Central nervous system adverse effects of new antiepileptic drugs. A meta-analysis of placebo-controlled studies.

OBJECTIVE: Systematic review and meta-analysis of the most frequent treatment-emergent central nervous system adverse events (CNS AEs) of new antiepileptic drugs (AEDs) from double-blind, add-on, placebo-controlled studies conducted in adult epileptic patients and identification of dose-adverse effect relationships. METHODS: Trial reports found by searching Medline and journals. Outcome was the number of patients complaining of treatment-emergent CNS AEs. Sixteen predefined CNS AEs were considered. Risk differences (RDs) were calculated for individual studies and summary statistics estimated using the random effect model. Predefined CNS AEs in patients treated with active drug (broken down into dose levels) or placebo were extracted and the RDs (95% CI) for CNS AEs were calculated. RESULTS: Thirty-six suitable studies identified. No meta-analysis was possible for oxcarbazepine and tiagabine (only one study each included). For these drugs RDs were calculated from single studies. Gabapentin was significantly associated with somnolence 0.13 (0.06-0.2) and dizziness 0.11 (0.07-0.15); lamotrigine with dizziness 0.11 (0.05-0.17), ataxia 0.12 (0.01-0.24) and diplopia 0.12 (0.00-0.24); levetiracetam with somnolence 0.06 (0.01-0.11); pregabalin with somnolence 0.11 (0.07-0.15), dizziness 0.22 (0.16-0.28), ataxia 0.10 (0.06-0.14) and fatigue 0.04 (0.01-0.08); topiramate with somnolence 0.09 (0.04-0.14), dizziness 0.06 (0.00-0.11), cognitive impairment 0.14 (0.06-0.22) and fatigue 0.06 (0.01-0.12); zonisamide with somnolence 0.06 (0.02-0.11) and dizziness 0.06 (0.00-0.12). The dose-response relationship was analysed only for those CNS AEs significantly associated with the AED. CONCLUSIONS: No comparison between drugs was possible. One CNS AE was significantly more frequent for levetiracetam, two for zonisamide and gabapentin, three for lamotrigine and four for pregabalin and topiramate.

Human heart rate variability and sleep stages.

With the aim of better understanding the dynamic changes in sympatho-vagal tone occurring during the night, human heart rate variability (HRV) during the various sleep stages was evaluated by means of autoregressive spectral analysis. Each recording consisted of an electroencephalogram, an electrooculogram, and electromyogram, and electrocardiogram, and a spirometry trace. All of the data were sampled and stored in digital form. Sleep was analysed visually, but HRV was analysed off-line by means of original software using Burg's algorithm to calculate the LF/HF ratio (LF: 0.04-0.12 Hz; HF: 0.15-0.35 Hz) for each sleep stage. Seven healthy subjects (four males; mean age 35 years) were enrolled in the study. Our findings show a progressive and significant reduction in the LF/HF ratio through sleep stages S1-S4, as a result of an increase in the HF component; this indicates the prevalence of parasympathetic activity during slow-wave sleep. During wakefulness, S1 and REM, the LF/HF values were similar and close to 1.

Smooth-pursuit eye movement and saccadic intrusions in obsessive-compulsive disorder.

Although several reports agree that smooth-pursuit eye movement (SPEM) is abnormal in some obsessive-compulsive disordered (OCD) patients, differences between treatments and lack of accuracy in control selection make the results controversial. Although reduced gain seems the most accepted abnormality, the characteristics of saccadic disruption of smooth pursuit are as yet unspecified. SPEMs in 21 OCD patients (DSM-III-R) and 21 healthy subjects recruited from the community were studied through a multiple target velocity task . The two groups were individually matched on age, gender, and level of education. None of the subjects had a history of substance dependence apart from the smokers who refrained from smoking in the 2 hours prior to the test. A significantly lower SPEM gain and increased number and frequency of anticipatory saccades (ASs) was found in OCD patients as compared with control subjects. No relationship emerged between eye movement abnormalities and clinical variables explored.

Peripheral nervous system involvement in systemic sclerosis: the median nerve as target structure.

OBJECTIVES: To investigate the frequency and the main electrophysiological characteristics of the canalicolar passage nerve involvement in patients with systemic sclerosis (SSc). METHODS: Thirty-two SSc patients were enrolled in the study, classified according to the type (diffuse or limited) and the duration (> / < 5 years) of the disease. Sensory-motor nerve conduction studies (NCS) of the upper and lower limbs, in particular at the critical canalicolar points, were conducted by recording the Compound Muscular Action Potential (CMAP) and the Sensory Action Potential (sNAP). The following parameters were evaluated: Motor Nerve Conduction Velocity (MNCV) and Sensory Nerve Conduction Velocity; distal and proximal latency of the CMAP and the onset and peak latency of the sNAP; peak-peak amplitude and negative-peak area of the CMAP and sNAP; and the Terminal Latency Index (TLI) (Terminal Distance/MCNV x Distal latency). RESULTS: Four (12.5%) patients had a distal neuropathy of the upper limbs (one with monolateral and two with bilateral involvement of the median nerve and one bilateral involvement of the ulnar nerve). Fourteen (43.7%) patients showed a decrement of the median nerve TLI and seven (21.8%) of either the median or the ulnar nerve (Table I). Motor and sensitive conduction velocity and latency studies did not show a statistical difference between SSc patients and controls. The amplitude and area of the CMAP (distal and proximal), sNAP and of the median nerve TLI were significantly decreased in patients with respect to controls. CONCLUSION: Distal mononeuropathy of the median nerve was the most frequent result in our patients. The involvement of the peripheral nervous system seems to be strictly topographical, following the modifications of the tissues and vascular tone (Raynaud's phenomenon) at the upper acral level. The neurophysiological alterations detected in our study at the wrist level may not be linked merely to a compressive event but also to microvascular involvement. Nerve involvement closely connected with the pathogenesis and distribution of SSc should be considered when peripheral nervous system involvement is the initial symptom of the disease.

Hand motor cortex activation in a patient with congenital mirror movements: a study of the silent period following focal transcranial magnetic stimulation.

Motor evoked potentials (MEPs) to focal transcranial magnetic stimulation (TMS) have demonstrated that abnormal ipsilateral corticospinal projections are active in patients with congenital mirror movements. In addition, movement-related potentials and PET suggest that an abnormal pattern of motor cortex activation could be associated with an anomaly of the corticospinal tracts. In the present study the silent period (SP) following focal TMS was investigated in a woman with familial congenital mirror movements. Recordings were made from both abductor pollicis brevis (APB) muscles. When focal TMS was delivered during an intended contralateral APB muscle contraction, MEP and SP were bilaterally recorded and SP was significantly shorter than the contralateral SP observed in normal controls. An abnormal bilateral activation of the hand motor cortex can explain our findings. The non-stimulated motor cortex causes an early partial recovery of the background EMG activity when the stimulated motor cortex is still inhibited (beginning as soon as the transcallosal and the short-lasting segmental inhibition are both complete).

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.

Influence of single and repeated doses of oxcarbazepine on the pharmacokinetic profile of felodipine.

Eight healthy male volunteers (age 25-41 years) entered an open-label, within-subject study. They were treated for 13 consecutive days with felodipine (FEL) extended-release tablets, 10 mg daily. On day 6, oxcarbazepine (OXC) 600 mg was given in the morning, and from day 7 to 13, the daily dose was increased to 450 mg b.i.d. Blood samples for measurement of FEL and its pyridine metabolite (determined by gas-chromatography) were drawn just before dosing and at 2, 4, 6, 8, 10, 12, and 24 h after dosing on days 5, 6, and 13. Steady-state pharmacokinetic parameters of FEL and its pyridine metabolite were not influenced by the single dose of OXC. Repeated coadministration of OXC significantly reduced the area under the concentration-time curve (AUC0-24) of FEL by 28% and the FEL maximum plasma concentration (Cmax) by 34%. This reduction in FEL bioavailability is much smaller than that observed after co-administration of carbamazepine (CBZ) (i.e., 94%).

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)

Effects of oxcarbazepine and carbamazepine on the central nervous system: computerised analysis of saccadic and smooth-pursuit eye movements.

Oxcarbazepine (OXC) is a new anti-epileptic agent structurally related to carbamazepine (CBZ). OXC seems to have a similar efficacy and a better tolerability profile than CBZ. In the present study we compared the subclinical side-effects on the CNS of OXC and CBZ using a computerised analysis of saccadic and smooth-pursuit eye movements. Six healthy male volunteers (mean age 29 yrs) participated in the study, which was conducted by a double-blind cross-over design. Each subject was given a single dose of either CBZ 400 mg or OXC 600 mg (according to the random assignment) after which the drug effects on eye movements were evaluated. One week later, the trial was repeated using the other drug. The parametrisation of both saccadic and smooth-pursuit eye movements was carried out by measuring a series of performance parameters [e.g. the maximum saccade peak velocity (MSPV) and the typical target velocity (TTV)]. OXC was found to induce a lesser degree of alteration on the values of both MSPV (p = 0.07) and TTV (p less than 0.03) than CBZ. In particular, the TTV values were virtually unaffected by OXC administration, while the effects of CBZ on both variables were particularly evident at 8 and 10 h after dosing which correspond to the time at which the plasma concentrations of CBZ and of its 10,11-epoxide reach the peak. In conclusion, our preliminary results indicate that OXC induces negligible alterations, if any, on the eye movement parameters evaluated in our study.

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.

A new method for analyzing smooth-pursuit eye movements. Description of a microcomputer program and evaluation in healthy volunteers.

The study of ocular movements has been increasingly used to detect subtle pathological modifications, caused by a wide variety of neurological diseases. We have developed a new microcomputer-based method for the analysis of smooth-pursuit ocular movements induced by constant velocity targets moving unpredictably at different velocities (including velocity values as high as 100 deg/s). The ocular movements are recorded by an electro-oculographic technique using silver-silver chloride electrodes fixed near the inner and outer canthi of both eyes. The signals are amplified by two DC amplifiers after a low-pass filtering (50 Hz), sampled at 250 Hz and digitized in a 12-bit form by an analog/digital converter. For each patient's evaluation, a series of 20 sweeps of the target is generated. The data analysis, which is performed automatically by the microcomputer, is based on the calculation of four parameters: average peak eye velocity (APEV); typical target velocity (TTV); percent target matching index after saccade removal (PTMI); typical matching target velocity (TMTV) after saccade removal. APEV is calculated as the average of the peak velocities estimated from the 20 sweeps. The purpose of TTV, which is defined as the value of target velocity at which the percent gain has decreased to slightly more than one third of the maximum percent gain, is to provide an overall index of the rate at which the percent gain decreases as the target velocity increases. PTMI describes the eye performance for each value of target velocity.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

Comparison of two nonlinear models for fitting saccadic eye movement data.

Saccadic eye movements are rapid shifts in the direction of gaze which are being studied increasingly for clinical and pharmacological purposes. The evaluation of the relationship between amplitude and peak velocity of these ocular movements (the so-called 'main sequence' plot) is particularly useful for characterising the saccade pattern in individual patients. This relationship is nonlinear and the peak velocity tends to achieve an asymptote for high values of amplitude. Since a standard parametrisation of the main sequence based on specific mathematical models has not yet been achieved, in the present study two simple models based on the Michaelis-Menten equation and on an exponential equation are proposed together with their implementation on a microcomputer. Two microcomputer programs are described which estimate the model parameters from the experimental data of the patients using a weighted nonlinear least-squares fit. The two procedures have been tested and compared in a series of 23 healthy volunteers. The following results (mean +/- S.D.) were obtained: Michaelis-Menten model. Km (degrees) = 31.2 +/- 7.7, Vmax (degrees/s) = 841.0 +/- 165.5, root-mean-squared error(%) = 6.0 +/- 1.6; exponential model. K (degrees) = 23.4 +/- 4.6, Vmax (degrees/s) = 578.0 +/- 97.4, root-mean-squared error(%) = 5.4 +/- 1.6. The two techniques of parametrisation provided similar indices of intra-individual variability in 4 healthy volunteers. In conclusion, our methods for saccade parametrisation can be regarded as simple but efficient tools for facilitating research on these ocular movements.

[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.

[Alterations of smooth-pursuit ocular movements in Alzheimer's disease]. / Alterazioni dei movimenti oculari di smooth pursuit nella malattia di Alzheimer.

Recent findings suggest that patients affected by Alzheimer's disease (AD) have evident alterations of smooth-pursuit ocular movements induced by a sinusoidal predictable target. For a better understanding of the possible modifications of this performance in patients with AD we evaluated, using a quantitative method, the smooth-Pursuit induced by ramps with constant, unpredictable velocities. Twelve patients with probable AD were studied. These patients were compared with twelve age matched healthy volunteers. Visual inspection of our recordings shows that AD patients have frequent, large saccades intrusions which in some cases appeared to disrupt smooth tracking, particularly for low target speeds. Furthermore, the smooth-pursuit eye velocity induced by target of high speed is significantly reduced in respect to that present in our control group. Some significant correlations between altered smooth-pursuit parameters and abnormal psychometric scores were noted.