Associations between electroencephalography power and Alzheimer's disease in persons with Down syndrome.

BACKGROUND: It is complicated to diagnose dementia in persons with Down syndrome (DS). Older studies have, however, demonstrated low-frequency activity in electroencephalography (EEG) in persons with concurrent DS and Alzheimer's disease (DS-AD). The aim of this study was to examine whether it was possible to identify AD-associated changes (increased high-frequency power and decreased low-frequency power) in persons with DS-AD compared with DS. METHODS: We included 21 persons with DS-AD and 16 with DS without cognitive deterioration assessed by the informant-based Dementia Screening Questionnaire in Intellectual Disability. EEG was recorded for all participants. Absolute power for each electrode and global power were calculated for all frequency bands for both eyes open and eyes closed. RESULTS: For global power in the eyes closed condition, we found an increased global slow-frequency activity and a decreased global high-frequency activity in DS-AD compared with DS. In addition, we found a significant difference in the global alpha/delta ratio with the largest difference found for global alpha power in DS-AD compared with DS. CONCLUSIONS: In the current study, we found that changes known to be associated with AD could also be identified when comparing DS-AD with DS using quantitative EEG. In general, these findings suggest that EEG might be a useful tool in diagnosing AD in persons with DS, but larger studies are needed.

A prospective observational longitudinal study of new-onset seizures and newly diagnosed epilepsy in dogs.

BACKGROUND: Seizures are common in dogs and can be caused by non-epileptic conditions or epilepsy. The clinical course of newly diagnosed epilepsy is sparsely documented. The objective of this study was to prospectively investigate causes for seizures (epileptic and non-epileptic) in a cohort of dogs with new-onset untreated seizures, and for those dogs with newly diagnosed epilepsy to investigate epilepsy type, seizure type and the course of disease over time, including the risk of seizure recurrence. Untreated client-owned dogs experiencing new-onset seizures were prospectively enrolled in a longitudinal observational study including clinical investigations and long-term monitoring at the Copenhagen University Hospital for Companion Animals. A baseline clinical assessment was followed by investigator/owner contact every eight weeks from inclusion to death or end of study. Inclusion of dogs was conducted from November 2010 to September 2012, and the study terminated in June 2014. RESULTS: One hundred and six dogs were included in the study. Seventy-nine dogs (74.5%) were diagnosed with epilepsy: 61 dogs (77.2%) with idiopathic epilepsy, 13 dogs (16.5%) with structural epilepsy and five dogs (6.3%) with suspected structural epilepsy. A non-epileptic cause for seizures was identified in 13 dogs and suspected in 10 dogs. Four dogs in which no cause for seizures was identified experienced only one seizure during the study. In dogs with idiopathic epilepsy 60% had their second epileptic seizure within three months of seizure onset. Twenty-six dogs with idiopathic epilepsy (43%) completed the study without receiving antiepileptic treatment. The natural course of idiopathic epilepsy (uninfluenced by drugs) was illustrated by highly individual and fluctuating seizure patterns, including long periods of remission. Cluster seizures motivated early treatment. In a few dogs with a high seizure frequency owners declined treatment against the investigators advice. CONCLUSIONS: Epilepsy is the most likely diagnosis in dogs presenting with new-onset seizures. The course of idiopathic epilepsy is highly individual and might not necessarily require long-term treatment. This must be considered when advising owners about what to expect with regard to treatment and prognosis.

Drug taper during long-term video-EEG monitoring: efficiency and safety.

OBJECTIVES: Anti-epileptic drugs (AED) are often tapered to reduce the time needed to record a sufficient number of seizure during long-term video-EEG monitoring (LTM). Fast AED reduction is considered less safe, but few studies have examined this. Our goal is to examine whether the rate of AED reduction affects efficiency and safety. MATERIALS & METHODS: We performed a retrospective observational study of patients referred for presurgical evaluation. Each patient was categorized by two dichotomous parameters of AED tapering: (i) fast vs slow AED reduction the first 24 h of LTM and (ii) complete vs partial AED discontinuation during LTM. RESULTS: Of 79 patients, 51% underwent a fast AED reduction and 58% ended up with AEDs completely discontinued. Complete AED discontinuation was associated with three times increased likelihood of receiving rescue therapy during LTM and double risk of having secondary generalized tonic-clonic seizures (sGTCS) compared to the group partially discontinued. Fast vs slow AED reduction had no effect on the safety of LTM. The fast AED reduction group and the complete AED discontinuation group had a significantly longer time to first seizure and total recording time compared to the slow AED reduction and partial discontinuation groups, respectively. CONCLUSIONS: Fast AED reduction was found safe in patients undergoing presurgical video-EEG monitoring. Patients completely discontinued from AEDs had more sGTCS than patients partially discontinued. Further studies are suggested to confirm this finding and to evaluate whether fast reduction is safe and efficient in other subgroups of patients referred for LTM.

A single-blinded phenobarbital-controlled trial of levetiracetam as mono-therapy in dogs with newly diagnosed epilepsy.

Treatment of canine epilepsy is problematic. Few antiepileptic drugs have proven efficacy in dogs and undesirable adverse effects and pharmacoresistance are not uncommon. Consequently, the need for investigation of alternative treatment options is ongoing. The objective of this study was to investigate the efficacy and tolerability of levetiracetam as mono-therapy in dogs with idiopathic epilepsy. The study used a prospective single-blinded parallel group design. Twelve client-owned dogs were included and were randomised to treatment with levetiracetam (30 mg/kg/day or 60 mg/kg/day divided into three daily dosages) or phenobarbital (4 mg/kg/day divided twice daily). Control visits were at days 30, 60 and then every 3 months for up to 1 year. Two or more seizures within 3 months led to an increase in drug dosage (levetiracetam: 10 mg/kg/day, phenobarbital: 1 mg/kg/day). Five of six levetiracetam treated dogs and one of six phenobarbital treated dogs withdrew from the study within 2-5 months due to insufficient seizure control. In the levetiracetam treated dogs there was no significant difference in the monthly number of seizures before and after treatment, whereas in the phenobarbital treated dogs there were significantly (P = 0.013) fewer seizures after treatment. Five phenobarbital treated dogs were classified as true responders (≥50% reduction in seizures/month) whereas none of the levetiracetam treated dogs fulfilled this criterion. Adverse effects were reported in both groups but were more frequent in the phenobarbital group. In this study levetiracetam was well tolerated but was not effective at the given doses as mono-therapy in dogs with idiopathic epilepsy.

Algorithm for lamotrigine dose adjustment before, during, and after pregnancy.

BACKGROUND: Treatment with lamotrigine (LTG) during pregnancy is associated with a pronounced risk of seizure deterioration, because pregnancy accelerates LTG elimination. The extent to which pregnancy affects LTG pharmacokinetics is unpredictable and varies considerably among patients. AIM: We propose an algorithm for systematic LTG plasma concentration monitoring and dose adjustment to guide the clinician between the risk of seizure deterioration and LTG toxicity by maintaining a stable LTG concentration, using the optimal prepregnancy target concentration as a reference. METHODS: The reference LTG plasma concentration (RC) should be determined before pregnancy or as early in pregnancy as possible. After conception, plasma concentration of LTG should be measured every 4 weeks throughout pregnancy. When the LTG plasma concentration falls below the RC, the dose of LTG should be increased by 20-25%. Post-partum, the plasma concentration of LTG should be measured within the first or second week, and if the LTG plasma concentration is higher than the RC, the LTG dose should be reduced by 20-25% and the procedure repeated until RC is re-established. CONCLUSIONS: Seizure deterioration during pregnancy may be prevented or reduced by closely and systematically following our proposed algorithm.

Progressive anticonvulsant hypersensitivity syndrome associated with change of drug product.

This report describes the laboratory and physical manifestations of lamotrigine-like toxicity in a young man with refractory epilepsy receiving lamotrigine presenting as anticonvulsant hypersensitivity syndrome (AHS) associated with an abrupt change of drug product.

Valproate effects on kinetics of lamotrigine in pregnancy and treatment with oral contraceptives.

In eight women treated with lamotrigine monotherapy, the lamotrigine dose/plasma concentration (D/C) ratio increased by 295% from baseline outside pregnancy to midgestation, whereas in six women treated with lamotrigine in combination with valproate, the increase was only 60%. No difference in lamotrigine D/C ratio was found between users and nonusers of oral contraceptives comedicated with valproate. Valproate seems to reduce the induction of lamotrigine metabolism associated with pregnancy or use of contraceptives.

Epilepsy and pregnancy: lamotrigine as main drug used.

OBJECTIVES: To study the risk of teratogenicity in infants of women with epilepsy. MATERIAL AND METHODS: Prospective data from 1996 to 2000 comprised 147 pregnancies. The most frequent antiepileptic drugs (AEDs) used were lamotrigine (LTG) 35% (n = 51), oxcarbazepine (OXC) 25% (n = 37) and valproate (VPA) 20% (n = 30). Seventy-four per cent (n = 109) received monotherapy. Folic acid supplementation was taken during first trimester by 118 patients (80%). RESULTS: The overall risk of malformations among newborns in the AED-exposed group was 3.1% (n = 4). Two children were born with multiple malformations (VPA monotherapy), two children had ventricular septal defects (one OXC monotherapy, and one OXC and LTG). The risk of malformations was 2.0% in women treated with LTG and 6.7% in women treated with VPA (NS). CONCLUSION: Despite the small number of cases in the study these data indicate that treatment with LTG during pregnancy might be relatively safe. Larger prospective studies are needed to obtain adequate power for statistical analysis.

Lamotrigine plasma levels reduced by oral contraceptives.

Although it is known that the use of oral contraceptives (OC's) can induce glucuronide conjugating enzymes, currently no data exists as to the potential that the elimination of the glucuronidated drug lamotrigine (LTG) is increased by OC's. We present seven cases in whom the plasma levels of LTG were significantly decreased by OC's (mean 49%, range 41-64%). The interaction was of clinical relevance in most of the patients who either experienced increased seizure frequency/recurrence of seizures after OC's had been added, or adverse effects following withdrawal of OC's.

Newer anticonvulsants: comparative review of drug interactions and adverse effects.

The tolerability and drug interaction profiles of 6 new anticonvulsants: oxcarbazepine, vigabatrin, lamotrigine, gabapentin, tiagabine and topiramate, are reviewed. In general, these new anticonvulsants are well tolerated and drug interaction problems are minor with the exception of the risk of failure of oral contraceptives during treatment with oxcarbazepine or topiramate. In this review, the clinical implications of the tolerability of these drugs are discussed for different patient groups. The choice of which new anticonvulsant for which patient depends upon individual factors, in particular, seizure type, tolerability and practical administration factors. Treating elderly patients may be complicated by an increased sensitivity to adverse effects as these patients very often receive polytherapy for accompanying diseases. Drugs with very simple pharmacokinetic properties may be preferred in this group. Women of childbearing age face specific problems related to the epilepsy and to treatment with anticonvulsants. These include impaired fertility, failure of oral contraceptives and the risk of birth defects. Some new anticonvulsants may be suggested in preference to classical drugs to avoid these problems, but the human experience with newer anticonvulsants is still limited and, therefore, so is knowledge of the risk of congenital malformations in the offspring of mothers taking anticonvulsants. Psychiatric and behavioural changes frequently complicate treatment of patients with mental retardation. Some of the new anticonvulsants, in particular those affecting the gamma-aminobutyric acid (GABA) system such as vigabatrin, seem to exacerbate this problem and should be used with caution in these patients.

Pregnancy and epilepsy: a retrospective study of 151 pregnancies.

OBJECTIVE: We studied the course of pregnancy in women with epilepsy to identify possible risk factors which might complicate the epilepsies and pregnancy outcomes. MATERIAL AND METHODS: Data were collected retrospectively from the records of 151 pregnancies in 124 women with epilepsy from 1978-1992. Epilepsy variables were compared with that of non-pregnant women with epilepsy matched for age. Obstetric and neonatal variables were compared with those of all deliveries in the same unit from 1979-1992 (n=38,983). RESULTS: Pregnancy among patients with epilepsy was more likely to occur in women with relatively mild epilepsy. In 12% of the pregnancies, the women were untreated while 71% were on monotherapy. Twenty-one percent had increased seizure frequency during the pregnancy. Perinatal deaths among newborns of epileptic mothers (1.3%) was more frequent but not significantly increased compared to the background population of 0.5% (95% CI 0.2-4.7). A total of 5.3% had congenital malformations compared to 1.5% in the controls (95% CI 2.3-10.3). No neural tube defects were observed. Maternal treatment with phenytoin was significantly related to the occurrence of congenital malformations, P=0.04. CONCLUSIONS: Most women with epilepsy have an uncomplicated pregnancy and normal healthy offsprings. Maternal treatment with phenytoin might be associated with congenital malformations. No other risk factors could be identified.

No loss in total neuron number in the thalamic reticular nucleus and neocortex in the genetic absence epilepsy rats from Strasbourg.

The thalamic reticular nucleus (nRt) as well as the neocortex are involved in the bilateral spike- and wave-discharge loop in genetic absence epilepsy rats from Strasbourg (GAERS). Neuron loss in different brain areas has been described in relation to epilepsy with convulsive seizures. We have previously investigated the ventrolateral/posterior nucleus of thalamus in GAERS and found no neuron loss. We applied the same efficient and unbiased stereological methods to nRt and to neocortex and again found no loss of neurons. The oscillatory properties of nRt are not related to neurons loss.

Drug treatment of epilepsy in the 1990s. Achievements and new developments.

There have been significant advances in the medical treatment of epilepsy in recent years. Improved formulations of several classical antiepileptic drugs (AEDs) have appeared, resulting in improved efficacy and decreased toxicity. A marked increase in the number of comparative investigations of AEDs has also made treatment choice somewhat simpler. Rational methods applied in the search for new AEDs have resulted in the introduction of several new AEDs. So far, evidence seems to indicate that progress has been made with regard to developing compounds not necessarily with superior efficacy but with simpler pharmacokinetics, avoiding enzyme induction as well as decreasing the number of interactions, and improving adverse effect profiles, in comparison to the previous generation of AEDs. A novel approach to the clinical testing of AEDs has made it possible to demonstrate unequivocal efficacy, as well as efficacy as monotherapy, very early in the development of novel compounds. Results of studies from developing countries seem to raise doubt with regard to the value of the old dogmatic principle that early treatment is important in terms of the long term prognosis for seizure control. Traditional ideas on the value of monotherapy have also been questioned on the basis of a novel concept of so-called 'rational polytherapy' which, however, still await scientific validation. On the basis of excellent epidemiological and large controlled clinical studies, our ideas of the necessary duration of AED treatment have become much more optimistic than before.

Cognitive function and anticonvulsant therapy: effect of monotherapy in epilepsy.

INTRODUCTION: The effect of antiepileptic drugs (AED) on cognitive function was studied in 87 patients with epilepsy. MATERIAL AND METHODS: Group A: (n = 52) started AED treatment (carbamazepine, oxcarbazepine, sodium-valproate, phenobarbital or phenytoin). Group B: (n = 27) had AED monotherapy withdrawn (carbamazepine or sodium-valproate). Group C: (n = 8) was switched from phenytoin to carbamazepine monotherapy. The patients were tested before and 4 months after change of the treatment. RESULTS: In group A the test performances were in general unchanged. Patients who had their drug treatment withdrawn (group B) and the patients who were switched from phenytoin to carbamazepine (group C) improved in single tests. The predominant changes in performance seem to be due to practice effect. CONCLUSION: Cognitive functions are only minimally influenced by AEDs after short-term treatment whereas there is a slight improvement after discontinuation of long-term administration of carbamazepine and valproate. A lack of practice effect might be the first indicator of a negative effect of AED on cognitive function.

Therapeutic experiences with 947 epileptic out-patients in oxcarbazepine treatment.

Efficacy and tolerability of the new antiepileptic drug oxcarbazepine, was evaluated in a retrospective multicentre study. The records of all 947 epilepsy patients treated with oxcarbazepine in the eight participating centres from 1981 through 1990 were examined. The median daily dose of oxcarbazepine was 30 mg/kg in children, 18 mg/kg in adults, and 15 mg/kg in elderly patients, given b.i.d. or t.i.d. The mean plasma levels of the main active metabolite of oxcarbazepine was 88, 79, and 68 mumol/l in children, adults, and elderly, respectively. In patients shifted to oxcarbazepine treatment, seizure frequency was unchanged in 51-66%, 32-48% had a decrease, and 1-10% an increase in seizure frequency, considering the individual seizure types separately. Adverse events were reported in one third of patients, most frequently affecting the CNS (dizziness: 6%; sedation: 6%; fatigue: 6%). Rash was reported in 6% of patients, half of these patients had previously had an allergic reaction to carbamazepine. Hyponatremia was found in about a quarter of the patients from whom data were available. No congenital malformations were seen in nine live-born, first trimester oxcarbazepine-exposed children.

Pharmacology of vigabatrin.

Vigabatrin (gamma-vinyl GABA) is a relatively new antiepileptic drug. Vigabatrin increases the concentration of gamma-aminobutyric acid (GABA) in the brain by inhibiting the major GABA metabolizing enzyme, GABA transaminase. Controlled clinical trials have demonstrated an excellent antiepileptic effect of vigabatrin, especially in the treatment of partial epilepsies. Long-term evaluations have shown no signs of tolerance development. Vigabatrin decreases the plasma concentration of phenytoin during concomitant therapy, the only drug with which an interaction seems to occur. In general, vigabatrin is well tolerated. Psychotic reactions occur in 3-6% of patients. Other frequent side effects are sedation and weight increase. Chronic vigabatrin intoxication in animals caused development of intramyelinic oedema, appearing as microvacuoles in brain white matter. No microvacuolation has been observed in humans, even after long-term treatment. Vigabatrin seems a very valuable new antiepileptic drug.

Treatment of pediatric epilepsies with gamma-vinyl GABA (vigabatrin).

Three large studies, all including more than 60 children, on the efficacy on gamma-vinyl GABA (vigabatrin, GVG) in the treatment of childhood epilepsy have been reviewed. On the basis of these and other studies, we conclude that (a) GVG is a promising drug for the treatment of childhood epilepsy, (b) GVG is effective both in partial and generalized epilepsies, (c) GVG seems to be effective in the treatment of symptomatic infantile spasms, (d) no clear dose-response relationship has been demonstrated, (e) a dose of 40-80 mg/kg/day is recommended, and (f) although tolerance is excellent, hyperactivity seems to occur more frequently in children than in adults.

[Preoperative and postoperative magnetoencephalography in a patient with partial epilepsy]. / Prae-og postoperativ magnetoencefalografisk undersøgelse af en patient med partiel epilepsi.

Magnetoencephalography (MEG) is a non-invasive method with a potential of clinical diagnostic use to localize epileptogenic foci in the brain. The aim of this study was to investigate whether the pathological focus localized by MEG was concurrent with the conventional preoperative examinations in a patient with medically intractable epilepsy who underwent surgery (left side uncohippocampectomy). A conventional preoperative test battery had already documented a left-hemisphere fronto-temporal epileptogenic focus. Postoperatively the patient was seizure free. MEG was performed three months before and ten months after the operation. The analysis of the MEG data indicated a left hemisphere fronto-temporal focus in agreement with results obtained by means of the conventional methods used for locating epileptic foci. Postoperatively the focus had disappeared.