Improvement of non-paraneoplastic voltage-gated potassium channel antibody-associated limbic encephalitis without immunosuppressive therapy

We describe a 61-year-old patient with clinical evidence of limbic encephalitis who improved with anticonvulsant treatment only, that is, without the use of immunosuppressive agents. Three years following occurrence of anosmia, increasing memory deficits, and emotional disturbances, he presented with new-onset temporal lobe epilepsy, with antibodies binding to neuronal voltage-gated potassium channels and bitemporal hypometabolism on FDG-PET scan; the MRI scan was normal. This is most likely a case of spontaneous remission, illustrating that immunosuppressive therapy might be suspended in milder courses of limbic encephalitis. It remains open whether treatment with anticonvulsant drugs played an additional beneficiary role through the direct suppression of seizures or, additionally, through indirect immunomodulatory side effects.

Inherited cavernous malformations of the central nervous system: clinical and genetic features in 19 Swiss families

Cavernous malformations (CCMs) are benign, well-circumscribed, and mulberry-like vascular malformations that may be found in the central nervous system in up to 0.5% of the population. Cavernous malformations can be sporadic or inherited. The common symptoms are epilepsy, hemorrhages, focal neurological deficits, and headaches. However, CCMs are often asymptomatic. The familiar form is associated with three gene loci, namely 7q21-q22 (CCM1), 7p13-p15 (CCM2), and 3q25.2-q27 (CCM3) and is inherited as an autosomal dominant trait with incomplete penetrance. The CCM genes are identified as Krit 1 (CCM1), MGC4607 (CCM2), and PDCD10 (CCM3). Here, we present the clinical and genetic features of CCMs in 19 Swiss families. Furthermore, surgical aspects in such families are also discussed.

Arterial spin-labeling MRI perfusion in tuberous sclerosis: correlation with PET

Neuroimaging using magnetic resonance imaging (MRI) is required for the investigation of surgically intractable epilepsy. In addition to the standard MRI techniques, perfusion sequences can be added to improve visualization of the underlying pathological changes. Also, as arterial spin-labeling (ASL) MRI perfusion does not require contrast administration, it may even be advantageous in these patients. We report here on three patients with epilepsy and tuberous sclerosis who underwent brain MRI with ASL and positron emission tomography (PET), both of which were found to correlate with each other and with electrophysiological data.

Nerve excitability studies characterize Kv1.1 fast potassium channel dysfunction in patients with episodic ataxia type 1

Episodic ataxia type 1 is a neuronal channelopathy caused by mutations in the KCNA1 gene encoding the fast K(+) channel subunit K(v)1.1. Episodic ataxia type 1 presents with brief episodes of cerebellar dysfunction and persistent neuromyotonia and is associated with an increased incidence of epilepsy. In myelinated peripheral nerve, K(v)1.1 is highly expressed in the juxtaparanodal axon, where potassium channels limit the depolarizing afterpotential and the effects of depolarizing currents. Axonal excitability studies were performed on patients with genetically confirmed episodic ataxia type 1 to characterize the effects of K(v)1.1 dysfunction on motor axons in vivo. The median nerve was stimulated at the wrist and compound muscle action potentials were recorded from abductor pollicis brevis. Threshold tracking techniques were used to record strength-duration time constant, threshold electrotonus, current/threshold relationship and the recovery cycle. Recordings from 20 patients from eight kindreds with different KCNA1 point mutations were compared with those from 30 normal controls. All 20 patients had a history of episodic ataxia and 19 had neuromyotonia. All patients had similar, distinctive abnormalities: superexcitability was on average 100% higher in the patients than in controls (P < 0.00001) and, in threshold electrotonus, the increase in excitability due to a depolarizing current (20% of threshold) was 31% higher (P < 0.00001). Using these two parameters, the patients with episodic ataxia type 1 and controls could be clearly separated into two non-overlapping groups. Differences between the different KCNA1 mutations were not statistically significant. Studies of nerve excitability can identify K(v)1.1 dysfunction in patients with episodic ataxia type 1. The simple 15 min test may be useful in diagnosis, since it can differentiate patients with episodic ataxia type 1 from normal controls with high sensitivity and specificity.

Forbidden ordinal patterns of periictal intracranial EEG indicate deterministic dynamics in human epileptic seizures

Epileptic seizures typically reveal a high degree of stereotypy, that is, for an individual patient they are characterized by an ordered and predictable sequence of symptoms and signs with typically little variability. Stereotypy implies that ictal neuronal dynamics might have deterministic characteristics, presumably most pronounced in the ictogenic parts of the brain, which may provide diagnostically and therapeutically important information. Therefore the goal of our study was to search for indications of determinism in periictal intracranial electroencephalography (EEG) studies recorded from patients with pharmacoresistent epilepsy.

Uniform approach to linear and nonlinear interrelation patterns in multivariate time series

Currently, a variety of linear and nonlinear measures is in use to investigate spatiotemporal interrelation patterns of multivariate time series. Whereas the former are by definition insensitive to nonlinear effects, the latter detect both nonlinear and linear interrelation. In the present contribution we employ a uniform surrogate-based approach, which is capable of disentangling interrelations that significantly exceed random effects and interrelations that significantly exceed linear correlation. The bivariate version of the proposed framework is explored using a simple model allowing for separate tuning of coupling and nonlinearity of interrelation. To demonstrate applicability of the approach to multivariate real-world time series we investigate resting state functional magnetic resonance imaging (rsfMRI) data of two healthy subjects as well as intracranial electroencephalograms (iEEG) of two epilepsy patients with focal onset seizures. The main findings are that for our rsfMRI data interrelations can be described by linear cross-correlation. Rejection of the null hypothesis of linear iEEG interrelation occurs predominantly for epileptogenic tissue as well as during epileptic seizures.

Mortality and morbidity in the city of Bern, Switzerland, 1805-1815 with special emphasis on infant, child and maternal deaths

This article contributes to the research on demographics and public health of urban populations of preindustrial Europe. The key source is a burial register that contains information on the deceased, such as age and sex, residence and cause of death. This register is one of the earliest compilations of data sets of individuals with this high degree of completeness and consistency. Critical assessment of the register's origin, formation and upkeep promises high validity and reliability. Between 1805 and 1815, 4,390 deceased inhabitants were registered. Information concerning these individuals provides the basis for this study. Life tables of Bern's population were created using different models. The causes of death were classified and their frequency calculated. Furthermore, the susceptibility of age groups to certain causes of death was established. Special attention was given to causes of death and mortality of newborns, infants and birth-giving women. In comparison to other cities and regions in Central Europe, Bern's mortality structure shows low rates for infants (q0=0.144) and children (q1-4=0.068). This could have simply indicated better living conditions. Life expectancy at birth was 43 years. Mortality was high in winter and spring, and decreased in summer to a low level with a short rise in August. The study of the causes of death was inhibited by difficulties in translating early 19th century nomenclature into the modern medical system. Nonetheless, death from metabolic disorders, illnesses of the respiratory system, and debilitation were the most prominent causes in Bern. Apparently, the worst killer of infants up to 12 months was the "gichteren", an obsolete German term for lethal spasmodic convulsions. The exact modern identification of this disease remains unclear. Possibilities such as infant tetanus or infant epilepsy are discussed. The maternal death rate of 0.72% is comparable with values calculated from contemporaneous sources. Relevance of childbed fever in the early 1800s was low. Bern's data indicate that the extent of deaths related to childbirth in this period is overrated. This research has an explicit interdisciplinary value for various fields including both the humanities and natural sciences, since information reported here represents the complete age and sex structure of a deceased population. Physical anthropologists can use these data as a true reference group for their palaeodemographic studies of preindustrial Central Europe of the late 18th and early 19th century. It is a call to both historians and anthropologists to use our resources to a better effect through combination of methods and exchange of knowledge.

Targeted next generation sequencing as a diagnostic tool in epileptic disorders

Epilepsies have a highly heterogeneous background with a strong genetic contribution. The variety of unspecific and overlapping syndromic and nonsyndromic phenotypes often hampers a clear clinical diagnosis and prevents straightforward genetic testing. Knowing the genetic basis of a patient's epilepsy can be valuable not only for diagnosis but also for guiding treatment and estimating recurrence risks.

Stimulus-induced, sleep-bound, focal seizures: a case report

In nocturnal frontal lobe epilepsy (NFLE), seizures occur almost exclusively during NREM sleep. Why precisely these seizures are sleep-bound remains unknown. Studies of patients with nonlesional familial forms of NFLE have suggested the arousal system may play a major role in their pathogenesis. We report the case of a patient with pharmaco-resistant, probably cryptogenic form of non-familial NFLE and strictly sleep-bound seizures that could be elicited by alerting stimuli and were associated with ictal bilateral thalamic and right orbital-insular hyperperfusion on SPECT imaging.

Spike-triggered reaction-time EEG as a possible assessment tool for driving ability

The impact of interictal epileptic activity (IEA) on driving is a rarely investigated issue. We analyzed the impact of IEA on reaction time in a pilot study. Reactions to simple visual stimuli (light flash) in the Flash test or complex visual stimuli (obstacle on a road) in a modified car driving computer game, the Steer Clear, were measured during IEA bursts and unremarkable electroencephalography (EEG) periods. Individual epilepsy patients showed slower reaction times (RTs) during generalized IEA compared to RTs during unremarkable EEG periods. RT differences were approximately 300 ms (p < 0.001) in the Flash test and approximately 200 ms (p < 0.001) in the Steer Clear. Prior work suggested that RT differences >100 ms may become clinically relevant. This occurred in 40% of patients in the Flash test and in up to 50% in the Steer Clear. When RT were pooled, mean RT differences were 157 ms in the Flash test (p < 0.0001) and 116 ms in the Steer Clear (p < 0.0001). Generalized IEA of short duration seems to impair brain function, that is, the ability to react. The reaction-time EEG could be used routinely to assess driving ability.

Self-organised transients in a neural mass model of epileptogenic tissue dynamics

Stimulation of human epileptic tissue can induce rhythmic, self-terminating responses on the EEG or ECoG. These responses play a potentially important role in localising tissue involved in the generation of seizure activity, yet the underlying mechanisms are unknown. However, in vitro evidence suggests that self-terminating oscillations in nervous tissue are underpinned by non-trivial spatio-temporal dynamics in an excitable medium. In this study, we investigate this hypothesis in spatial extensions to a neural mass model for epileptiform dynamics. We demonstrate that spatial extensions to this model in one and two dimensions display propagating travelling waves but also more complex transient dynamics in response to local perturbations. The neural mass formulation with local excitatory and inhibitory circuits, allows the direct incorporation of spatially distributed, functional heterogeneities into the model. We show that such heterogeneities can lead to prolonged reverberating responses to a single pulse perturbation, depending upon the location at which the stimulus is delivered. This leads to the hypothesis that prolonged rhythmic responses to local stimulation in epileptogenic tissue result from repeated self-excitation of regions of tissue with diminished inhibitory capabilities. Combined with previous models of the dynamics of focal seizures this macroscopic framework is a first step towards an explicit spatial formulation of the concept of the epileptogenic zone. Ultimately, an improved understanding of the pathophysiologic mechanisms of the epileptogenic zone will help to improve diagnostic and therapeutic measures for treating epilepsy.

A Systems-Level Approach to Human Epileptic Seizures

Epileptic seizures are due to the pathological collective activity of large cellular assemblies. A better understanding of this collective activity is integral to the development of novel diagnostic and therapeutic procedures. In contrast to reductionist analyses, which focus solely on small-scale characteristics of ictogenesis, here we follow a systems-level approach, which combines both small-scale and larger-scale analyses. Peri-ictal dynamics of epileptic networks are assessed by studying correlation within and between different spatial scales of intracranial electroencephalographic recordings (iEEG) of a heterogeneous group of patients suffering from pharmaco-resistant epilepsy. Epileptiform activity as recorded by a single iEEG electrode is determined objectively by the signal derivative and then subjected to a multivariate analysis of correlation between all iEEG channels. We find that during seizure, synchrony increases on the smallest and largest spatial scales probed by iEEG. In addition, a dynamic reorganization of spatial correlation is observed on intermediate scales, which persists after seizure termination. It is proposed that this reorganization may indicate a balancing mechanism that decreases high local correlation. Our findings are consistent with the hypothesis that during epileptic seizures hypercorrelated and therefore functionally segregated brain areas are re-integrated into more collective brain dynamics. In addition, except for a special sub-group, a highly significant association is found between the location of ictal iEEG activity and the location of areas of relative decrease of localised EEG correlation. The latter could serve as a clinically important quantitative marker of the seizure onset zone (SOZ).

Polymorphisms in the ABCB1 gene in phenobarbital responsive and resistant idiopathic epileptic Border Collies

BACKGROUND: Variation in the ABCB1 gene is believed to play a role in drug resistance in epilepsy. HYPOTHESIS/OBJECTIVES: Variation in the ABCB1 gene encoding the permeability-glycoprotein could have an influence on phenobarbital (PB) resistance, which occurs with high frequency in idiopathic epileptic Border Collies (BCs). Animals: Two hundred and thirty-six client-owned BCs from Switzerland and Germany including 25 with idiopathic epilepsy, of which 13 were resistant to PB treatment. METHODS: Prospective and retrospective case-control study. Data were collected retrospectively regarding disease status, antiepileptic drug (AED) therapy, and drug responsiveness. The frequency of a known mutation in the ABCB1 gene (4 base-pair deletion in the ABCB1 gene [c.296_299del]) was determined in all BCs. Additionally, the ABCB1 coding exons and flanking sequences were completely sequenced to search for additional variation in 41 BCs. Association analyses were performed in 2 case-control studies: idiopathic epileptic and control BCs and PB-responsive and resistant idiopathic epileptic BCs. RESULTS: One of 236 BCs (0.4%) was heterozygous for the mutation in the ABCB1 gene (c.296_299del). A total of 23 variations were identified in the ABCB1 gene: 4 in exons and 19 in introns. The G-allele of the c.-6-180T > G variation in intron 1 was significantly more frequent in epileptic BCs resistant to PB treatment than in epileptic BCs responsive to PB treatment (P(raw) = .0025). CONCLUSIONS AND CLINICAL IMPORTANCE: A variation in intron 1 of the ABCB1 gene is associated with drug responsiveness in BCs. This might indicate that regulatory mutations affecting the expression level of ABCB1 could exist, which may influence the reaction of a dog to AEDs.

Fine structure of hippocampal mossy fiber synapses following rapid high-pressure freezing

Synapses of hippocampal neurons play important roles in learning and memory processes and are involved in aberrant hippocampal function in temporal lobe epilepsy. Major neuronal types in the hippocampus as well as their input and output synapses are well known, but it has remained an open question to what extent conventional electron microscopy (EM) has provided us with the real appearance of synaptic fine structure under in vivo conditions. There is reason to assume that conventional aldehyde fixation and dehydration lead to protein denaturation and tissue shrinkage, likely associated with the occurrence of artifacts. However, realistic fine-structural data of synapses are required for our understanding of the transmission process and for its simulation. Here, we used high-pressure freezing and cryosubstitution of hippocampal tissue that was not subjected to aldehyde fixation and dehydration in ethanol to monitor the fine structure of an identified synapse in the hippocampal CA3 region, that is, the synapse between granule cell axons, the mossy fibers, and the proximal dendrites of CA3 pyramidal neurons. Our results showed that high-pressure freezing nicely preserved ultrastructural detail of this particular synapse and allowed us to study rapid structural changes associated with synaptic plasticity.

Epileptogenic developmental venous anomaly: insights from simultaneous EEG/fMRI

Developmental venous anomalies (DVAs) are associated with epileptic seizures; however, the role of DVA in the epileptogenesis is still not established. Simultaneous interictal electroencephalogram/functional magnetic resonance imaging (EEG/fMRI) recordings provide supplementary information to electroclinical data about the epileptic generators, and thus aid in the differentiation of clinically equivocal epilepsy syndromes. The main objective of our study was to characterize the epileptic network in a patient with DVA and epilepsy by simultaneous EEG/fMRI recordings. A 17-year-old woman with recently emerging generalized tonic-clonic seizures, and atypical generalized discharges, was investigated using simultaneous EEG/fMRI at the university hospital. Previous high-resolution MRI showed no structural abnormalities, except a DVA in the right frontal operculum. Interictal EEG recordings showed atypical generalized discharges, corresponding to positive focal blood oxygen level dependent (BOLD) correlates in the right frontal operculum, a region drained by the DVA. Additionally, widespread cortical bilateral negative BOLD correlates in the frontal and parietal lobes were delineated, resembling a generalized epileptic network. The EEG/fMRI recordings support a right frontal lobe epilepsy, originating in the vicinity of the DVA, propagating rapidly to both frontal and parietal lobes, as expressed on the scalp EEG by secondary bilateral synchrony. The DVA may be causative of focal epilepsies in cases where no concomitant epileptogenic lesions can be detected. Advanced imaging techniques, such as simultaneous EEG/fMRI, may thus aid in the differentiation of clinically equivocal epilepsy syndromes.