Congenital subpendymal giant cell astrocytoma in children with tuberous sclerosis complex: growth patterns and neurological outcome.

BACKGROUND: Literature regarding congenital subependymal giant cell astrocytomas (SEGA) is limited, and suggests they are at risk of rapid growth and complications. We sought to characterise the growth patterns of congenital SEGA. The second part of the study was an exploratory analysis of congenital SEGA as a possible biomarker for poor neurological outcome. METHODS: This single-centre case series describes ten patients with TSC who had SEGA diagnosed before 12 months. SEGA diameter and volumetric growth were analysed using serial MRIs. Neurological outcomes were compared to a genotype-matched group. RESULTS: All children with congenital SEGA had a TSC2 mutation. Patients were followed for 1-8.7 years, during which median SEGA growth rate was 1.1 mm/yr in diameter or 150 mm3/yr volumetrically. SEGA with volume > 500 mm3 had a significantly higher growth rate compared with smaller SEGA (462 mm3/yr vs. 42 mm3/yr, p = 0.0095). Children with congenital SEGA had a high prevalence of severe epilepsy, developmental disability and autism spectrum disorder. CONCLUSION: Congenital SEGA can follow a relatively benign course with a lower growth rate compared with published literature. Frequent neuroimaging surveillance is recommended for congenital SEGA with volumes exceeding 500 mm3. IMPACT: Congenital SEGA occur in 9.2% of paediatric patients with tuberous sclerosis complex. There are few published cases of congenital SEGA to date. This case series of ten patients adds our experience seen in a tertiary referral hospital over 10 years. Congenital SEGA can follow a relatively benign course with a lower growth rate compared with published literature. Congenital SEGA with volume exceeding 500 mm3 had a significantly higher growth rate compared with smaller SEGA and should have more frequent neuroimaging surveillance.

Mammalian target of rapamycin inhibitors for intractable epilepsy and subependymal giant cell astrocytomas in tuberous sclerosis complex.

OBJECTIVES: To evaluate the efficacy and side effects of oral mammalian target of rapamycin (mTOR) inhibitors in children and adolescents with tuberous sclerosis complex (TSC) and intractable epilepsy or subependymal giant cell astrocytoma (SEGA). STUDY DESIGN: Single-center series of 13 children and adolescents with TSC who received sirolimus or everolimus (mTOR inhibitors). The anticonvulsant response was evaluated in 7 patients with TSC and refractory seizures. Six patients with SEGAs were treated with either sirolimus or everolimus for nonsurgical management. SEGA volumes were assessed longitudinally using 1.5-T magnetic resonance imaging. RESULTS: Of the intractable seizure group (7 patients), 1 patient had >90% reduction, 4 had 50%-90% reduction, and 2 had <50% reduction. Three reported subjective improvements in learning. By 12 months of treatment, there were statistically significant reductions in the SEGA volumes in 4 patients who received mTOR inhibitors (P < .04). The mean SEGA volume after 6 months of treatment was 2.18 cm(3), which represents 33% reduction in the mean baseline volume of 3.26 cm(3). The mTOR inhibitors were well tolerated. Adverse effects include dyslipidaemia (3 of 13), gingivitis (1 of 13), anorexia (1 of 13), and mild gastrointestinal side effects (1 of 13). CONCLUSION: This case series suggests that mTOR inhibitors can improve seizures in those with TSC and refractory epilepsy. They are also an effective treatment for reducing the volume of SEGAs in patients with TSC not amenable to surgery with an acceptable side effect profile.

Frontal-midline theta from the perspective of hippocampal "theta".

Electrical recordings from the surface of the skull have a wide range of rhythmic components. A major task of analysis of this EEG is to determine their source and functional significance. The hippocampal "theta rhythm" has been extensively studied in rats and its rhythmicity has recently been shown to be functionally significant, per se. Here, we use relevant aspects of the hippocampal literature to provide perspective on one of the most studied human EEG rhythms: frontal-midline theta. We review its electrographic features, localization, prevalence, age distribution, behavioural modulation (particularly in relation to working memory, spatial navigation, episodic memory, internalised attention and meditation), relationship to personality, drug interactions, neurochemical relationships, and coherence with rhythmic activity at other sites. We conclude that FM-theta, like hippocampal theta, appears to play a role in (or at least occur during) processing of memory and emotion. It is correlated with working memory and/or sustained attention; but this does not entail a role in function since clear behavioural correlates of hippocampal theta have been demonstrated that are not sensitive to hippocampal damage. FM-theta is increased by anxiolytic drug action and personality-related reductions in anxiety, whereas hippocampal theta is decreased by anxiolytic drugs. In animals, frontal theta and hippocampal theta can be phase-locked or independent, depending on behavioural state. So, the cognitive functions of FM-theta, and their relationship to hippocampal theta, are unclear and definitive evidence for functional involvement in cognitive or emotional processing is lacking. One possible solution to this problem is analysis of FM-theta in animals-provided homology can be determined. The issues of sporadicity and low incidence of FM-theta also need to be addressed in the future. Changes in functional connectivity, indicated by changes in coherence, are also a largely untapped resource. We suggest that the most hopeful path to assessing the functions of FM-theta will be through the use of drugs, and the variation of their effects depending on baseline levels of FM-theta. Finally, we review some theories of theta function. Despite the apparent richness of the current data, we conclude that it is difficult (and may ultimately be impossible) to formulate a theory that attributes a specific cognitive function to FM-theta. However, the theories share some general computational assumptions and these should be a useful guide to future work and, ultimately, a definite theory of the function or functions of FM-theta.

Single-pulse electrical stimulation helps to identify epileptogenic cortex in children.

PURPOSE: The usefulness of single-pulse electrical stimulation (SPES) during intracranial recordings was evaluated in a pediatric population. This method is useful in identifying epileptogenic cortex in adult subjects. METHODS: We studied 35 children who were undergoing intracranial electroencephalography (EEG) recordings from two hospitals (King's College Hospital and Great Ormond Street Hospital for Sick Children, London, United Kingdom). In each patient we studied all available contacts using a series of 10 or more single, brief (1ms) electrical stimuli. The cortical responses were reviewed in detail. The data were examined for associations between response type, ictal onset zone, lesion boundary, and seizure outcome. RESULTS: We identified cortical responses to SPES that were similar to those reported in adults. In agreement with previous studies we found that two types of responses ("delayed" and "repetitive" responses) were associated with the ictal onset zone and the area of the presumed epileptogenic lesion. When these responses were present (54% of cases), the removal of the entire area responsible for the abnormal responses to SPES was associated with good outcome. CONCLUSION: Cortical responses to SPES in children provide new and additional information in the investigation of epileptogenic cortex in children during assessment for epilepsy surgery. This may improve the outcome for this difficult but important group.

Multifocal epilepsy: the role of palliative resection - intractable frontal and occipital lobe epilepsy secondary to radiotherapy for acute lymphoblastic leukaemia.

Patients with multifocal epilepsy are often considered unsuitable for epilepsy surgery. We report an adolescent with intractable frontal and occipital lobe seizures, secondary to complications of treatment for acute lymphoblastic leukaemia as a young child. Chemotherapy and radiotherapy were complicated by bilateral, posterior leukoencephalopathy and later an acquired frontal cerebral cavernous malformation (CCM). Detailed electro-clinical and imaging studies showed multiple, frontal lobe seizures per day with less frequent and non-debilitating, simple, occipital lobe seizures. Focal resection of the frontal CCM abolished the socially-disabling seizures with resultant marked improvement in the patient's quality of life at 12 months. Careful analysis of the type and impact of focal seizures in the setting of multifocal epilepsy may demonstrate that one seizure type is more deleterious to quality of life and may be amenable to surgery. In this situation, the patient may benefit significantly from surgery to resect the more active epileptic focus.

Computer-aided spatial classification of epileptic spikes.

The authors present a method that can be used to identify exemplar spikes from prolonged EEG recordings. To achieve this they have calculated single dipole source models for each automatically detected spike-like waveform. They used a dipole source algorithm that is computationally light and can be run on-line during EEG acquisition. Although a single dipole source model may not provide anatomically accurate information about the location of generators of all epileptiform abnormalities, it does provide a novel spatial parameter that may be useful in its own right. The authors use this spatial parameter and present the relative spatial density of the dipole locations in the form of three planar projections of the spherical model (a view from above, a view from the right, and a view from behind) and allow users to define the x-, y-, and z-coordinates of points of interest within the spherical model. They then present 10 example waveforms of events that have dipole source model locations that occur close to that seed coordinate. Overall, they found that this method performs very well for frequent events, but does not perform well for rare events or for diffuse EEG abnormalities.

Networks underlying paroxysmal fast activity and slow spike and wave in Lennox-Gastaut syndrome.

OBJECTIVE: To use EEG-fMRI to determine which structures are critically involved in the generation of paroxysmal fast activity (PFA) and slow spike and wave (SSW) (1.5-2.5 Hz), the characteristic interictal discharges of Lennox-Gastaut syndrome (LGS). METHODS: We studied 13 well-characterized patients with LGS using structural imaging and EEG-fMRI at 3 tesla. Ten patients had cortical structural abnormalities. PFA and SSW were considered as separate events in the fMRI analysis. RESULTS: Simultaneous with fMRI, PFA was recorded in 6 patients and SSW in 9 (in 2, both were recorded). PFA events showed almost uniform increases in blood oxygen level-dependent (BOLD) signal in "association" cortical areas, as well as brainstem, basal ganglia, and thalamus. SSW showed a different pattern of BOLD signal change with many areas of decreased BOLD signal, mostly in primary cortical areas. Two patients with prior callosotomy had lateralized as well as generalized PFA. The lateralized PFA was associated with a hemispheric version of the PFA pattern we report here. CONCLUSION: PFA is associated with activity in a diffuse network that includes association cortices as well as an unusual pattern of simultaneous activation of subcortical structures (brainstem, thalamus, and basal ganglia). By comparison, the SSW pattern is quite different, with cortical and subcortical activations and deactivations. Regardless of etiology, it appears that 2 key, but distinct, patterns of diffuse brain network involvement contribute to the defining electrophysiologic features of LGS.

High inter-reviewer variability of spike detection on intracranial EEG addressed by an automated multi-channel algorithm.

OBJECTIVE: The goal of this study was to determine the consistency of human reviewer spike detection and then develop a computer algorithm to make the intracranial spike detection process more objective and reliable. METHODS: Three human reviewers marked interictal spikes on samples of intracranial EEGs from 10 patients. The sensitivity, precision and agreement in channel ranking by activity were calculated between reviewers. A computer algorithm was developed to parallel the way human reviewers detect spikes by first identifying all potential spikes on each channel using frequency filtering and then block scaling all channels at the same time in order to exclude potential spikes that fall below an amplitude and slope threshold. Its performance was compared to the human reviewers on the same set of patients. RESULTS: Human reviewers showed surprisingly poor inter-reviewer agreement, but did broadly agree on the ranking of channels for spike activity. The computer algorithm performed as well as the human reviewers and did especially well at ranking channels from highest to lowest spike frequency. CONCLUSIONS: Our algorithm showed good agreement with the different human reviewers, even though they demonstrated different criteria for what constitutes a 'spike' and performed especially well at the clinically important task of ranking channels by spike activity. SIGNIFICANCE: An automated, objective method to detect interictal spikes on intracranial recordings will improve both research and the surgical management of epilepsy patients.

How wrong can we be? The effect of inaccurate mark-up of EEG/fMRI studies in epilepsy.

OBJECTIVE: The aim of this investigation was to determine the effect of inaccurate or inconsistent marking up of events in the EEG on statistical analysis of EEG/fMRI studies of patients with epilepsy. METHODS: EEGs obtained during EEG/fMRI studies conducted on 10 patients with epilepsy and six normal control subjects were reviewed. All clear epileptiform events were marked up in the patient EEGs, as were all small movement-related artefacts in the patient and control subject EEGs. We then considered the effect on the numbers of voxels above threshold in the resulting Statistical Parametric Mapping (SPM) analysis if events were omitted, mislabelled, or if event times were inconsistently marked up. RESULTS: Omitting true epileptiform events resulted in a decrease in the number of voxels that survive statistical threshold. Mixing epileptiform and non-epileptiform events in the SPM analysis generally (but not always) decreased the number of voxels that survived threshold. Inconsistent event mark-up had little effect if the inconsistency was small (<200 ms), but had more effect if it was large (>500 ms). CONCLUSION: It is important to accurately mark-up EEGs acquired during EEG/fMRI studies in order to get the best results from subsequent analyses. SIGNIFICANCE: Our study reveals the consequences of inaccurate review of the EEG in EEG/fMRI studies and suggests guidelines for the review of EEG in these investigations which, if followed, should result in studies of acceptable quality.

Heart rate changes and ECG abnormalities during epileptic seizures: prevalence and definition of an objective clinical sign.

PURPOSE: To determine the prevalence of heart rate changes and ECG abnormalities during epileptic seizures and to determine the timing of heart rate changes compared to the first electrographic and clinical signs. To assess the risk factors for the occurrence of ECG abnormalities. METHODS: We analyzed retrospectively 281 seizures in 81 patients with intractable epilepsy who had prolonged video-EEG and two-channel ECG. The nature and timing of heart rate changes compared to the electrographic and clinical seizure onset was determined. The ictal period (including one minute preictally and three minutes postictally) was analyzed for cardiac arrhythmias, conduction and repolarization abnormalities. Risk factors for cardiac abnormalities were investigated using parametric and non-parametric statistics. RESULTS: There was an increase in heart rate of at least 10 beats/minute in 73% of seizures (93% of patients) and this occurred most often around seizure onset. In 23% of seizures (49% of patients) the rate increase preceded both the electrographic and the clinical onset. ECG abnormalities were found in 26% of seizures (44% of patients). One patient had an asystole for 30 seconds. Long seizure duration increased the occurrence of ECG abnormalities. No other risk factor was found. CONCLUSIONS: Heart rate changes occur frequently and occur around the time or even before the earliest electrographic or clinical change. The change can clarify the timing of seizure onset and the specific rate pattern may be useful for seizure diagnosis and for automatic seizure detection. ECG abnormalities occur often and repeatedly in several seizures of the same patient.