Correction to: COVID-19-associated acute cerebral venous thrombosis: clinical, CT, MRI and EEG features.

An amendment to this paper has been published and can be accessed via the original article.

Report on Electroencephalographic Findings in Critically Ill Patients with COVID-19.

In March 2020, we treated a cohort of 26 critically ill hospitalized SARS-CoV-2-infected patients who underwent electroencephalography to assess unexplained altered mental status, loss of consciousness, or poor arousal and responsiveness. Of the 26 patients studied, 5 patients had electroencephalograms that showed periodic discharges consisting of high-amplitude frontal monomorphic delta waves with absence of epileptic activity. These findings may suggest central nervous system injury potentially related to COVID-19 in these patients. ANN NEUROL 2020;88:626-630.

Herpes simplex encephalitis: A new type of "ICU-acquired infection"?

PURPOSE: Although it is a well-known disease, the occurrence of Herpes simplex encephalitis (HSE) during a hospital stay may render the diagnosis particularly challenging. The objective of this report is to alert clinicians about the diagnostic pitfalls arising from hospital-developed HSE. MATERIALS AND METHODS: Clinical observation of one patient. CASE REPORT: An 87-year-old male was admitted to the Intensive Care Unit (ICU) because of respiratory failure due to an exacerbation of myasthenia gravis. After corticoids and azathioprine treatment, his clinical condition improved, allowing weaning from mechanical ventilation. One month after admission, while still hospitalized in the ICU, the patient developed fever and confusion. In the context of confounding factors, HSE was not suspected before a convulsive status epilepticus occurred, resulting in a significant delay in treatment. Diagnosis was confirmed by PCR-analysis in the cerebrospinal fluid. Serological status confirmed reactivation of prior herpes simplex infection. The patient died one week after the onset of confusion. CONCLUSIONS: Hospital-"acquired" HSE must be suspected in case of new neurologic symptoms associated with fever, even in ICU-hospitalized patients. The diagnosis is made even more difficult by nonspecific symptoms due to previous diseases, leading to an even more severe prognosis in those vulnerable patients.

Outcome of intravenous recombinant tissue plasminogen activator for acute ischemic stroke in patients aged over 80 years.

AIM: Practitioners are faced with a substantial challenge when considering recombinant tissue plasminogen activator (rt-PA) therapy for older patients with ischemic stroke. Patients aged over 80 years suffer from the most severe cerebral infarcts. The benefit of rt-PA treatment compared with single standard care only in stroke units remains to be clearly assessed. METHODS: We collected data from 321 patients aged over 80 years admitted for acute cerebral infarction to the stroke unit of Nancy University Hospital in France between 1 January 2009 and 31 December 2012. Patients were stratified into two groups: treated or not with rt-PA. Baseline characteristics and outcome were collected and compared between both groups. Good outcome at 3 months was defined as modified Rankin Scale score ≤2. RESULTS: The 55 patients treated with rt-PA had a higher National Institute of Health Stroke Scale score on admission than those without (15 vs 5; P < 0.001). They were more likely to have intracranial haemorrhage (20 vs 5%; P < 0.001) without an increased mortality rate (28 vs 27%; P = 0.95). Multivariate analysis showed a more favorable outcome (odds ratio 7, 95% confidence interval 3-16.5; P < 0.001). Slightly higher percentages of patients with modified Rankin Scale ≤2 were found after intention-to-treat analysis (49 vs 45%) and after exclusion of patients with baseline modified Rankin Scale >2 (57 vs 54 %), but without reaching significance (P > 0.05). CONCLUSIONS: Rt-PA therapy would appear to improve prognosis in the elderly with ischemic stroke. This suggests that age alone should no longer be a barrier to rt-PA therapy. Geriatr Gerontol Int 2016; 16: 843-849.

Beyond the core face-processing network: Intracerebral stimulation of a face-selective area in the right anterior fusiform gyrus elicits transient prosopagnosia.

According to neuropsychological evidence, a distributed network of regions of the ventral visual pathway - from the lateral occipital cortex to the temporal pole - supports face recognition. However, functional magnetic resonance imaging (fMRI) studies have generally confined ventral face-selective areas to the posterior section of the occipito-temporal cortex, i.e., the inferior occipital gyrus occipital face area (OFA) and the posterior and middle fusiform gyrus fusiform face area (FFA). There is recent evidence that intracranial electrical stimulation of these areas in the right hemisphere elicits face matching and recognition impairments (i.e., prosopagnosia) as well as perceptual face distortions. Here we report a case of transient inability to recognize faces following electrical stimulation of the right anterior fusiform gyrus, in a region located anteriorly to the FFA. There was no perceptual face distortion reported during stimulation. Although no fMRI face-selective responses were found in this region due to a severe signal drop-out as in previous studies, intracerebral face-selective event-related potentials and gamma range electrophysiological responses were found at the critical site of stimulation. These results point to a causal role in face recognition of the right anterior fusiform gyrus and more generally of face-selective areas located beyond the "core" face-processing network in the right ventral temporal cortex. It also illustrates the diagnostic value of intracerebral electrophysiological recordings and stimulation in understanding the neural basis of face recognition and visual recognition in general.

Catching the invisible: mesial temporal source contribution to simultaneous EEG and SEEG recordings.

Mesial temporal sources are presumed to escape detection in scalp electroencephalographic recordings. This is attributed to the deep localization and infolded geometry of mesial temporal structures that leads to a cancellation of electrical potentials, and to the blurring effect of the superimposed neocortical background activity. In this study, we analyzed simultaneous scalp and intracerebral electroencephalographic recordings to delineate the contribution of mesial temporal sources to scalp electroencephalogram. Interictal intracerebral spike networks were classified in three distinct categories: solely mesial, mesial as well as neocortical, and solely neocortical. The highest and earliest intracerebral spikes generated by the leader source of each network were marked and the corresponding simultaneous intracerebral and scalp electroencephalograms were averaged and then characterized both in terms of amplitude and spatial distribution. In seven drug-resistant epileptic patients, 21 interictal intracerebral networks were identified: nine mesial, five mesial plus neocortical and seven neocortical. Averaged scalp spikes arising respectively from mesial, mesial plus neocortical and neocortical networks had a 7.1 (n = 1,949), 36.1 (n = 628) and 10 (n = 1,471) µV average amplitude. Their scalp electroencephalogram electrical field presented a negativity in the ipsilateral anterior and basal temporal electrodes in all networks and a significant positivity in the fronto-centro-parietal electrodes solely in the mesial plus neocortical and neocortical networks. Topographic consistency test proved the consistency of these different scalp electroencephalogram maps and hierarchical clustering clearly differentiated them. In our study, we have thus shown for the first time that mesial temporal sources (1) cannot be spontaneously visible (mean signal-to-noise ratio -2.1 dB) on the scalp at the single trial level and (2) contribute to scalp electroencephalogram despite their curved geometry and deep localization.

Self-face hallucination evoked by electrical stimulation of the human brain.

OBJECTIVES: Self-face hallucination (autoscopic hallucination or AH) has been reported in patients with widespread brain damage or retrospectively after epileptic seizures. The neural basis and the self-processing operations underlying AH remain unknown. METHODS: We report the results of intracerebral electrical stimulations of the right medial occipitoparietal cortex (right precuneus and occipitoparietal sulcus) in 2 patients with epilepsy who underwent a stereo-EEG. RESULTS: Immediately after the onset of the stimulation, the 2 patients reported seeing their current own face, facing themselves, in their left visual field. CONCLUSIONS: Our study shows that the medial occipitoparietal junction has a key role in generating AH. This region has been shown to have a central role in various self-processing operations and especially in self-face recognition. Our observations further reveal that this region is involved in a visual representation of our own face, which is generated during the pathologic phenomenon of AH. This visual representation of our own face may be useful for self-face recognition and social cognition processes involving judgment of self-facial resemblance to others.

Intracerebral electrical stimulation of a face-selective area in the right inferior occipital cortex impairs individual face discrimination.

During intracerebral stimulation of the right inferior occipital cortex, a patient with refractory epilepsy was transiently impaired at discriminating two simultaneously presented photographs of unfamiliar faces. The critical electrode contact was located in the most posterior face-selective brain area of the human brain (right "occipital face area", rOFA) as shown both by low- (ERP) and high-frequency (gamma) electrophysiological responses as well as a face localizer in fMRI. At this electrode contact, periodic visual presentation of 6 different faces by second evoked a larger electrophysiological periodic response at 6 Hz than when the same face identity was repeated at the same rate. This intracerebral EEG repetition suppression effect was markedly reduced when face stimuli were presented upside-down, a manipulation that impairs individual face discrimination. These findings provide original evidence for a causal relationship between the face-selective right inferior occipital cortex and individual face discrimination, independently of long-term memory representations. More generally, they support the functional value of electrophysiological repetition suppression effects, indicating that these effects can be used as an index of a necessary neural representation of the changing stimulus property.

Right hemispheric dominance of visual phenomena evoked by intracerebral stimulation of the human visual cortex.

Electrical brain stimulation can provide important information about the functional organization of the human visual cortex. Here, we report the visual phenomena evoked by a large number (562) of intracerebral electrical stimulations performed at low-intensity with depth electrodes implanted in the occipito-parieto-temporal cortex of 22 epileptic patients. Focal electrical stimulation evoked primarily visual hallucinations with various complexities: simple (spot or blob), intermediary (geometric forms), or complex meaningful shapes (faces); visual illusions and impairments of visual recognition were more rarely observed. With the exception of the most posterior cortical sites, the probability of evoking a visual phenomenon was significantly higher in the right than the left hemisphere. Intermediary and complex hallucinations, illusions, and visual recognition impairments were almost exclusively evoked by stimulation in the right hemisphere. The probability of evoking a visual phenomenon decreased substantially from the occipital pole to the most anterior sites of the temporal lobe, and this decrease was more pronounced in the left hemisphere. The greater sensitivity of the right occipito-parieto-temporal regions to intracerebral electrical stimulation to evoke visual phenomena supports a predominant role of right hemispheric visual areas from perception to recognition of visual forms, regardless of visuospatial and attentional factors.

Electrical source imaging in cortical malformation-related epilepsy: a prospective EEG-SEEG concordance study.

OBJECTIVE: Delineation of the epileptogenic zone (EZ) in refractory epilepsy related to malformations of cortical development (MCDs) often requires intracranial electroencephalography (EEG) recordings, especially in cases of negative magnetic resonance imaging (MRI) or discordant MRI and video-EEG findings. It is therefore crucial to promote the development of noninvasive methods such as electrical source imaging (ESI). We aimed to (1) analyze the localization concordance of ESI derived from interictal discharges and EZ estimated by stereo-EEG (SEEG); (2) compare the concordance of ESI, MRI, and electroclinical correlations (ECCs) with SEEG-EZ; and (3) assess ESI added value in the EZ localization. METHODS: We prospectively analyzed 28 consecutive patients undergoing presurgical investigation for MCD-related refractory epilepsy in 2009-2012. ESI derived from 64-channel scalp EEG was interpreted with blinding to, and subsequently compared with, SEEG-estimated EZ. Anatomic concordance of ESI with SEEG-EZ was compared with that of video-EEG and MRI. We further assessed ESI added value to ECC and MRI. RESULTS: Twelve patients (43%) had temporal and 16 (57%) had extratemporal epilepsy. MRI was negative in 11 (39%) and revealed a cortical malformation in 17 (61%). ESI was fully concordant with the EZ in 10 (36%) and partly concordant in 15 (53%). ECC presented a full and partial concordance with EZ in 11% and 82% of cases, respectively, and MRI in 11% and 46%, respectively. Of 11 patients with negative MRI, ESI was fully concordant with the EZ in 7 (64%) and partly concordant in 4 (36%). ESI correctly confirmed restricted or added localizations to ECC and MRI in 12 (43%) of 28 patients and in 8 (73%) of 11 patients with negative MRI. SIGNIFICANCE: ESI contributes to estimating the EZ in MCD-related epilepsy. The added value of ESI to ECC is particularly high in patients with MCD and negative MRI, who represent the most challenging cases for epilepsy surgery. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.

Doxycycline in Creutzfeldt-Jakob disease: a phase 2, randomised, double-blind, placebo-controlled trial.

BACKGROUND: Creutzfeldt-Jakob disease (CJD) is a fatal, untreatable prion encephalopathy. Previous studies showed that doxycycline is effective in in-vitro and in-vivo models of disease, and patients with CJD who received compassionate treatment with doxycycline showed increased survival time compared with historical series. We therefore did a randomised, double-blind study of doxycycline versus placebo in CJD. METHODS: We recruited patients older than 18 years old who had a diagnosis of definite or probable sporadic CJD or genetic forms of the disease via Italian reference centres and the French national referral system. Patients were randomly assigned (ratio 1:1) to receive oral doxycycline (100 mg daily) or placebo under double-blind conditions from the day of randomisation to death. Centralised randomisation was done independently of enrolment or evaluation of patients using a minimisation method in Italy and a simple randomisation in France. Participants, caregivers, and clinicians were masked to group assignment. The primary efficacy variable was the survival time from randomisation. Interim analyses were planned to detect a significant effect of treatment as early as possible. This trial is registered with EudraCT, 2006-001858-27 for the Italian study and 2007-005553-34 for the French study. FINDINGS: From April 12, 2007, to Aug 19, 2010, in Italy, and from Jan 30, 2009, to Jan 10, 2012, in France, 121 patients with CJD were enrolled in the study, 62 of whom were randomly assigned to the treatment group and 59 to the placebo group. The first interim analysis showed absence of superiority of doxycycline compared with placebo, and the trial was stopped for futility. Efficacy analyses did not show significant differences between patients treated with doxycycline and placebo with regard to survival times (HR 1.1, 95% CI 0.8-1.7, p=0.50). Serious adverse events were judged not to be related to treatment, whereas a relation was deemed probable or possible for five non-serious adverse events that occurred in each treatment group. INTERPRETATION: Doxycycline at a dose of 100 mg per day was well tolerated but did not significantly affect the course of CJD, at variance with the results of previous observational studies. Our experience could be useful in the design of large multinational controlled trials of potential anti-prion molecules in this rare disease. FUNDING: Agenzia Italiana Farmaco, Italian Ministry of Health, AIEnP, and French Ministry of Health.

[Adherence to medication and epilepsy: a current issue]. / Adhésion au traitement médicamenteux et épilepsie : un enjeu d'actualité

As in other chronic diseases, adherence to medication in epilepsy is critical for seizure control. Its assessment remains challenging in research as in clinical practice. Recent evidences showed another face of nonadherence: the overconsumption of antiepileptic drugs. Some educational interventions with easy implementation were found to be effective in improving adherence and should be therefore more used in everyday practice.

[Use of drug reimbursement as markers of disease for epidemiological and cost analysis: The case of severe epilepsy in France]. / Intérêt des bases de remboursement de l'Assurance maladie pour l'analyse de la prise en charge des maladies chroniques : le cas de l'épilepsie.

OBJECTIVES: Population characteristics of epileptic patients remain poorly documented in France. Health Insurance claims database may be useful to perform cost and epidemiological studies provided that patients' diagnosis could be identified especially through drugs used as markers. This study explored the possibility to use the French Sickness Fund (FSF) database to determine the prevalence and direct cost of epilepsy. METHOD: The "FSF" reimbursement database is a 1/97 representative sample of the population covered under the French General Scheme. Only the fraction of patients fully covered for epilepsy may be identified by a diagnosis in the database. Others can only be identified through their claims for antiepileptic drugs (AEDs) with the limitation that, among the 19 AEDs used, some are not specific for epilepsy. An algorithm was built to select patients to get a range of prevalence estimates whereas medical expenses of patients were derived on the fully covered sub-population. RESULTS: Only patients treated in polytherapy (≥2 AEDs) were deemed to be identified in a relevant way by an algorithm based on drug usage. The prevalence of epilepsy in this sub-group in 2009 was estimated between 1.83 and 2.79‰ (93,000-142,000 patients). A proportion of 70.1 to 71.6% were fully covered for their expenses, with epilepsy alone as a cause in only 27 to 33% of them. The most frequent other co-morbidities were psychiatric disorders and invalidating stroke. The annual per capita expenses were in the range 6.696-6.601€ in patients in polytherapy. Inpatient care and drug costs represented about 50 and 27% of overall expenses, respectively. The increase by 24.4% of polytherapy patients mean costs as compared to monotherapy raised to 72% (IC 95: 44-106%) after adjustment for age, gender and presence of severe co-morbidity. CONCLUSION: In France, in 2009, 93,000 to 142,000 epileptic patients have been treated for epilepsy with a polytherapy. About one out of three patients only benefited from a full coverage of their medical expenses for epilepsy but half of them were fully covered for another disease. This resulted from the frequent presence of a severe co-morbidity especially psychiatric or due to a history of an invalidating stroke. Conversely, about 30% of epileptic patients in polytherapy, fully eligible to a full coverage did not benefit from it, which suggested an important sub-declaration of severe epilepsy.

Direct evidence of nonadherence to antiepileptic medication in refractory focal epilepsy.

The adherence to medication in drug-resistant focal epilepsy (RFE) remains largely unknown. The present work aimed to assess the frequency of recent adherence to antiepileptic drugs (AEDs) in patients with RFE. This prospective observational study screened all patients with RFE, admitted to the Nancy University Hospital between April 2006 and September 2008, for a 5-day hospitalization without AED tapering. The adherence to AEDs was assessed by measuring serum drug levels on day 1 (reflecting the recent "at home" adherence) and day 5 (reflecting the individual reference concentration when drug ingestion was supervised). A patient was considered nonadherent if at least one of their serum drug levels was different between days 1 and 5. The day-1 value was considered different from day 5 when it was at least 30% lower (underdosed) or 30% higher (overdosed). Nonadherent patients were classified as under-consumers in the case of one or more underdosed day-1 values, over-consumers in the case of one or more overdosed day-1 values, or undefined if they exhibited both underdosed and overdosed day-1 values. Forty-four of the 48 screened patients were included. Eighteen (40.9%) of 44 patients were nonadherent. Among them, 12 (66.7%) were over-consumers, 4 (22.2%) were under-consumers, and 2 (11.1%) were undefined nonadherents. The study indicates that recent adherence to antiepileptic medication in this group of patients with RFE is poor. Overconsumption is the most frequent form of nonadherence in this population and should be specifically assessed to prevent its possible consequences in terms of AEDs dose-dependent adverse events.

ESPERA study: applicability of the new ILAE criteria for antiepileptic drug resistance of focal epilepsies in current clinical practice.

A European observational cross-sectional study, ESPERA, was conducted in France and Spain in 2010. A random sample of neurologists, including specialists in epilepsy, prospectively enrolled adult patients treated for focal epilepsy with at least two antiepileptic drugs (AEDs) in combination. Investigators were asked to classify AED responsiveness of each enrolled patient according to the new 2009 ILAE criteria. These classifications were then reviewed by three experts. Potential factors of misclassification were then analyzed in order to evaluate the applicability of the new ILAE criteria for antiepileptic drug resistance in current clinical practice. Because of their complexity, use of the new ILAE criteria needs to be supported by relevant information and training to be adequately applied by neurologists in everyday practice.

Seizure freedom is not adversely affected by early discontinuation of concomitant anti-epileptic drugs in the EULEV cohort of levetiracetam users.

PURPOSE: Fear of discontinuing concomitant anti-epileptic drugs (AEDs) may lead to potentially unnecessary and perhaps unsafe polypharmacy. The effect of withdrawing concomitant AEDs on epilepsy control was therefore studied in long-term users of levetiracetam. METHODS: The EULEV cohort followed patients initiating levetiracetam in France in 2005 or 2006 for one year. In those maintaining levetiracetam throughout the study period, the association of a reduction in the number of concomitant AEDs during the first six months with seizure-freedom during the last six months of follow-up was investigated using logistic regression. RESULTS: Of the 356 patients continuing levetiracetam for at least 1 year, 140 (39.3%) were seizure-free during the last six months of follow-up. Partial symptomatic or generalised idiopathic epilepsy were associated with greater seizure-freedom than partial cryptogenic disease. Factors associated with seizures were: longer disease duration, initial incapacity, increased number of seizures in the six months preceding levetiracetam initiation, and number of consultations for epilepsy in the six months preceding levetiracetam initiation. There was a trend for the association between the early reduction in the number of concomitant AEDs and seizure-free status later during follow-up, which however did not reach statistical significance in the final propensity score-adjusted multivariate model (OR = 1.8, 95%CI [0.8;4.0]). CONCLUSIONS: Taking into account the various risk factors for seizures, the early reduction of concomitant AEDs was not associated with worse seizure rates during follow-up in real-life users of levetiracetam.

Clinical classification of psychogenic non-epileptic seizures based on video-EEG analysis and automatic clustering.

BACKGROUND: Psychogenic non-epileptic seizures (PNES) or attacks consist of paroxysmal behavioural changes that resemble an epileptic seizure but are not associated with electrophysiological epileptic changes. They are caused by a psychopathological process and are primarily diagnosed on history and video-EEG. Clinical presentation comprises a wide range of symptoms and signs, which are individually neither totally specific nor sensitive, making positive diagnosis of PNES difficult. Consequently, PNES are often misdiagnosed as epilepsy. The aim of this study was to identify homogeneous groups of PNES based on specific combinations of clinical signs with a view to improving timely diagnosis. METHODS: The authors first retrospectively analysed 22 clinical signs of 145 PNES recorded by video-EEG in 52 patients and then conducted a multiple correspondence analysis and hierarchical cluster analysis. RESULTS: Five clusters of signs were identified and named according to their main clinical features: dystonic attack with primitive gestural activity (31.6%); pauci-kinetic attack with preserved responsiveness (23.4%); pseudosyncope (16.9%); hyperkinetic prolonged attack with hyperventilation and auras (11.7%); axial dystonic prolonged attack (16.4%). When several attacks were recorded in the same patient, they were automatically classified in the same subtype in 61.5% of patients. CONCLUSION: This study proposes an objective clinical classification of PNES based on automatic clustering of clinical signs observed on video-EEG. It also suggests that PNES are stereotyped in the same patient. Application of these findings could help provide an objective diagnosis of patients with PNES.