Long-term vagus nerve stimulation in children with focal epilepsy.

OBJECTIVES: The aim of the study was to evaluate the long-term efficacy and hospitalization rates in children with refractory focal epilepsy treated by vagus nerve stimulation. MATERIALS AND METHODS: We retrospectively analyzed 15 children with intractable focal epilepsy treated by vagus nerve stimulation (mean age of 14.6 ± 2.5 years at the time of implantation). We analyzed the treatment effectiveness at 1, 2, and 5 year follow-up visits. We counted the average number of urgent hospitalizations and number of days of urgent hospitalization per year for each patient before and after the VNS implantation. RESULTS: The mean seizure reduction was 42.5% at 1 year, 54.9% at 2 years, and 58.3% at 5 years. The number of responders was 7 (46.7%) at 1 year and 9 (60%) at both 2 and 5 years. The mean number of urgent hospitalizations per patient was 1.0 ± 0.6 per year preoperatively and 0.3 ± 0.5 per year post-operatively (P < 0.0001). The mean number of days of urgent hospitalization per patient was 9.3 ± 6.1 per year preoperatively and 1.3 ± 1.8 per year post-operatively ( < 0.0001). CONCLUSIONS: Vagus nerve stimulation is an effective method of treating children with refractory focal epilepsy. It leads to a substantial decrease in the number and duration of urgent hospitalizations.

Perampanel Study 207: long-term open-label evaluation in patients with epilepsy.

OBJECTIVES: Evaluate interim long-term tolerability, safety and efficacy of adjunctive perampanel, a novel α-amino-3-hydroxy-5-methyl-5-isoxazolepropionic acid (AMPA)-receptor antagonist, in patients with refractory partial-onset seizures. MATERIALS AND METHODS: Study 207, an open-label extension (OLE) study (ClinicalTrials.gov identifier: NCT00368472), enrolled patients (18-70 years) who completed one of two randomized, placebo-controlled, dose-escalation Phase II studies. The OLE Treatment Phase comprised a 12-week Titration Period (2 mg increments of perampanel every 2 weeks to 12 mg/day, maximum) and a Maintenance Period, during which patients continued treatment up to a planned maximum of 424 weeks (~8 years). Interim analysis data cut-off date was 1 December, 2010. RESULTS: Of 180 patients completing the Phase II studies, 138 enrolled in study 207. At the time of interim analyses (approximately 4 years after study start), over a third (n = 53, 38.4%) remained on perampanel; 41.3% (n = 57) of patients had >3 years of exposure; and 13.0% (n = 18) had at least 4 years' exposure. Mean ± standard deviation (SD) duration of exposure was 116 ± 75 weeks and mean ± SD dose during the OLE Maintenance Period was 7.3 ± 3.3 mg. No new safety signals emerged with long-term treatment. Consistent with previous studies, the most common treatment-emergent adverse events were as follows: dizziness, headache and somnolence. Overall median (range) per cent change from baseline in seizure frequency per 28 days during open-label treatment was -31.5% (-99.2 to 512.2). CONCLUSIONS: Long-term - up to 4 years - adjunctive perampanel had a favourable tolerability profile in patients with refractory partial-onset seizures. Improvements in seizure control were maintained with long-term treatment.

Peri-ictal bed leaving in temporal lobe epilepsy: incidence and lateralizing value.

We analyzed peri-ictal bed leaving (PBL) symptoms in 105 patients with temporal lobe epilepsy (TLE). All patients were classified as Engel I at the 2-year follow-up visit. Histopathological examination revealed hippocampal sclerosis (TLE-HS) in 64 patients and other lesions in 38 patients (TLE-other); 3 patients had no lesions. We reviewed 412 seizures. PBL was defined as lateralized leaving of the bed occurring during the seizure or up to 3 minutes after the end of the seizure. PBL was observed in 28 of 105 patients (26.7%), and in 45 of 412 seizures (10.9%). PBL occurred more frequently in patients with TLE-HS than in patients with TLE-other (32.8% vs 17.1%, P=0.058). PBL was ipsilateral to the seizure onset in 71.4% of patients and 71.2% of seizures (P=0.012 and P<0.001). In patients with TLE-HS, PBL was ipsilateral to seizure onset in 76.2% of patients and 81.2% of seizures (P=0.008 and P<0.001). In patients with TLE-other, PBL was ipsilateral to seizure onset in 42.8% of patients and 46.1% of seizures. There were no differences in the incidence and lateralizing value between patients with right-sided and those with left-sided TLE. PBL is a relatively frequent peri-ictal sign in patients with TLE. The side of PBL in patients with TLE-HS lateralizes the seizure onset to the ipsilateral temporal lobe.

Occurrence and lateralizing value of "rare" peri-ictal vegetative symptoms in temporal lobe epilepsy.

We retrospectively investigated rare peri-ictal vegetative symptoms (PIVS) in 380 seizures of 97 patients with temporal lobe epilepsy (TLE): 234 seizures of 60 patients with TLE with mesiotemporal sclerosis (TLE/MTS) and 146 seizures of 37 patients with TLE with other lesions (TLE/non-MTS) who were at least 2 years after epilepsy surgery and classified as Engel I. We assessed the following PIVS: peri-ictal cough (pC), peri-ictal water drinking (pWD), peri-ictal vomiting (pV), and peri-ictal spitting (pS). We observed pC in 24.7% of patients and 10% of seizures; pWD in 14.4% of patients and 5.9% of seizures; pV and pS occurred more rarely. Both pWD and pC occurred significantly more often in those with TLE of the non- language-dominant hemisphere. The limited occurrence of pV and pS made it impossible to perform statistical analysis for these symptoms. In patients with TLE, pC and pWD were quite frequent; we observed pV and pS less frequently. Both pC and pWD have a significant lateralizing value in TLE.

Long-term levetiracetam treatment in patients with epilepsy: 3-year follow up.

OBJECTIVES: To assess the long-term efficacy and tolerability of levetiracetam in routine clinical practice. MATERIALS AND METHODS: We retrospectively analysed 218 patients, mostly adults, presenting mostly with localisation-related epilepsy, treated with levetiracetam as adjunctive therapy or monotherapy for up to 36 months. The primary points evaluated were: long-term retention rate, reasons for discontinuing levetiracetam and the percentage of seizure-free patients. RESULTS: The retention rate at 6, 12, 24 and 36 months following the commencement of levetiracetam treatment was 91.7, 75.2, 60.1 and 53.7% respectively. Sixty-seven (30.7%) patients discontinued levetiracetam treatment. During the clinical audit evaluation period, surgical resection or implantation of VNS was performed in 31 (14.3%) patients. In 53 of the 67 patients (79.1%), the treatment was discontinued due to lack of efficacy; in 14 patients (20.9%) treatment was discontinued due to adverse events. In total, 24 of 218 patients (11.0%) were seizure-free for 36 months. CONCLUSIONS: Levetiracetam is an effective and well-tolerated option for long-term treatment of epilepsy in adults.

Long-term levetiracetam treatment of epilepsy patients: clinical audit.

PURPOSE: The long-term efficacy and tolerability of levetiracetam (LEV) was analysed in 218 epilepsy patients. One hundred and ninety-nine patients were treated for at least 6 months. We evaluated LEV efficacy for all types of seizures together, and for simple partial, complex partial and secondary generalized seizures individually. RESULTS: A significant decrease in the number of seizures occurred after 6 months of treatment (p<0.001). Mean seizure frequency (irrespective of type) before LEV was 19.2 a month. The mean monthly frequency at 6, 12, 24 and 36 months dropped to 12.7, 10.5, 9.7 and 7.1 seizures a month, respectively. The mean percentage reduction in seizures at these times was 45.7, 52.1, 59.1 and 64.2% and the number of responding patients was 51.3, 54.2, 59.8 and 62.2%. The number of patients completely seizure free was 18.6, 16.7, 15.2 and 16.2%. We found similar results in the last three categories for partial simple, complex and secondary generalized seizures individually. Side effects in 18.3% of patients caused treatment discontinuation in 6.4%. The most frequent were somnolence, moodiness and dizziness. The retention rate at 6, 12, 24 and 36 months was 0.848, 0.72, 0.62 and 0.5, respectively. CONCLUSIONS: LEV is effective and well tolerated for long-term treatment of epilepsy.

Symptomatic rotational occlusion of the vertebral artery -- case report and review of the literature.

BACKGROUND: Intermittent symptomatic vertebral artery (VA) occlusion associated with voluntary turning of the head is known as bow hunter's stroke. A total of 40 such cases have been reported in the literature to date. We report a case successfully treated with surgical decompression and review the literature on this topic. Treatment options, including vertebral artery decompression and cervical fusion, are reviewed. CASE REPORT: A 54-year-old Caucasian male experienced headache, vertigo, and nausea in the past 20 years whenever he turned his head to the right. In a neutral head position all symptoms immediately disappeared. Six years before admission to our department the patient complained that prolonged rotation to the right caused vertigo and nausea accompanied by right-sided hemianopia and transient right-sided hemiparesis. At that time, no treatment was recommended and hemianopia did not improve spontaneously. The patient was referred to our department in 2002. Angiography disclosed normal carotid arteries, occlusion of the right VA, while the left VA was patent in the neutral position. However, during head rotation to the right, the artery became occluded at the C1-2 level. The left vertebral artery at level C1-2 was decompressed. RESULT: Postoperative angiography indicated patent left VA, both in the neutral position and during maximal rotation to the right. The patient is symptom-free for more than 24 months. CONCLUSION: Surgical treatment of bow hunter's syndrome is easy and effective; this case should draw more attention to a very rare cause of VBI. The authors believe that vertebral artery decompression represents a more physiological treatment modality, and hence decompression is recommended as a first-line procedure.

Lateralized ictal immobility of the upper limb in patients with temporal lobe epilepsy.

The primary aim of this study was to establish the incidence and the lateralizing value of 'lateralized ictal immobility of the upper limb' (LIL) in patients suffering from temporal lobe epilepsy (TLE), and to describe the connection between LIL and other clinical ictal signs. We retrospectively reviewed video records of 87 patients with TLE. We reviewed a total of 276 focal epileptic seizures with or without secondary generalization. We studied the incidence of LIL, its lateralizing value, and its relationship to other ictal clinical signs. Of the 87 patients, 49 had undergone a successful resective surgery at least 1 year prior to the study. LIL is a late sign in the course of partial seizure. It occurred in 25 of our 87 patients (28.7%), and in 47 of 276 seizures (17.1%). In all of the evaluated seizures, LIL occurred contralateral to the side of seizure onset (P < 0.001). LIL was always associated with ipsilateral upper limb automatisms, and in 63.1% of the occurrences, it was immediately followed by ictal dystonia. LIL is a more accurate term to describe what has previously been called 'ictal paresis' in the literature. Due to the inability to execute proper testing during a partial seizure, it is better to use the term LIL when making a visual analysis of a seizure. LIL is a more suitable term to describe the studied ictal sign. It is a relatively frequent sign in patients with TLE. LIL has an excellent lateralizing value for the contralateral hemisphere. It is a negative motor sign, and its genesis is probably associated with the epileptic involvement of the contralateral frontal lobe.

Ictal limb dystonia in temporal lobe epilepsy. an invasive video-EEG finding.

The aim of the investigation was to evaluate the ictal EEG in the putamen and the temporal and frontal lobes during contralateral ictal limb dystonia (ID). Ten epilepsy surgery candidates participated in the study. All of them were investigated using intracerebral and/or subdural electrodes. In four of the patients, the putamen was investigated with diagonal depth electrodes (patients 1-4), in six of the patients, both the temporal and frontal lobes were investigated (patients 5-10). All of the investigated contacts were located contralateral to the side of the ictal dystonia. All of the patients suffered from temporal lobe epilepsy (TLE); in patient 10, both temporal and frontal seizure types were recorded. A total of 20 complex partial seizures (CPS) were analysed. ID was never an early symptom in the course of CPS. Slow activity was recorded in the putamen in all 10 seizures of the four patients in whom the putamen was investigated (patients 1-4). In five of these seizures, there was a time-locked change in the ictal EEG in relation to the ID (slowing of activity in three seizures; acceleration in two seizures). At the time of the onset of ID, several cortical regions were involved in the ictal discharge, within both the contralateral temporal and frontal lobes. In all 10 seizures of the six patients in whom both the temporal and frontal lobes on the contralateral side were evaluated (patients 5-10), the ictal paroxysmal discharge was noted in both lobes (i.e. frontal and temporal) at the time of ID onset. We can conclude that ID is a late symptom in TLE. Widespread activation of the contralateral temporal and frontal lobes is needed for the appearance of ID; however, the critical region responsible for the genesis of ID was not revealed. Although there are some non-specific changes in the putamen contralateral to ID, the changes were never epileptic in type. The putamen probably collaborates in the genesis of ID, but it does not generate the epileptic discharge during its course.

A SEEG study of ERP in motor and premotor cortices and in the basal ganglia.

OBJECTIVE: Our intention was to study the electrical activity related to the cognitive processing of simple sensory stimuli in the brain structures that participate in motor control. We focused our interest on the 250-600 ms time window, in which cognitive activity most probably provides the basis for the activity recorded. METHODS: Intracerebral stereoelectroencephalography (SEEG) recordings were made from 15 epilepsy surgery candidates. We studied potentials that were recorded in a time window in which P300 usually could be recorded on the scalp and that were directly recorded from brain structures involved in motor control: the primary motor cortex (MC, Brodmann's area 4); the lateral and mesial (SMA) premotor cortices (Brodmann's area 6); and the basal ganglia. We evaluated the first distinctive potential to occur in the 250-600 ms time window that displayed an amplitude gradient in several adjacent contacts. Four protocols were performed: an auditory oddball (aP3); a visual oddball (vP3); and contingent negative variation (CNV) protocols, in which the potentials evoked by the auditory warning (aCNV) and visual imperative (vCNV) stimuli were evaluated. In the protocols aP3, vP3, and vCNV, the tested person responded by flexing his/her thumb or hand. In the aCNV paradigm, and in a further auditory oddball paradigm (aP3c), no motor response was required. We compared the presence of an event-related potential (ERP) with an amplitude gradient to the absence of a generator. RESULTS: The frequency of P3-like potential components was statistically significantly higher in the basal ganglia when compared with the explored cortical sites. Statistically non-significant latency differences between the basal ganglia and the cortex were displayed. The differences in the distribution of the potentials in the individual cortical areas were insignificant. The mean latency of vP3 was longer than the latencies of aP3, aP3c and vCNV. There was no significant difference between the distribution and latency of aP3 and aP3c. CONCLUSIONS: (1) ERPs are generated in cortical as well as in subcortical structures. (2) The cognitive processing of sensory information in all the tested protocols occurred in the basal ganglia; the occurrence in the investigated cortical areas was less frequent and more dependent on the task. The basal ganglia may play an integrative role in cognitive information processing, in motor and non-motor tasks.

Effect of vagal nerve stimulation on patients with bitemporal epilepsy.

Patients with bitemporal epilepsy are characterized by the existence of independent bitemporal seizure onset zones. The aim of this study was to evaluate the effect of chronic vagal nerve stimulation (VNS) on eight patients with bitemporal epilepsy. We demonstrated the gradually increased effect of VNS on the reduction of seizures as compared with baseline seizure frequency in patients with bitemporal epilepsy. The average seizure reduction increased from 4.2% at the 3-month follow-up visit to 18.2, 34.4 and 42.2% at the 6, 12 and 18-month follow-up visits. Similarly, a >or=50% reduction of complex partial seizures was reported at the 3-month follow-up visit in no patients (0%); at the 6-month follow-up visit in one patient (12.5%); at the 12-month follow-up visit in three patients (37.5%); and at the 18-month follow-up visit in five patients (62.5%). These data demonstrate the positive and long-lasting effect of VNS on seizure reduction in patients with intractable bitemporal epilepsy. The main mechanism of this chronic effect is not fully understood.

Effect of vagal nerve stimulation on auditory and visual event-related potentials.

Chronic unilateral vagal nerve stimulation (VNS) has been recently introduced into the therapy for intractable epileptic seizures. Its effect on cognitive functions in VNS-treated patients remains controversial. The aim of the present study was to evaluate the possible impact of therapeutic VNS on cognitive functions by means of event-related potentials analysis. Ten patients with medically intractable epilepsy, who had been implanted with VNS devices, participated in the study. Auditory and visual event-related potentials (ERPs) were repeatedly recorded, first just before the implantation of VNS devices, and then again 3-6 months after the device activation. The effect of lower intensity stimulation on the P3 component of ERPs was assessed. No significant differences were found in auditory ERPs; the latencies of P3 as well as N2/P3 peak-to-peak amplitudes were virtually identical. The same was true for mean P3 latencies of visual ERPs. However, higher visual N2/P3 peak-to-peak amplitudes were observed in the responses to targets that followed VNS, with a significant finding at the electrodes investigated. When comparing the effect of VNS on visual N2/P3 amplitude in each electrode separately, the most expressive differences were found in the frontal region. This observation supports the theory of a possible positive effect of low-intensity VNS on the cognitive functions.

The role of frontal and temporal lobes in visual discrimination task--depth ERP studies.

Visual event-related potentials were simultaneously recorded from different anatomical structures within frontal and temporal lobes in 12 epileptic patients. A simple discrimination task was performed to complement previous studies on the localization of P3 generators in the human brain. The role of multiple cortical structures in the generation of both P3a and P3b components was confirmed. Activities contemporary to a visual P3b were recorded in the hippocampus, amygdala and temporal pole. Anterior cingulate and orbitofrontal cortices-generated activities more closely related in time to the surface P3a. Earlier events related to visual discrimination took place in more lateral sites of the frontal lobe, but their contribution to the scalp P3 remains uncertain. Subsequently, mutual temporal relations among single generators were analyzed. The results suggested a processing-level hierarchy within the neural network for directed attention with a key role played by the dorsolateral prefrontal cortex.

Analysis of genomic integrity and p53-dependent G1 checkpoint in telomerase-induced extended-life-span human fibroblasts.

Life span determination in normal human cells may be regulated by nucleoprotein structures called telomeres, the physical ends of eukaryotic chromosomes. Telomeres have been shown to be essential for chromosome stability and function and to shorten with each cell division in normal human cells in culture and with age in vivo. Reversal of telomere shortening by the forced expression of telomerase in normal cells has been shown to elongate telomeres and extend the replicative life span (H. Vaziri and S. Benchimol, Curr. Biol. 8:279-282, 1998; A. G. Bodnar et al., Science 279:349-352, 1998). Extension of the life span as a consequence of the functional inactivation of p53 is frequently associated with loss of genomic stability. Analysis of telomerase-induced extended-life-span fibroblast (TIELF) cells by G banding and spectral karyotyping indicated that forced extension of the life span by telomerase led to the transient formation of aberrant structures, which were subsequently resolved in higher passages. However, the p53-dependent G1 checkpoint was intact as assessed by functional activation of p53 protein in response to ionizing radiation and subsequent p53-mediated induction of p21(Waf1/Cip1/Sdi1). TIELF cells were not tumorigenic and had a normal DNA strand break rejoining activity and normal radiosensitivity in response to ionizing radiation.

Prostate-specific antigen induction by a steroid hormone in T47D cells growing in SCID mice.

Previous studies revealed that prostate-specific antigen (PSA) is present in > 30% of human breast tumor cytosols. Survival analysis showed that patients with PSA-producing tumors have a reduced risk for relapse, suggesting PSA to be an independent favorable prognostic marker for a large subset of breast cancer patients. The present investigation established an in vivo model for the induction of PSA in human breast cancer tumors growing as xenografts in severe combined immunodeficient (SCID) mice. The human mammary cancer cell-line T47D was grown i.m. in female mice. When the tumor and leg diameter reached 10 mm, the mice were stimulated daily with norgestrel for either 5 or 7 days to produce PSA, and sacrificed on day 8. The prostate cancer cell-line LNCaP was grown in male mice and functioned as a positive control for PSA production. After T47D and LNCaP mice were sacrificed, a highly sensitive immunofluorometric assay was used to analyze the PSA concentration in the tumor, muscle, liver, and kidney cytosols. Norgestrel-stimulated T47D mice showed significantly more PSA in the tumors compared to tumors of the control mice. However, PSA levels in tumors of the stimulated mice were significantly lower than those in the LNCaP xenografts. No PSA levels above background were present in the blood and normal tissue of the norgestrel-stimulated or control T47D xenografts. This mouse model will be a valuable tool for investigating and screening new therapies for a subgroup of breast cancer patients who have significant PSA concentrations in their tumors.

Hereditary hemorrhagic telangiectasia with florid osseous dysplasia. Report of a case with differential diagnostic considerations.

The clinical presentation of hereditary hemorrhagic telangiectasia with various manifestations has been well described as has florid osseous dysplasia. There have been no cases reported of the two pathologic entities in the same patient. We present a case with the simultaneous occurrence of hereditary hemorrhagic telangiectasia and florid osseous dysplasia with important considerations for differential diagnosis, and we discuss whether this case presents a potential syndrome.

A twin study of genetic variation in proportional radiographic alveolar bone height.

The purpose of this study was to estimate the genetic variance for alveolar bone height by means of the classic twin method and the study of monozygous twins reared apart. Panoramic radiographs were obtained from 120 pairs of adult twins (mean age = 40.4 years, S.D. = 10.4 years), for comparison of 62 pairs of monozygous twins reared together (MZT), 25 pairs of like-sexed dizygous twins reared together (DZT), and 33 pairs of monozygous twins reared apart (MZA). Mesial and distal bone heights were determined as a proportion of tooth length. A full-mouth bone score was computed for each twin by averaging these proportions from all measurable teeth. Between-pair (B) and within-pair (W) variances were computed for each twin group. The population variances (B + W) of the MZT and DZT twin groups were similar, which validated a basic assumption of the twin model. Intraclass correlations and heritability estimates were also computed for the reared-together and reared-apart twin groups. Boot-strap sampling was used to provide estimates and confidence limits for these values. The intraclass correlations for the twin groups were: MZT = 0.70, DZT = 0.52, and MZA = 0.55. The results of this study suggest that there is significant genetic variance in the population for proportional alveolar bone height.

An improved head-and-neck phantom for radiation dosimetry.

To obtain accurate estimates of radiation doses within the head and neck, a phantom was constructed. The osseous structures were represented by a human skull and cervical vertebrae with Mix D simulating the soft tissues originally with the bone. The soft tissues of the head and neck were also represented by this mixture of wax, plastic, magnesium oxide, and titanium dioxide with the x-ray absorption and scattering properties nearly equal to water and soft tissue. Soft tissue thicknesses and facial contours were based on depths reported in the literature and supplemented by cadaver measurements. Air passages, air cells, sinuses, and the oral cavity were left open to accurately simulate the patient. The locations of 16 anatomic sites were based on cadaver dissection and measured relationships to osseous landmarks and the skin surface. To confirm the accuracy of the phantom, doses were measured with lithium fluoride thermoluminescent dosimeters and compared with the results of other investigations reported in the literature.