Neurological manifestations and neuro-invasive mechanisms of the severe acute respiratory syndrome coronavirus type 2.

BACKGROUND AND PURPOSE: Infections with coronaviruses are not always confined to the respiratory tract and various neurological manifestations have been reported. The aim of this study was to perform a review to describe neurological manifestations in patients with COVID-19 and possible neuro-invasive mechanisms of Sars-CoV-2. METHODS: PubMed, Web of Science and COVID-dedicated databases were searched for the combination of COVID-19 terminology and neurology terminology up to 10 May 2020. Social media channels were followed up between 15 March and 10 May 2020 for postings with the same scope. Neurological manifestations were extracted from the identified papers and combined to provide a useful summary for the neurologist in clinical practice. RESULTS: Neurological manifestations potentially related to COVID-19 have been reported in large studies, case series and case reports and include acute cerebrovascular diseases, impaired consciousness, cranial nerve manifestations and autoimmune disorders such as the Guillain-Barré syndrome often present in patients with more severe COVID-19. Cranial nerve symptoms such as olfactory and gustatory dysfunctions are highly prevalent in patients with mild to moderate COVID-19 even without associated nasal symptoms and often present in an early stage of the disease. CONCLUSION: Physicians should be aware of the neurological manifestations in patients with COVID-19, especially when rapid clinical deterioration occurs. The neurological symptoms in COVID-19 patients may be due to direct viral neurological injury or indirect neuroinflammatory and autoimmune mechanisms. No antiviral treatments against the virus or vaccines for its prevention are available and the long-term consequences of the infection on human health remain uncertain especially with regard to the neurological system.

Neurophysiological investigations of drug resistant epilepsy patients treated with vagus nerve stimulation to differentiate responders from non-responders.

BACKGROUND AND PURPOSE: In patients treated with vagus nerve stimulation (VNS) for drug resistant epilepsy (DRE), up to a third of patients will eventually not respond to the therapy. As VNS therapy requires surgery for device implantation, prediction of response prior to surgery is desirable. It is hypothesized that neurophysiological investigations related to the mechanisms of action of VNS may help to differentiate VNS responders from non-responders prior to the initiation of therapy. METHODS: In a prospective series of DRE patients, polysomnography, heart rate variability (HRV) and cognitive event related potentials were recorded. Polysomnography and HRV were repeated after 1 year of treatment with VNS. Polysomnography, HRV and cognitive event related potentials were compared between VNS responders (≥50% reduction in seizure frequency) and non-responders. RESULTS: Fifteen out of 30 patients became VNS responders after 1 year of VNS treatment. Prior to treatment with VNS, the amount of deep sleep (NREM 3), the HRV high frequency (HF) power and the P3b amplitude were significantly different in responders compared to non-responders (P = 0.007; P = 0.001; P = 0.03). CONCLUSION: Three neurophysiological parameters, NREM 3, HRV HF and P3b amplitude, were found to be significantly different in DRE patients who became responders to VNS treatment prior to initiation of their treatment with VNS. These non-invasive recordings may be used as characteristics for response in future studies and help avoid unsuccessful implantations. Mechanistically these findings may be related to changes in brain regions involved in the so-called vagal afferent network.

Cognitive deterioration in adult epilepsy: clinical characteristics of "Accelerated Cognitive Ageing".

OBJECTIVES: "Epileptic dementia" is reported in adults with childhood-onset refractory epilepsy. Cognitive deterioration can also occur in a "second-hit model". MATERIALS AND METHODS: We studied the clinical and neuropsychological characteristics of patients with cognitive deterioration (≥1 SD discrepancy between current IQ and premorbid IQ). Memory function, reaction time and processing speed were also evaluated. Analyses were performed to investigate which clinical characteristics correlated with cognitive deterioration. RESULTS: Twenty-seven patients were included with a mean age of 55.7 years old, an average age at epilepsy onset of 33.9 years and a mean duration of 21.8 years. Over 40% had experienced at least one status epilepticus. About 77.8% had at least one comorbid disease (most of (cardio)vascular origin). Cognitive deterioration scores were significant for both Performance IQ and Full Scale IQ, but not for Verbal IQ. Impairments in fluid functions primarily affected the IQ-scores. Memory was not impaired. Epilepsy factors explained 7% of the variance in deterioration, whereas 38% was explained by relatively low premorbid IQ and educational level, high age at seizure onset and older age. CONCLUSIONS: A subgroup of patients with localization-related epilepsy exhibits cognitive decline characterized by deterioration in PIQ and FSIQ, but with preserved higher order functions (VIQ and memory). Patients typically have epilepsia tarda, comorbid pathology, relatively low educational level and older age. These are factors known to increase the vulnerability of the brain by diminishing cognitive reserve. Cognitive deterioration may develop according to a stepwise "second-hit model", affecting and accelerating the cognitive ageing process.

The effect of neuropeptide FF in the amygdala kindling model.

OBJECTIVE: Neuropeptide FF (NPFF) and its receptors (NPFF1 R and NPFF2 R) are differentially distributed throughout the central nervous system. NPFF reduces cortical excitability in rats when administered intracerebroventricularly (i.c.v.), and both NPFF and NPFF1 R antagonists attenuate pilocarpine-induced limbic seizures. In this study, our aim was to determine whether NPFF exerts anticonvulsant or anti-epileptogenic effects in the rat amygdala kindling model for temporal lobe seizures. METHODS: Male Wistar rats were implanted with a recording/stimulation electrode in the right amygdala and a cannula in the left lateral ventricle. In a first group of animals, the afterdischarge threshold (ADT) was determined after a single i.c.v. infusion of saline (n = 8) or NPFF (1 nmol/h for 2 h; n = 10). Subsequently, daily infusion of saline (n = 8) or NPFF (1 nmol/h for 2 h; i.c.v.; n = 9) was performed, followed by a kindling stimulus (ADT+200 µA). Afterdischarge duration and seizure severity were evaluated after every kindling stimulus. A second group of rats (n = 7) were fully kindled, and the effect of saline or a high dose of NPFF (10 nmol/h for 2 h, i.c.v.) on ADT and the generalized seizure threshold (GST) was subsequently determined. RESULTS: In naive rats, NPFF significantly increased the ADT compared to control (435 ± 72 µA vs 131 ± 23 µA [P < 0.05]). When rats underwent daily stimulations above the ADT, NPFF did not delay or prevent kindling acquisition. Furthermore, a high dose of NPFF did not alter ADT or GST in fully kindled rats. CONCLUSIONS: I.c.v. administration of NPFF reduced excitability in the amygdala in naive, but not in fully kindled rats, and had no effect on kindling acquisition.

Intensity-dependent modulatory effects of vagus nerve stimulation on cortical excitability.

OBJECTIVES: Vagus nerve stimulation (VNS) is an effective treatment for refractory epilepsy. It remains unknown whether VNS efficacy is dependent on output current intensity. The present study investigated the effect of various VNS output current intensities on cortical excitability in the motor cortex stimulation rat model. The hypothesis was that output current intensities in the lower range are sufficient to significantly affect cortical excitability. MATERIAL AND METHODS: VNS at four output current intensities (0 mA, 0.25 mA, 0.5 mA and 1 mA) was randomly administered in rats (n = 15) on four consecutive days. Per output current intensity, the animals underwent five-one-hour periods: (i) baseline, (ii) VNS1, (iii) wash-out1, (iv) VNS2 and (v) wash-out2. After each one-hour period, the motor seizure threshold (MST) was measured and compared to baseline (i.e. ∆MSTbaseline , ∆MSTVNS 1 , ∆MSTwash-out1 , ∆MSTVNS 2 and ∆MSTwash-out2 ). Finally, the mean ∆MSTbaseline , mean ∆MSTwash-out1 , mean ∆MSTwash-out2 and mean ∆MSTVNS per VNS output current intensity were calculated. RESULTS: No differences were found between the mean ∆MSTbaseline , mean ∆MSTwash-out1 and mean ∆MSTwash-out2 within each VNS output current intensity. The mean ∆MSTVNS at 0 mA, 0.25 mA, 0.5 mA and 1 mA was 15.3 ± 14.6 µA, 101.8 ± 23.5 µA, 108.1 ± 24.4 µA and 85.7 ± 18.1 µA respectively. The mean ∆MSTVNS at 0.25 mA, 0.5 mA and 1 mA were significantly larger compared to the mean ∆MSTVNS at 0 mA (P = 0.002 for 0.25 mA; P = 0.001 for 0.5 mA; P = 0.011 for 1 mA). CONCLUSIONS: This study confirms efficacy of VNS in the motor cortex stimulation rat model and indicates that, of the output current intensities tested, 0.25 mA is sufficient to decrease cortical excitability and higher output current intensities may not be required.

Subgroup classification in patients with psychogenic non-epileptic seizures.

INTRODUCTION: In this open non-controlled clinical cohort study, the applicability of a theoretical model for the diagnosis of psychogenic non-epileptic seizures (PNES) was studied in order to define a general psychological profile and to specify possible subgroups. METHODS: Forty PNES patients were assessed with a PNES "test battery" consisting of eleven psychological instruments, e.g., a trauma checklist, the global cognitive level, mental flexibility, speed of information processing, personality factors, dissociation, daily hassles and stress and coping factors. RESULTS: The total PNES group was characterized by multiple trauma, personality vulnerability (in a lesser extent, neuropsychological vulnerabilities), no increased dissociation, many complaints about daily hassles that may trigger seizures and negative coping strategies that may contribute to prolongation of the seizures. Using factor analysis, specific subgroups were revealed: a 'psychotrauma subgroup', a 'high vulnerability somatizing subgroup' (with high and low cognitive levels) and a 'high vulnerability sensitive personality problem subgroup'. CONCLUSION: Using a theoretical model in PNES diagnosis, PNES seem to be a symptom of distinct underlying etiological factors with different accents in the model. Hence, describing a general profile seems to conceal specific subgroups with subsequent treatment implications. This study identified three factors, representing two dimensions of the model, that are essential for subgroup classification: psychological etiology (psychotrauma or not), vulnerability, e.g., the somatization tendency, and sensitive personality problems/characteristics ('novelty seeking'). For treatment, this means that interventions could be tailored to the main underlying etiological problem. Also, further research could focus on differentiating subgroups with subsequent treatment indications and possible different prognoses.

Severe autonomic nervous system imbalance in Lennox-Gastaut syndrome patients demonstrated by heart rate variability recordings.

OBJECTIVE: Patients diagnosed with Lennox Gastaut syndrome (LGS), an epileptic encephalopathy characterized by usually drug resistant generalized and focal seizures, are often considered as candidates for vagus nerve stimulation (VNS). Recent research shows that heart rate variability (HRV) differs in epilepsy patients and is related to VNS treatment response. This study investigated pre-ictal HRV in generalized onset seizures of patients with LGS in correlation with their VNS response. METHODS: In drug resistant epilepsy (DRE) patients diagnosed with LGS video-electroencephalography recording was performed during their pre-surgical evaluation. Six HRV parameters (time and-, frequency domain, non-linear parameters) were evaluated for every seizure in epochs of 10 min at baseline (60 to 50 min before seizure onset) and pre-ictally (10 min prior to seizure onset). The results were correlated to VNS response after one year of VNS therapy. RESULTS: Seven patients and 31 seizures were included, two patients were classified as VNS responders (≥ 50 % seizure reduction). No difference in pre-ictal HRV parameters between VNS responders and VNS non-responders could be found, but high frequency (HF) power, reflecting the parasympathetic tone increased significantly in the pre-ictal epoch in both VNS responders and VNS non-responders (p = 0.017, p = 0.004). SIGNIFICANCE: In this pilot data pre-ictal HRV did not differ in VNS responders compared to VNS non-responders, but showed a significant increase in HF power - a parasympathetic overdrive - in both VNS responders and VNS non-responders. This sudden autonomic imbalance might have an influence on the cardiovascular system in the ictal period. Generalized tonic-clonic seizures are regarded as the main risk factor for SUDEP and severe seizure-induced autonomic imbalance may play a role in the pathophysiological pathway.

Modulation of seizure threshold by vagus nerve stimulation in an animal model for motor seizures.

OBJECTIVE: The precise mechanism of action of vagus nerve stimulation (VNS) in suppressing epileptic seizures remains to be elucidated. This study investigates whether VNS modulates cortical excitability by determining the threshold for provoking focal motor seizures by cortical electrical stimulation before and after VNS. MATERIAL AND METHODS: Male Wistar rats (n = 8) were implanted with a cuff-electrode around the left vagus nerve and with stimulation electrodes placed bilaterally on the rat motor cortex. Motor seizure threshold (MST) was assessed for each rat before and immediately after 1 h of VNS with standard stimulation parameters, during two to three sessions on different days. RESULTS: An overall significant increase of the MST was observed following 1 h of VNS compared to the baseline value (1420 microA and 1072 microA, respectively; P < 0.01). The effect was reproducible over time with an increase in MST in each experimental session. CONCLUSIONS: VNS significantly increases the MST in a cortical stimulation model for motor seizures. These data indicate that VNS is capable of modulating cortical excitability.

Seizures in the intrahippocampal kainic acid epilepsy model: characterization using long-term video-EEG monitoring in the rat.

OBJECTIVE: Intrahippocampal injection of kainic acid (KA) in rats evokes a status epilepticus (SE) and leads to spontaneous seizures. However to date, precise electroencephalographic (EEG) and clinical characterization of spontaneous seizures in this epilepsy model using long-term video-EEG monitoring has not been performed. MATERIALS AND METHODS: Rats were implanted with bipolar hippocampal depth electrodes and a cannula for the injection of KA (0.4 lg /0.2 ll) in the right hippocampus. Video-EEG monitoring was used to determine habitual parameters of spontaneous seizures such as seizure frequency, severity, progression and day-night rhythms. RESULTS: Spontaneous seizures were detected in all rats with 13 out of 15 animals displaying seizures during the first eight weeks after SE. A considerable fraction (35%) of the spontaneous seizures did not generalize secondarily. Seizure frequency was quite variable and the majority of the KA treated animals had less than one seizure per day. A circadian rhythm was observed in all rats that showed sufficient seizures per day. CONCLUSIONS: This study shows that the characteristics of spontaneous seizures in the intrahippocampal KA model display many similarities to other SE models and human temporal lobe epilepsy.

Vagal nerve stimulation--a 15-year survey of an established treatment modality in epilepsy surgery.

Neurostimulation is an emerging treatment for neurological diseases. Electrical stimulation of the tenth cranial nerve or vagus nerve stimulation (VNS) has become a valuable option in the therapeutic armamentarium for patients with refractory epilepsy. It is indicated in patients with refractory epilepsy who are unsuitable candidates for epilepsy surgery or who have had insufficient benefit from such a treatment. Vagus nerve stimulation reduces seizure frequency with > 50% in 1/3 of patients and has a mild side effects profile. Research to elucidate the mechanism of action of vagus nerve stimulation has shown that effective stimulation in humans is primarily mediated by afferent vagal A- and B-fibers. Crucial brainstem and intracranial structures include the locus coeruleus, the nucleus of the solitary tract, the thalamus and limbic structures. Neurotransmitters playing a role may involve the major inhibitory neurotransmitter GABA but also serotoninergic and adrenergic systems. This manuscript reviews the clinical studies investigating efficacy and side effects in patients and the experimental studies aiming to elucidate the mechanims of action.

Deep brain stimulation for epilepsy: knowledge gained from experimental animal models.

Since the development of Deep Brain Stimulation (DBS) for Parkinson's Disease, DBS has been suggested as a treatment option for various other neurological disorders. Stimulation of deep brain structures for refractory epilepsy appears to be a safe treatment option with promising results. As research on the evaluation and optimization of DBS for refractory epilepsy may be difficult and unethical in patients, studies on animal models of epilepsy are indispensable. Various brain structures and specific nuclei such as the basal ganglia, the cerebellum, the locus coeruleus and temporal lobe structures have been investigated as target areas for DBS. Additionally, a wide variety of stimulation parameters are available, with a range of stimulation frequencies, pulse widths and stimulation intensities. This review provides an overview of the relevant literature on experimental animal studies of DBS for epilepsy. Knowledge gained from animal studies can be used to answer questions regarding the optimal brain targets and stimulation parameters in human applications.

Cell therapy in models for temporal lobe epilepsy.

For patients with refractory epilepsy it is important to search for alternative treatments. One of these potential treatments could be introducing new cells or modulating endogenous neurogenesis to reconstruct damaged epileptic circuits or to bring neurotransmitter function back into balance. In this review the scientific basis of these cell therapy strategies is discussed and the results are critically evaluated. Research on cell transplantation strategies has mainly been performed in animal models for temporal lobe epilepsy, in which seizure foci or seizure propagation pathways are targeted. Promising results have been obtained, although there remains a lot of debate about the relevance of the animal models, the appropriate target for transplantation, the suitable cell source and the proper time point for transplantation. From the presented studies it should be evident that transplanted cells can survive and sometimes even integrate in an epileptic brain and in a brain that is subjected to epileptogenic interventions. There is evidence that transplanted cells can partially restore damaged structures and/or release substances that modulate existent or induced hyperexcitability. Even though several studies show encouraging results, more studies need to be done in animal models with spontaneous seizures in order to have a better comparison to the human situation.

Serial day rapid kindling is an effective tool in screening the anti-epileptic properties of topiramate.

INTRODUCTION: In this study, a serial day rapid kindling protocol was used to fully kindle rats in a matter of days. Subsequently, the anticonvulsant profile of a relatively new anti-epileptic drug, topiramate, was evaluated in a cross-over design to further validate this rapid kindling model. METHODS: Rats were kindled during three consecutive days, according to the serial day rapid kindling protocol. Topiramate was tested at a dose of 100mg/kg, i.p., over the next 2 days using a cross-over design. The stability of the kindled state was evaluated in all rats during two retest paradigms. During the drug-testing procedure, rats received a single i.p. injection of either topiramate or verhicle. Starting 1 h later the rats received additional kindling stimulations during which their response was measured. RESULTS: Serial day rapid kindling induced a long lasting and stable fully kindled state that allowed for the anti-epileptic drug screening procedure. Topiramate reduced both the afterdischarge duration and ameliorated seizure semiology in the kindled rats. DISCUSSION: Serial day rapid kindling provided a tool to rapidly kindle rats in 3 days. Using a cross-over design, clear indications on anti-epileptic activity of a given drug can be determined using few laboratory animals.

Anatomical and physiological basis and mechanism of action of neurostimulation for epilepsy.

Neurostimulation is an emerging treatment for neurological diseases. Different types of neurostimulation exist mainly depending of the part of the nervous system that is being affected and the way this stimulation is being administered. Vagus nerve stimulation (VNS) is a neurophysiological treatment for patients with medically or surgically refractory epilepsy. Over 30,000 patients have been treated with VNS. No clear predictive factors for responders have been identified. To date, the precise mechanism of action remains to be elucidated. Better insight in the mechanism of action may identify seizure types or syndromes that respond better to VNS and may guide the search for optimal stimulation parameters and finally improve clinical efficacy. Deep brain stimulation (DBS) has been used extensively as a treatment for movement disorders. Several new indications such as obsessive compulsive behaviour and cluster headache are being investigated with promising results. The vast progress in biotechnology along with the experience in other neurological diseases in the past ten years has led to a renewed interest in intracerebral stimulation for epilepsy. Epilepsy centers around the world have recently reinitiated trials with deep brain stimulation in different intracerebral structures such as the thalamus, the hippocampus and the subthalamic nucleus.

Neurosurgical aspects of temporal deep brain stimulation for epilepsy.

Deep brain stimulation (DBS), which mimics the effect of ablative surgery in movement disorders, is considered by analogy as potentially useful in the epileptic temporal lobe as an alternative to resection. It could be applied to patients in whom resective surgery is less beneficial, e.g. cases without memory impairment or with bilateral hippocampal involvement. In patients who undergo invasive presurgical analysis, the necessary intrahippocampal leads can serve for the application of DBS, provided that they are suited for chronic use. The hippocampus, in which the focus of epilepsy is detected, is stimulated continuously using high-frequency square-wave pulses. The reduction of interictal spike activity during a period of acute stimulation is the criterion for deciding whether the leads will be connected to an internal pulse generator. We are conducting a pilot study, with 16 patients enrolled so far, ten of whom have been followed up for more than one year. Some theoretical considerations are dedicated to hippocampal DBS.

Clinical experience with vagus nerve stimulation and deep brain stimulation in epilepsy.

Patients with refractory epilepsy present a particular challenge to new therapies. Vagus nerve stimulation (VNS) for the control of intractable seizures has become available since 1989. VNS is a relatively noninvasive treatment. It reduces seizure frequency by > or =50% in 1/3 of patients; an additional 1/3 of patients experience a worthwhile reduction of seizure frequency between 30 and 50%. In the remaining 1/3 of the patients there is little or no effect. Efficacy has a tendency to improve with longer duration of treatment up to 18 months postoperatively. Deep brain stimulation (DBS) or direct electrical stimulation of brain areas is an alternative neurostimulation modality. The cerebellum, various thalamic nuclei, the pallidum, and, more recently, medial temporal lobe structures have been chosen as targets. DBS for epilepsy is beyond the stage of proof-of-concept but still needs thorough evaluation in confirmatory pilot studies before it can be offered to larger patient populations. Analysis of larger patient groups and insight in the mode of action may help to identify patients with epileptic seizures or syndromes that respond better either to VNS or to DBS. Randomized and controlled studies in larger patient series are mandatory to identify the potential treatment population and optimal stimulation paradigms. Further improvements of clinical efficacy may result from these studies.

Vagus nerve stimulation does not affect spatial memory in fast rats, but has both anti-convulsive and pro-convulsive effects on amygdala-kindled seizures.

Vagus nerve stimulation (VNS) is an adjunctive treatment for refractory epilepsy. Using a seizure-prone Fast-kindling rat strain with known comorbid behavioral features, we investigated the effects of VNS on spatial memory, epileptogenesis, kindled seizures and body weight. Electrodes were implanted in both amygdalae and around the left vagus nerve of 17 rats. Following recovery, rats were tested in the Morris water-maze utilizing a fixed platform paradigm. The VNS group received 2 h of stimulation prior to entering the Morris water-maze. Rats were then tested in the kindling paradigm wherein the VNS group received 2 h of stimulation prior to daily kindling stimulation. Finally, the abortive effects of acute VNS against kindling-induced seizures were determined in fully kindled rats by applying VNS immediately after the kindling pulse. Body weight, water consumption and food intake were measured throughout. Memory performance in the Morris water-maze was not different between control and vagus nerve stimulation rats. Similarly, kindling rate was unaffected by antecedent VNS. However, pro-convulsive effects (P<0.05) were noted, when VNS was administered prior to the kindling pulse in fully kindled rats. Yet, paradoxically, VNS showed anti-convulsant effects (P<0.01) in those rats when applied immediately after the kindling stimulus. Body weight was significantly lower throughout kindling (P<0.01) in VNS-treated rats compared with controls, which was associated with reduced food intake (P<0.05), but without difference in water consumption. VNS appears to be devoid of significant cognitive side effects in the Morris water-maze in Fast rats. Although VNS exhibited no prophylactic effect on epileptogenesis or seizure severity when applied prior to the kindling stimulus, it showed significant anti-convulsant effects in fully kindled rats when applied after seizure initiation. Lastly, VNS prevented the weight gain associated with kindling through reduced food intake.

Technical aspects of neurostimulation: Focus on equipment, electric field modeling, and stimulation protocols.

Neuromodulation is a field of science, medicine, and bioengineering that encompasses implantable and non-implantable technologies for the purpose of improving quality of life and functioning of humans. Brain neuromodulation involves different neurostimulation techniques: transcranial magnetic stimulation (TMS), transcranial direct current stimulation (tDCS), vagus nerve stimulation (VNS), and deep brain stimulation (DBS), which are being used both to study their effects on cognitive brain functions and to treat neuropsychiatric disorders. The mechanisms of action of neurostimulation remain incompletely understood. Insight into the technical basis of neurostimulation might be a first step towards a more profound understanding of these mechanisms, which might lead to improved clinical outcome and therapeutic potential. This review provides an overview of the technical basis of neurostimulation focusing on the equipment, the present understanding of induced electric fields, and the stimulation protocols. The review is written from a technical perspective aimed at supporting the use of neurostimulation in clinical practice.

Language activation distributions revealed by fMRI in post-operative epilepsy patients: differences between left- and right-sided resections.

OBJECTIVE: To reveal differences of cerebral activation related to language functions in post-operative temporal lobe epilepsy (TLE) patients. METHODS: Right (RTL) and left temporal lobe (LTL) resected patients, and healthy controls were studied using functional magnetic resonance imaging (fMRI). Only patients with complete left-hemispheric language dominance according to the intracarotid amytal procedure (IAP) were included. Language-related activations were evoked by performing word generation and text reading language tasks. Activation lateralization and temporo-frontal distribution effects were analysed. RESULTS: For word generation, only LTL patients showed reduced left lateralized activation compared to controls, due to a decrease in activation in the left prefrontal cortex and an increase in the right prefrontal cortex. For reading, the left-hemispheric lateralization in RTL patients increased because of enhanced activity in the left prefrontal cortex, whereas for LTL patients the activation became bilaterally distributed over the temporal lobes. Lateralization results between pre-operative IAP and post-operative fMRI were highly discordant. Significant temporo-frontal distribution changes manifested from the reading but not from the word generation task. CONCLUSION: The cerebral language representation in post-operative LTL epilepsy patients is more bi-hemispherically lateralized than in controls and RTL patients. Post-operative temporo-frontal and interhemispheric redistribution effects, involving contralateral homologous brain areas, are suggested to contribute to the cerebral reorganisation of language function.

In search of optimal DBS paradigms to treat epilepsy: bilateral versus unilateral hippocampal stimulation in a rat model for temporal lobe epilepsy.

BACKGROUND: In many temporal lobe epilepsy (TLE) patients both hippocampi are seizure onset zones. These patients are unsuitable candidates for epilepsy surgery but may be amenable to hippocampal deep brain stimulation (DBS). The optimal DBS parameters for these patients are unknown. Recent observations suggest that even in patients with a unilateral focus switching from unilateral hippocampal DBS to bilateral hippocampal DBS could improve seizure control. OBJECTIVE: Compare the effect of unilateral with bilateral hippocampal DBS on seizures in a rat model for TLE. METHODS: In the post status epilepticus (SE) kainic acid rat model for TLE continuous EEG monitoring was performed for 50 days during which rats were subjected to 10 days of unilateral and 10 days of bilateral Poisson-distributed high frequency hippocampal DBS in a cross-over trial. During bilateral DBS, each hippocampus was stimulated with a separate stimulator and its own generated Poisson distribution with a mean and variance of 1/130 s. RESULTS: Electrographic seizure rate was 23% lower during bilateral compared to unilateral hippocampal DBS (P < 0.05). No effect of unilateral nor bilateral hippocampal DBS was observed on seizure duration. When bilateral hippocampal DBS was applied, lower stimulation intensities were required to evoke after discharges (P < 0.05), reflecting a higher potency of bilateral hippocampal DBS compared to unilateral hippocampal DBS to affect hippocampal networks. CONCLUSIONS: Superior outcome in seizure control with bilateral compared to unilateral hippocampal DBS indicates that targeting larger regions of the hippocampal formation with more than one stimulation electrode may be more successful in suppressing seizures in TLE.