Marja Äikiä

Children exposed to valproate in utero--population based evaluation of risks and confounding factors for long-term neurocognitive development.

PURPOSE To evaluate neurological and cognitive functioning of school-aged (> or =6 years) children exposed to valproate monotherapy in utero in a population based, evaluator-blinded, controlled study. METHODS Studied children (N=39, aged 6.6-13.4 years) and their mothers were identified through a population based pregnancy registry. Mothers with carbamazepine monotherapy and mothers with epilepsy but without antiepileptic drug (AED) treatment during pregnancy and their age and gender matched children served as controls. Hospital records were reviewed and neurological examination (Touwens test), intelligent quotients (IQ) of mothers (WAIS), and children (WISC-III) and neuropsychological assessment of children (NEPSY) were performed evaluator-blinded. RESULTS The prevalence of low intelligence (FIQ<80) was 19% (4/21) and the prevalence of exceptionally low intelligence (FIQ<70) 10% (2/21) in valproate (VPA) monotherapy exposed children. Children exposed to carbamazepine (CBZ) and children of women with epilepsy but without AED exposure during pregnancy had all at least low average intelligence. The mothers using valproate scored significantly lower (p<0.05) in FIQ, VIQ and PIQ tests and had also significantly lower (p=0.035) educational level. Altogether 21% (8/39) of the children had minor neurological dysfunctions. CONCLUSIONS In a population based setting inheritance and cumulating environmental factors may partly explain the increased prevalence of neurocognitive symptoms in children exposed to valproate in utero although concern about the possible long-term effects of intrauterine valproate exposure does exist.

Cognitive effects of oxcarbazepine and phenytoin monotherapy in newly diagnosed epilepsy: one year follow-up

We evaluated the effect of initial oxcarbazepine (OXC) monotherapy on memory, attention and simple psychomotor speed in 14 patients; 15 patients with initial phenytoin (PHT) monotherapy served as reference patients. Neuropsychological assessments were performed before starting the treatment and after 6 and 12 months follow-up with steady-state drug treatment. Differential cognitive effects of OXC and PHT were not apparent in our study. As the efficacy of present antiepileptic drugs in adult epilepsy is analogous, the choice of drug is determined by the comparative side effects of the drugs. In the present study the number of successfully treated patients was similar in both OXC and PHT groups. As far as cognitive side effects are concerned our results revealed no evidence favoring either antiepileptic over the other.

Long-term epilepsy surgery outcomes in patients with MRI-negative temporal lobe epilepsy

Purpose:  The outcome of surgery in patients with temporal lobe epilepsy (TLE) and normal high‐resolution magnetic resonance imaging (MRI) has been significantly worse than in patients with unilateral hippocampal damage upon MRI. The purpose of this study was to determine the long‐term outcomes of consecutive true MRI‐negative TLE patients who all underwent standardized preoperative evaluation with intracranial electroencephalography (EEG) electrodes.

Verbal Memory in Newly Diagnosed Patients and Patients with Chronic Left Temporal Lobe Epilepsy

The objective of this study was to evaluate verbal memory in newly diagnosed and chronic left temporal lobe epilepsy (LTLE). Verbal memory performance of 39 newly diagnosed, previously untreated adult patients with LTLE and 16 patients with chronic LTLE, as well as 46 healthy controls, was analyzed. The patients with newly diagnosed and chronic LTLE had impaired verbal memory performance compared with normal controls. Memory performance was more affected in chronic LTLE. However, preliminary data from 5-year follow-up of 20 newly diagnosed LTLE patients did not show any deterioration in verbal memory performance. The memory impairment was not associated with the etiology of epilepsy or the hippocampal volumes, but was associated with early onset of epilepsy in LTLE and with secondarily generalized seizure type in newly diagnosed LTLE. The results of this study show that verbal memory is impaired not only in chronic LTLE but also in newly diagnosed, untreated LTLE. This suggests that the memory problems observed in patients with chronic LTLE cannot be attributed solely to medication effects or the chronic effects of recurrent seizures.

Long-term cognitive and EEG effects of tiagabine in drug-resistant partial epilepsy.

A new anti-epileptic drug, tiagabine, is a potent inhibitor of GABA uptake into neurons and glia. Tiagabine has shown promising efficacy and safety profiles as add-on treatment for partial seizures. We evaluated the long-term effects of tiagabine on cognition and EEG in 37 patients with partial epilepsy. The study protocol consisted of a randomized, double-blind, placebo-controlled, parallel-group add-on study and an open-label extension study. During the 3 month double-blind phase at low doses (30 mg/day) tiagabine treatment did not cause any cognitive or EEG changes as compared with placebo. Tiagabine treatment did not cause deterioration in cognitive performance or produce any rhythmic slow-wave activity or other constant, new abnormalities on EEG during longer follow-up with successful treatment on higher doses after 6-12 months (mean 65.7 mg/day, range 30-80 mg/day) and after 18-24 months (mean dose 67.6 mg/day, range 24-80 mg/day). The daily dosages in the long-term follow-up of the present study are higher than in the previous reports.

Brain atrophy and neuropsychological outcome after treatment of ruptured anterior cerebral artery aneurysms: a voxel-based morphometric study

IntroductionCognitive impairment after aneurysmal subarachnoid hemorrhage (aSAH) is frequently detected. Here, we describe the pattern of cerebral (gray matter) atrophy and its clinical relevance after treatment of aSAH caused by a ruptured anterior cerebral artery (ACA) aneurysm.MethodsThirty-seven aSAH patients with ACA aneurysm (17 surgical, 20 endovascular treatment) and a good or moderate clinical outcome (Glasgow Outcome Scale V or IV) and 30 controls underwent brain MRI. Voxel-based morphometric analysis was applied to compare the patients and controls. Patients also underwent a detailed neuropsychological assessment.ResultsThe comparisons between controls and either all patients (n = 37) or the subgroup of surgically treated patients (n = 17) revealed bilateral cortical atrophy in the frontal lobes, mainly in the basal areas. The brainstem, bilateral thalamic and hypothalamic areas, and ipsilateral caudate nucleus were also involved. Small areas of atrophy were detected in temporal lobes. The hippocampus and parahippocampal gyrus showed atrophy ipsilateral to the surgical approach. In the subgroup of endovascularly treated patients (n = 15), small areas of atrophy were detected in the bilateral orbitofrontal cortex and in the thalamic region. Twenty patients (54%) showed cognitive deficits in neuropsychological assessment.ConclusionGroup analysis after aSAH and treatment of the ruptured ACA aneurysm revealed gray matter atrophy, principally involving the frontobasal cortical areas and hippocampus ipsilateral to the surgical approach. Areas of reduced gray matter were more pronounced after surgical than endovascular treatment. Together with possible focal cortical infarctions and brain retraction deficits in individual patients, this finding may explain the neuropsychological disturbances commonly detected after treatment of ruptured ACA aneurysms.

Memory and attention in newly diagnosed epileptic seizure disorder

Interictal disturbances of memory and attention were evaluated in 74 adults with newly-diagnosed untreated epileptic seizures and no other known brain pathology. In approximately 30% of the patients with cryptogenic seizures, the average memory and attention scores indicated subtle dysfunction compared with normal control group. The patients had difficulties in tasks requiring memory, sustained attention and flexible mental processing, whereas they had normal attention span, simple speed of tracking and simple psychomotor speed. The memory difficulties may be related to attentional dysfunction leading to impaired or slowed initial encoding of memory trace, and also to a deficit in storing process and hippocampal dysfunction. These findings could have important implications for establishing criteria for identifying patients who develop chronic epilepsy and who thereby would benefit from early therapeutic intervention.

Verbal learning and memory in newly diagnosed partial epilepsy

Verbal learning and memory of 56 adults with newly diagnosed partial epilepsy and no other known brain pathology were compared with memory performance of a normal control group. Memory was evaluated with a list learning test and with recall of logical prose under both immediate and delayed recall conditions. The patients and the controls did not differ in immediate and delayed recall of logical prose. Also learning and immediate recall of the word list was comparable in both groups. After delay the patients recalled fewer words than the control group (P < 0.001), and the percent retention of words was lower in the patients (P < 0.001). The patients with newly diagnosed epilepsy more frequently exhibited mild verbal memory dysfunction as shown in delayed recall of word list. Moderate memory impairment is seen in a group of patients who have deficits in immediate and delayed memory. Follow-up is needed to find out whether patients with memory deficits at the time of diagnosis are those who develop intractable chronic epilepsy.

MRI-based Hippocampal Volumetry and T sub 2 Relaxometry: Correlation to Verbal Memory Performance in Newly Diagnosed Epilepsy Patients with Left-sided Temporal Lobe Focus

The structural damage in the left hippocampus measured by volumetric MRI was shown to correlate with the impairment of verbal memory performance in chronic left-sided temporal lobe epilepsy. [1] In addition to volumetric measurements, MRI T2 relaxometry was suggested to provide a sensitive quantitative means of assessing the degree of hippocampal pathology in temporal lobe epilepsy. [2] We showed earlier in separate patient populations that patients with partial epilepsy of unknown etiology exhibit subtle verbal memory dysfunction measured by neuropsychological tests [3] and mild hippocampal damage measured by MRI volumetry [4] already at the time of diagnosis. There are no data of the correlation of MRI-based quantitative measurements of hippocampus with the memory performance in newly diagnosed patients. We measured hippocampal volumes and T2 relaxation times using a 1.5-T MRI imager in …

Cognitive Adverse Effects of Antiepileptic Drugs

SummarySeveral early studies suggested that differences exist between antiepileptic drugs (AEDs) in terms of their propensity to cause adverse effects on cognitive functions, favouring carbamazepine over phenobarbital (phenobarbitone), phenytoin and valproic acid (sodium valproate). The combined results of recent studies in patients and healthy volunteers reveal that at therapeutic serum concentrations phenobarbital, phenytoin, carbamazepine, oxcarbazepine and valproic acid produce nearly comparable adverse effects on higher cognitive functions.The newer AEDs (with the exception of zonisamide and topiramate) appear to induced fewer cognitive adverse effects than the older agents. Furthermore, there is limited evidence that gabapentin, lamotrigine and vigabatrin may have beneficial effects on cognitive function. Some of the newer AEDs may also have neuroprotective effects that can prevent seizure-induced neuronal damage, and so reduce cognitive dysfunction. This is an important clinical consideration, as even modest differences between older and newer AEDs are relevant for patients.