Installation of the 1.5 T MRI accelerator next to clinical accelerators: impact of the fringe field.

In the UMC Utrecht a prototype MRI accelerator has been installed to investigate the feasibility of real-time, MRI guided radiotherapy. The system consists of a 6 MV Elekta (Crawley, UK) accelerator and a 1.5 T Philips (Best, The Netherlands) MRI system. The system is installed in a standard radiotherapy bunker. The bunker is at the corner of a block of six bunkers, so there are three neighbouring clinical Elekta accelerators. During ramping of the magnet, the magnetic fringe field in the two nearest bunkers was measured as a function of the magnetic field strength of the MRI magnet. At 8 m, a maximum increase of 1.5 G was measured, at 12 m, 0.6 G. This is up to three times the earth's magnetic field. The clinical accelerators are needed to be re-calibrated in order to operate in such an external magnetic field. The resulting radiation field flatness of the clinical accelerators was measured and was similar to the situation before ramping the magnet.

Integrating a 1.5 T MRI scanner with a 6 MV accelerator: proof of concept.

At the UMC Utrecht, The Netherlands, we have constructed a prototype MRI accelerator. The prototype is a modified 6 MV Elekta (Crawley, UK) accelerator next to a modified 1.5 T Philips Achieva (Best, The Netherlands) MRI system. From the initial design onwards, modifications to both systems were aimed to yield simultaneous and unhampered operation of the MRI and the accelerator. Indeed, the simultaneous operation is shown by performing diagnostic quality 1.5 T MRI with the radiation beam on. No degradation of the performance of either system was found. The integrated 1.5 T MRI system and radiotherapy accelerator allow simultaneous irradiation and MR imaging. The full diagnostic imaging capacities of the MRI can be used; dedicated sequences for MRI-guided radiotherapy treatments will be developed. This proof of concept opens the door towards a clinical prototype to start testing MRI-guided radiation therapy (MRIgRT) in the clinic.

Eight-channel transmit/receive body MRI coil at 3T.

Multichannel transmit magnetic resonance imaging (MR) systems have the potential to compensate for signal-intensity variations occurring at higher field strengths due to wave propagation effects in tissue. Methods such as RF shimming and local excitation in combination with parallel transmission can be applied to compensate for these effects. Moreover, parallel transmission can be applied to ease the excitation of arbitrarily shaped magnetization patterns. The implementation of these methods adds new requirements in terms of MRI hardware. This article describes the design of a decoupled eight-element transmit/receive body coil for 3T. The setup of the coil is explained, starting with standard single-channel resonators. Special focus is placed on the decoupling of the elements to obtain independent RF resonators. After a brief discussion of the underlying theory, the properties and limitations of the coil are outlined. Finally, the functionality and capabilities of the coil are demonstrated using RF measurements as well as MRI sequences.

A multicenter, randomized clinical study to evaluate the effect on cognitive function of topiramate compared with valproate as add-on therapy to carbamazepine in patients with partial-onset seizures.

PURPOSE: This study compares the cognitive effects of topiramate (TPM) with those of valproate (VPA) using efficacious doses of each drug when used as adjunctive therapy to carbamazepine (CBZ). A key question of the study is to what extent a more gradual introduction of TPM improves tolerability and prevents cognitive impairment. METHODS: The study is a multicenter, randomized, observer-blinded, parallel-group clinical trial with VPA or TPM given as first-line add-on therapy to steady-state treatment with CBZ. TPM is introduced at 25 mg and increased with weekly 25mg/d increments to a minimum dosage of 200 mg/d. The target dosage ranges from 200 to 400 mg/d for TPM and is 1800 mg/d for VPA. The study evaluates cognitive function changes from baseline to end point (after 20 weeks of treatment) and during titration (after 8 weeks of treatment). The primary outcome measure is the difference between the treatments (TPM versus VPA) in change from baseline to end point and change from baseline to titration, using a 95% confidence interval approach. RESULTS: For the 10 baseline-to-end point comparisons, one test measuring short-term verbal memory (Rey Auditory Verbal Learning Test) yields a statistically significant difference between the treatments (p = 0.02), showing worsening for TPM and improvement of scores for VPA. The 10 baseline-to-titration comparisons also show one statistically significant difference, again for a test measuring short-term memory (Recognition of Words; p = 0.04), showing a larger change in the negative direction for TPM. None of the mood tests or the test for subjective complaints shows statistically significant differences between the treatments, although more scores are in the negative direction for TPM during titration. CONCLUSION: Although the pattern of changes in the negative direction seems consistent with clinical information, the differences found between the treatments are small. An important finding of our study is that, when the results are compared with those of other studies, it is clear that gradual introduction of TPM can reduce the extent of cognitive impairment (with a maximum of about 0.6 SD).

[Antiepileptics]. / Anti-epileptica.

Despite introduction of new antiepileptic drugs the established drugs phenytoin, carbamazepine and valproate still provide the treatment of choice in most forms of epilepsy, being efficacious in approximately two-thirds of all newly referred patients. In 20-60% of patients resistant to treatment with the older drugs, a 50% reduction of seizure frequency can be achieved by adding ethosuximide, clobazam, vigabatrine, oxcarbazepine, lamotrigine, felbamate, tiagabine or topiramate to the classic treatment. The majority of the new drugs are free of the problematic enzyme induction of the older compounds, making monotherapy as well as combination therapy much easier. To what extent the new antiepileptic drugs are going to be used for the treatment of patients with epilepsy will depend on the analysis of cost and benefits. This will be based on efficacy, side effects, interactions and teratogenicity of these new compounds.

Prospective study of the prevalence of Alzheimer-type dementia in institutionalized individuals with Down syndrome.

Institutionalized patients with Down syndrome (n = 307) were monitored for 5 to 10 years prospectively to determine prevalence of Alzheimer-type dementia. Clinical signs, cognitive functioning, and EEGs were assessed. When possible, postmortem neuropathological examinations were conducted. Progressive mental and physical deterioration was found for 56 of the residents. Mean age at onset of dementia was 56 years. Prevalence increased from 11% between ages 40 and 49 to 77% between 60 and 69. All patients 70 and over had dementia. Neuropathological findings were consistent with clinical diagnosis. Use of a dementia checklist, cognitive skills inventory, and EEG reliably detected Alzheimer-type dementia at an early stage.

Use of electroencephalography to detect Alzheimer's disease in Down's syndrome.

We studied the role of electroencephalography (EEG) in the diagnosis of Alzheimer-type dementia in patients with Down's syndrome. 197 patients with Down's syndrome were monitored for 5 to 8 years. Aspects of cognitive functioning were assessed twice yearly. EEGs were scored in a blind fashion, and changes in the EEG were compared to changes in cognitive functioning. When possible, a neuropathological post-mortem examination was performed. Cognitive functioning was drastically reduced in 29 patients. The dominant occipital rhythm became slower at the onset of the cognitive deterioration, and eventually disappeared. In 11 of these patients neuropathological examination showed a severe form of Alzheimer's disease. Changes in the frequency of the dominant occipital rhythm could distinguish between Alzheimer's disease or other causes as underlying the cognitive decline. Slowing of the dominant occipital rhythm seems to be related to Alzheimer's disease in patients with Down's syndrome, and the frequency of the dominant occipital activity decreases at the onset of cognitive deterioration. The EEG is thus an important tool in the clinical diagnosis of Alzheimer-type dementia in patients with Down's syndrome.

Effect of epilepsy, seizures and epileptiform EEG discharges on cognitive function.

Patients with an established diagnosis of epilepsy were included in three groups on the basis of the absence (Group 2) or presence (Group 3) of epileptiform EEG discharges or subtle seizures (Group 4) during the cognitive assessment procedure. A separate age-matched non-epileptic control group (Group 1) was formed. Twenty-five patients were included in each of the four groups. Thus, a total of 100 patients were investigated. The patients were assessed with continuous 21-channel EEG and video-monitoring, combined with cognitive testing. The results show consistently lower performance on cognitive tests for Group 4, the group with subtle seizures. The difference with the control group was significant for the intelligence subtests and for the complex information processing test (p < 0.05). No transient cognitive impairment was found. The results are discussed in the light of possible factors that may be responsible for the lower test-scores in the patients of Group 4: both the ictal effects of the seizures themselves, postictal effects and the effects of the epileptiform EEG discharges may have had an impact on cognitive performance. Finally the absence of evidence for transient cognitive impairment in a group with frequent epileptiform EEG discharges is discussed in detail.

Withdrawal of antiepileptic drugs (AEDs) in seizure-free patients, risk factors for relapse with special attention for the EEG.

When a patient has remained free from seizures for several years while taking antiepileptic drugs (AED) the question arises whether or not the medication can be withdrawn. Therefore it would be desirable to be able to identify reliably those patients who will remain seizure-free without treatment. Numerous variables might be of prognostic importance but our knowledge about the significance of demographic, genetic, aetiological, pathophysiological and treatment-related factors remains extremely poor. Although an abnormal inter-ictal EEG has been repeatedly cited as predictive of relapse during and after AED withdrawal, there is little evidence to support this view. There is a need for more precise individual prediction of risk but as long as patients with forms of epilepsy with widely varying prognosis are grouped together in AED withdrawal trials the outcome of these trials will never reach consensus about the relapse risk and about the possibility of predict relapse in individual patients.

Effect of sabeluzole (R 58,735) on memory functions in patients with epilepsy.

Sabeluzole, a new benzothiazol derivative, has shown positive effects on memory function in animals and in normal volunteers. The present study reports the results of sabeluzole, in memory-impaired patients with localization-related (partial) epilepsy. A randomized, double-blind placebo-controlled parallel-group design was used. A total of 38 patients entered a prospective baseline. Five patients dropped out from the study, thus 33 patients were randomly assigned to either a 12-weeks treatment with sabeluzole (n = 14) or placebo (n = 19). The treatment phase was preceded by a titration phase of 4 weeks to obtain serum levels of sabeluzole between 50 and 130 ng/ml. In order to maintain blindness, a sham titration was carried out in the placebo group. The number of 'responders', i.e. patients with a > 1 SD improvement on at least three of the memory tests was 9 out of 14 (64.3%) in the sabeluzole group and 7 out of 19 (36.8%) in the placebo group. This suggests a clinically relevant effect of sabeluzole. The analysis of the memory tests showed a statistically significant improvement with sabeluzole on the verbal long-term memory test. This could represent a specific drug effect and is in line with previous results of normal volunteer studies that also found improvement mainly restricted to the area of verbal long-term memory.

Gamma-vinyl GABA (vigabatrin) and mood disturbances.

We explored factors that may predispose patients to adverse mood effects during treatment with vigabatrin (gamma-vinyl GABA; VGB): mood disorders before VGB treatment, type of epilepsy, seizure type and seizure frequency, type and number of comedication, and VGB dose. The clinical relevance of such a study is that it may help identify circumstances in which VGB should be administered with caution. Seventy-three patients (40 males, 33 females), all with refractory epilepsies, who received VGB as add-on therapy, were assessed by the Amsterdamse Stemmingslyst (ASL), a mood-rating scale, before the start of treatment, and demographic and clinical data were recorded. The patients were followed for 6 months after the start of VGB treatment. Treatment with VGB had to be discontinued in 38 patients (52% of the total sample). Mood problems were the main reason for discontinuation in 9 (12.3% of the total sample). In 6 other patients, mood problems were mentioned as the reason for discontinuing treatment, in combination with lack of drug efficacy. Development of adverse mood effects could not be predicted by a specific mood profile on the ASL. Before treatment, the "mood problems discontinuation group" did not show extreme scores for any assessed areas of mood and no significant differences from other patients were noted on the mood scales. Neither did clinical or demographic data show statistically confirmed specific characteristics for the mood problems discontinuation group, though the patients tended to use more antiepileptic drugs (AEDs) as cotherapy, to have a slightly lower daily dose of VGB, to be slightly older, and were mostly female.(ABSTRACT TRUNCATED AT 250 WORDS)

Cognitive side-effects of phenytoin compared with carbamazepine in patients with localization-related epilepsy.

In continuation of an earlier study of our group (Neurology, 43 (1) (1993) 41-51), we present the results of an investigation of the adverse effects of carbamazepine versus phenytoin on cognitive function. Two groups of twenty-five patients are compared in an open, parallel group and non-randomized clinical investigation: a group of patients on carbamazepine (CBZ) monotherapy versus a group of similar size on phenytoin (PHT) monotherapy. The two groups do not show significant differences on variables that could confound the comparison of drug-specific adverse effects: age, gender, intelligence, type of epilepsy, seizure type, seizure frequency, EEG focus and age at onset of the epilepsy. All patients were investigated with a comprehensive neuropsychological test battery ('FePsy'), assessing the cognitive domains of 'speed factors', memory and attention. The results show lower performance in the PHT group compared to the CBZ group on all tests measuring motor speed. Additionally, there is evidence that PHT also affects the speed of central 'higher cortical' processing systems. Our investigation also shows slower performance in tasks that measure speed of information processing ('mental speed'). The other investigated areas, i.e. short-term memory, long-term (verbal and non-verbal) memory and selective attention, do not reveal statistically significant differences between the two groups. These results reconfirm that patients on PHT may suffer from cognitive side-effects even when the medication is sufficiently controlled and the drugs are given within the assumed therapeutical interval.

Home EEG and video monitoring in epilepsy: first experiences.

In an out-patient epilepsy clinic methods were developed for mobile epilepsy diagnosis and treatment. One of the diagnostic facilities is long-term EEG/video monitoring at home. Method and first results are presented together with a case report of an 8-year-old boy with persistent seizures.

Memory complaints, memory disorders and focus localization in patients with partial epilepsy.

Our study aimed at analysing effects of epileptic foci on memory function in patients with partial epilepsy. Twenty-eight patients with spontaneous memory complaints and psychometrically established memory disorders were assessed by 21-channel electroencephalography recorded both during cognitive testing and during 99mTc-HMPAO single photon emission computed tomography (SPECT). Computed tomography (CT) was performed on the same day. None of the epilepsy-related factors (seizure type, seizure frequency, type of epilepsy, age at onset of the seizures, type of antiepileptic treatment) could be related directly to severity or type of memory impairment (classified into the categories 'global', 'verbal' and 'non-verbal'). Remarkably, this study found no significant relationship between EEG focus localization and severity of measured memory impairment. Most areas with hypoperfusion on the SPECT were found in the group with global (severe) amnesia, typically with a right frontal localization. Abnormalities on CT were predominantly found in the same group, however, with a right-sided parietal localization. An unanticipated finding was that the majority of temporal CT and SPECT lesions were found in the group with relatively better memory performance.

Focus localization in patients with partial epilepsy with 99Tcm-HMPAO SPECT under continuous surface EEG monitoring.

Our study was aimed at determining the validity of 99Tcm-HMPAO single photon emission computed tomography (SPECT) in the localization of the epileptogenic focus by correlating this diagnostic method with other auxiliary investigations such as surface EEG and X-ray transmission computed tomography (CT). Twenty-eight patients with partial epilepsy and spontaneous memory complaints were assessed with a 21-channel EEG recorded during psychometric evaluation of the memory complaints and with a 12-channel EEG during 99Tcm-HMPAO SPECT. No significant agreement was observed for total focus localization by the two EEGs, CT or SPECT. The EEGs were highly reproducible. Frontal and temporal pathology on CT resulted in frontal and temporal cold spots on SPECT on the same side in six patients. In addition, SPECT demonstrated frontal, temporal or posterior temporal-inferior parietal cold spots in nine patients without accompanying pathology on CT. It is concluded that CT and SPECT may provide complementary anatomical and functional information, respectively, to the EEG. Furthermore, SPECT may be complementary to CT in visualizing functional deficits without an anatomical correlate. The value of SPECT studies in partial epilepsy may be improved by increasing the resolution of the SPECT system and by simultaneous EEG monitoring.

Epilepsy care in The Netherlands.

In this article models of epilepsy care in the Netherlands are outlined. Mostly this care is aimed at people with uncontrolled epilepsy who may have suffered from the adverse effects of ignorance, prejudice and even discrimination. Many of these adverse factors should be avoidable in future as the educational programmes for people with epilepsy, professionals and the general public take full effect. Meanwhile there is a great deal that can be done to rehabilitate people whose seizures are a problem and whose social abilities fall short of the standards that are required for independent and self-fulfilling living in any society. The models of care described are very sophisticated and they have been developed over many years. They require well-trained and motivated staff and sometimes elaborate and expensive medical diagnostic equipment. But this should not put anybody off as the principles behind any model of care should be the same: Accurate diagnosis. Optimal drug and other treatment (this should be optimal treatment available in that country). Education of the patient and family about all aspects of epilepsy. Opportunity to share experiences. A multidisciplinary approach to identified problems (a multidisciplinary approach can be taken by one person, although a team of people from different disciplines is ideal.) Objectives agreed by all participants.

Syncope or seizure? A matter of opinion.

We studied the diagnostic interpretation by physicians of written histories of 118 patients with a transient loss of consciousness. Considerable disagreement about a diagnosis of either syncope or seizure was found. Overall agreement was only 31%; an erroneous diagnosis was made in 16% of cases. We concluded that the diagnosis of a seizure after a single event is often too unreliable to justify early treatment.

Syncope or seizure? The diagnostic value of the EEG and hyperventilation test in transient loss of consciousness.

In a prospective study of consecutive patients (age 15 or over) with transient loss of consciousness 45 patients had a history of seizure and 74 patients had a history of syncope. All patients had an EEG, ECG, laboratory tests and a hyperventilation test and were followed for an average of 14.5 months. Epileptiform activity in the interictal EEG had a sensitivity of 0.40 and a specificity of 0.95 for the diagnosis of a seizure. Epileptiform activity nearly doubled the probability of a seizure in doubtful cases. If no epileptiform activity was found, this probability remained substantially the same. The hyperventilation test had a sensitivity of 0.57 and a specificity of 0.84 for the diagnosis of syncope. A positive test increased the probability of syncope half as much in doubtful cases. A negative test did not exclude syncope. Laboratory tests were not helpful except for an ECG which was helpful in elderly patients.

A double-blind, placebo-controlled evaluation of the efficacy and safety of loreclezole as add-on therapy in patients with uncontrolled partial seizures.

Sixty-two patients with uncontrolled partial seizures participated in a 12-week, double-blind, placebo-controlled add-on-trial. Thirty-two patients received loreclezole and 30 a placebo as add-on therapy. Loreclezole was targeted at a plasma level of 1-2 mg/l. In spite of an antiepileptic therapy, usually with 2 or 3 antiepileptic drugs, these patients had at least 4 seizures a month during the baseline period. At the end of the treatment phase with loreclezole and placebo, individual responses varied widely. The median change in the daily seizure frequency was not significantly different in the 2 groups. However, when individual responses are considered, 6 patients in the verum group (19%) experienced a seizure reduction of 50% or more, compared with no patients in the placebo group. During the trial, only mild adverse events were reported in both the loreclezole and the placebo group, nor were any clinically relevant abnormalities seen in the haematological and biochemical analysis. The efficacy and safety of higher loreclezole plasma concentrations were studied in a long-term follow-up trial, the results of which are presented in the following article.