Primidone improves symptoms in TRPM3-linked developmental and epileptic encephalopathy with spike-and-wave activation in sleep.

Developmental and epileptic encephalopathy with continuous spike-and-wave activation in sleep (CSWS) or DEE-SWAS is an age-dependent disease, often accompanied by a decline in cognitive abilities. Early successful treatment of CSWS is associated with a better cognitive outcome. We retrospectively analyzed the clinical, electrophysiological, radiological, and genetic data of children with DEE-SWAS associated with melastatin-related transient receptor type 3 gene (TRPM3) missense variants. We report two unrelated children with pharmacoresistant DEE-SWAS and developmental delay/regression and different heterozygous de novo missense variants in the TRPM3 gene (NM_001366145.2; c.3397 T > C/p.Ser1133Pro, c.2004G > A/p.Val1002Met). The variant p.Val1002Met (previously known as p.Val990Met or p.Val837Met) and p.Ser1133Pro were recently shown to result in a gain-of-function effect. Based on this finding, previous drug resistance, and the experimentally demonstrated inhibitory effect of primidone on TRPM3, we initiated an individualized therapy with this drug. In both children, developmental regression was stopped, psychomotor development improved, and CSWS was no longer detectable. To our knowledge, this is the first report of a treatment with primidone in TRPM3-associated CSWS. Our results highlight the importance of early genetic diagnosis in patients with epilepsy and the possibility of precision medicine, which should be considered in the future in individuals with a TRPM3-linked DEE-SWAS.

[Diagnosis and treatment of tremor in Parkinson's disease and essential tremor]. / Benigner Tremor oder Morbus Parkinson? Die Abgrenzung ist für die Therapie entscheidend.

For patients presenting predominantly or purely with tremor, the correct diagnosis of tremor-dominant Parkinson's disease (PD) versus essential tremor (ET) is very important for prognosis and effective therapy. ET tremor is usually characterized by symmetric bilateral postural and kinetic tremor, which may respond to low alcohol consumption. Many patients have a family history of ET tremors. Medical treatment with primidone or beta-blockers effectively controls ET tremor, but in many cases no treatment is needed at all. The typical tremor form of PD is an asymmetric rest tremor, which is treated with dopaminergic agents such as levodopa. Differential diagnosis of ET and PD may be difficult in a subset of PD patients who present with additional postural and kinetic tremor and in a minority of ET patients who show a clear asymmetry of their postural and kinetic tremor. In some patients with ET, the tremor can later become severe and even require treatment with deep brain stimulation.

Therapeutic monitoring of antiepileptic drugs for epilepsy.

BACKGROUND: The aim of drug treatment for epilepsy is to prevent seizures without causing adverse effects. To achieve this, drug dosages need to be individualised. Measuring antiepileptic drug levels in body fluids (therapeutic drug monitoring) is frequently used to optimise drug dosage for individual patients. OBJECTIVES: To review the evidence regarding the effects of therapeutic drug monitoring upon outcomes in epilepsy. SEARCH STRATEGY: We searched the Cochrane Epilepsy Group Specialised Register (September 2006), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2005, Issue 4), MEDLINE (January 1966 to April 2005) and EMBASE (1974 to May 2005). No language restrictions were imposed. We checked the reference lists of retrieved articles for additional reports of relevant studies. SELECTION CRITERIA: Randomised controlled trials comparing the outcomes of antiepileptic drug monotherapy guided by therapeutic drug monitoring with drug treatment without the aid of therapeutic drug monitoring. DATA COLLECTION AND ANALYSIS: We based this review on published aggregate data. The main outcomes measured were the proportions of patients achieving a 12-month remission from seizures, reporting adverse effects, and being withdrawn from the treatment they had been randomised to receive. MAIN RESULTS: Only one study met the inclusion criteria for the review. In this open study, 180 patients with newly-diagnosed, untreated epilepsy were randomised to treatment with the antiepileptic drug selected by their physician either with or without therapeutic drug serum level monitoring as an aid to dosage adjustments. The antiepileptic drugs used were carbamazepine, valproate, phenytoin, phenobarbital and primidone. A 12-month remission from seizures was achieved by 60% of the patients randomised to therapeutic drug monitoring (intervention group) and by 61% in the control group. A total of 56% in the intervention group and 58% in the control group were seizure free during the last 12 months of follow up. Adverse effects were reported by 48% in the intervention group and 47% of the control group patients. Of those randomised to therapeutic drug monitoring, 62% completed the two-year follow up compared with 67% of the control group. AUTHORS' CONCLUSIONS: We found no clear evidence to support routine antiepileptic drug serum concentration measurement with the aim of reaching predefined target ranges for the optimisation of treatment of patients with newly-diagnosed epilepsy with antiepileptic drug monotherapy. However, this does not exclude the possible usefulness of therapeutic drug monitoring of specific antiepileptic drugs during polytherapy, in special situations or in selected patients, although evidence is lacking.

[Tremor]. / Tremor.

Tremor is one of the most frequent neurological signs. The correct clinical classification is mainly clinical. The most frequent primarily neurological tremor is essential tremor (prevalence 2 to 5%). It presents in most cases as a more or less symmetrical postural and kinetic tremor. In about 60% of cases an autosomal-dominant inheritance is found. Tremor may manifest not only in the hands but also in the head and voice. In about 60 to 70% of the patients alcohol may improve the tremor. Parkinsonian tremor is normally a tremor at rest and it starts asymmetrically. The legs and the face are frequently involved. Cerebellar tremor is intentional. Orthostatic tremor, which has a high frequency, mainly manifests in the legs and gives rise to postural instability. Dystonic tremor is an action tremor of the affected region of the body. Drug therapy, which is purely symptomatic, mostly depends on clinical manifestation. Postural and action tremors respond to non selective betablockers (propranolol), primidone, some antiepileptics (gabapentin, toparimate) and benzodiazepines. Classical rest tremors are improved by dopaminergic substances (levodopa, dopamine agonists) or anticholinergics. Dystonic tremor may successfully be treated by injections of botulinum toxin. Orthostatic tremor responds to gabapentin or benzodiazepines in some of the patients. In severely handicapped patients with refractory tremors the implantation of thalamic stimulation electrodes may be considered. This treatment may be very successful, however, its inherent risks have to be taken into account.

Determination of levetiracetam in human plasma with minimal sample pretreatment.

We here present a method for the routine quantification of the novel antiepileptic drug levetiracetam in human serum by HPLC-UV. The procedure is very easy, quick, inexpensive and rugged. The sample preparation consists only in the precipitation of serum proteins by perchloric acid and extraction of unpolar components by cyclohexane. The aqueous phase containing the analyte levetiracetam is injected onto a porous graphitic carbon analytical HPLC-column and separated by gradient elution with diluted phosphoric acid/acetonitrile. Detection is carried out at a wavelength of 205 nm. The calibration function is linear in the range of 1-75 microg/ml. The detection limit is 0.1 microg/ml. Using four quality control sample concentrations, the inter-day relative standard deviations (R.S.D.) are lower than 3% and the accuracies are better than 6%. The respective inter-day values are: R.S.D. < 4% and accuracies better than 2%. Frequently co-administered antiepileptic drugs do not interfere with the assay. The method has been successfully applied to patient samples.

Use of primidone in low doses (250 mg/day) versus high doses (750 mg/day) in the management of essential tremor. Double-blind comparative study with one-year follow-up.

Essential tremor is the most common involuntary movement; we studied 113 affected subjects (54 men, 59 women) with an average age of 63.9 years and average duration of 9.05 years. These patients participated in a double-blind study with a 1-year follow-up to compare treatment efficiency using primidone dosages of 250 mg/day (G 250, 56 patients) versus 750 mg/day (G 750, 57 patients). The study was designed with an 80% power and 95% confidence level. The statistical analysis used was an ANOVA (with Bonferroni multiple comparison test corrections); a value of p<0.004 was accepted as significant. To compare other values, a chi-square test was used; p<0.05 was considered significant. To evaluate the efficacy of the drug, clinical protocol employed the 'clinical evaluation scale for tremor'. All of the patients were evaluated a total of 13 times, once prior to the introduction of primidone and the other 12 evaluations following the initiation of the treatment. Eighty-seven patients completed the study: 15 patients abandoned the study due to undesirable side effects, five due to negative response, and six who were lost to follow-up. The percentage of patients who didn't complete the study was significantly higher in the group that received 750 mg/day of primidone (p<0.04) and more frequent as well in this same group, due to undesirable side effects (p<0.03). The patients of both G250 and G750 showed a significant improvement in each of the controls compared to the basal value (p<0.0001). No significant differences (p<0.06) were found when the averages of the evaluations of each group were compared. These responses were maintained during the entire treatment period. Low doses of primidone (250 mg/day) were equally or more effective than high doses (750 mg/day) in the control of essential tremor; this response was maintained for 12 months and furthermore, demonstrated fewer undesirable effects.

[Evaluation of antiepileptic therapy during pregnancy]. / Ocena terapii przeciwpadaczkowej w okresie ciazy.

OBJECTIVE: The aim of the study was to analyse the course of pregnancy and labour in women with epilepsy. MATERIAL AND METHODS: The study was carried out on 53 pregnant women with epilepsy who delivered in the Department of Obstetrics and Perinatology of the University School of Medicine in Lublin (group E). RESULTS: In the group of women with epilepsy there were observed more pregnancy complications. The mean birth weight of infants and the condition of the infant after birth evaluated were lower in the study group E according to Apgar score. The increased risk of congenital malformations and intrauterine foetal growth retardation were observed in children exposed to valproate or carbamazepine in monotherapy or combination of phenobarbital and phenytoin and the combination of phenobarbital, phenytoin and primidone in polytherapy. CONCLUSION: Women with epilepsy require appropriate pregnancy planning and appropriate neurologic and obstetric care preconceptionally and during pregnancy.

Randomized trial comparing primidone initiation schedules for treating essential tremor.

Early side effects are common when primidone is used to treat essential tremor, with as many as one-third of patients failing to tolerate the tablets. Lower doses can be prescribed initially using a suspension formulation. We suspected suspension initiation would result in fewer early side effects, allow better acclimatization, and improve compliance. Forty patients with essential tremor were randomized to begin primidone treatment using either 2.5 mg doses in the suspension form or 25 mg doses in the tablet form. Doses gradually increased over 3 weeks to 150 mg/day. This was a double-blind, double-dummy trial. Medication cessation due to side effects was designated the primary end-point. Four patients in the suspension group and two in the tablet group dropped out due to early side effects, resulting in a relative risk of 1.9 (95% confidence interval 0.4 to 9.2). Side effects in the first 48 hours of treatment were equally common, affecting seven subjects in each group. Treatment benefits were the same in both groups. We concluded that use of a very low initial dose and a graduated titration schedule in suspension formulation did not appear to improve primidone tolerability. If anything, compliance tended to be worse when compared with the tablet formulation, though the study was under-powered to reject the null hypothesis of equivalence.

Clinical and electromyographic assessment of essential tremor treatment.

It is a matter of debate whether beta-blockers or primidone have a better influence on essential tremor. It is also controversial whether essential tremor with synchronous electromyographic activity is influenced by the administration beta-blockers, while tremor with alternating electromyographic activity is influenced by primidone. The aim of this study was to reevaluate the effects of beta-blockers and primidone on essential tremor. We also aimed to evaluate the differential effects of beta-blockers and primidone on tremor with synchronous or alternating electromyographic activity and on tremor in different limb positions. One hundred patients (57 female, 43 male) with essential tremor were included in this study. According to the electromyographic pattern recorded from the antagonistic muscles, the patients were subdivided into group with synchronous (SYN) and group with alternating (ALT) activity. After the initial clinical and electromyographic examinations the patients were randomly assigned first to treatment with propranolol (180 mg daily), or to treatment with primidone (500 mg daily) for 30 days. After a washout period of 20 days the patients were assigned to the other treatment. Our results revealed that the effects of propranolol and primidone on essential tremor and on SYN or ALT tremor were similar. Differences between both drugs existed as regards to better primidone influence on the kinetic and intention tremors and to tremor localized outside the limbs. In conclusion it is better to treat patients with kinetic and intention essential tremor and tremor localized outside the limbs with primidone.

[Febrile convulsions, Treatment and prognosis]. / Feberkramper. Behandling og prognose.

Epidemiological data indicate that the long-term prognosis in the vast majority of children with febrile seizures is good. Three main problems are important for the treatment: febrile seizures are extremely upsetting for the parents, the recurrence rate is 30-40% and the febrile status occurs unpredictably and is potentially damaging to the CNS. There is universal agreement that daily prophylaxis with valproate, primidone, or phenobarbital should only be used in highly selected cases, if at all. The effectiveness of phenytoin and carbamazepine has not been documented. Antipyretic treatment does not reduce the recurrence rate. Intermittent diazepam prophylaxis at times of fever may or may not reduce the recurrence rate significantly, but there is no data to suggest that it improves the long-term outcome, as compared with short-term seizure control, in terms of IQ, cognition, academic progress, motor control, and subsequent epilepsy. Acute anticonvulsive treatment with rectal diazepam in solution or other benzodiazepines is effective in aborting recurrent seizures with almost the effectiveness of i.v. treatment and is safe, simple, and easy to use for the parents. The long-term prognosis is probably uninfluenced by the type of treatment given in early childhood. It has not been established that acute anticonvulsive treatment with benzodiazepine is better than placebo.

Effects of encapsulation of primidone on its oxidative metabolism in rats.

The aim of this study was to evaluate the influence of primidone (PRM) nanoencapsulation on its metabolism. Suspensions of PRM powder and PRM-loaded poly-epsilon-caprolactone nanocapsules were administered orally in the same way to rats. Primidone-loaded poly-epsilon-caprolactone nanocapsules were prepared according to the interfacial deposition technique. Free PRM suspensions were obtained by addition of PRM powder to a suspension of 0.212% carboxymethylcellulose CMC 12H in water. The dose was 20 mg/kg, n = 6, for each experiment. Urinary and faecal levels of PRM and of its three major metabolites, phenylethylmalonamide (PEMA), phenobarbital (PB), and p-hydroxyphenobarbital (p-HO-PB), were determined. Concentrations were evaluated by high-performance liquid chromatography (HPLC) according to a validated analytical method. After PRM nanocapsule administration, non-metabolised PRM urinary levels were increased compared to those observed after administration of a suspension of primidone powder (43.7+/-8.8% after PRM-loaded nanocapsule and 37.7+/-8.1% after free PRM administration). For phenylethylmalonamide, no difference was observed in urinary excretion in the two cases. For two of the oxidised metabolites, PB and p-HO-PB, excretion was delayed and shortened. The amount of these oxidised metabolites was lowered from 0.95% after free PRM administration to 0.25% after PRM-loaded nanocapsule administration. No difference was noted in non-metabolised primidone excretion in faeces. These results suggest that primidone-loaded nanocapsules could be used as a vehicle for oral primidone administration in order to minimise the phenobarbital metabolic pathway.

Tremor ortostático primário: relato de quatro casos / Primary orthostatic tremor: report of 4 cases

Relatamos quatro casos de tremor ortostático primário. O motivo do relato está na raridade da doença e no seu diagnóstico diferencial com outros tremores, muitas vezes confuso. Nossos casos foram estudados eletrofisiologicamente e a frequência dos tremores variou entre 15 e 20 Hz. Existem diferenças clínicas, eletrofisiológicas e terapêuticas entre o tremor ortostático primário e outros tremores de membros inferiores, de acordo com a literatura e com as características de nossos quatro casos.

Childhood head tremor.

We report here four children (three girls, one boy) with head tremor followed longitudinally, ages 15 months to 11 years, with follow-up over 1 to 8 years. Each demonstrated onset of head tremor between the ages of 5 and 10 months. In each case head tremor was characterized by a predominant "yes-yes" or "no-no" movement of the head. In two of the children the movement was slightly skewed with chin movement toward the shoulder. Oscillations were at a frequency of about 1 to 2 Hz. They were accentuated when sitting upright without head support, increased at times of movement, and dissipated while lying flat or sleeping. The children were unable to voluntarily suppress the action and did not experience any sensation of movement. Three of the children had shuddering spells prior to onset of head tremor. Two children have developed mild dystonic posturing of the legs when intently concentrating. Their general and neurologic examinations were normal. Normal investigations included brain magnetic resonance imaging and computed tomography, urine amino acids and organic acids screening, serum lactate, erythrocyte sedimentation rate, antinuclear antibodies, and ceruloplasmin and copper levels. A family history of tremor was present in two children, maternal epilepsy in one child, and infantile shuddering occurred in the father of one child. Therapy included trials of selective and nonselective beta-adrenergic blockers, alpha-adrenergic agonists, anticholinergics, anticonvulsants, and amantadine. One child responded well to both timolol and trihexyphenidyl. A second child responded moderately to primidone. Two have not been treated. Two have had head tremor spontaneously remit. We conclude from this small series of children with head tremor that it can evolve from a prior history of shuddering spells, occurs in the context of a positive family history of tremor, and can be accompanied by the development of a mild dystonia. Therapeutic response is variable to multiple agents. Spontaneous remission occurs, suggesting a benign course.

Lack of in vivo/in vitro correlations for 50 mg and 250 mg primidone tablets.

PURPOSE: To determine if large differences in the in vitro dissolution profiles for primidone tablets would result in significant bioavailability differences. METHODS: Two separate bioavailability studies were conducted. The first study used 18 healthy subjects and compared the bioavailability of an old 50 mg tablet formulation, a new 50 mg tablet formulation, and a suspension containing 50 mg/ml of primidone. The second study enrolled 24 subjects who were to receive a new 250 mg tablet formulation, two lots of an old 250 mg tablet formulation and a 250 mg tablet from a second manufacturer. In vitro dissolution was conducted over 90 minutes, using USP 23 Apparatus 2 at 50 rpm, with 900 ml of water. RESULTS: Dissolution at 90 minutes for the old and new 50 mg tablets was approximately 20% and 100%, respectively. The dissolution of the four 250 mg tablets ranged from approximately 30% to 100%. The 50 mg tablet that dissolved slower had a longer Tmax and a 14% lower Cmax than the more rapidly dissolving tablet, but the AUC(0-infinity) values differed by only 3%. Only nine subjects completed the 250 mg study because of side effects. The differences in Cmax and AUC(0-infinity) among the four 250 mg tablets were less than 7%. CONCLUSIONS: Even though there were large differences in the in vitro dissolution of the 50 mg and the 250 mg primidone tablets, the two 50 mg tablets were shown to be bioequivalent, as were the four 250 mg tablets.

Rapid switchover to carbamazepine using pharmacokinetic parameters.

PURPOSE: The standard practice of switching patients to carbamazepine (CBZ) involves initiating a low dose and raising it by small increments until the desired dose is reached, to avoid intolerable adverse effects (AE). In a pilot study, a protocol using single-dose kinetic studies was developed to switch patients to CBZ through rapid-dose increments and to manage concurrent rapid taper of the previous antiepileptic drugs (AEDs) without causing AE. The purpose of this prospective study was (a) to reassess whether a rapid switchover to CBZ could be done with minimal or no AE and without causing an increase in seizures; (b) to determine whether the maintenance dose of CBZ predicted at the time of the single-dose kinetic study can yield the desired concentration at steady state (Css); and (c) to determine the degree to which the calculated maintenance dose of CBZ will need to be adjusted after the previous AED has been discontinued for a four-week period. METHODS: Twenty-five patients taking phenytoin (PHT) and/ or phenobarbital (PB) and/or primidone (PRM) underwent a rapid switchover to CBZ following a 10 mg/kg single-dose kinetic study (day 1) which allowed calculation of a maintenance dose necessary to yield a mean Css of 10.2 (+/-2.2) mg/l. On day 2, patients received a CBZ dose equivalent to 10 mg/kg + 200 mg; thereafter, they underwent daily dose increments of 200 mg until the calculated maintenance dose was reached. Dose increments were modified in the case of AE. Concurrent tapering of the previous AED was started as of day 1: PHT by 100 mg/day, while PB and PRM were stopped on day 1; PB was restarted before patients were to be discharged from the hospital if a PB serum concentration above 10 mg/l was identified at that time. Pharmacokinetic data and occurrence of AE were compared between the two groups at the time of the single-dose kinetic study, at the completion of the switchover to CBZ, and 4 weeks after discontinuation of the previous AED. RESULTS: All patients completed the switchover to CBZ within a mean time period of 6 days (+/-2), reaching a mean maintenance dose of 1,639 mg/day (+/-370) which yielded a mean Css of 11.3 (+/-3.2) mg/l. The maintenance dose had to be lowered by 20.4% (+/-8.3) in 59% of patients within the four-week period following discontinuation of at least one of the previous AEDs. None of the patients experienced an increase in seizure frequency relative to baseline. Fifteen (60%) patients had no AE; five (20%) experienced AE of mild severity. AE rated as moderately severe (n = 4) or severe (n = 1) occurred in patients with a static encephalopathy (p = 0.02, Fisher's exact test) and among patients > or =55 years (p = 0.017, Fisher's exact test). CONCLUSIONS: A rapid switch-over to CBZ from PHT, PB, or PRM can be carried out safely with no, or minimal, AE in young adults, unless they suffer from static encephalopathy.

Outcome evaluation of gabapentin as add-on therapy for partial seizures. "NEON" Study Investigators Group. Neurontin Evaluation of Outcomes in Neurological Practice.

OBJECTIVE: The safety, tolerability, efficacy, and impact on quality of life of gabapentin (Neurontin) as adjunctive therapy to carbamazepine (CBZ) and/or phenytoin (PHT) was assessed in epileptic patients with partial seizures. METHODS: NEON (Neurontin Evaluation of Outcomes in Neurological Practice) was an open-label, prospective, multicentre study conducted in patients on a stable dose of CBZ and/or PHT and experiencing an average of up to 4 complex partial seizures with or without secondary generalization per month, with no seizure-free months. The treatment lasted 20 weeks. Gabapentin was started at 400 mg/day and was individually titrated to effective tolerable dose up to 2400 mg/day. Quality of life was evaluated using the QOLIE-10 questionnaire. RESULTS: A total of 141 patients were enrolled at 36 sites; 114 patients were evaluable for efficacy analyses. The mean maintenance dose of gabapentin was 1600 mg/day (range = 300-3200). A decrease of 50% or more in frequency of complex partial + secondary generalized seizures was observed in 81 (71%) patients (p = 0.0001). Fifty two (46%) patients were seizure-free during the last 8 weeks of treatment. A significant improvement (p < 0.05) was observed in 5 of the 10 questions of the QOLIE-10, as well as in the composite QOL score (p = 0.0002). The most frequent adverse events included somnolence (16%), dizziness (9%), and asthenia (6%). Twenty-five (18%) patients prematurely discontinued the study, 16 (11%) of them due to adverse events. CONCLUSIONS: This study indicates that treatment with gabapentin as adjunctive therapy to standard antiepileptic drugs in this group of patients not only provides significant improvement in seizure control, but also has a positive impact on quality of life. The clinical benefits in efficacy, safety and tolerability demonstrated at 20 weeks are sustained, and no tolerance develops with gabapentin in longer term use.

Epilepsia na infância e adolescência / Epilepsy in infancy, childhood and adolescence

Os jovens, ainda mais as crianças, são particularmente susceptíveis às crises epiléticas. Em uma estreita faixa etária, os mais diferentes tipos de crises e síndromes podem se apresentar, com diversidade clínica, etiológica e prognóstica. Esta revisão sumariamente aborda várias dessas questões: etiologia, tipos de crises nos diferentes períodos em seus aspectos clínicos, eletroencefalográficos e prognósticos, além dos terapêuticos.