens of CBZ and VPA therapy in real clinical settings.     

Seizure prophylaxis in patients with brain tumors: a meta-analysis

OBJECTIVE: To assess whether antiepileptic drugs (AEDs) should be prescribed to patients with brain tumors who have no history of seizures. METHODS: We performed a meta-analysis of randomized controlled trials (1966-2004) that evaluated the efficacy of AED prophylaxis vs no treatment or placebo to prevent seizures in patients with brain tumors who had no history of epilepsy. Summary odds ratios (ORs) were calculated using a random-effects model. Three subanalyses were performed to assess pooled ORs of seizures in patients with primary glial tumors, cerebral metastases, and meningiomas. RESULTS: Of 474 articles found in the initial search, 17 were identified as primary studies. Five trials met inclusion criteria: patients with a neoplasm (primary glial tumors, cerebral metastases, and meningiomas) but no history of epilepsy who were randomized to either an AED or placebo. The 3 AEDs studied were phenobarbital, phenytoin, and valproic acid. Of the 5 trials, 4 showed no statistical benefit of seizure prophylaxis with an AED. Meta-analysis confirmed the lack of AED benefit at 1 week (OR, 0.91; 95% confidence interval [CI], 0.45-1.83) and at 6 months (OR, 1.01; 95% CI, 0.51-1.98) of follow-up. The AEDs had no effect on seizure prevention for specific tumor pathology, including primary glial tumors (OR, 3.46; 95% CI, 0.32-37.47), cerebral metastases (OR, 2.50; 95% CI, 0.25-24.72), and meningiomas (OR, 0.62; 95% CI, 0.10-3.85). CONCLUSIONS: No evidence supports AED prophylaxis with phenobarbital, phenytoin, or valproic acid in patients with brain tumors and no history of seizures, regardless of neoplastic type. Subspecialists who treat patients with brain tumors need more education on this issue. Future randomized controlled trials should address whether any of the newer AEDs are useful for seizure prophylaxis.     

Optimizing antiepileptic drug therapy in the elderly

OBJECTIVE: To review and evaluate the medical literature concerning antiepileptic drug (AED) therapy in elderly patients. DATA SOURCES: A MEDLINE search (1982-December 2004) was conducted. Bibliographies of the articles identified were also reviewed, and an Internet search engine was used to identify additional pertinent references. STUDY SELECTION AND DATA EXTRACTION: Clinical studies and reviews were evaluated, and relevant information was included. DATA SYNTHESIS: The elderly have the highest incidence of seizures among all age groups. Complex partial seizures are the most common, followed by primary generalized tonic-clonic seizures. An accurate diagnosis may prove difficult because of a low suspicion of epilepsy in the elderly and other diseases that may mimic seizures. Most AEDs are approved for treatment of elderly patients who have partial and tonic-clonic seizures. However, a number of age-related variables should be addressed when selecting an appropriate AED. Age-dependent differences in pharmacokinetics and pharmacodynamics of AEDs must be taken into account. Drug-drug interactions must be considered since elderly people often take multiple medications. The ultimate factor that often determines AED selection is tolerability. CONCLUSIONS: Numerous factors must be considered in treating elderly patients for seizures, but maximizing the ability of patients to tolerate drug therapy is often the basis for AED selection. Special consideration should be made along several lines, including elderly patients' cognitive functioning and their tendency to respond to lower AED concentrations.     

Epilepsy

Seizures are common and are treated in all branches of medicine. Approximately 10% of the population will have one or more seizures during their lifetime. Seizures are symptoms that occur in acute illness, ie, provoked seizures, or in epilepsy, ie, unprovoked seizures. Epilepsy is any disorder in which spontaneous recurrence of unprovoked seizures is the main symptom. It is a common chronic neurologic disorder and affects 1% to 3% of the population. Classification of seizure type is important because it enables identification of the region of the brain where the seizure originated and guides initial diagnostic testing. Classification of epilepsy syndrome, rather than only type of seizure, is more important. Epilepsy syndromes are defined by many factors, including type of seizures, age at onset of seizures, family history of seizures, and findings at physical examination, electroencephalography (EEG), and neurologic imaging studies. Identifying the epilepsy syndrome provides insight into natural history, prognosis, diagnostic testing, and therapy of the disorder and facilitates communication between health care professionals. Understanding seizure type provides useful information even when the epilepsy syndrome cannot be classified. Many sudden events are easily confused with seizures, in particular, pseudoseizures, syncope, migraine, cerebrovascular disease, movement disorders, and sleep disorders. In most cases a detailed history and physical examination concentrated on the details of the event, and results of routine EEG and magnetic resonance imaging can aid in determination of which events are seizures. Video EEG monitoring is occasionally necessary to capture events to enable definitive determination of whether they are seizures and to further characterize them. Provoked seizures are treated with relief of the provoking factor. Antiepileptic drugs (AEDs) are not indicated. However, AEDs may be required to treat unprovoked seizures of new onset in patients at high risk for seizure recurrence or when a second seizure can have devastating psychosocial effects. High risk for recurrence is present when there is a history of brain insult, an EEG demonstrates epileptiform abnormalities, and magnetic resonance images demonstrate a structural lesion. AED therapy is the standard treatment for epilepsy, ie, two or more seizures. Selection of the appropriate AED depends on type of seizure and epilepsy present, and individual drug characteristics, including pharmacokinetics, side effects, dosing interval, and cost. All available AEDs except ethosuximide are effective as adjunctive therapy, and most are effective as initial monotherapy for partial seizures. Generalized seizures preferentially respond to valproate, lamotrigine, and topiramate, among other drugs. If trials of more than two AEDs do not control seizures, additional AEDs are unlikely to be effective, and the patient should be referred to an epilepsy center, where other treatment options, in particular, epilepsy surgery, can be offered. Epilepsy surgery renders 60% to 70% of patients with temporal lobe epilepsy free of disabling seizures.     

Clinical pharmacology and therapeutic use of the new antiepileptic drugs

Although older generation antiepileptic drugs (AEDs) such as carbamazepine, phenytoin and valproic acid continue to be widely used in the treatment of epilepsy, these drugs have important shortcomings such as a highly variable and nonlinear pharmacokinetics, a narrow therapeutic index, suboptimal response rates, and a propensity to cause significant adverse effects and drug interactions. In an attempt to overcome these problems, a new generation of AEDs has been introduced in the last decade. Compared with older agents, some of these drugs offer appreciable advantages in terms of less variable kinetics and, particularly in the case of gabapentin, levetiracetam and vigabatrin, a lower interaction potential. Lamotrigine, topiramate, zonisamide and felbamate protect against partial seizures and a variety of generalized seizure types, vigabatrin is effective against partial seizures (with or without secondary generalization) and infantile spasms, while the use of oxcarbazepine, tiagabine and gabapentin is mainly restricted to patients with partial epilepsy (and, in the case of oxcarbazepine, also primarily generalized tonic-clonic seizures). Levetiracetam, the latest AED to be introduced, has been found to be effective in partial seizures, but its potentially broader efficacy spectrum remains to be determined in clinical studies. Currently, the main use of new generation AEDs is in the adjunctive therapy of patients refractory to older agents. However, due to advantages in terms of tolerability and ease of use, some of these drugs are increasingly used for first-line management in certain subgroups of patients. Due to serious toxicity risks, felbamate and vigabatrin should be prescribed only in patients refractory to other drugs. In the case of vigabatrin, however, first line use may be justified in infants with spasms.     

Use of phenytoin for the long-term treatment of partial seizures: Results of a survey conducted during the 2004 meeting of the American Academy of Neurology

Background:

Epilepsy is a chronic disorder that typically requires lifelongpharmacologic treatment. The choice of an antiepileptic drug (AED), therefore, requires careful consideration of efficacy and tolerability. However, the majority of patients with new-onset seizures are initially treated by physicians in the emergency department (ED) or by non-ED physicians (primary care physicians or internists), with phenytoin being the most common AED prescribed for initial therapy, and the long-term adverse effects of AEDs are often overlooked.

Objective:

The aim of this survey was to examine the perspectives of neurologistsand epileptologists concerning initial therapies prescribed by ED physicians and non-ED physicians for newly diagnosed partial seizures, particularly phenytoin, and the suitability of these therapies for long-term management of the disease.

Methods:

A computerized survey was conducted during the 2004 AmericanAcademy of Neurology meeting. The survey consisted of 10 questions concerning the use of AEDs in the initial and long-term treatment of newly diagnosed partial seizures.

Results:

The responses of 268 practitioners were analyzed. Survey participants indicated that 71% of patients referred to them by ED physicians were receiving phenytoin, whereas 59% of patients referred to them by non-ED physicians were receiving phenytoin. Seventy-six percent of survey participants responded that they would switch a patient having partial seizures referred from the ED to another AED. Seventy-eight percent indicated that they did not believe that the medications being received by patients with newly diagnosed partial seizures in the ED were suitable for long-term epilepsy treatment.

Conclusion:

Although appropriate treatment might vary in the acute and chronic settings, and phenytoin is used as a primary agent for acute treatment of seizures presenting in the ED, the results of the present survey suggest a discrepancy between the medications that primary care and ED physicians prescribe for newly diagnosed partial seizures and those that specialists prescribe for long-term therapy.     

Therapeutics in pediatric epilepsy,Part 1: The new antiepileptic drugs and the ketogenic diet

Epilepsy is one of the most common and challenging neurologic disorders affecting children. Although various modalities exist to treat pediatric-onset seizures, seizures in 25% of children who are diagnosed as having epilepsy remain refractory to available therapies. Of the 8 new antiepileptic drugs (AEDs) (felbamate, gabapentin, lamotrigine, topiramate, tiagabine, levetiracetam, oxcarbazepine, and zonisamide), all but 2 (zonisamide and levetiracetam) have received Food and Drug Administration approval for adjunctive use in the pediatric population. However, most of the new AEDs used in adults have also been used in children, beyond the AEDs' approved indications. The ultimate goal of patient management is to choose the therapeutic option that provides the best chance of improving the patient's quality of life. Issues that relate to treatment choice include the likelihood of seizure recurrence, type and severity of seizures, available AED efficacies and toxicities, need for hematologic monitoring, ease of dosing, underlying medical conditions, medication interactions, urgency of initiating therapy, and cost. In this review, we discuss these issues for each of the 8 new AEDs; we also discuss the ketogenic diet and briefly review the older AEDs. Knowledge of the available AEDs will enable the practitioner to choose the best drug or drugs for individual patients.     

Improved sexual function in three men taking lamotrigine for epilepsy

Little information exists about the effects of newer antiepileptic drugs (AEDs) on sexual function in men with epilepsy. We report a series of three male veterans whose sexual disorders improved with lamotrigine. All three had partial seizures. One patient was taking phenobarbital and gabapentin and complained of decreased potency and anorgasmia. After lamotrigine was added for better seizure control and the dosage of gabapentin was tapered, anorgasmia improved. The second patient complained of impotence after a rash while taking phenytoin and carbamazepine. Impotence persisted with phenobarbital, valproate, and gabapentin. Eight months after gabapentin was replaced with lamotrigine, impotence improved. The third patient complained of long-standing impotence. Treatment with five AEDs had no effect on the dysfunction. Lamotrigine was added to the carbamazepine regimen; impotence improved with decrease in carbamazepine and increase in lamotrigine. The favorable effect of lamotrigine on sexual disorders in these three patients suggests this drug should be considered under appropriate circumstances for men who have sexual dysfunction while taking other antiepileptic agents.     

Review of Transcranial Magnetic Stimulation in Epilepsy

PurposeDespite the availability of numerous pharmacologic and nonpharmacologic antiseizure therapies, a fraction of patients with epilepsy remain refractory to current treatment options, underscoring the need for novel drugs and neuromodulatory therapies. Transcranial magnetic stimulation (TMS), coupled with either electromyography or electroencephalography, enables rapid measurement of the cortical excitation/inhibition ratio, which is pathologically shifted toward excess excitability in patients with epilepsy. In this review, we summarize: (1) TMS protocols that have been deployed to identify promising compounds in the antiepilepsy drug (AED)-development pipeline, and (2) the therapeutic potential of TMS in the treatment of drug-resistant seizures.MethodsA focused literature review of the use of TMS in epilepsy, using a PubMed search, was performed. Over 70 articles were included that pertained to: (1) the use of TMS-EMG and TMS-EEG in elucidating the mechanisms of action of AEDs and in discovering potential new AEDs; and (2) the use of repetitive TMS in the treatment of seizures.FindingsStudies from the literature have reported that AEDs alter TMS-derived metrics, typically by leading to a net increase in cortical inhibition with successful therapy. Preclinical TMS work in rodent models of epilepsy has led to the development of novel antiseizure drug compounds. Clinical translational studies of TMS have been used to determine guidelines on the dosages of other agents in the AED pipeline in preparation for clinical trials. Several studies have described the use of therapeutic repetitive TMS in both the ictal and interictal states of epilepsy, with inconsistent results.ImplicationsTMS has diagnostic and therapeutic potential in epilepsy. TMS-derived markers can enable early-stage measures of AED target engagement, and can facilitate studies of the pharmacokinetic and pharmacodynamic properties of AEDs. TMS may also be used in the early prediction of the efficacy of different AEDs in treating patients, and in direct neuromodulation of epileptic networks. From the therapeutics perspective, despite favorable results in some trials, the optimization of treatment paradigms and the determination of ideal candidates for TMS are still needed. Finally, preclinical experiments of TMS have provided mechanistic insight into its effects on the excitation/inhibition ratio, and may facilitate rational drug–device coupling paradigms. Overall, the capacity of TMS in both the modulation and measurement of changes in cortical excitability highlights its unique role in advancing antiepilepsy therapeutics     

Seizures in the elderly: Nuances in presentation and treatment

Acute symptomatic seizures and epilepsy are two of the most common neurologic complaints in the elderly. Stroke is the leading underlying etiology for both. Because clinical seizure manifestations in the elderly often differ from those in younger adults, they may be difficult to recognize or may be misdiagnosed. Interpretation of diagnostic tests in elderly patients with seizures is often complicated by comorbidities, and treatment decisions require careful consideration in the context of age-related physiologic changes, comorbidities, and the use of concomitant medications. Treatment of an acute seizure with a clear precipitating cause involves correcting the underlying etiology; antiepileptic drug (AED) therapy is generally reserved for patients with epilepsy (recurrent unprovoked seizures). The prognosis for elderly epilepsy patients treated with AEDs is generally good. Both older and newer AEDs are efficacious but have respective advantages and disadvantages; no ideal AED yet exists. Status epilepticus is a neurologic emergency that is particularly frequent in the elderly and associated with high mortality, although treatment can be effective.     

Drug interactions between chemotherapeutic regimens and antiepileptics

BACKGROUND: Drug-drug interactions (DDIs) are commonly seen in daily clinical practice, particularly in the treatment of patients with cancer. Seizures are often seen in patients with brain tumors and brain metastases, in whom antiepileptic drugs (AEDs) are often indicated. The risk for DDIs between anticancer drugs and AEDs is high. OBJECTIVE: This review aimed to investigate the types of interactions that are observed between the AEDs and the most commonly prescribed chemotherapeutic regimens. The risk for DDIs is discussed with regard to tumor type. METHODS: Data on DDIs between anticancer drugs and AEDs were compiled from the British National Formulary, Drug Information Handbook, and Micromedex Healthcare Series version 5.1. Product information of the individual drugs, as well as literature on anticancer drug-AED interactions, was searched using PubMed (years: December 1970 to January 2008; search terms: anticancer, antiepileptic, chemotherapy regimen, drug interactions, and the generic names of the individual anticancer drugs and AEDs [acetazolamide, carbamazepine, ethosuximide, felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, phenobarbital, phenytoin, primidone, tiagabine, topiramate, valproic acid, vigabatrin, and zonisamide]). RESULTS: Our search identified clinically important DDIs observed with single-agent and combination regimens used for the treatment of breast cancers, colorectal cancers, lung cancers, lymphomas, and renal cell carcinomas. Carbamazepine, phenytoin, phenobarbital, and primidone were found to have prominent cytochrome P450 (CYP) enzyme-induction effects, while valproic acid had an inhibitory effect. The isozymes of major relevance to anticancer drug-AED interactions included CYP3A4, CYP2C9, and CYP2C19. Induction or inhibition of these isozymes by AEDs can cause a decrease or increase in anticancer drug concentrations. Similarly, enzyme inhibition or induction by anticancer drugs can lead to toxicity or loss of seizure control. CONCLUSIONS: In this review of anticancer drug-AED DDIs, carbamazepine, phenytoin, phenobarbital, primidone, and valproic acid were found to interact the most frequently with anticancer drugs. Based on the results of this review, clinicians should be vigilant when AEDs are prescribed concurrently with anticancer drugs. DDIs can be avoided or minimized by selecting alternative AEDs that are less likely to interact. However, if potentially interacting drug combinations must be used for treatment, serum drug concentrations should be closely monitored to avoid toxicity in the patient, as well as to ensure adequate chemotherapeutic and antiepileptic coverage.     

Topiramate titration to response: analysis of individualized therapy study (TRAITS)

OBJECTIVE: To evaluate the relationship between baseline seizure frequency and stabilized topiramate dosage and the effect of individualized treatment on tolerability in adults with partial-onset seizures receiving other antiepileptic drugs (AEDs). METHODS: In this 20-week, open-label trial, dosages of medications were adjusted according to clinical response. Dosage and seizure response data were analyzed for 2 groups defined by baseline seizure frequency: <4 and >/=4 seizures per month. RESULTS: In the outcome evaluable population (n = 471), the mean +/- SEM stable topiramate dosage was 303 +/- 139 mg/d when baseline seizure frequency was <4 seizures/month and 341 +/- 153 mg/d when baseline seizure frequency was >/=4 seizures/month (p = 0.005). The most common adverse events were somnolence (8.5%), fatigue (7.3%), nausea (5.3%), and dizziness (5.0%). Cognitive complaints were reported by <3% of patients. When concomitant AED dosages were reduced, 14% of patients discontinued topiramate due to adverse events compared with 23% if the concomitant AED dosage was unchanged or increased. CONCLUSIONS: When clinicians individualize topiramate dosage according to clinical response, the stabilized topiramate dosage as add-on therapy is influenced by baseline seizure frequency. Topiramate tolerability is improved when dosages of concomitant AEDs are reduced.     

Levetiracetam: a new therapeutic option for refractory epilepsy

Levetiracetam (LEV) is the most recently licensed antiepileptic drug (AED) for adjunctive therapy of partial seizures. Its mechanism of action is uncertain but it exhibits a unique profile of anticonvulsant activity in models of chronic epilepsy. Three randomised, double-blind, placebo-controlled trials enrolling 904 patients with refractory partial epilepsy have demonstrated the efficacy of LEV as adjunctive therapy, with a responder rate (> or = 50% reduction in seizure frequency) of 28-41%. Long-term efficacy studies suggest retention rates of 60% after one year, with 13% of patients seizure-free for six months of the study and 8% seizure-free for one year. Adverse effects of LEV, including somnolence, lethargy and dizziness, were generally mild and the frequency of incidents was not significantly different between the active treatment and placebo groups in clinical trials. LEV has no clinically significant pharmacokinetic interactions (PKI) with other AEDs, or with commonly prescribed medications. Preliminary data suggest that LEV has efficacy in primary generalised epilepsy and further randomised trials are under way. The combination of potent antiepileptic properties with a relatively mild adverse effect profile makes LEV an attractive adjunctive therapy for partial seizures.     

精神类疾病患者常用药物TDM结果的回顾性分析

目的探讨5种常用精神类疾病治疗药物的治疗药物监测(TDM)的临床应用价值。方法回顾性分析721例精神类疾病患者2种心境稳定剂(丙戊酸、卡马西平)和3种抗精神类药物(氯氮平、奥氮平、帕利哌酮)的TDM结果,比较TDM前、后5种药物在控率的差异。结果丙戊酸、卡马西平TDM前的在控率分别为31.15%、33.33%,TDM后总在控率分别提升至81.53%、81.82%;氯氮平、奥氮平、帕利哌酮TDM前的在控率分别为24.35%、67.32%、68.75%,TDM后总在控率分别提升至62.61%、83.01%、83.13%;与TDM前比较,5种药物TDM后的在控率均明显升高(P<0.05)。丙戊酸TDM后在控率的提升幅度(50.38%)显著高于氯氮平、奥氮平、帕利哌酮的提升幅度(38.26%、15.69%、14.38%)(P<0.05);卡马西平TDM后在控率的提升幅度(48.49%)显著高于奥氮平、帕利哌酮的提升幅度(15.69%、14.38%)(P<0.05)。结论 TDM可以有效指导临床用药,实现个体化给药,达到最佳治疗效果。     

IS VALPROATE MONOTHERAPY A PRACTICAL POSSIBILITY IN CHRONICALLY UNCONTROLLED EPILEPSY?

In a prospective open study of 20 male epileptic residents of a mental handicap institution, polytherapy was gradually reduced to valproate monotherapy in 18 subjects. In terms of seizure frequency this was significantly disadvantageous but when carbamazepine was added or substituted, seizure control improved significantly. Drugs with documented adverse effects on cognitive function such as phenobarbitone and phenytoin were phased out. In the 18 subjects who achieved valproate monotherapy, no association between serum levels and seizure control could be demonstrated. Adverse effects of valproate were pancreatitis and thrombocytopenia; in one subject thrombocytopenia appeared to be associated with levels in the toxic range but in six other subjects 'toxic' levels of valproate did not give rise to any clinically detectable toxic signs. There was no instance of tremor or weight gain. It was concluded that, in the population studied (institutionalized patients with chronically uncontrolled seizures) valproate monotherapy was inappropriate but carbamazepine with or without valproate was a better option. Phasing out phenytoin and phenobarbitone was successful. Valproate serum levels did not contribute significantly to the conduct of the study; no general relationship between valproate serum levels and either seizure control or toxicity could be demonstrated.     

AED use in businesses, public facilities and homes by minimally trained first responders

BACKGROUND: Automated external defibrillators (AEDs) have become increasingly available outside of the Emergency Medical Systems (EMS) community to treat sudden cardiac arrest (SCA). We sought to study the use of AEDs in the home, businesses and other public settings by minimally trained first responders. The frequency of AED use, type of training offered to first responders, and outcomes of AED use were investigated. In addition, minimally trained responders were asked if they had encountered any safety problems associated with the AED. METHODS: We conducted a telephone survey of businesses and public facilities (2683) and homes (145) owning at least one AED for at least 12 months. Use was defined as an AED taken to a medical emergency thought to be a SCA, regardless of whether the AED was applied to the patient or identified a shockable rhythm. RESULTS: Of owners that participated in the survey, 13% (209/1581) of businesses and 5% (4/73) of homes had responded with the AED to a suspected cardiac arrest. Ninety-five percent of the businesses/public facilities offered training that specifically covered AED use. The rate of use for the AEDs was highest in residential buildings, public places, malls and recreational facilities with an overall usage rate of 11.6% per year. In-depth interviews were conducted with lay responders who had used the AED in a suspected cardiac arrest. In the four cases where the AED was used solely by a lay responder, all four patients survived to hospital admission and two were known to be discharged from the hospital. There were no reports of injury or harm. CONCLUSIONS: This survey demonstrates that AEDs purchased by businesses and homes were frequently taken to suspected cardiac arrests. Lay responders were able to successfully use the AEDs in emergency situations. Further, there were no reports of harm or injury to the operators, bystanders or patients from lay responder use of the AEDs.     

So-called late epilepsy (author's transl)

411 patients with epileptic seizures manifest only after the age of 25 were investigated as to aetiology, seizure type and frequency and age and sex distribution. Neurological, neuro-radiological and EEG findings are reported: There was a clear prevalence of male patients (67%). Manifestation occurred mainly between 30 and 40 years of age (65%). Most seizures were primarily of the generalized grand mal type (68%). Grand mal with focal onset occurred in 13%, partial seizures in 11%, complex partial seizures (psychomotor seizures) in 5%, the latter plus grand mal seizures in 2% and other types in 1% of the cases. Aetiological factors were: chronic alcoholism (31%), vascular diseases (17%), tumours (12%), traumatic brain lesions (8,5%), toxic metabolic lesions (6%) and other factors (6%). Idiopathic epilepsy of late onset was a rare cause (4%). The aetiology remained unknown in 15% of cases. We found that the differences in age distribution, seizure type and the EEG findings are significant factors in the differential diagnosis and we compared them with those found in similar investigations.