Favorable change of lipid profile after carbamazepine withdrawal.

OBJECTIVE: Patients treated with carbamazepine (CBZ) have increased serum levels of total cholesterol (TC), high-density lipoproteins (HDL), and low-density lipoproteins (LDL). We aimed to investigate whether these changes of serum lipids are reversible after CBZ withdrawal. MATERIAL AND METHODS: We used a prospective, randomized double-blinded design. A total of 160 patients who had been seizure free on anti-epileptic drug monotherapy for more than 2 years were included and randomized to withdrawal or not. The intervention was completed by 150 (80 females, 53%) patients. Serum samples from before and 4 months after completed withdrawal or no withdrawal were obtained from 130 patients (63 females, 48%). Of these, 84 were treated with CBZ, 28 with valproate, nine with phenytoin, four with phenobarbital, and five with lamotrigine. Of the patients who had been treated with CBZ, 47 were randomized to the withdrawal group, and 37 were randomized to the non-withdrawal group. RESULTS: Among the CBZ-treated patients, a significant decrease in serum levels of TC, LDL, and apolipoprotein B (ApoB) were found in the withdrawal group compared with the non-withdrawal group. Mean differences in change were as follows: TC 0.68 mmol/l (P = 0.005, CL - 1.15 to -0.21); LDL - 0.67 mmol/l (P = 0.001, CL - 1.03 to -0.29); ApoB - 0.13 g/l (P = 0.02, CL - 0.23 to -0.03). No significant changes in HDL, apolipoprotein A, and C-reactive protein were detected. CONCLUSION: Our results indicate that CBZ may have unfavorable effects on serum levels of TC, LDL, and ApoB. However, these changes seem to be reversible even after years of treatment.

Repeated neuropsychological assessment in well-controlled epilepsy.

BACKGROUND: The majority of patients with epilepsy are seizure-free, and repeated neuropsychological assessment may be highly relevant in this group. However, previous studies have not addressed the possible influence of important clinical variables on repeated neuropsychological assessment in this population. METHODS: Using data from a large antiepileptic drug (AED) withdrawal study, we calculated the neuropsychological practice effects for 139 seizure-free patients with epilepsy and analysed the influence of different epilepsy-related factors on improvement that were observable 7 months after the initial neuropsychological assessment. RESULTS: A clear and significant improvement in neuropsychological test performance was found for all the tests employed, regardless of AED withdrawal. Furthermore, patients characterized by evidence of brain pathology, such as known cerebral aetiology, pathological MRI and pathological EEG, showed less practice effects than patients not characterized by these variables. The differences were primarily evident for measures of verbal learning and memory. CONCLUSION: The data obtained from this study suggest that the development of general norms for change in the particular patient population, as well as specific norms for change related to important clinical variables, might be necessary to be able to determine whether genuine neuropsychological changes have occurred in individual patients in this group.

Improvement in verbal memory after withdrawal of carbamazepine and valproate in patients with well-controlled epilepsy: a randomized, double-blind study.

BACKGROUND: For most major antiepileptic drugs, neuropsychological side effects have been reported. Healthy volunteer studies have found that both carbamazepine and valproate impair aspects of verbal memory. OBJECTIVE: The aim of this study was to assess the effects of carbamazepine and valproate on verbal memory, in a well-controlled epilepsy population. METHODS: This was carried out with a randomized, double-blind and placebo-controlled study of anticonvulsant withdrawal in patients receiving monotherapy. RESULTS: In the carbamazepine group (n=92), withdrawal significantly improved recall after 30 min (P=0.03). In the valproate group (n=32), withdrawal significantly improved performance of immediate word span (P=0.04). CONCLUSIONS: Withdrawal was randomized to placebo, but the choice of medication was not randomized to placebo. This means that the shown differences in neuropsychological outcome cannot with full certainty be attributed to either antiepileptic drug. The improvement of memory, after both carbamazepine and valproate withdrawal, was slight, and the impact on daily life function is uncertain.

Multimodal imaging in mild cognitive impairment: Metabolism, morphometry and diffusion of the temporal-parietal memory network.

This study compared sensitivity of FDG-PET, MR morphometry, and diffusion tensor imaging (DTI) derived fractional anisotropy (FA) measures to diagnosis and memory function in mild cognitive impairment (MCI). Patients (n=44) and normal controls (NC, n=22) underwent FDG-PET and MRI scanning yielding measures of metabolism, morphometry and FA in nine temporal and parietal areas affected by Alzheimer's disease and involved in the episodic memory network. Patients also underwent memory testing (RAVLT). Logistic regression analysis yielded 100% diagnostic accuracy when all methods and ROIs were combined, but none of the variables then served as unique predictors. Within separate ROIs, diagnostic accuracy for the methods combined ranged from 65.6% (parahippocampal gyrus) to 73.4 (inferior parietal cortex). Morphometry predicted diagnostic group for most ROIs. PET and FA did not uniquely predict group, but a trend was seen for the precuneus metabolism. For the MCI group, stepwise regression analyses predicting memory scores were performed with the same methods and ROIs. Hippocampal volume and FA of the retrosplenial WM predicted learning, and hippocampal metabolism and parahippocampal cortical thickness predicted 5 minute recall. No variable predicted 30 minute recall independently of learning. In conclusion, higher diagnostic accuracy was achieved when multiple methods and ROIs were combined, but morphometry showed superior diagnostic sensitivity. Metabolism, morphometry and FA all uniquely explained memory performance, making a multi-modal approach superior. Memory variation in MCI is likely related to conversion risk, and the results indicate potential for improved predictive power by the use of multimodal imaging.

Antiepileptic monotherapy significantly impairs normative scores on common tests of executive functions.

BACKGROUND: Understanding how antiepileptic (AED) monotherapy influences normative test scores is of importance in the clinic for correct interpretation of neuropsychological profiles. Previous studies have primarily reported minor influence on neuropsychological raw scores, and the clinical relevance of these findings is unclear. AIM OF THE STUDY: To obtain a clinical valid answer to this question, we analysed changes in T-scores after AED withdrawal in a large group of well-controlled epilepsy patients, for tests previously shown to be sensitive to AED withdrawal. METHODS: We report outcomes on measures of choice reaction time from the California Computerized Assessment Package, on the Controlled Oral Word Association Test and on the Stroop Color-Word Interference Test. RESULTS: Significantly improved T-scores were revealed after AED withdrawal on five of the six tests of executive functions with mean improvement of 5 T-scores. Comparable results were achieved in the subgroup taking carbamazepine, with a mean improvement of 6.2 T-scores. CONCLUSION: The present results suggest that T-scores for computerized tests of choice reaction time and tests of verbal fluency and response inhibition may be significantly impaired as a consequence of AED monotherapy, and that careful interpretation of these scores is required in diagnostic assessment of patients receiving AED monotherapy.

A retrospective view on research in neuroscience in Norway.

This brief historical review on neuroscience in Norway shows a comparatively high research activity with many important results. The Norwegian zoologist Fridtjof Nansen, who later became a famous Arctic explorer, was the first to formulate the neuron doctrine. 'The Oslo School of Neuroanatomy' contributed enormously to the understanding of the detailed anatomy and chemistry of the central nervous system. Norwegian neurophysiologists made important findings from studies of hippocampus including the inhibitory basket cell, the LTP phenomenon and the 'hippocampal-slice-technique'. In clinical neuroscience the description of Refsum's disease and studies of myasthenia gravis and multiple sclerosis have been of particular importance. Two of 13 centres of excellence in Norway selected in 2003 were from neuroscience, and The Norwegian Research Council has its own programme for neuroscience. The Norwegian Neurological Association arranges annual meetings to promote interest in neurological research.

G protein beta3 subunit C825T polymorphism modifies the presentation of temporal lobe epilepsy.

PURPOSE: Experimental studies suggest a role of G protein-mediated signaling pathways in epileptogenesis. A genetic variation affecting the G protein subunit Gbeta3 denoted the C825T polymorphism has been reported to increase the signaling efficiency through G(i) proteins and to modify responses to certain drugs. The C825T polymorphism has also been associated with several diseases including hypertension, diabetes type II, obesity, and major depressive disorder. In this study, we have explored whether the G protein polymorphism C825T is associated with or influences temporal lobe epilepsy (TLE). METHODS: The study included 227 TLE patients, 186 controls, and 106 family members of TLE patients. DNA was extracted from blood samples and typing of the polymorphism was performed. Case record forms were analyzed for all the homozygote TLE patients and homozygote controls, i.e., carrying the TT genotype as well as for 28 matched TLE patients (16 females, 12 males) without the polymorphism (CC genotype). RESULTS: Typing of the C825T polymorphism showed that 6.0% of the TLE patients, 7.0% of the controls, and 7.5% of the family members were homozygote for the polymorphism; i.e., carrying the TT genotype. TLE patients carrying the TT genotype had higher severity score on eight out of nine predefined parameters compared with the TLE patients without polymorphism, i.e., carrying CC genotype. TT genotype TLE patients also had increased body mass index, body weight, and waist circumference compared with the TLE patients carrying the CC genotype. There was no increased frequency of hypertension or diabetes. CONCLUSIONS: There was no increased frequency of TLE between the carriers of the TT genotype compared with the healthy controls and/or family members without epilepsy. However, the TLE patients with the TT genotype showed tendencies of a more severe disease phenotype.

White matter lesion severity is associated with reduced cognitive performances in patients with normal CSF Abeta42 levels.

OBJECTIVE: To identify possible associations between white matter lesions (WML) and cognition in patients with memory complaints, stratified in groups with normal and low cerebrospinal fluid (CSF) Abeta42 values. MATERIAL AND METHODS: 215 consecutive patients with subjective memory complaints were retrospectively included. Patients were stratified into two groups with normal (n = 127) or low (n = 88) CSF Abeta42 levels (cut-off is 450 ng/l). Cognitive scores from the Mini-Mental State Examination (MMSE) and the Neurobehavioral Cognitive Status Examination (Cognistat) were used as continuous dependent variables in linear regression. WML load was used as a continuous independent variable and was scored with a visual rating scale. The regression model was corrected for possible confounding factors. RESULTS: WML were significantly associated with MMSE and all Cognistat subscores except language (repetition and naming) and attention in patients with normal CSF Abeta42 levels. No significant associations were observed in patients with low CSF Abeta42. CONCLUSIONS: WML were associated with affection of multiple cognitive domains, including delayed recall and executive functions, in patients with normal CSF Abeta42 levels. The lack of such associations for patients with low CSF Abeta42 (i.e. with evidence for amyloid deposition), suggests that amyloid pathology may obscure cognitive effects of WML.

Valproate is an effective, well-tolerated drug for treatment of status epilepticus/serial attacks in adults.

OBJECTIVE: Status epilepticus (SE) and serial attacks (SA) represent neurological emergencies, and mortality rate for SE/SA is high, ranging from 3% to 25%, depending on cause and co-morbidity. As SE/SA become more refractory to treatment over time, rapid, appropriate treatment is extremely important. Here, we report a prospective registration of the effect of intravenous (IV) valproate (VPA) on SE/SA in a group of Norwegian patients. PATIENTS AND METHODS: Forty-one adult patients (18 males, 23 females) were included in the study. All had previously been unsuccessfully treated with diazepam. For 19, the main SE/SA seizure type was generalized tonic-clonic, while 16 had complex-partial seizures. Six had seizures that were difficult to classify. The treatment protocol recommended 25 mg/kg of VPA loading dose over 30 min, followed by continuous infusion of 100 mg/h for at least 24 h, then per oral administration. If seizures persisted after the loading dose, general anaesthesia (barbiturates/propofol/midazolam) was administered. RESULTS: No serious side effects were reported. In 76% of the cases (31 of 41), SE/SA stopped and anaesthesia was not required. Of the patients treated within 3 h, only 5% needed anaesthesia, whereas of those treated after 3-24 h, 38% needed anaesthesia. Of those who waited for more than 24 h before treatment, 60% required anaesthesia. Furthermore, 60% of the patients who needed anaesthesia were given loading doses below 2100 mg. CONCLUSIONS: VPA seems to be a safe, effective treatment of SE/SA, but efficacy is dependent on time lapse between symptoms and VPA treatment, and administration of a sufficiently high loading dose.

Diaschisis after thalamic stroke: a comparison of metabolic and structural changes in a patient with amnesic syndrome.

INTRODUCTION: We present a patient with a left anteromedial thalamic lesion with an amnesic syndrome. The patient underwent neuropsychological testing, cerebrospinal fluid (CSF) analyses, magnetic resonance imaging (MRI) [T2, flair, and diffusion tensor imaging (DTI)] and [18F]-2-fluoro-deoxy-d-glucose positron emission tomography (FDG-PET) to assess indirect effects of thalamic lesions on cortical function. CASE REPORT: A 67-year-old right-handed woman was admitted to a university-based memory unit because of memory and concentration problems. Neuropsychological testing revealed dysfunction of episodic memory, semantic memory and working memory. General intellectual function and attention capacity were preserved. MRI revealed an anteromedial thalamic lesion in the left hemisphere. FDG-PET showed decreased uptake in the frontal, parietal and temporal lobes of the left hemisphere. Regions of interest (ROI) in white matter were selected and left and right hemispheres were compared. Fractional anisotropy (FA) in ROI representing thalamo-cortical connections were decreased in the left hemisphere when compared with the right. CONCLUSION: The results show the importance of a network that include the anterior and dorsomedian nuclei, which influence the activity in areas of the cortex responsible for memory processes. The imaging findings suggest that areas of cortical diaschisis after thalamic infarction correspond to areas affected by thalamo-cortical fibre loss as measured with FA.

Changes in autonomic cardiac control in patients with epilepsy after discontinuation of antiepileptic drugs: a randomized controlled withdrawal study.

The aim of this study was to assess cardiac autonomic control in patients with epilepsy before and after withdrawal of antiepileptic drugs (AEDs). The study was prospective, randomized and double blinded. Spectral analysis of heart rate variability (HRV) in 24 h ECG-registration before and after withdrawal of AEDs was used to assess autonomic cardiac control. The assessment of HRV with spectral analysis was based on sinus rhythm and normal heart beats [normal to normal beat (NN)]. Thirty-nine patients had 24 h rhythms free from any ectopic beats both before and after intervention, and were included in the analysis. Significant differences were found in the withdrawal group: filtered RR intervals for all 5 min segments of the analysis; percentage of differences between adjacent filtered RR intervals that are greater than 50 ms for the whole analysis; very low frequency power; low frequency power and high frequency power. The results demonstrate that slow withdrawal of AEDs in seizure-free patients with epilepsy on drug mono-therapy resulted in an increase in both parasympathetic and sympathetic functions, indicative of increased power amongst patients following cessation of AED treatment. As low HRV has been associated with increased mortality in patients with other diseases, this increased HRV may be beneficial.

Focal retrograde amnesia associated with vascular headache.

We report the case of a 42-year-old man with repeated attacks of headache associated with retrograde amnesia. Neuropsychological tests before and after the major episode of amnesia showed mild neuropsychological deficits but with spared anterograde memory and learning functions. The amnesia was dense for a period of 15-20 years and included people and events (public and private). There was also a suggestion of amnesia for learned skills. Neurologically he had mild clinical signs and focal EEG-abnormalities in the left fronto-temporal region, but CT, MRI, and SPECT showed no abnormality. Five years after the onset of amnesia there was no recovery of the retrograde memory deficit, but a PET (glucose) scan was normal and neuropsychological testing showed no deficits. An association with migraine has been reported for some non-classical amnesias, but this is the first case of selective retrograde amnesia in a patient with headache as a primary neurological diagnosis.

Altered ovarian function and cardiovascular risk factors in valproate-treated women.

PURPOSE: Polycystic ovaries and menstrual disturbances seem to be common among women taking valproate for epilepsy. The purpose of the present study was to assess the frequency of valproate-related metabolic and endocrine disorders in different groups of women with epilepsy. SUBJECTS AND METHODS: Seventy-two women with epilepsy and 52 control subjects from centers in three European countries (Finland, Norway, and the Netherlands) participated in the study. Thirty-seven of the women with epilepsy were taking valproate monotherapy and 35 carbamazepine monotherapy. RESULTS: The frequency of polycystic ovaries or hyperandrogenism, or both, among valproate-treated women with epilepsy was 70% (26 of 37) compared with 19% (10 of 52) among control subjects (P <0.001). They were found in 79% (11 of 14) of obese and 65% (15 of 23) of lean women on valproate, and in 20% (7 of 35) of carbamazepine-treated women. The obese valproate-treated women with polycystic ovaries or hyperandrogenism, or both, had hyperinsulinemia and associated unfavorable changes in serum lipid levels consistent with insulin resistance. CONCLUSIONS: Polycystic ovaries and related hyperandrogenism are frequently encountered in both obese and lean women taking valproate for epilepsy. The use of valproate is associated with risk factors for cardiovascular disease in obese women.

Effects of electroconvulsive therapy (ECT) on thyroid function parameters.

Serum concentrations of thyroxine, triiodothyronine, TSH and prolactin were measured in 10 patients with affective disorders receiving ECT. Samples were drawn at -15 min, 0, +30 min, +60 min and +3 hr after ECT. A significant increase in both prolactin and TSH was observed 30 min after ECT. A small but significant decrease in triiodothyronine but no change in thyroxine was found in all post-ECT samples. The increase in TSH may be caused by an anti-dopaminergic effect of ECT at either the pituitary or the hypothalamic level.

The progesterone metabolite 5 alpha-pregnan-3 alpha-ol-20-one reduces K(+)-induced GABA and glutamate release from identified nerve terminals in rat hippocampus: a semiquantitative immunocytochemical study.

5 alpha-Pregnan-3 alpha ol-20-one (3 alpha-OH-DHP) reduced the depolarization-induced loss of GABA and, to a lesser extent, the glutamate-like immunoreactivities from nerve terminals in the in vitro hippocampal slice. Phenobarbital (PB) had similar effects. These results suggest that 3 alpha-OH-DHP affects presynaptic transmitter release, possibly in a barbiturate-like manner.

Temporal distribution of seizures in epilepsy.

A major problem in epileptology is why a seizure occurs at a particular moment in time. An initial step in solving this problem is a detailed analysis of the temporal distribution of seizures. Using methods and theories of stochastic processes, seizure patterns in a group of epileptic outpatients were examined for stationarity, randomness, dependency and periodicity in a prospective study. Sixteen of the 21 seizure diaries included in the study showed stationarity; 2 were non-stationary and 3 inconclusive. Eleven of the 16 stationary diaries were non-Poisson (P less than 0.005), indicating that in the majority of patients seizures did not occur randomly. The most frequently encountered phenomenon was seizure clustering. Clustering was considered when the diaries fulfilled all three criteria: (1) a positive R-test (P less than 0.001); (2) deviation from the fitted Poisson distribution towards clustering; and (3) the feature of an autoregressive process in the autocorrelogram plot. Dependency between seizure events was demonstrated in 8 of the 16 stationary diaries, computing first order transition probabilities. A detailed analysis of seizure occurrence is a major step towards a better understanding of the mechanisms underlying seizure precipitation. This is exemplified by our finding of a relation between seizure frequency and the menstrual cycle.

Chronic lamotrigine treatment increases rat hippocampal GABA shunt activity and elevates cerebral taurine levels.

The mechanism of action of the antiepileptic drug lamotrigine has previously been investigated only in acute experiments and is thought to involve inhibition of voltage-dependent sodium channels. However, lamotrigine is effective against more forms of epilepsies than other antiepileptic drugs that also inhibit sodium channels. We investigated whether chronic lamotrigine treatment may affect cerebral amino acid levels. Rats received lamotrigine, 10 mg/kg/day, for 90 days. The hippocampal level of GABA increased 25%, and the activities of glutamate decarboxylase and succinic semialdehyde/GABA transaminase increased 12 and 21% (p< 0.05), respectively, indicating increased GABA turnover. The uptake of GABA and glutamate into proteoliposomes remained unaltered. The level of taurine increased 27% in the hippocampus and 16% in the frontal and parietal cortices. The activities of hexokinase and alpha-ketoglutarate dehydrogenase, remained at control values. Serum lamotrigine was 41.7+/-1.5 microM (mean+/-S.E.M.), which is within the range seen in epileptic patients. Acute experiments with 5, 20 or 100 mg lamotrigine/kg, caused no changes in brain amino acid levels. The results suggest that chronic lamotrigine treatment increases GABAergic activity in the hippocampus. The cerebral increase in taurine, which has neuromodulatory properties, may contribute to the antiepileptic effect of lamotrigine.

Acute effects of 17 beta-estradiol on brain excitability studied in vitro and in vivo.

The acute effects of 17 beta-estradiol on brain excitability were studied in vitro and in vivo utilizing rat hippocampal slices and a cat cerveau isolé preparation. The hippocampal slices were perfused with 17 beta-estradiol (10(-7)-10(-10) M) for 30 min. No effects were observed on synaptic activation and inhibition and on the response to iontophoretically applied GABA in intact and ovariectomized female rats (n = 43). In males (n = 32), however, a small (12%) but significant increase in population spike amplitude was observed after 30 min exposure to 10(-9) M 17 beta-estradiol. Higher and lower concentrations were ineffective. In vivo, no acute effects of 17 beta-estradiol on focal epileptic seizure thresholds, evoked potentials, or augmenting response were observed in the visual cortex of non-estrous female cats (n = 11; median dose 1 micrograms/kg, range 0.5 microgram/kg-10 mg/kg).

A new injectable carbamazepine solution--antiepileptic effects and pharmaceutical properties.

Carbamazepine (CBZ) could be dissolved in Glycofurol (polyethylene glycol monotetra-hydrofurfuryl ether) with concentrations up to 100 mg/ml, and the solutions were stable for at least 14 days. Ethanol or benzyl alcohol was added without loss in solubility, while water, human serum albumin or Intralipid always led to immediate precipitation. The effect of a CBZ/Glycofurol solution on focal seizure threshold in the visual cortex in cats was investigated using a cerveau isolé preparation. Fourteen experiments were performed using i.v. injections of CBZ with concentrations ranging from 0.2 to 20 mg/kg. In all experiments with doses greater than 1 mg/kg the CBZ/Glycofurol injections exerted a pronounced and immediate effect on the seizure threshold, while Glycofurol alone was ineffective. On average, seizure threshold increased more than 5-fold with doses in the range of 5-20 mg/kg. Investigating the effect of CBZ/Glycofurol on picrotoxin-induced seizure activity in cats, 2 injections of 5 mg/ml of CBZ immediately stopped the seizure activity as evaluated by electrocorticography, while interictal activity remained.

Neurological examination, computerized tomography, cerebral blood flow and neuropsychological examination in workers with long-term exposure to carbon disulfide.

Sixteen males, formerly exposed to carbon disulfide (CS2) for at least 10 years (mean 20 years), were administered a neurological examination, cerebral computerized tomography (CT), regional cerebral blood flow (rCBF) examination and neuropsychological examination. The clinical neurological examination revealed abnormalities in 15; cerebral CT showed signs of atrophy in 13; and neuropsychological examination indicated brain organic changes in 13. With the rCBF examination, slight abnormalities were found in 8. The findings indicate that long-term exposure to CS2 involves a risk of developing toxic encephalopathy, demonstrable on both neurological and neuropsychological examination. Furthermore, structural changes in the brain may be demonstrable by cerebral CT.