Epileptic patients refractory to drug therapy

We compared two groups of patients with idiopathic epilepsy, 41 patients whose seizure frequency was not controlled by adequate therapy and 39 patients in good seizure control, in respect of hematology, kidney and liver function tests, serum IgG, IgA and IgM concentrations and drug concentrations. The only difference that emerged were in the serum immunoglobulins, which were raised in the drug refractory group, significantly (p less than 0.01) so in the case of IgG. Failure of seizure control did not depend on inadequacy of drug dose or of blood concentration. Although the serum Ig changes do not warrant the assumption of an immunological origin for drug resistance, they do suggest a useful research line.     

Epileptic patients who are refractory to anticonvulsant medications

To evaluate criteria that predict success or failure of currently available anticonvulsant medications, we studied 194 epileptic patients who were admitted to an intensive treatment unit. Seizures were present in the hospital in 78.3% and could not be controlled in 33.7%. Combinations of at least two of the following criteria were associated with limited treatment responses: multiple handicap (intellectual limitations or abnormal neurologic signs), different seizure types, cluster seizures, slowing of EEG background rhythms, and seizures discharges in the EEG despite adequate anticonvulsant blood levels. Presumed etiology was not associated with predictive ability. Patients who were neurologically and intellectually intact and had frequent clinical attacks, normal EEG background rhythms, and no seizure discharges usually had pseudoseizures.     

Epilepsy and antiepileptic drug therapy in juvenile neuronal ceroid lipofuscinosis

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

Oxcarbazepine treatment of refractory bipolar disorder: a retrospective chart review

Objective: To determine if oxcarbazepine is effective as treatment for refractory bipolar illness in a naturalistic setting.

Methods: All charts of out-patients treated with oxcarbazepine (n=13) were reviewed and clinical response assessed retrospectively using the Clinical Global Impression of Improvement (CGI-I) rating scale. All patients had failed treatment with at least one previous mood stabilizer.

Results: Mild improvement was seen in 46% (n=6) and moderate improvement in 16% (n=2). Fifty-four percent (n=7) of the total sample discontinued treatment because of adverse effects.

Conclusion: Oxcarbazepine may possess mild to moderate mood-stabilizing properties in this refractory, mostly depressed, bipolar sample. This naturalistic study is limited by its uncontrolled nature.     

Cost-effectiveness of add-on therapy with pregabalin in patients with refractory partial epilepsy

PURPOSE: To estimate the cost-effectiveness of pregabalin as add-on therapy in patients with refractory partial epilepsy. METHODS: We developed a model to estimate clinical and economic outcomes over 1 year in a hypothetical cohort of patients with refractory partial epilepsy assumed alternatively to receive add-on therapy with pregabalin (300 mg/day) or no add-on therapy. For each patient in the model, we estimated the occurrence of seizure and side effects, using techniques of stochastic simulation. We assigned health-state utilities to each day of follow-up based on whether or not seizure or side effects were predicted to occur. Patients could discontinue therapy due to lack of efficacy or side effects. Outcomes included expected numbers of days without seizure ("seizure-free [SF] days"), quality-adjusted life-years (QALYs), and costs of therapy. Cost-effectiveness was assessed alternatively in terms of incremental cost per SF day gained and incremental cost per QALY gained. RESULTS: Add-on therapy with pregabalin was estimated to result in an average gain of 23.8 SF days over one year; the estimated additional cost of therapy was $678. Incremental cost (mean, 95% CI) per SF day gained was $28.45 ($27.25, $29.44); corresponding estimates of incremental cost per QALY gained were $52,893 ($49,249, $56,983). CONCLUSIONS: In patients with refractory partial epilepsy, the cost-effectiveness of pregabalin 300 mg/day compares favorably with published estimates of cost-effectiveness for other add-on antiepileptic drugs.     

Cutaneous adverse drug reaction in patients with epilepsy after acute encephalitis

Patients with epilepsy after encephalitis/encephalopathy (EAE) often have refractory seizures, resulting in polytherapy with the risk of adverse reactions due to anti-epileptic drugs (AEDs). We focused on the characteristics of cutaneous adverse reaction (CAR). In this retrospective study, the medical records of 67 patients who were diagnosed as having EAE in our hospital were reviewed and the clinical characteristics were analyzed. Immunological biomarkers including cytokines, chemokines, granzyme B, soluble tumor necrosis factor receptor 1 (s-TNFR 1), matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1) were measured in 22 patients. CARs attributed to AEDs were observed in 16 of 67 EAE patients (23.9%) (CAR group). High CAR rates were observed with phenytoin, lamotrigine, phenobarbital, and carbamazepine. Severe CARs were found in three of 67 patients (4.5%). The frequencies of CARs were significantly higher in patients with encephalitis onset older than five years of age. CAR occurred only in patients who had onset of EAE within 6 months after encephalitis. The durations from acute encephalitis to CARs were within one year for almost all AEDs, except lamotrigine. The proportion of patients with serumregulated on activation normal T cell expressed and secreted (RANTES) levels higher than the upper limit of normal range was significantly higher in CAR group than in non-CAR group. Patients in the early stage of EAE and patients with encephalitis onset older than five years of age may be at higher risk of CARs to AEDs, especially to phenytoin, lamotrigine, phenobarbital, and carbamazepine. RANTES may be a biomarker for susceptibility to CARs in EAE patients.     

Antiepileptic effect and serum levels of clorazepate on children with refractory seizures

Clorazepate dipotassium is rapidly decarboxylated to yield desmethyl diazepam. The antiepileptic effect of clorazepate was studied in 29 epileptic children with refractory seizures. Their ages were ranged from one year 9 months to 20 years (mean 11 years 6 months). Serum clorazepate levels were also determined in 16 patients. The mean initial dose was 0.91 mg/kg/day, and the dose was increased up to 3 mg/kg/day. Within several days after initiation of clorazepate therapy, a decrease in seizure frequency was seen in patients in whom clorazepate was effective. Excellent results (decrease in seizure frequency by more than 80%) were obtained in 7 patients (24.1%), a moderate improvement with a 50 to 80% decrease was seen in 7 patients (24.1%), and a partial improvement with less than 50% decrease was seen in 7 patients (24.1%). No benefit was seen in 8 patients (27.7%). Serum clorazepate levels in patients with excellent results were 31 to 77 ng/ml (mean 55 ng/ml), those in patients with a moderate improvement were 130 to 225 ng/ml (mean 163 ng/ml), and those in patients with a partial improvement were 142 to 518 ng/ml (mean 273 ng/ml). Serum clorazepate levels in patients with no benefit were 34 to 97 ng/ml (mean 56 ng/ml). There was no direct relationship between serum clorazepate levels and clinical response. The results of this study indicate the efficacy of clorazepate for epileptic children with refractory seizures.     

难治性癫痫患者脑组织中耐药蛋白表达与卡马西平浓度的相关性

目的 通过对难治性癫痫患者脑组织中P-糖蛋白、肺耐药相关蛋白表达与卡马西平浓度的比较及相关性研究,探讨难治性癫痫耐药的机制.方法 选取2007年至2009年间于宣武医院功能神经外科行癫痫致痫灶切除术治疗且术前服用卡马西平半年以上的26例药物难治性癫痫患者的脑组织标本(其中局灶性皮质发育不良ⅠblO例、Ⅱa4例、Ⅱb2例,神经节细胞胶质瘤6例,胚胎发育不良性神经上皮瘤4例).应用Envision二步法进行免疫组织化学标记,观察两种耐药蛋白在脑组织中的表达部位和表达强度.应用Western blot法进行十二烷基硫酸钠-聚丙烯酰胺凝胶电泳,对两种耐药蛋白在脑组织病灶区域和病灶周围区域的表达分别进行定量分析.应用荧光偏振免疫分析法对病灶区域和病灶周围区域的卡马西平浓度进行测定.结果 P-糖蛋白在局灶性皮质发育不良Ⅱ型和难治性癫痫相关脑肿瘤病例的病灶区域表达(μg/ml)均高于病灶周围区域(分别是2.593±0.829和1.711±0.292,t=-2.201,P=0.028;1.352±0.445和1.179±0.593,t=2.698,P=0.028).肺耐药相关蛋白在局灶性皮质发育不良Ⅱ型和难治性癫痫相关脑肿瘤病例的病灶区域表达(μg/ml)亦均高于病灶周围区域(分别是1.567±0.092和0.775±0.101,t=-2.516,P=0.024;1.091±0.239和0.825±0.297,t =3.997,P=0.003).卡马西平在难治性癫痫相关脑肿瘤病灶区域平均浓度(μg/ml)低于病灶周围区域(0.848±0.726和0.948±0.785,t=-3.056,P=0.014),在病灶区域卡马西平浓度低于病灶周围区域的8例中,病灶区域P-糖蛋白和肺耐药相关蛋白同时升高.但是P-糖蛋白、肺耐药相关蛋白表达量与难治性癫痫患者脑组织卡马西平浓度无显著的等级相关性.结论 耐药蛋白参与了难治性癫痫耐药的过程,同时提示癫痫的耐药是一个复杂的过程,不同病变可能有不同的机制参与了耐药过程.     

Predicting Serum Vitamin E Concentrations from the Age of Normal and Anticonvulsant Drug-Treated Epileptic Children Using Regression Equations

Serum vitamin E was assayed in 100 patients who were apparently normal, with no medical problems and on no medication, and whose ages ranged from 2 to 12 years. Serum vitamin E was also assayed in 100 patients with grand mal convulsive disorders, on anticonvulsants, but on no other drugs, with no gastrointestinal problems and in a similar age range. In the 100 control children, there was a tendency for serum vitamin E to increase with age. Serum vitamin E concentrations in 100 anticonvulsant drug-treated epileptic children were significantly lower than in the control group and did not increase with age. In the control group, a regression analysis was used to predict serum vitamin E concentrations in different age groups. This information would be useful for population and metabolic studies of serum vitamin E concentrations.     

A Psychosocial Approach to Epileptic Patients

Summary: A psychoeducational approach was taken with 174 epileptic patients. Using this approach, no family problems were recognized among patients with idiopathic generalized epilepsy (IGE) or among those with symptomatic generalized epilepsy (SGE). However, 11 patients with temporal lobe epilepsy (TLE) and 1 patient with non-temporal lobe epilepsy (non-TLE) did exhibit family problems indicating that such problems involving IGE or SGE cases can be prevented through educational programs using a psychoeducational approach. This fails, however, to prevent such problems for TLE or non-TLE cases. Furthermore, small group psychotherapy was given to 10 patients with intractable TLE. They were directed to make self-evaluations regarding therapeutic factors originally introduced by Yalom but specially modified for these particular patients. Relatively high evaluations were given on every factor when compared with the results of individual psychotherapy. These results point out the importance of providing such psychotherapeutic approaches as group psychotherapy and self-help groups in addition to educational programs in order to enhance the quality of life (QOL) of epileptic patients and their families.     

Characteristics of a large population of patients with refractory epilepsy attending tertiary referral centers in Italy

The characteristics of 1,124 consecutive adults and children with refractory epilepsy attending 11 tertiary referral centers in Italy were investigated at enrollment into a prospective observational study. Among 933 adults (age 16–86 years), the most common syndromes were symptomatic (43.7%) and cryptogenic (39.0%) focal epilepsies, followed by idiopathic (8.1%) and cryptogenic/symptomatic generalized (6.2%) epilepsies. The most common syndrome among 191 children was symptomatic focal epilepsy (35.1%), followed by cryptogenic focal (18.8%), cryptogenic/symptomatic generalized (18.3%), undetermined whether focal or generalized (16.8%), and idiopathic generalized (7.3%). Primarily and secondarily generalized tonic–clonic seizures were reported in 27.8% of adults and 16.8% of children. The most commonly reported etiologies were mesial temporal sclerosis (8.0%) and disorders of cortical development (6.2%) in adults, and disorders of cortical development (14.7%) and nonprogressive encephalopathies (6.8%) in children. More than three‐fourths of subjects in both age groups were on antiepileptic drug (AED) polytherapy.     

Antiepileptic drug therapy and its management in sudden unexpected death in epilepsy: a case-control study

PURPOSE: Because frequent seizures constitute a major risk factor for sudden unexpected death in epilepsy (SUDEP), the treatment with antiepileptic drugs (AEDs) may play a role for the occurrence of SUDEP. We used data from routine therapeutic drug monitoring (TDM) to study the association between various aspects of AED treatment and the risk of SUDEP. METHODS: A nested case-control study was based on a cohort consisting of 6,880 patients registered in the Stockholm County In Ward Care Register with a diagnosis of epilepsy. Fifty-seven SUDEP cases, and 171 controls, living epilepsy patients, were selected from the cohort. Clinical data including data on TDM were collected through medical record review. RESULTS: The relative risk (RR) of SUDEP was 3.7 (95% CI, 1.0-13.1) for outpatients who had no TDM compared with those who had one to three TDMs during the 2 years of observation. RR was 9.5 (1.4-66.0) if carbamazepine (CBZ) plasma levels at the last TDM were above and not within the common target range (20-40 microM). High CBZ levels were associated with a higher risk in patients receiving polytherapy and in those with frequent dose changes. Although the subgroup of patients with high CBZ levels was small (six cases of 33 with CBZ therapy), and the result should be interpreted with caution, no similar associations were demonstrated for phenytoin plasma levels and risk of SUDEP. No association was found between SUDEP risk and within-patient variation in AED levels over time. CONCLUSIONS: Polytherapy, frequent dose changes, and high CBZ levels as identified risk factors for SUDEP all point to the risks associated with an unstable severe epilepsy. It is unclear whether high CBZ levels per se represent a risk factor or just reflect other unidentified aspects of a severe epilepsy. Our results, however, prompt further detailed analyses of the possible role of AEDs in SUDEP in larger cohorts and suggest that reasonable monitoring of the drug therapy may be useful to reduce risks.     

Effect of dosage failed of first antiepileptic drug on subsequent outcome

Purpose: The recent definition of drug‐resistant epilepsy proposed by the International League Against Epilepsy (ILAE) stipulated failure of an adequate trial of two tolerated, appropriately chosen and used antiepileptic drug (AED) schedules to achieve seizure freedom. Doses failed were not specifically discussed. We explored the effect of the doses at which the first and second AED regimens failed on subsequent outcomes in a population of adults with newly diagnosed epilepsy followed for up to 20 years. Methods: Patients in whom epilepsy was diagnosed and the first AED prescribed between July 1, 1982 and April 1, 2006, were followed until March 31, 2008. Dosage at which an AED failed was categorized according to the World Health Organization’s defined daily dose (DDD) for each drug. Cumulative incidence curves for time to final seizure freedom (no seizure for at least 1 year on unchanged dosage at last follow up) were stratified by whether the first regimen was failed at doses above or below the 25%, 50%, or 75% cutoffs for the DDD of each AED. Key Findings: Among patients who had taken a second regimen (n = 327), those in whom the first AED failed at doses above the various cutoffs (particularly 50% and 75% DDD) had lower probability of becoming seizure‐free at last follow‐up (p = 0.06 for 25% DDD, p < 0.001 for both 50% and 75% DDD). The same difference was observed for patients who had taken a third regimen (n = 141; p = 0.23 for 25% DDD, p < 0.01 for 50% DDD; and p = 0.002 for 75% DDD). A trend to higher seizure‐free rate was observed in patients who had taken the third regimen when both the first and second regimens failed at <75% DDD. The difference remained significant after adjusting for covariates when using 50% DDD as the cutoff for patients who took a second regimen (hazard ratio 1.60, 95% confidence interval 1.08–2.37). Significance: Higher failure dosage of the first AED predicts poorer subsequent outcome. This methodology could be used to refine further the ILAE definition of drug‐resistant epilepsy by exploring the doses need to fail to provide an adequate AED trial.     

Peripheral neuropathy in children on long-term phenytoin therapy

Nerve conduction studies of the ulnar, median, posterior tibial, peroneal and sural nerves were performed in 21 epileptic children aged 6 to 17 years on long-term phenytoin therapy. Auditory brain stem evoked responses were obtained in 16 patients to evaluate the effect of phenytoin on central nervous system synapses. Of the 21 patients examined, 15 (71.4%) showed abnormal findings. The most frequent abnormality was slowed motor conduction velocity of the ulnar nerve (33.3%) and posterior tibial nerve (23.8%), followed by slowed sensory conduction velocity of the sural nerve (20%), lowered H/M ratio (14.3%), slowed motor conduction velocity of the peroneal nerve (14.3%) and of the median nerve (14.2%). A significant correlation was noted between the total dosage and duration of therapy with PHT and the reduction of motor conduction velocity in the posterior tibial nerve. Auditory brain stem evoked responses showed no significant differences in each peak latency between the patients and the normal control group. The study indicates that long-term phenytoin therapy can cause latent impairment of peripheral nerve function in children with no clinical evidence of peripheral neuropathy.     

Comparison of antiepileptic drug levels in sudden unexpected deaths in epilepsy with deaths from other causes

PURPOSE: (a) To compare postmortem antiepileptic drug (AED) levels in patients with sudden unexpected death in epilepsy (SUDEP) with those in a control group of subjects with epilepsy. If SUDEP patients more frequently had undetectable or subtherapeutic AED levels, this would suggest that compliance with AED treatment is poorer in this group and that poor compliance is a risk factor for SUDEP. (b) To determine whether a particular AED was detected more commonly in the SUDEP group, suggesting that this AED is associated with a higher risk of SUDEP. METHODS: A retrospective study of coronial cases was performed. Postmortem AED levels in 44 SUDEP cases and 44 control cases were compared. The control group consisted of epileptics who died of causes other than epilepsy, including natural disease (e.g., ischemic heart disease, accidents, and suicide). The AEDs measured included carbamazepine (CBZ), phenytoin, (PHT), valproate (VPA), phenobarbitone (PB), lamotrigine (LTG), clonazepam (CZP), and clobazam (CLB). The number of SUDEP and control cases in which CBZ only was detected were compared, as were the number in which PHT only was detected. RESULTS: Compared with the controls, the SUDEP group showed no difference in the number with no detectable AEDs (13 vs. 11), the number with subtherapeutic AEDs (10 vs. 13), and the number with therapeutic levels (21 in both groups). CBZ only was detected in 11 SUDEPs and 11 controls, and PHT only in five SUDEPs and 10 controls. CONCLUSIONS: Our study suggests the SUDEP group were no less compliant with AED treatment than the control group. This study does not support the hypothesis that poor compliance with AED treatment is a risk factor for SUDEP. There was no evidence that PHT or CBZ is associated with a higher risk of SUDEP.     

Conversion disorder and coexisting nonepileptic seizures in patients with refractory seizures

Nonepileptic seizures (NES) are commonly observed in patients with seizures resistant to antiepileptic drugs (AEDs). However, NES may be symptomatic of different diagnoses, in particular, conversion disorder (CD) and coexisting NES and epileptic seizures (CENES). We compared the clinical characteristics of these disorders in 219 patients with refractory seizures. The prevalence of NES was similar in children (11%) and adults (16%). In both groups, CENES represented the most frequent cause of NES (75%). In adults, CD was associated with a shorter duration of illness and normal neuroimaging and interictal EEG compared with the other groups. Patients with CD represented one-quarter of all patients with AED-resistant seizures with normal presentation during interictal investigations. In both children and adults with AED-resistant seizures, NES are frequently observed and are three times more likely to be CENES than CD.     

Suboptimal anti-epilepsy drug use is common among Indigenous patients with seizures presenting to the emergency department

We aimed to explore the causes of higher than expected rates of Indigenous emergency department (ED) seizure presentations. A questionnaire was administered to adult patients presenting with seizure to an ED in Far North Queensland. Over 15 months, among 260 presentations with seizure (22% Indigenous), 50% non-Indigenous patients, and 45% Indigenous patients completed the questionnaire. Risk factors for alcohol misuse were common in both groups (50% Indigenous, 43% non-Indigenous; p = 0.50), as were rates of reported head injury (50% Indigenous, 44% non-Indigenous; p = 0.50). However, 47% Indigenous patients, compared to 19% non-Indigenous patients (p < 0.05) reported missing anti-epileptic tablets at least twice weekly, representing clinically relevant medication non-adherence. This was the first reported seizure presentation for 12% Indigenous patients and 26% non-Indigenous patients. We conclude that among ED seizure presentations, alcohol excess and prior head injury are commonly observed, in both Indigenous and non-Indigenous patients. However, Indigenous patients have higher rates of anti-convulsant non-adherence, likely contributing to ED presentations.     

Relationship between adverse effects of antiepileptic drugs,number of coprescribed drugs,and drug load in a large cohort of consecutive patients with drug‐refractory epilepsy

Purpose: To evaluate the adverse effects (AEs) of antiepileptic drugs (AEDs) in adults with refractory epilepsy and their relationship with number of coprescribed AEDs and AED load. Methods: Patients with refractory epilepsy were enrolled consecutively at 11 tertiary referral centers. AEs were assessed through unstructured interview and the Adverse Event Profile (AEP) questionnaire. AED loads were calculated as the sum of prescribed daily dose (PDD)/defined daily dose (DDD) ratios for each coprescribed AED. Results: Of 809 patients enrolled, 709 had localization‐related epilepsy and 627 were on polytherapy. AED loads increased with increasing number of AEDs in the treatment regimen, from 1.2 ± 0.5 for patients on monotherapy to 2.5 ± 1, 3.7 ± 1.1, and 4.7 ± 1.1 for those on two, three, and ≥4 AEDs, respectively. The number of spontaneously reported AEs correlated with the number of AEs identified by the AEP (r = 0.27, p < 0.0001). AEP scores did not differ between patients with monotherapy and patients with polytherapy (42.8 ± 11.7 vs. 42.6 ± 11.2), and there was no correlation between AEP scores and AED load (r = ?0.05, p = 0.16). Conclusions: AEs did not differ between monotherapy and polytherapy patients, and did not correlate with AED load, possibly as a result of physicians’ intervention in individualizing treatment regimens. Taking into account the limitations of a cross‐sectional survey, these findings are consistent with the hypothesis that AEs are determined more by individual susceptibility, type of AEDs used, and physicians’ skills, than number of coprescribed AEDs and AED load.     

A Case of Anorexia Nervosa Associated with Epileptic Seizures Showing Favorable Responses to Sodium Valproate and Clonazepam

Abstract: We reported the case of a 13-year-old anorectic girl with epileptic seizures who showed marked favorable responses to sodium valproate and clonazepam. These two anticonvulsants were effective not only for controlling her epileptic seizures, but also against anorexia nervosa itself. The mechanism of their action to anorexia nervosa is unknown, but Fepeated EBGs and a trial of sodium valproate with or without clonazepam may be useful in evaluating the diverse pathologies of anorexia nervosa which seems to be a heterogeneous clinical entity.