VISUAL SNOW SYNDROME IN A PEDIATRIC CASE.

INTRODUCTION Visual snow (VS) is a rare condition that is characterized by continuous dynamically flickering dots in the entire visual field that imitate the 'static' or 'snow' of an analogue television set that is not connected to the antenna (1). VS was first described in 3 of 10 migraineurs patients who presented with a spectrum of positive visual symptoms (2). The symptoms of VS can persist for many years. Although VS might be expressed in patients with migraine as visual aura, persistent VS has been accepted as a distinct clinical entity and termed as visual snow syndrome (VSS) independently from migraine. Schankin et al. proposed that the criteria for diagnosis of VSS consisted of visual snow as the main criterion, with some additional criteria (3). A few cases with childhood VSS have been described in literature (4-6). Herein, the case of a teenager was presented to emphasize the importance of differential diagnosis in persistent positive visual phenomena.

A genetic locus for sensory epilepsy precipitated by contact with hot water maps to chromosome 9p24.3-p23.

Hot water epilepsy (HWE) is a rare form of sensory epilepsy where seizures are precipitated by a stimulus of contact with hot water. While earlier studies have suggested causal role of genes for HWE, specific underpinnings are beginning to be explored only recently. We carried out a whole genome-based linkage analysis in a family where most of its members affected by HWE and found evidence of a previously unknown locus at chromosome 9p24.3-p23. Parametric two-point analysis suggested linkage with the greatest LOD score of 3.42 for the marker D9S286 at 9p24.1 at recombination fraction (θ) = 0, 90% penetrance value and 1% phenocopy rate. The highest multipoint LODscore of 3.42 was obtained for same marker at 9p24. The critical genetic interval of about 10 Mb of DNA was defined by the markers D9S917 and D9S168 corresponding to the centromere-distal and centromere-proximal recombination boundaries, respectively. This observation along with our previous findings of hot water genetic loci at 10q21.3-q22.3 (OMIM: 613339) and 4q24-q28 (OMIM: 613340), indicates unanticipated genetic heterogeneity for the disorder in families from a relatively small geographic region in the southern parts of India.

Spontaneous out-of-body experience in a child with refractory right temporoparietal epilepsy.

The authors describe the case of a spontaneous out-of-body experience (OBE) in a 15-year-old right-handed boy with intractable epilepsy in whom psychosis had been misdiagnosed. After successful resection of a right temporoparietal focal cortical dysplasia, the OBE and seizures resolved. The authors analyzed the underlying causes of the OBE and discussed the mechanism of the OBE caused by an epileptic lesion.

LGI1 microdeletions are not a frequent cause of partial epilepsy with auditory features (PEAF).

Heterozygous mutations of the leucine-rich, glioma-inactivated 1 gene (LGI1) are the major known cause of partial epilepsy with auditory features (PEAF), accounting for roughly 50% of families. Recently, a partial gene microdeletion has been reported in a single family. To assess the contribution of LGI1 microrearrangements to the pathogenesis of PEAF, we screened 50 patients negative for point mutations through multiplex ligation-dependent probe amplification (MLPA) analysis. No cryptic imbalances were found in LGI1, suggesting that LGI1 microdeletions are not a frequent cause of PEAF. Despite the small number of examined patients and the need for replication studies, these findings support the hypothesis that diagnostic screening for LGI1 microrearrangements lacks clinical utility, especially for sporadic cases, and further highlight genetic heterogeneity of familial and sporadic PEAF.

Identification of QTLs involved in the development of amygdala kindling in the rat.

Amygdala kindling is useful for modeling human epilepsy development. It has been known that genetic factors are involved in the development of amygdala kindling. The purpose of this study was to identify the loci that are responsible for the development of amygdala kindling. To achieve this, rat strains from a LEXF/FXLE recombinant inbred (RI) strain panel were used. The phenotypes of amygdala kindling-related parameters for seven RI strains and parental LE/Stm and F344/Stm strains were determined. They included the afterdischarge threshold (ADT), the afterdischarge duration (ADD), and the kindling rate, an incidence of development of kindling. Quantitative trait loci (QTL) analysis was performed to identify linkage relationships between these phenotypes and 1,033 SNP markers. Although no significant differences in pre-kindling ADT and ADD were observed, a significant difference in the kindling rate was found for the LEXF/FXLE RI strain. Two QTLs for the amygdala kindling rate (Agkr1 and Agkr2) were identified on rat chromosome 2. These findings clearly prove the existence of genetic influences that are involved in kindling development and suggest that substantial genetic components contribute to the progression of partial seizures into generalized seizures.

The effects of focal epileptic activity on regional sensory-evoked neurovascular coupling and postictal modulation of bilateral sensory processing.

While it is known that cortical sensory dysfunction may occur in focal neocortical epilepsy, it is unknown whether sensory-evoked neurovascular coupling is also disrupted during epileptiform activity. Addressing this open question may help to elucidate both the effects of focal neocortical epilepsy on sensory responses and the neurovascular characteristics of epileptogenic regions in sensory cortex. We therefore examined bilateral sensory-evoked neurovascular responses before, during, and after 4-aminopyridine (4-AP, 15 mmol/L, 1 µL) induced focal neocortical seizures in right vibrissal cortex of the rat. Stimulation consisted of electrical pulse trains (16 seconds, 5 Hz, 1.2 mA) presented to the mystacial pad. Consequent current-source density neural responses and epileptic activity in both cortices and across laminae were recorded via two 16-channel microelectrodes bilaterally implanted in vibrissal cortices. Concurrent two-dimensional optical imaging spectroscopy was used to produce spatiotemporal maps of total, oxy-, and deoxy-hemoglobin concentration. Compared with control, sensory-evoked neurovascular coupling was altered during ictal activity, but conserved postictally in both ipsilateral and contralateral vibrissal cortices, despite neurovascular responses being significantly reduced in the former, and enhanced in the latter. Our results provide insights into sensory-evoked neurovascular dynamics and coupling in epilepsy, and may have implications for the localization of epileptogenic foci and neighboring eloquent cortex.

Ictal asystole: case report with review of literature.

Cardiac arrhythmias are frequently observed during epileptic seizures. Mostly they are benign, but severe bradycardia and asystole occur in 0.27-0.5% of patients who have seizures on video-EEG monitoring units. Especially patients with partial seizures involving the insular, orbital frontal and anterior temporal lobe regions, are at risk. Ictal bradycardia could be a cause of SUDEP (sudden unexpected death in epilepsy) and pacemaker insertion might therefore improve survival in selected cases, although more research is needed to prove this. We present a case of prolonged ictal asystole in a patient with newly diagnosed partial epilepsy originating from the temporal lobe.

Comparison of heart rate variability parameters during complex partial seizures and psychogenic nonepileptic seizures.

PURPOSE: Psychogenic nonepileptic seizures (PNES) superficially resemble epileptic seizures. Little is known about ictal autonomic nervous system (ANS) activity changes in epilepsy and PNES. This study compares ictal heart rate variability (HRV) parameters as a reflection of ANS tone in epileptic seizures and PNES, and explores differences between interictal and ictal ANS tone in both patient groups. METHODS: Ictal HRV parameters were extracted from single-lead electrocardiography (ECG) data collected during video-electroencephalography (EEG) recordings of 26 patients with medically refractory temporal lobe epilepsy and 24 age- and sex-matched patients with PNES. One seizure per patient in a resting, wake, supine state was analyzed. Interictal ECG data were available for comparison from 14 patients in both groups. HRV parameters in time and frequency domains were analyzed (low frequency [LF], high frequency [HF], standard deviation of all consecutive normal R wave intervals [SDNN], square root of the mean of the sum of the squares of differences between adjacent normal R wave intervals [RMSSD]). CVI (cardiovagal index), CSI (cardiosympathetic index), and ApEn (approximate entropy) were calculated from Lorenz plots. KEY FINDINGS: There were significant differences between ictal HRV measures during epileptic and nonepileptic seizures in the time and frequency domains. CSI (p < 0.001) was higher in epileptic seizures. Time interval between two consecutive R waves in the ECG (RR interval) (p = 0.002), LF (p = 0.02), HF (p = 0.003), and RMSSD (p = 0.003) were significantly lower during epileptic seizures. Binary logistic regression yielded a significant model based on the differences in CSI classifying 88% of patients with epilepsy and 73% of patients with PNES correctly. The comparison between resting and ictal states in both seizure disorders revealed significant differences in RR interval (epilepsy p < 0.001, PNES p = 0.01), CSI (epilepsy p < 0.001, PNES p = 0.02), HF (epilepsy p = 0.002, PNES p = 0.03), and RMSSD (epilepsy p = 0.004, PNES p = 0.04). In patients with epilepsy there were also significant differences in ictal versus interictal mean values of ApEn (p = 0.03) and LF (p = 0.04). Although CSI was significantly higher, the other parameters were lower during the seizures. Stepwise binary regression in the 14 patients with epilepsy produced a significant model differentiating resting state from seizures in 100% of cases. The same statistical approach did not yield a significant model in the PNES group. SIGNIFICANCE: Our results show greater ANS activation in epileptic seizures than in PNES. The biggest ictal HRV changes associated with epileptic seizures (CSI, HF, and RMSSD) reflect high sympathetic system activation and reduced vagal tone. The reduced ApEn also reflects a high sympathetic tone. The observed ictal alterations of HRV patterns may be a more specific marker of epileptic seizures than heart rate changes alone. These altered HRV patterns could be used to detect seizures and also to differentiate epileptic seizures from PNES. Larger studies are justified with intergroup and intragroup comparisons between ictal and resting states.

Budget impact analysis of adjunctive therapy with lacosamide for partial-onset epileptic seizures in Belgium.

OBJECTIVE: This study aims to compute the budget impact of lacosamide, a new adjunctive therapy for partial-onset seizures in epilepsy patients from 16 years of age who are uncontrolled and having previously used at least three anti-epileptic drugs from a Belgian healthcare payer perspective. METHODS: The budget impact analysis compared the 'world with lacosamide' to the 'world without lacosamide' and calculated how a change in the mix of anti-epileptic drugs used to treat uncontrolled epilepsy would impact drug spending from 2008 to 2013. Data on the number of patients and on the market shares of anti-epileptic drugs were taken from Belgian sources and from the literature. Unit costs of anti-epileptic drugs originated from Belgian sources. The budget impact was calculated from two scenarios about the market uptake of lacosamide. RESULTS: The Belgian target population is expected to increase from 5333 patients in 2008 to 5522 patients in 2013. Assuming that the market share of lacosamide increases linearly over time and is taken evenly from all other anti-epileptic drugs (AEDs), the budget impact of adopting adjunctive therapy with lacosamide increases from €5249 (0.1% of reference drug budget) in 2008 to €242,700 (4.7% of reference drug budget) in 2013. Assuming that 10% of patients use standard AED therapy plus lacosamide, the budget impact of adopting adjunctive therapy with lacosamide is around €800,000-900,000 per year (or 16.7% of the reference drug budget). CONCLUSIONS: Adjunctive therapy with lacosamide would raise drug spending for this patient population by as much as 16.7% per year. However, this budget impact analysis did not consider the fact that lacosamide reduces costs of seizure management and withdrawal. The literature suggests that, if savings in other healthcare costs are taken into account, adjunctive therapy with lacosamide may be cost saving.

Persistent ictal-like visual cortical excitability in chronic migraine.

Episodic migraine (EM) may evolve into the more disabling chronic migraine (CM, monthly migraine days ≥ 8 and headache days ≥ 15) with unknown mechanism. Aiming to elucidate the pathophysiology of CM and its relationship with EM, this study characterized the visual cortical responses in CM and EM. Neuromagnetic visual-evoked responses to left-hemifield checkerboard reversals were obtained in patients with EM (interictal or ictal states), CM (interictal) and age-matched controls. For each subject, the 1500 evoked responses were sequentially divided into 30 blocks and percentage changes of P100m amplitude in blocks 2, 9, 16, 23, and 30 compared to the first block were computed to assess habituation. At the end of visual stimulation (block 30), P100m amplitude was decreased (habituated) in the controls (n=32) (35.2±2.6nAm vs. 41.9±2.7, p=0.005) but increased (potentiated) in the interictal state of EM (n=29) (39.7±3.8 vs. 33.5±3.0, p=0.007). In CM (n=25), P100m was habituated (46.5±2.9 vs. 51.6±3.7, p=0.013) but higher at the initial block than in those of the interictal state of EM (p=0.001). These CM features also characterized the P100m in the ictal state of EM (n=9). There was no difference of P100m between CM and ictal state of EM. In conclusion, patients with CM demonstrate a persistent ictal-like excitability pattern of the visual cortex between migraine attacks which may implicate central inhibitory dysfunction.

Modelos experimentales en epilepsia / Experimental models in epilepsy

Introducción: La epilepsia es una de las enfermedades neurológicas más frecuentes, y además conlleva una tasa de consecuencias negativas muy importante, tanto para el paciente como para los familiares. Su manifestación clínica principal es la aparición de crisis epilépticas recurrentes, que en el 70-80% de los casos se controlan con la medicación. Sin embargo, a pesar de que van apareciendo nuevos fármacos para el control de las crisis, no disponemos todavía de fármacos que consigan evitar la epileptogénesis. Método: Revisamos las publicaciones más relevantes de modelos animales experimentales en epilepsia utilizando para ello la base de datos de PubMed. Resultados: Se han encontrado un amplio número de publicaciones sobre tipos de modelos experimentales tanto genéticos (transgénicos, genéticamente determinados) como lesionales (químicos o eléctricos), que intentan imitar los diferentes tipos de epilepsia en humanos. Conclusiones: A pesar de que en las últimas décadas se han hecho importantes avances en el campo de la epilepsia, aún quedan muchos aspectos por dilucidar. En este sentido, los modelos experimentales pueden suponer una herramienta muy útil para el avance en el conocimiento de los mecanismos fisiopatológicos y en la búsqueda de tratamientos eficaces (AU)

Introduction: Epilepsy is one of the neurological pathologies with the highest rate of incidence and with a significant number of negatives consequences. Current pharmacological treatments have an antiepileptic effect, allowing control over 70% of the patients, but they are not able to prevent the development of epileptogenesis from occurring. Method: Ee have reviewed the most relevant publications of experimental animal models with epilepsy by using the PubMed data base. Results: We found a large number of publications related to different kinds of experimental models, both genetic (transgenic, genetically determined) and lesional which appeared to resemble the different types of human epilepsy. Conclusions: Even though many important improvements have been accomplished in the area of epilepsy in the last decades, there are still many aspects to be clarified. In this regard, experimental models might become a very useful means for a better understanding of pathophysiological mechanisms and in the search for more efficient treatments (AU)

Disruption of LGI1-linked synaptic complex causes abnormal synaptic transmission and epilepsy.

Epilepsy is a devastating and poorly understood disease. Mutations in a secreted neuronal protein, leucine-rich glioma inactivated 1 (LGI1), were reported in patients with an inherited form of human epilepsy, autosomal dominant partial epilepsy with auditory features (ADPEAF). Here, we report an essential role of LGI1 as an antiepileptogenic ligand. We find that loss of LGI1 in mice (LGI1(-/-)) causes lethal epilepsy, which is specifically rescued by the neuronal expression of LGI1 transgene, but not LGI3. Moreover, heterozygous mice for the LGI1 mutation (LGI1(+/-)) show lowered seizure thresholds. Extracellularly secreted LGI1 links two epilepsy-related receptors, ADAM22 and ADAM23, in the brain and organizes a transsynaptic protein complex that includes presynaptic potassium channels and postsynaptic AMPA receptor scaffolds. A lack of LGI1 disrupts this synaptic protein connection and selectively reduces AMPA receptor-mediated synaptic transmission in the hippocampus. Thus, LGI1 may serve as a major determinant of brain excitation, and the LGI1 gene-targeted mouse provides a good model for human epilepsy.

Computational modeling of high-frequency oscillations at the onset of neocortical partial seizures: from 'altered structure' to 'dysfunction'.

In this paper, a neural mass model is proposed to analyze some mechanisms underlying the generation of fast oscillations (80 Hz and beyond) at the onset of seizures. This model includes one sub-population of pyramidal cells and one sub-population of interneurons targeting the perisomatic region of pyramidal cells where fast GABAergic currents are mediated. We identified some conditions for which the model can reproduce the features of high-frequency, chirp-like (from approximately 100 to approximately 70 Hz) signatures observed in real depth-EEG signals recorded in epileptic patients at seizure onset ("fast onset activity"). These conditions included appropriate alterations in (i) the strengths of GABAergic and glutamatergic connections, and (ii) the amplitude of average EPSPs/IPSPs. Results revealed that a subtle balance between excitatory and inhibitory feedbacks is required in the model for reproducing a 'realistic' fast activity, i.e., showing a reduction of frequency with a simultaneous increase in amplitude, as actually observed in epileptogenic cerebral cortex. Results also demonstrated that the number of scenarios (variation, in time, of model parameters) leading to chirp-like signatures was rather limited. First, to produce high-frequency output signals, the model should operate in a "resonance" region, at the frontier between a stable and an unstable region. Second both EPSP and IPSP amplitudes should decrease with time in order to obey the frequency/amplitude constraint. These scenarios obtained through a mathematical analysis of the model show how some alteration in the structure of neural networks can lead to dysfunction. They also provide insights into potentially important mechanisms for high-frequency epileptic activity generation.