Conversion from thrice daily to twice daily administration of gabapentin (GBP) in partial epilepsy: analysis of clinical efficacy and plasma levels.

Gabapentin has been administered in placebo-controlled studies with a thrice daily (T.I.D.) schedule, because of its short half-life. However, clinical efficacy does not seem strictly related to plasma levels: a twice daily (B.I.D.) schedule might therefore be possible. The aim of our study was to verify if the conversion from a T.I.D. to a B.I.D. regimen affected the efficacy and safety of gabapentin therapy. Out of 171 patients treated with add-on gabapentin, we selected 29 stable responders, who were followed for three months with a T.I.D. schedule and then switched to B.I.D. regimen for further three months. Seizure number, side-effects and trough plasma levels of gabapentin were collected during both periods. Gabapentin mean dose was 2117.2 mg/day. Mean number of seizures/months was: 4.2 at baseline, 1.0 during the T.I.D., and 0.9 during the B.I.D. period. Mean trough plasma level of gabapentin was 5.9 microgram/ml during the T.I.D. and 5.2 microgram/ml during the B.I.D. period. Twelve side-effects were reported by 11 patients during the T.I.D. and 6 by 5 patients during the B.I.D. period., sedation and vertigo were the most frequent in both. Results of our study suggest that gabapentin can be administered safely and effectively either with a T.I.D. and a B.I.D. regimen.

Correlations of topographical EEG features with clinical severity in mild and moderate dementia of Alzheimer type.

Quantitative electroencephalography (qEEG) and the Folstein Mini Mental State examination (MMSE) were obtained from 31 patients affected by probable dementia of Alzheimer's type (DAT). qEEG data were examined both by spectral analysis (Fast Fourier Transformation) and by single frequency band topographical centroid, and compared with those of 24 healthy subjects of the same age group. DAT patients were found to have higher absolute power in the slow (delta and theta) frequency bands. Quantitative topographical assessment showed significantly more anteriorly located centers of gravity for the alpha and beta activity. Only alpha anteriorization was correlated with the degree of cognitive impairment as measured by the global deterioration scale and MMSE. It is concluded that quantitative topographical assessment was successful for the statistical handling of the EEG power maps, and to identify a potential parameter for the functional staging of the disease.

Decreased EEG microstate duration and anteriorisation of the brain electrical fields in mild and moderate dementia of the Alzheimer type.

Spatially oriented segmentation allows researchers to break down the continuous stream of the ongoing EEG into microstates with stable topography of the brain electrical landscapes. The resulting microstates were shown to be related to conscious mental experience as well as to psychiatric disorders typically associated with thought disorders. In the present study, the microstates of the resting EEG of patients presenting with mild or moderate probable dementia of the Alzheimer type (DAT) were investigated. A significant anteriorisation of the centers of gravity of the microstate fields, an increase of the microstates' optimal window size and a reduced duration of sustained microstates were found. These differences were statistically more robust than the typical changes in the frequency domain (diffuse slowing) and were significantly correlated with the cognitive decline. The adaptive spatial segmentation into microstates is discussed as a method to extract meaningful EEG parameters for the early diagnosis and staging of Alzheimer's disease.

Brain electrical activity (quantitative EEG and bit-mapping neurocognitive CNV components), psychometrics and clinical findings in presenile subjects with initial mild cognitive decline or probable Alzheimer-type dementia.

Clinical, neuropsychological and neuropsychophysiological data (Q-EEG, ERPs and CNV/RT activity) were obtained from 24 patients who had more or less severe presenile primary cognitive decline without depression, and compared with similar data from 10 age-matched healthy volunteers (mean age, 59.4 years). All of the patients (15 M and 9 F; mean age 59.6 years) were selected according to the DSM III-R, ICD-10 and NINCDS-ADRDA criteria and underwent CT and MRI scanning, in addition to a standard clinical examination, a battery of psychometric tests, spectral EEG, and bit-mapped CNV complex and RT to S2 analyses. Twelve of the 24 patients presented an initial presenile idiopathic cognitive decline (PICD) but did not wholly fulfil the clinical and neuropsychological criteria for primary dementia or for a diagnosis of probable AD; the remaining 12 patients showed characteristic clinical signs and symptoms of a very probable early stage of presenile Alzheimer-type dementia (PAD). ANOVA, correlational and discriminant analyses of the neuropsychological test scores, and the neurophysiological and RT to S2 data revealed 22 highest-ranked between-group discriminant factors (all with a significance level of p < 0.01). The conclusive discriminant analysis retained 13 of these factors as final canonical functions, and these showed a 97% grouping accuracy (33 of the 34 subjects examined); the same percentage of correct classifications was also achieved using only the 15 best indicators in the group of CNV/RT findings. Using both of these sets of highest-ranked discriminators, all of the normal subjects and all of the PAD patients were correctly classified; only 1 PICD patient was misclassified as normal when the first group of 13 factors was used, and another PICD patient was misclassified as PAD using the second group of 15 factors. Our findings suggest that, providing they are correctly performed and interpreted, these non-invasive techniques may be an important tool for identifying incipient stages of presenile Alzheimer-type dementia.

MRI of congenital Foix-Chavany-Marie syndrome.

MRI findings of bilateral central macrogyria allowed the diagnosis of a congenital variant of Foix-Chavany-Marie syndrome in four patients aged between 13 and 32 years, with facio-pharyngo-glosso-masticatory central diplegia, mental retardation and seizures.

MRI of pleomorphic xanthoastrocytoma: case report.

MRI showed a cortically-based partially cystic and markedly enhancing mass in the uncus of the right temporal lobe in a patient with long standing refractory partial complex seizures. Histopathological examination revealed a pleomorphic xanthoastrocytoma, a rare, usually benign tumour thought to originate from subpial astrocytes.

Smooth-pursuit eye movements: alterations in Alzheimer's disease.

Smooth-pursuit eye movements induced by targets moving at constant velocities (from 5 to 100 deg/sec) were recorded from 13 patients with Alzheimer's disease (AD) and from 11 healthy subjects. Four variables were evaluated to quantify the patients' response to the eye movement tests: (1) average peak velocity of smooth-pursuit; (2) percent target matching index after saccade removal (percent ratio between the area of the velocity curve of smooth-pursuit eye movement after saccade removal and the area of target velocity) which is related to the eye performance for each value of target velocity; (3) total amplitude of anticipatory saccades; (4) total number of anticipatory saccades. Compared to the controls, AD patients were found to have significantly lower values of average peak velocity of smooth pursuit and of percent target matching index and a significantly increased number and amplitude of anticipatory saccades. A discriminant stepwise analysis indicated that 5 oculographic variables were significantly associated with the patient's clinical condition (healthy volunteer or AD patient). These statistics yielded an equation for predicting the patient's status according to which the percentage of cases classified correctly was 82.6% in the overall group (n = 23). The predictive performance was similar between the healthy volunteers subgroup (81.8%, n = 11) and the AD subgroup (83.3%, n = 12). The discriminant score was significantly correlated with the score resulting from the MiniMental test (r = 0.67). A significant correlation was also found between the MiniMental score and the number of anticipatory saccades (r = -0.61). No significant correlation was present between the gain of smooth pursuit and the patients' cognitive decline.(ABSTRACT TRUNCATED AT 250 WORDS)

Changes in bit-mapped contingent negative variation (CNV) activity due to initial normal involutional processes of the human brain.

Bit-color mapped multicomponent CNV complexes and RTs to S2 evoked with a simple warned CNV/RT paradigm were recorded and measured in 20 selected right-handed very healthy volunteers (10 young adults and 10 presenile subjects, mean age 28.3 and 59.6, respectively). EEG and CNV components (post S1, N1, P2, P3; early CNV; N1200; late CNV; CNV resolution) were recorded from Fz, C3, Cz, C4, P3, Pz, and P4 referenced to linked mastoid electrodes. EOG, RT and stimuli were also recorded. The presenile group differed significantly from the younger group in the auditory post-S1 N1 and early (O-wave) and late (P-wave) CNV complex components. A progressive amplitude reduction limited to frontal leads between O-wave and P-wave, the lowest point being reached in the P-wave, was characteristic in the presenile group. Moreover, presenile subjects showed relatively flat CNV waveshapes of low amplitude and, on the whole, performed a little less well than young ones. This finding suggests that the statistically significant changes in auditory post-S1 N1 and CNV activity recorded in our presenile subjects, without any appreciable deficits in behavioral or mental performance, could be alerting signs of early brain involutional processes related to minimal and subclinical decline in orienting, attentiveness and response preparation capabilities. If such is the case, and it could be confirmed in a larger sample of very healthy subjects, these age-related changes in the presenium might prove to be of considerable practical importance for clinical research.

Effect of physiological and pathological aging processes on topographic bit-mapped cognitive evoked potentials in presenile subjects.

Bit-mapped multicomponent CNV complex and reaction time (RT) were recorded and measured in 24 presenile patients with initial symptoms of very mild to moderately severe primary mental deterioration without depression, and in 10 age-matched controls. All patients underwent CT and MRI examinations, EEG spectral analysis and a battery of psychometric test. Significant group differences were obtained for measures of some post-S1 ERP and CNV components, particularly of the post-S1 N1b, P300 and early and late pre-S2 CNV. P300 with increased latency, no significant CNV activity, very prolonged RTs, EEG slowing down and diffuse brain atrophy were observed in the majority of patients with probable presenile Alzheimer's dementia. These results suggest that CNV/RT and EEG activity changes similar to those observed in our patients may constitute a valuable clue for the study of brain dysfunction in the early stage of presenile idiopathic cognitive impairment.

Topographic CNV activity mapping, presenile mild primary cognitive decline and Alzheimer-type dementia.

The CNV complex evoked with a standard paradigm (S1-2 sec-S2-motor response) and reaction time (RT) to the imperative signal (S2) were recorded and measured in 12 patients with initial presenile idiopathic cognitive decline (PICD), 12 with presenile Alzheimer-type dementia (PAD) and 10 healthy age-matched controls. Significant group differences were obtained for measures of some CNV components, particularly of the late pre-S2 CNV. No significant CNV activity, very prolonged RTs and sometimes characteristic post-imperative negative variations (PINV) were observed in the majority of patients with PAD. These results suggest that similar CNV complex and RT changes to those observed in our patients may constitute a valuable clue in the study of pathophysiological brain functioning in the early stages of presenile idiopathic mental deterioration.

[MRI and HM-PAO SPECT in 20 patients with drug-resistant partial epilepsy]. / Studio RM e HM-PAO SPECT in 20 pazienti con epilessia parziale farmacoresistente.

Twenty consecutive patients with chronic partial seizures with onset before twenty years of age were investigated by means of 0.5 T MRI (20) and HM-PAO (19) in order to identify focal alterations amenable to surgical therapy. MRI evidentiated parenchymal lesions in 7 patients. Findings consistent with unilateral medial temporal sclerosis and cortico-subcortical parietal scars were found in two patients each. Small solid nodular lesions in the temporal lobe were observed in two patients. These and one additional patient with nodular partially cystic lesions in temporal lobe were administered a paramagnetic contrast agent (Gadolinium DPA) intravenously. In one case a contrast enhancement was observed. Histologic examination post surgery revealed a low grade glioma in one patient. HM-PAO SPECT examination showed area of abnormal captation in 9 of 19 patients. Aspects of EEG correlation with the MRI and SPECT findings are discussed. Our data supported the usefulness of magnetic resonance and SPECT imaging in the completion of pre-surgical assessment in this kind of patients.

Conventional vs controlled-release carbamazepine: a multicentre, double-blind, cross-over study.

The tolerability and pharmacokinetics of a new controlled-release (CR) formulation of carbamazepine (CBZ), were assessed in a multicentre, double-blind, cross-over trial, carried out in 48 epileptic patients (21 men, 27 women; mean age 34.2 years) on conventional CBZ monotherapy, but without complete seizure control (n = 22) or with intermittent side effects (n = 4), or with both (n = 22). Eligible patients were randomized to conventional CBZ or CR CBZ, each given in sequence at individualized daily doses, subdivided into the lowest number of administrations. Each period of the cross-over consisted of a first phase of optimal dose finding (lasting up to two months) and a second one of maintenance (lasting one month) used for evaluation. At the end of each period, a 10-h plasma CBZ and CBZ-epoxide concentration profile, as well as the tolerability and the efficacy of the drugs, were evaluated. The mean CBZ daily dose increased by 16% during the administration of the CR formulation. Fluctuations of total CBZ and 10, 11-epoxide plasma level daily profiles at steady-state were significantly (p less than 0.001) lower during CR CBZ treatment, leading to a significant (p less than 0.001) decrease in intermittent side effects (6 patients on CR CBZ vs 26 on conventional CBZ). Finally, 38 patients on CR CBZ (vs 15 patients on conventional CBZ) were treated with a b.i.d. regimen.

Clinical features, pathogenesis and management of drug-induced seizures.

Many classes of pharmacological agents have been implicated in cases of drug-induced seizures. The list includes antidepressant drugs, lithium salts, neuroleptics, antihistamines (H1-receptor antagonists), anticonvulsants, central nervous system stimulants, general and local anaesthetics, antiarrhythmic drugs, narcotic and non-narcotic analgesics, non-steroidal anti-inflammatory drugs, antimicrobial agents, antifungal agents, antimalarial drugs, antineoplastic drugs, immunosuppressive drugs, radiological contrast agents and vaccines. For each of these classes of drugs, this article offers a revision of the literature and emphasises in particular the frequency of the adverse reaction, its clinical presentation, its presumed epileptogenic mechanism and the therapeutic strategy for the management of drug-induced seizures. An attempt is also made to distinguish seizures induced by standard dosages from those provoked by accidental or self-induced intoxication. For some classes of drugs such as antidepressants, neuroleptics, central nervous system stimulants (e.g. theophylline, cocaine, amphetamines) and beta-lactam antibiotics, seizures are a well recognised adverse reaction, and a large body of literature has been published discussing exhaustively the major aspects of the issue; sufficient data are available also for the other classes of pharmacological agents mentioned above. In contrast, several other drugs [e.g. allopurinol, digoxin, cimetidine, protirelin (thyrotrophin releasing hormone), bromocriptine, domperidone, insulin, fenformin, penicillamine, probenecid, verapamil, methyldopa] have not been studied thoroughly under this aspect, and the only source of information is the occasional case report. This review does not address the issue of seizures induced by drug withdrawal.

Predictive performance of pharmacokinetic methods for phenytoin dosing: a multi-center evaluation in 282 patients with epilepsy.

A retrospective study was conducted in 282 patients with epilepsy to assess the predictive performance of pharmacokinetic methods for individualizing dosage of phenytoin. Two population-based dosing methods (population clearance method and bayesian feedback method) and one individual-based method (the so-called linearized Michaelis-Menten method) were evaluated, when applicable, for single-point and/or 2-point dose predictions of phenytoin. In single-point predictions, we found a generally low percentage of dose calculations falling inside the +/- 10% range (48.9% and 51.1% for the population clearance and the bayesian methods, respectively). In 2-point predictions, the bayesian method was 'accurate' (dose within the +/- 10% range) in approximately 54.3% or 55.0% of cases (depending on the particular method of implementation adopted). An even worse percentage of 'accurate' dose predictions (38.3%) was obtained by using the linearized Michaelis-Menten method. Our data do not confirm results from previous studies indicating a generally good performance of pharmacokinetic methods for predicting phenytoin dosage.

Urinary 6-beta-OH-cortisol and paracetamol metabolites as a probe for assessing oxidation and conjugation of chemicals in humans.

The ratio between urinary 6-beta-OH-cortisol and 17-OH-corticosteroids was taken as an indirect estimate of monoxygenase activity in a population of controls and epileptic patients undergoing therapy with diphenylhydantoin and phenobarbital. Cortisol hydroxylation was increased in the group of epileptics with large inter-individual variations notwithstanding a similar dosage of inducers. The levels of some phase II conjugating enzymes were followed by administering paracetamol and measuring the urinary excretion of its main metabolites. Paracetamol glucuronate was increased by levels of cysteine and mercapturic derivatives of paracetamol did not vary, whereas sulfate derivatives were decreased in epileptic patients. Plasma N-acetyl-transferase activity did not vary in either group. Hydroxylated cortisol and paracetamol glucuronide excretion were not correlated in the same individuals, and no correlation was found between the ratio of 6-beta-OH-cortisol/17-OH-corticosteroids and the plasma levels of diphenylhydantoin or phenobarbital. Oxidation of cortisol and conjugation of paracetamol were controlled with different mechanisms, varied considerably between individuals and were not predictive of the pharmacokinetics of the inducers in treated patients.

Clinical application of the Mullen and Foster method for individualizing phenytoin dosage.

The Mullen and Foster method was prospectively applied for individualizing phenytoin dosage in 24 epileptic patients. Accuracy and reliability of the method were assessed by comparing predicted and measured values of plasma phenytoin steady-state concentration. The absolute difference between predicted and measured phenytoin levels was less than 15 percent in 22 of 35 cases (63 percent), between 15 and 25 percent in 8 of 35 cases (23 percent) and more than 25 percent in 6 of 35 cases (17 percent).

Comparative analysis of the pharmacokinetic techniques available for individualizing phenytoin dosage.

Over the past few years, numerous pharmacokinetic techniques based on Michaelis-Menten principles have been proposed to individualize PHT dosage and predict plasma levels. The choice of one of these techniques for clinical use depends on the number of steady state concentration-versus-dose (Css-D) data pairs that are known in the patient for whom the predictive technique is to be applied. The most frequent clinical situations in which these predictions are made can be divided into three groups for each patient considered--Case A: only one previous Css-D data pair is known; Case B: two previous Css-D data pairs are known; Case C: three previous Css-D data pairs are known. Of the available techniques that can be applied in case A, we compared the population clearance (PC) method and the Bayesian feedback (BF) method. The procedure for comparing the predictive capabilities of these methods was very similar to that adopted in a recent report by Vozeh et al. Our findings showed that the PC method should be preferred for clinical use under this circumstance. Two predictive techniques suitable for use in Case B (BF and Mullen & Foster methods) were compared. In this case, the BF method was shown to be more accurate. As regards Case C, three pharmacokinetic techniques were compared: the Mullen and Foster method, the iterative least-squares (ILS) technique, and the BF method. The ILS technique was found to be the most accurate in this case. Finally, we describe a programmable calculator procedure which uses the PC, BF or ILS methods in Cases A, B and C respectively.(ABSTRACT TRUNCATED AT 250 WORDS)