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Small fiber neuropathy (SFN) causes damage to small-calibre nerve fibers (unmyelinated C fibers and myelinated A-delta fibers). The symptoms of SFN usually are sensitive including paresthesia, dysesthesia or burning pain, and protopathic deficits, sometimes associated with dysautonomia. The causes of SFN can be classified in six main groups: idiopathic, toxic, metabolic, immunological, infectious and hereditary. In this article, we present the diagnostic approach to SFN, the most common autoimmune aetiologies, as well as elements of their therapeutic management.La neuropathie des petites fibres (NPF) implique une atteinte des fibres nerveuses de petit calibre : les fibres C non myélinisées et les fibres A-delta myélinisées. Elle se manifeste principalement par des troubles sensitifs : paresthésies, dysesthésies ou douleurs neuropathiques (brûlures) et déficits protopathiques, associés à des symptômes dysautonomiques. Les étiologies possibles des NPF sont variées : idiopathiques, toxiques, métaboliques, immunologiques, infectieuses et héréditaires. Nous présentons dans cet article la démarche diagnostique des NPF, les étiologies autoimmunes les plus fréquemment associées aux NPF, ainsi que des éléments de prise en charge thérapeutique.

Background No studies assessing rabies vaccine (RV) tolerability in persons with multiple sclerosis (MS) have been conducted. Given the lack of safety data, RV is recommended essentially only for post-exposure prophylaxis, which is difficult to administer effectively in many rabies-endemic countries. We sought to determine whether RV administration as pre-exposure prophylaxis was associated with MS relapse. Methods This retrospective cohort study compared the clinical courses of MS patients in the year before and after rabies vaccination. The year before vaccination was defined as the pre-exposure risk period, the three months thereafter as the exposure-risk period, and the following nine months as the post-risk period. All adult MS patients immunized with RV between 2014 and 2018 and with available medical records in the two-year window were included. The primary outcome was the incidence of symptomatic MS relapse in the exposure-risk period versus the pre-exposure period. Results Fifty-five patients received at least one dose of RV. Most (38/55, 69%) were female; mean age was 38.5 years (SD ±9.2). While 21 (38%) patients experienced 24 relapses in the year before vaccination, only three (5%) experienced one relapse each in the post-vaccination exposure-risk period; three others (5%) experienced a total of four relapses in the subsequent post-risk period. The annualized relapse rates in the pre-exposure, exposure-risk, and post-risk periods were 0.44, 0.22, and 0.10, respectively (rate ratio for exposure-risk to pre-exposure periods, 0.509 [95% CI 0.098-1.677]). Conclusions In this cohort, rabies vaccination was not associated with clinical MS relapse. Larger, prospective studies are needed to confirm these results.

ObjectiveTo determine whether CSF interleukin 8 (IL-8) concentration can help to distinguish Guillain-Barré syndrome (GBS) from chronic inflammatory demyelinating polyneuropathy (CIDP) at the initial stage of the disease.MethodsWe performed retrospective immunoassay of IL-8 in CSF, collected at the University Hospitals of Geneva between 2010 and 2018, from patients diagnosed with GBS (n = 45) and with CIDP (n = 30) according to the Brighton and European Federation of Neurological Societies/Peripheral Nerve Society criteria by a physician blinded to biological results.ResultsCSF IL-8 was higher in GBS (median: 83.9 pg/mL) than in CIDP (41.0 pg/mL) (p < 0.001). Receiver operating characteristic analyses indicated that the optimal IL-8 cutoff was 70 pg/mL. Above this value, patients were more likely to present GBS than CIDP (specificity 96.7%, sensitivity 64.4%, positive predictive value [PPV] 96.7%, and negative predictive value [NPV] 64.4%). Among GBS subcategories, IL-8 was higher in acute inflammatory demyelinating polyneuropathy (AIDP, median: 101.8 pg/mL) than in other GBS variants (median: 53.7 pg/mL). In addition, with CSF IL-8 above 70 pg/mL, patients were more likely to present AIDP than acute-onset CIDP (p < 0.001; specificity 100%, sensitivity 78.8%, PPV 100%, and NPV 46.2%) or other CIDP with nonacute presentation (p < 0.0001; specificity 95.8%, sensitivity 78.8%, PPV 96.3%, and NPV 76.7%).ConclusionCSF IL-8 levels can help to differentiate AIDP variant of GBS from CIDP, including acute-onset CIDP, with high specificity and PPV. This may improve early and appropriate treatment.Classification of EvidenceThis study provides Class II evidence that CSF IL-8 levels accurately distinguish patients with GBS from those with CIDP.

The spectrum of COVID-19, caused by severe acute respiratory syndrome coronavirus 2 infection (SARS-CoV-2), includes different neurologic manifestations of the central and peripheral nervous system. From March through April 2020, in two university hospitals located in western Switzerland, we examined three patients with Guillain-Barré syndrome (GBS) following SARS-CoV-2. These cases were characterized by a primary demyelinating electrophysiological pattern (Acute inflammatory demyelinating polyneuropathy or AIDP) and a less severe disease course compared to recently published case series. Clinical improvement was observed in all patients at week five. One patient was discharged from hospital after full recovery with persistence of minor neurological signs (areflexia). Two of the three patients remained hospitalized: one was able to walk and the other could stand up with assistance. We report three cases of typical GBS (AIDP) occurring after SARS-CoV-2 infection and presenting with a favourable clinical course. Given the interval between COVID-19-related symptoms and neurological manifestations (mean of 15 days) we postulate a secondary immune-mediated mechanism rather than direct viral damage.

Myasthenia gravis (MG) is an autoimmune disease of the neuromuscular junction. Immunosuppressive treatments are part of the therapeutic armamentarium in MG. Long-term systemic steroid administration carry considerable risks and adverse events. Consequently, steroid-free immunosuppressive therapy is necessary to reduce the dose or discontinue steroids. First immunosuppressive drug trials in MG were performed in the mid-60s using standard and nonspecific immunosuppression. Since then, only few randomized controlled clinical trials were conducted in MG and assesed drug efficacy in terms of its steroid-sparing capacity and the ability to reduce myasthenic signs and symptoms. Treatment strategy in MG is quite challenging, mainly due to the disease heterogeneity in terms of clinical presentation, immunopathogenesis and drug response. To solve this dilemma, emerging treatment are based on biological drugs and use new targets of the immune pathway.

Myasthenia gravis (MG) is an autoimmune disease characterised by fluctuating muscle weakness with potentially life-threatening symptoms due to insufficiency of respiratory muscles. Treatment usually includes immunosuppressive drugs and cholinesterase inhibitors. COVID-19 is an infection caused by the newly discovered severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), defined as a pandemic by the World Health Organisation (WHO). Although guidelines for the management of patients with MG during the COVID-19 pandemic have been published,1 these recommendations are based on theoretical considerations only, as no clinical data are available. We describe four patients with generalised MG affected by COVID-19 (around 10% of patients in our cohort). Clinical data are summarised in table 1. View this table: Table 1 Clinical data of four patients with generalised gravis and SARS-CoV-2 ### Case 1 A 36-year-old female patient, class IIa according to the Myasthenia Gravis Foundation of America (MGFA) score (166 cm, 67 kg), presented to Geneva University Hospital on 15 March 2020 with myalgia, coughing and fever >38°C on the same day. She was taking azathioprine (AZA) 50 mg, reintroduced at the end of January 2020, and pyridostigmine 60 mg five to six times per day. The last deterioration of MG had occurred in January 2020 requiring intravenous immunoglobulin (IVIG) treatment (Myasthenia Muscle Score 65/100). COVID-19 real-time PCR (RT-PCR) revealed a positive result. Chest X-ray showed no pulmonary infiltration and peak flow was at 400 mL (82%). The Myasthenia Muscle …

ObjectiveTo determine whether live-attenuated yellow fever vaccine (YFV) was associated with MS relapse, we evaluated the clinical courses of 23 patients in the year before and the year after immunization at the university hospital of Geneva, Switzerland.MethodsThis self-controlled retrospective cohort included adult patients with MS receiving YFV between 2014 and 2018 and defined the year before vaccination, the 3 months thereafter, and the 9 months following as the pre-exposure (PEP), exposure-risk (ERP), and postrisk (PRP) periods, respectively. The primary outcome was the relative incidence of relapse in the ERP vs the PEP. Secondary end points included the presence of new T2-weighted (T2) or T1-weighted gadolinium-positive (T1Gd+) MRI lesions.ResultsOf 23 patients with MS receiving YFV (20 relapsing MS and 3 primary progressive MS), 17 (74%) were women; mean age was 34 years (SD ±10); and 10 of 23 (40%) were treated with disease-modifying therapies (DMTs). Although 9 patients experienced 12 relapses in the PEP, only one experienced a relapse in the ERP; 3 other patients experienced one relapse each in the PRP. None of the 8 patients receiving natalizumab at the time of vaccination experienced relapse thereafter. In the PEP, ERP, and PRP, 18, 2, and 9 patients had new brain and/or spinal cord lesions on T2 or T1Gd + MRI, respectively.ConclusionsIn this cohort, YF vaccination was associated with neither an increase in MS relapse nor emergence of brain and/or spinal lesions. Further studies are warranted to confirm these findings.Classification of evidenceThis study provides Class IV evidence that for persons with MS, YFV may not increase relapse risk.

We report the case of a patient affected by systemic sclerosis (SSc) who developed autoimmune limbic encephalitis, which improved under immunosuppressant agents and high-dose intravenous immunoglobulins. In our patient the autoimmune encephalitis occurred during apparently quiescent SSc, though concomitantly with novel arthritis. Moreover, our patient showed auto-antibodies directed against SSA antigen but the panel of auto-antibodies associated with autoimmune encephalitis was negative. We discuss the potential for immunopathogenic inflammatory events affecting the central nervous system in SSc then favoring the occurrence of autoimmune encephalitic disorders. The possibility of a "neuro-scleroderma" may have important consequences in terms of therapeutic approaches.

Tandem spinal stenosis (TSS) is an entity which refers to spinal canal diameter narrowing in at least two distinct regions of the spine. When symptomatic, management of TSS is controversial. In this study, we present a consecutive series of patients with symptomatic TSS and report diagnostic and surgical challenges. We retrospectively reviewed a consecutive series of N = 8 patients with symptomatic TSS who underwent surgical treatment in at least one region of the spine. Patients presented with multiple complaints, including neurogenic claudication, progressive gait disturbances, and signs of radiculopathy and/or myelopathy, among others. Modified Japanese Orthopedic Association (mJOA) and Oswestry Low Back Pain Disability Questionnaire (ODI) were obtained in pre- and postoperative period. Electroneurophysiological examinations were limited to patients whose clinical and radiological signs were not sufficient to determine which region was more affected. From 2015 to 2018, we included N = 8 consecutive patients with TSS who underwent surgery by a staged approach. The stenosis was localized in the cervical and lumbar region in six patients (75%) and in the cervical, dorsal, and lumbar level (triple TSS) in two patients (25%). Four patients (50%) underwent cervical and lumbar surgery, two (25%) underwent cervical surgery alone, and two (25%) were operated in all three involved regions. Surgical treatment allowed an improvement of the mean mJOA score (from 12.5/17 to 15/17) and mean ODI score (from 41 to 28%). TSS represents a clinical, diagnostic, and surgical challenge. We recommend to systematically obtain electrophysiological and radiological examinations and then to perform a staged surgery, beginning at the most symptomatic region.

Background Fingolimod is the first approved oral disease-modifying treatment for relapsing-remitting multiple sclerosis. Fingolimod targets lymphocytes, exerting a modulator effect on cell-surface sphingosine-1-phosphate receptors and thus blocking lymphocytes egression from secondary lymphoid organs. Recent reports describe fingolimod cessation being followed by severe or pseudo-tumoral relapse, but it usually does not happen on continuous long-term treatment. Case presentation Here we present the case of a patient on continuous long-term fingolimod treatment who presented with fulminant atypical multifocal relapse involving over 30 new and active lesions. Conclusion This case is unique since this fulminant multifocal relapse occurred in a patient with grade 3 lymphopenia and irreproachable adherence. This observation should be known as a possible side effect of fingolimod treatment.

Background/Aims: The monitoring of interictal epileptiform discharge rates (IEDRs) all along anterior temporal lobe resections (ATLRs) has never been reported. Here the effect of ATLR on continuous IEDR monitoring is described. Methods: IEDRs computed automatically during entire interventions were recorded in 34 patients (38.2%, 13/34 depth; 61.8%, 21/34 scalp electrodes only). Monitorings were invalidated when burst suppression occurred or if initial IEDRs were Results: Monitoring was successful for 69.2% (9/13) of the patients with depth recordings and for 4.8% (1/21) of the patients with scalp recordings. Burst suppressions precluded it in 30.8% (4/13) of the depth and in 57.1% (12/21) of the scalp recordings. Initial IEDRs were Conclusion: IEDR monitoring was possible with depth, but not with scalp electrodes. IEDR decreases started with resection of the superior temporal gyrus. A larger patient cohort is necessary to confirm the high predictive values of IEDR monitoring that could become a tool for surgery customization.

Background Autoimmune encephalitis (AE) refers to a central nervous system (CNS) antibody-mediated entity characterized by a rapid onset behavioural and cognitive decline that can be associated with movement disorders, epileptic and dysautonomic features. Interestingly, it is thought to be as common as its infectious disease counterpart and can share some clinical, radiological, and laboratory findings. Objectives The aim is to describe the main clinical features of AE caused by antibodies targeting cell-surface neuronal agents and the diagnostic means to identify them. Paraneoplastic syndromes, associated with intracellular antibodies, will not be tackled in this review. Sources PubMed/MEDLINE were the sources. Content According to a recent population-based study, autoimmunity is one of the most frequent cause of encephalitis after infectious agents. Its diagnosis lies upon ‘classic' clinical features, which are dominated by neuropsychiatric symptoms and epileptic seizures. Cerebral spinal fluid (CSF) and serum autoantibody testing can confirm AE. Complementary examination with magnetic resonance imaging (MRI) and electroencephalogram (EEG) may be helpful for excluding other causes and managing seizures. In addition, exclusion of infectious and other origins must be considered. Implications AE misdiagnosis can lead to a delay in treatment onset and, thus, clinical worsening. In this sense, identifying the causative agent is of utmost importance. However, the absence of CSF or serum antibody detection does not exclude the diagnosis of AE. Despite extensive testing, many encephalitis cases remain of unknown origin. It is obvious that some autoantibodies have not yet been identified in AE. Since radiological and biological examinations are not always contributive, early symptom recognition might help to hasten the diagnostic process.

Background Encephalitis and meningoencephalitis imply inflammation of the brain parenchyma, and comprise many diagnostic entities, such as various infections and causes of dysimmunity. The cause remains unknown in around 50% of cases. Objectives To summarize the main infectious causes of encephalitis and meningoencephalitis acquired in Europe, and the diagnostic means to identify them. Sources PubMed, ECDC and WHO websites, personal experience. Content The principal infectious causes of encephalitis and meningoencephalitis acquired in Europe in adults are discussed in this review, with special emphasis on the microbiological and imaging diagnostic approaches. The role of electroencephalography in diagnosing encephalitis is also mentioned. Among infections, viruses are more frequent than other pathogen types, and their epidemiology varies according to geographic area. A few bacteria, such as Listeria monocytogenes and Mycobacterium tuberculosis, are also to be considered. In contrast, parasites and fungi are rare encephalitis causes in Europe. Implications Identifying the causative pathogen of infectious encephalitis and meningoencephalitis is complex because of the variety of pathogens, the epidemiology of which is determined by geography and environmental factors. Furthermore, despite extensive microbiological testing, many cases of encephalitis remain of unknown origin. Brain magnetic resonance imaging and electroencephalography are useful complementary diagnostic tools, and newer unbiased sequencing technologies might help to fill in the diagnostic gap.

Resection of abnormal brain tissue lying near the sensorimotor cortex entails precise localization of the central sulcus. Mapping of this area is achieved by applying invasive direct cortical electrical stimulation. However, noninvasive methods, particularly functional magnetic resonance imaging (fMRI), are also used. As a supplement to fMRI, localization of somatosensory-evoked potentials (SEPs) recorded with an electroencephalogram (EEG) has been proposed, but has not found its place in clinical practice.To assess localization accuracy of the hand somatosensory cortex with SEP source imaging.We applied electrical source imaging in 49 subjects, recorded with high-density EEG (256 channels). We compared it with fMRI in 18 participants and with direct cortical electrical stimulation in 6 epileptic patients.Comparison of SEP source imaging with fMRI indicated differences of 3 to 8 mm, with the exception of the mesial-distal orientation, where variances of up to 20 mm were found. This discrepancy is explained by the fact that the source maximum of the first SEP peak is localized deep in the central sulcus (area 3b), where information initially arrives. Conversely, fMRI showed maximal signal change on the lateral surface of the postcentral gyrus (area 1), where sensory information is integrated later in time. Electrical source imaging and fMRI showed mean Euclidean distances of 13 and 14 mm, respectively, from the contacts where electrocorticography elicited sensory phenomena of the contralateral upper limb.SEP source imaging, based on high-density EEG, reliably identifies the depth of the central sulcus. Moreover, it is a simple, flexible, and relatively inexpensive alternative to fMRI.

Summary Purpose Patients with tuberous sclerosis complex (TSC) often suffer from medically refractory epilepsy. Despite the multifocality of the disease, resection of the most epileptogenic tuber can lead to major improvement of seizure control. Therefore, non-invasive imaging methods are needed for detecting epileptogenic sources. We assessed the utility of electric source imaging (ESI) in the presurgical work-up of TSC patients and its combination with Positron Emission Tomography (PET) and ictal/interictal Single Photon Emission Computed Tomography (SISCOM). Methods Thirteen patients underwent high density ESI (8/13) and/or low density ESI (13/13). We investigated the concordance between ESI, PET, SISCOM and the resection area in the 11 operated patients (nine seizure-free). Results High resolution ESI was partially or completely concordant with the resected area in 5/5 seizure free patients. Low resolution ESI was partially or completely concordant in 7/9 seizure free patients. PET and SPECT were concordant (partially or completely) in 8/9 and 6/9 cases, respectively. We found multifocal ESI sources in 2/9 seizure free patients, marked multifocal PET hypometabolism in 3/9 and multifocal SISCOM in 4/9. The region of concordant ESI and PET accurately predicted the dominant epileptogenic source in 6/9 patients. The same was true for concordant ESI and SISCOM in 4/9 patients, whereas the coregistration of only PET and SISCOM was insufficient in 3/9 successfully operated cases. The combination of all three imaging modalities could successfully identify the resection area in all but one patient with a favorable post-operation outcome. Conclusion ESI is an important tool for the pre-surgical evaluation of TSC patients. It complements PET and SPECT results and can improve the management of candidates for surgery when integrated with electro-clinical information.

A first seizure is a life-changing event with physical and psychological consequences. We aimed to assess the role of early comprehensive patient care after a first unprovoked seizure to improve diagnostic accuracy and follow-up adherence. From April 2011 to March 2012, patients presenting a first unprovoked epileptic seizure received standard patient care (SPC), i.e., a consultation in the ED, an EEG and a CT scan. The patients were notified of the follow-ups. We compared this protocol to subsequently acquired "early comprehensive patient care" (ECPC), which included a consultation by an epileptologist in the emergency department (ED), a routine or long-term monitoring electroencephalogram (LTM-EEG), magnetic resonance imaging and three follow-up consultations (3 weeks, 3 months, 12 months). 183 patients were included (113 ECPC, 70 SPC). LTM-EEG and MRI were performed in 51 and 85 %, respectively, of the patients in the ECPC group vs in 7 and 52 % of the patients in the SPC group (p

Introduction L’encephalite limbique (EL) est souvent associee a des auto-anticorps specifiques. L’association d’anticorps anti-γ-Aminobutyrique-acide-B (GABAB1) et anti-acid-glutamique-decarboxylase (GAD) est rare, et frequemment paraneoplasique. Observation Patiente de 50 ans, diabetique, presente une faiblesse proximale des membres inferieurs ainsi que des crises d’epilepsie evoluant rapidement vers un etat de mal epileptique pharmaco-resistant necessitant une sedation. L’IRM cerebrale revele une hyperintensite T2 des hippocampes, symetrique. L’analyse du liquide cephalo-rachidien (LCR) montre une hyperleucorachie a 38 M/l. Le bilan infectieux et immunologique revient negatif. En raison de la clinique hautement suggestive, de l’IRM, du resultat du LCR et de la presence d’anticorps anti-GABAB1 et anti-GAD dans le sang, le diagnostic d’EL est retenu. Un PET-FDG-CT revele un hypermetabolisme mesio-temporal bilateral, ainsi qu’un nodule thyroidien, qui sera ponctionne montrant une neoplasie folliculaire oncocytaire. Un traitement par immunoglobulines et corticoides est instaure, supplee par du rituximab, qui est rapidement arrete en raison d’un syndrome de Lyell severe. L’evolution est lentement favorable avec disparition des crises sous traitement d’immunoglobulines I.V. 1×/mois pendant 6 mois avec ensuite un espacement progressif des cures et introduction du mycophenolate mofetil 2 g/jour. La patiente garde d’importantes sequelles neuropsychologiques (amnesie globale, ralentissement), mais est cliniquement stable. L’IRM a 1 an montre une sclerose hippocampique sans nouvelle lesion. Discussion L’association d’anticorps anti-GABAB1 et anti-GAD est rare. Huit cas ont ete decrits, dont 37,5 % idiopathiques, 62,5 % paraneoplasiques. Le phenotype semble different de l’EL avec un seul anticorps, se manifestant par une epilepsie pharmaco-resistante. L’EL a anti-GAD est plus rarement paraneoplasique (26 %). La reponse au traitement est variable et depend de la pathologie tumorale sous-jacente, ou de la severite de l’epilepsie. Conclusion La recherche d’anticorps anti-GABAB1 et anti-GAD devait etre effectuee en cas d’EL seronegative et une recherche active de tumeur s’impose.

Introduction Le mecanisme physiopathologique du syndrome de Guillain-Barre (SGB) demeure encore d’indetermine. Il existe des arguments parlant en faveur d’un role des cytokines inflammatoires dans l’atteinte des nerfs peripheriques. Objectifs Comparer le taux d’interleukine 8 (IL-8) dans le liquide cephalorachidien (LCR) dans le SGB versus des autres maladies neurologiques tel que la polyradiculonevrite demyelinisante inflammatoire chronique (PIDC). Patients et methodes Etude retrospective basee sur une cohorte des patients suivis dans le Service de neurologie des hopitaux universitaires de Geneve, pendant l’annee 2010 et 2017. Le taux de l’IL-8 dans le LCR a ete determine. L’analyse de variance ou Anova a ete employe pour analyser les parametres quantitatifs, permettant comparer chaque groupe avec l’autre (p Resultats Nous avons inclus 4 patients avec SGB, 5 avec PIDC, 4 polyneuropathies (PNP) non-inflammatoires, 3 migraines et 6 avec trouble fonctionnel. La concentration moyenne d’IL-8 dans le LCR etait : SGB = 106 pg/mL, PIDC = 43 pg/mL, PNP = 53 pg/mL, migraine = 36 pg/mL et troubles fonctionnels = 28 pg/mL. L’Anova a montre des resultats significatifs (p Discussion Les resultats de cette etude pilote montre que le taux d’IL-8 dans le LCR est tres elevee dans le groupe SGB (p Conclusion L’IL-8 dans le LCR pourrait etre consideree comme biomarqueur permettant differencier le SBG des autres PNP inflammatoires tel que la PIDC.

Traditionally, subcortical structures such as the cerebellum are supposed to exert a modulatory effect on epileptic seizures, rather than being the primary seizure generator. We report a 14-month old girl presenting, since birth, with seizures symptomatic of a right cerebellar dysplasia, manifested as paroxystic contralateral hemifacial spasm and ipsilateral facial weakness. Multimodal imaging was used to investigate both anatomical landmarks related to the cerebellar lesion and mechanisms underlying seizure generation. Electric source imaging (ESI) supported the hypothesis of a right cerebellar epileptogenic generator in concordance with nuclear imaging findings; subsequently validated by intra-operative intralesional recordings. Diffusion spectrum imaging-related tractography (DSI) showed severe cerebellar structural abnormalities confirmed by histological examination. We suggest that hemispheric cerebellar lesions in cases like this are likely to cause epilepsy via an effect on the facial nuclei through ipsilateral and contralateral aberrant connections.

Evoked potentials (EPs) are a powerful and cost-effective tool for evaluating the integrity and function of the central nervous system. Although imaging techniques, such as MRI, have recently become increasingly important in the diagnosis of neurological diseases, over the past 30 years, many neurologists have continued to employ EPs in specific clinical applications. This review presents an overview of the recent evolution of 'classical' clinical applications of EPs in terms of early diagnosis and disease monitoring and is an extension of a previous review published in this journal in 2005 by Walsh and collaborators. We also provide an update on emerging EPs based on gustatory, olfactory and pain stimulation that may be used as clinically relevant markers of neurodegenerative disorders such as Parkinson's disease, Alzheimer's disease and cortical or peripheral impaired pain perception. EPs based on multichannel electroencephalography recordings, known as high-density EPs, help to better differentiate between healthy subjects and patients and, moreover, they provide valuable spatial information regarding the site of the lesion. EPs are reliable disease-progression biomarkers of several neurological diseases, such as multiple sclerosis and other demyelinating disorders. Overall, EPs are excellent neurophysiological tools that will expand standard clinical practice in modern neurology.

Despite intensive research activity leading to many important discoveries, the pathophysiological mechanisms underlying seizures and epilepsy remain poorly understood. An important number of specific gene defects have been related to various forms of epilepsies, and autoimmunity and epilepsy have been associated for a long time. Certain central nervous system proteins have been involved in epilepsy or acute neurological diseases with seizures either due to underlying gene defects or immune dysfunction. Here, we focus on 2 of them that have been the object of particular attention and in-depth research over the past years: the N-methyl-D-aspartate receptor and the leucin-rich glioma-inactivated protein 1 (LGI1). We also describe illustrative examples of situations in which genetics and immunology meet in the complex pathways that underlie seizures and epilepsy.

Stroke lesions induce not only loss of local neural function, but disruptions in spatially distributed areas. However, it is unknown whether they affect the synchrony of electrical oscillations in neural networks and if changes in network coherence are associated with neurological deficits. This study assessed these questions in a population of patients with subacute, unilateral, ischemic stroke. Spontaneous cortical oscillations were reconstructed from high-resolution electroencephalograms (EEG) with adaptive spatial filters. Maps of functional connectivity (FC) between brain areas were created and correlated with patient performance in motor and cognitive scores. In comparison to age matched healthy controls, stroke patients showed a selective disruption of FC in the alpha frequency range. The spatial distribution of alpha band FC reflected the pattern of motor and cognitive deficits of the individual patient: network nodes that participate normally in the affected functions showed local decreases in FC with the rest of the brain. Interregional FC in the alpha band, but not in delta, theta, or beta frequencies, was highly correlated with motor and cognitive performance. In contrast, FC between contralesional areas and the rest of the brain was negatively associated with patient performance. Alpha oscillation synchrony at rest is a unique and specific marker of network function and linearly associated with behavioral performance. Maps of alpha synchrony computed from a single resting-state EEG recording provide a robust and convenient window into the functionality and organization of cortical networks with numerous potential applications.

Electroencephalography is mandatory to determine the epilepsy syndrome. However, for the precise localization of the irritative zone in patients with focal epilepsy, costly and sometimes cumbersome imaging techniques are used. Recent small studies using electric source imaging suggest that electroencephalography itself could be used to localize the focus. However, a large prospective validation study is missing. This study presents a cohort of 152 operated patients where electric source imaging was applied as part of the pre-surgical work-up allowing a comparison with the results from other methods. Patients (n = 152) with >1 year postoperative follow-up were studied prospectively. The sensitivity and specificity of each imaging method was defined by comparing the localization of the source maximum with the resected zone and surgical outcome. Electric source imaging had a sensitivity of 84% and a specificity of 88% if the electroencephalogram was recorded with a large number of electrodes (128-256 channels) and the individual magnetic resonance image was used as head model. These values compared favourably with those of structural magnetic resonance imaging (76% sensitivity, 53% specificity), positron emission tomography (69% sensitivity, 44% specificity) and ictal/interictal single-photon emission-computed tomography (58% sensitivity, 47% specificity). The sensitivity and specificity of electric source imaging decreased to 57% and 59%, respectively, with low number of electrodes (

PURPOSE: Patients with magnetic resonance (MR)-negative focal epilepsy (MRN-E) have less favorable surgical outcomes (between 40% and 70%) compared to those in whom an MRI lesion guides the site of surgical intervention (60-90%). Patients with extratemporal MRN-E have the worst outcome (around 50% chance of seizure freedom). We studied whether electroencephalography (EEG) source imaging (ESI) of interictal epileptic activity can contribute to the identification of the epileptic focus in patients with normal MRI. METHODS: We carried out ESI in 10 operated patients with nonlesional MRI and a postsurgical follow-up of at least 1 year. Five of the 10 patients had extratemporal lobe epilepsy. Evaluation comprised surface and intracranial EEG monitoring of ictal and interictal events, structural MRI, [(18)F]fluorodeoxyglucose positron emission tomography (FDG-PET), ictal and interictal perfusion single photon emission computed tomography (SPECT) scans. Eight of the 10 patients also underwent intracranial monitoring. RESULTS: ESI correctly localized the epileptic focus within the resection margins in 8 of 10 patients, 9 of whom experienced favorable postsurgical outcomes. DISCUSSION: The results highlight the diagnostic value of ESI and encourage broadening its application to patients with MRN-E. If the surface EEG contains fairly localized spikes, ESI contributes to the presurgical decision process.

SUMMARY: This study presents a method to record and analyze multichannel visual-evoked potential (VEP) and somatosensory-evoked potential (SEP) in an objective, automatic, and quantitative manner. The intention of this study was to assess their diagnostic value in multiple sclerosis (MS). A 256-channel VEP and SEP were recorded in 44 healthy subjects, 26 patients with MS, and 20 patients with other neurologic diseases. Topographic pattern recognition methods were applied and a normative database was established. Z-score statistics allowed identifying the number of subjects with significant abnormal values in each group. These values were compared with conventional single-channel waveform analysis. The diagnostic value of the new measures for MS reached a sensitivity of 72% and a specificity of 100% for the VEP, which was significantly higher than the conventional analysis. For the SEP, the specificity was also high (93%) but the sensitivity remained low as in the conventional analysis (30%). The quantitative topographic analysis of multichannel VEP revealed high-diagnostic sensitivity and specificity for MS. Moreover, the method reliably identified the most dominant VEP and SEP components in the healthy subject group. The results indicate that objective topographic analysis of multichannel recordings increase the value of VEP as surrogate marker for MS.

Objective We investigated the contribution of electrocortical stimulation (ECS), induced high gamma electrocorticography (hgECoG) and functional magnetic resonance imaging (fMRI) for the localization of somatosensory and language cortex. Methods 23 Epileptic patients with subdural electrodes underwent a protocol of somatosensory stimulation and/or an auditory semantic decision task. 14 Patients did the same protocol with fMRI prior to implantation. Results ECS resulted in the identification of thumb somatosensory cortex in 12/16 patients. Taking ECS as a gold standard, hgECoG and fMRI identified 53.6/33% of true positive and 4/12% of false positive contacts, respectively. The hgECoG false positive sites were all found in the hand area of the post-central gyrus. ECS localized language-related sites in 7/12 patients with hgECoG and fMRI showing 50/64% of true positive and 8/23% of false positive contacts, respectively. All but one of the hgECoG/fMRI false positive contacts were located in plausible language areas. Four patients showed post-surgical impairments: the resection included the sites positively indicated by ECS, hgECoG and fMRI in 3 patients and a positive hgECoG site in one patient. Conclusions HgECoG and fMRI provide additional localization information in patients who cannot sufficiently collaborate during ECS. Significance HgECoG and fMRI make the cortical mapping procedure more flexible not only by identifying priority cortical sites for ECS or when ECS is not feasible, but also when ECS does not provide any result.

Although brain structures involved in central nervous olfactory processing in humans have been well identified with functional neuroimaging, little is known about the temporal sequence of their activation. We recorded olfactory event-related potentials (ERP) to H(2)S stimuli presented to the left and right nostril in 12 healthy subjects. Topographic and source analysis identified four distinct processing steps between 200 and 1000 ms. Activation started ipsilateral to the stimulated nostril in the mesial and lateral temporal cortex (amygdala, parahippocampal gyrus, superior temporal gyrus, insula). Subsequently, the corresponding structures on the contralateral side became involved, followed by frontal structures at the end of the activation period. Thus, based on EEG-related data, current results suggest that olfactory information in humans is processed first ipsilaterally to the stimulated nostril and then activates the major relays in olfactory information processing in both hemispheres. Most importantly, the currently described techniques allow the investigation of the spatial processing of olfactory information at a high temporal resolution.

Objective To test the accuracy of EEG source imaging in epilepsy patients with large cerebral lesions. It is hypothesized that lesions are most likely to change conductivity properties and to significantly impair the accuracy of electromagnetic source imaging (ESI) based on the EEG. This has, however, not been tested in patients’ EEG. Methods Fourteen patients with focal epilepsy and large cerebral lesions underwent high-resolution (128–256 channels) interictal EEG recordings. Thirteen patients were operated, leading to seizure freedom in 12. The spike sources were localized with a distributed linear inverse solution (LAURA) and compared to the post-operative MRI or the results of other invasive or non-invasive exams. Results In 12 patients ESI indicated the maximum source of the epileptic activity to be located within the epileptogenic zone (85%). One of the remaining cases was not seizure free after surgery. According to the ESI result, however, the focus was incompletely removed. Conclusion High resolution ESI constrained to the individual anatomy identifies the epileptogenic focus in patients with volume relevant brain lesions with excellent accuracy, comparable to that of other non-invasive methods. Significance Our results are of particular clinical importance, as they show that ESI can be extended to patients with large inhomogeneous lesions.

Human functional imaging studies are increasingly focusing on the identification of large-scale neuronal networks, their temporal properties, their development, and their plasticity and recovery after brain lesions. A method targeting large-scale networks in rodents would open the possibility to investigate their neuronal and molecular basis in detail. We here present a method to study such networks in mice with minimal invasiveness, based on the simultaneous recording of epicranial EEG from 32 electrodes regularly distributed over the head surface. Spatiotemporal analysis of the electrical potential maps similar to human EEG imaging studies allows quantifying the dynamics of the global neuronal activation with sub-millisecond resolution. We tested the feasibility, stability and reproducibility of the method by recording the electrical activity evoked by mechanical stimulation of the mystacial vibrissae. We found a series of potential maps with different spatial configurations that suggested the activation of a large-scale network with generators in several somatosensory and motor areas of both hemispheres. The spatiotemporal activation pattern was stable both across mice and in the same mouse across time. We also performed 16-channel intracortical recordings of the local field potential across cortical layers in different brain areas and found tight spatiotemporal concordance with the generators estimated from the epicranial maps. Epicranial EEG mapping thus allows assessing sensory processing by large-scale neuronal networks in living mice with minimal invasiveness, complementing existing approaches to study the neurophysiological mechanisms of interaction within the network in detail and to characterize their developmental, experience-dependent and lesion-induced plasticity in normal and transgenic animals.

Objective In patients with drug-resistant epilepsy who are candidate for surgery, non-invasive functional imaging methods are helpful in guiding surgical resections. Our main aim was to determine localisation precision of the epileptogenic focus with electric source imaging (ESI) and to compare it to other well-established imaging tools. Methods One hundred fifty-two pharmaco-resistant epileptic patients with more than 1 year post-operative follow-up were included. Sensitivity (defined as % of seizure free patients with focus localization within the resected zone) and specificity (defined as % of patients with focus localization outside the operated area) of different techniques was assessed: ESI, magnetic resonance imaging (MRI), positron emission tomography (PET) and single-photon emission-computed tomography (SPECT). Results A total of 43 patients underwent all examinations. High-resolution ESI (>64 electrodes) using individual MRI as a head model rendered the highest sensitivity (80%) and, principally, specificity rate (88%), followed by MRI (71.4% and 50%), PET (62.9% and 37.5%) and SPECT (54.3% but a higher specificity as compared to MRI and PET of 62.5%). The sensitivity of ESI was high in both temporal and extratemporal lobe epilepsy (91% and 75%, resp). The chance to become seizure-free if the focus source maximum is resected is 97%. Conclusion From a clinical point of view, ESI is a very attractive non-invasive technique with a high localization yield which provides superior temporal resolution in the millisecond range, as compared to methods based on changes in metabolic or vascular correlates of neural activity. From a practical perspective, this type of examination does not require sedation, it can be performed at patient’s bedside and it is suitable in the pediatric population and cognitively impaired patients.