The impact of epilepsy and antiseizure medications on sleep: Findings from a large European survey in adults with epilepsy and matched controls.

OBJECTIVE: To assess the impact of epilepsy and antiseizure medications (ASMs) on sleep quality in people with epilepsy (PWE). METHODS: An online survey was conducted in France, Germany, Italy, Spain and the UK among PWE taking >1 ASM and matched controls. Sleep quality was evaluated using the Pittsburgh Sleep Quality Index (PSQI). Associations between sleep quality (global PSQI) and overall quality of life (QoL; assessed using the 12-Item Short Form Survey [SF-12]) and sleep quality and depressive symptoms (assessed using the Neurological Disorders Depression Inventory for Epilepsy [NDDI-E]) were also evaluated. RESULTS: Overall, 500 PWE and 500 matched controls were included. PWE had significantly greater mean global PSQI scores than controls (9.32 vs 7.56; p < 0.0001), with 80% reporting a score >5 versus 66% of controls (p < 0.001). PWE experienced significantly more problems with most PSQI components than controls. Mean global PSQI scores in PWE receiving 2 versus ≥3 ASMs were 9.03 and 10.18, respectively (p < 0.004); global PSQI scores >5 were reported in 76% versus 90%, respectively (p = 0.001). Regimens containing lamotrigine or phenobarbital were associated with poorer sleep quality than those without these ASMs. In PWE, negative correlations were identified between global PSQI scores and both the SF-12 physical and mental components (Pearson's correlation coefficient [PCC], -0.61 and -0.40, respectively); NDDI-E and global PSQI scores were positively correlated (PCC, 0.6). CONCLUSIONS: PWE experience significantly worse sleep quality than people without epilepsy, with some ASMs contributing to poorer sleep. QoL and physical and mental health were all affected by sleep quality in PWE.

The impact of epilepsy on quality of life: Findings from a European survey.

INTRODUCTION: Epilepsy is a serious neurological disorder affecting the quality of life (QoL) of people with this condition. A survey was conducted in five European countries (France, Germany, Italy, Spain, and the UK) to understand the impact and burden of epilepsy and its treatment on the lives of people with epilepsy (PWE). METHODS: Five hundred PWE (taking >1 antiseizure medication [ASM]) and 500 matched controls completed a 30-minute online questionnaire. The 12-Item Short Form Survey (SF-12) was used to measure QoL and the Neurological Disorders Depression Inventory for Epilepsy (NDDI-E) was used to screen for major depressive disorder (MDD) symptoms. RESULTS: Comorbidities such as migraine, high cholesterol, osteoporosis, and Type 1 diabetes were reported more commonly in PWE, while anxiety disorders, high blood pressure, skin disorders, and mood disorders were more common in controls. However, compared to controls, a significantly higher percentage of PWE had an NDDI-E score of 15-24 (54% vs 35%; p < 0.0001), indicative of MDD symptoms. Significantly more PWE than controls were part-time employed (15% vs 11%; p = 0.03). People with epilepsy had a significantly lower total SF-12 score than controls across the physical and the mental components; compared to controls, a significantly higher proportion of PWE defined their general health as 'poor' or 'fair' and felt limited in carrying out daily and work activities. Among PWE, those taking ≥3 ASMs were more likely to experience difficulties in carrying out these activities than those on two ASMs. Ability to drive, mood, and level of self-esteem were reported as concerns for PWE. CONCLUSION: Epilepsy has a major impact on the physical and mental health of PWE, interfering with their daily and work activities and overall QoL, and its treatment might also contribute to a lower QoL. The impact of epilepsy on mood and mental health might be under-recognized.

Specific exposure of ICU staff to SARS-CoV-2 seropositivity: a wide seroprevalence study in a French city-center hospital.

BACKGROUND: Most hospital organizations have had to face the burden of managing the ongoing COVID-19 outbreak. One of the challenges in overcoming the influx of COVID-19 patients is controlling patient-to-staff transmission. Measuring the specific extent of ICU caregiver exposure to the virus and identifying the associated risk factors are, therefore, critical issues. We prospectively studied SARS-CoV-2 seroprevalence in the staff of a hospital in Lyon, France, several weeks after a first epidemic wave. Risk factors for the presence of SARS-CoV-2 antibodies were identified using a questionnaire survey. RESULTS: The overall seroprevalence was 9% (87/971 subjects). Greater exposure was associated with higher seroprevalence, with a rate of 3.2% [95% CI 1.1-5.2%] among non-healthcare staff, 11.3% [8.9-13.7%] among all healthcare staff, and 16.3% [12.3-20.2%] among healthcare staff in COVID-19 units. The seroprevalence was dramatically lower (3.7% [1.0-6.7%]) in the COVID-19 ICU. Risk factors for seropositivity were contact with a COVID-19-confirmed household (odds ratio (OR), 3.7 [1.8-7.4]), working in a COVID-19 unit (OR, 3.5 [2.2-5.7], and contact with a confirmed COVID-19 coworker (OR, 1.9 [1.2-3.1]). Conversely, working in the COVID-19-ICU was negatively associated with seropositivity (OR, 0.33 [0.15-0.73]). CONCLUSIONS: In this hospital, SARS-CoV-2 seroprevalence was higher among staff than in the general population. Seropositivity rates were particularly high for staff in contact with COVID-19 patients, especially those in the emergency department and in the COVID-19 unit, but were much lower in ICU staff. Clinical trial registration NCT04422977.

Autoimmune N-methyl-D-aspartate receptor encephalitis is a differential diagnosis of infectious encephalitis.

BACKGROUND: For 60% of acute febrile encephalitis cases, the cause is unknown. Autoantibodies directed against different synaptic proteins or receptors in patients with autoimmune encephalitis have recently been described and could indicate a differential diagnosis of infectious encephalitis. OBJECTIVE: The aim of this study was to retrospectively investigate the presence of autoantibodies directed against synaptic proteins or receptors in patients with acute febrile encephalitis. Samples were collected in France in 2007 during a national prospective study. METHODS: A total of 253 patients with acute febrile encephalitis were enrolled in 2007. Clinical data were collected with a standardized questionnaire. When possible, cerebrospinal fluid CSF was collected and stored at -80 °C. A total of 108 CSF samples were available for retrospective autoantibody screening. Among the 108 patients, infectious etiology had been detected in 38 cases (35%); of these 38 patients, 29 (27%) had viral encephalitis, and 9 (8%) had bacterial encephalitis. No specific diagnosis was indicated for the other 70 patients (65%). Autoantibodies were detected using a cell-based assay in which HEK293 cells were transfected with plasmids coding for different synaptic proteins or receptors. RESULTS: Two patients had anti-NMDA receptor antibodies (NMDAR-Abs), and all patients were negative for anti-Lgi1, CASPR2, GABABR, AMPAR, and mGluR5 antibodies. The two patients with NMDAR-Abs presented neurological and psychiatric symptoms typical of NMDAR-Abs encephalitis. CONCLUSIONS: Autoimmune etiology seems to be rare (less than 2%) in patients with acute febrile encephalitis. However, patients should be systematically screened for the presence of NMDAR-Abs, particularly patients presenting with psychiatric symptoms.

Paraneoplastic disorders of the central and peripheral nervous systems.

Paraneoplatic neurologic syndromes (PNS) have been seminally defined as acute or subacute neurological syndromes resulting from nervous system dysfunction that is remote from the site of a malignant neoplasm or its metastases. However, in respect to our current understanding of their pathogenesis we may redefine these disorders as cancer-related dysimmune neurologic syndromes. We first deal with the epidemiology and the pathogenesis of PNS, then the different classic PNS are reviewed with clinical features according to the associated onconeuronal antibodies. Finally, therapeutic approaches are discussed.

Autoimmune limbic encephalopathy and anti-Hu antibodies in children without cancer.

OBJECTIVE: The aim of this study was to describe the clinical presentation of children and adolescents with anti-Hu antibodies (Hu-Abs). METHODS: This was a retrospective study of children and adolescents with Hu-Abs collected by the French Paraneoplastic Neurological Syndrome (PNS) Reference Center between January 1, 2000 and December 31, 2011. RESULTS: The center identified 251 patients with Hu-Abs. Only 8 patients were younger than 18 years. All of the 243 adult patients had PNS. In contrast, of the 8 children, only 2 (25%, Fisher exact test p = 0.0003) had neuroblastoma and opsoclonus-myoclonus. The other 6 children (5 female and 1 male) presented with limbic encephalitis (progressive personality changes, memory loss, and seizure) and were free of cancer (mean follow-up time: 50 months; range: 34-72 months). Brain MRI scans were abnormal in 4 of the 6 patients, with left, right, or bitemporal T2/fluid-attenuated inversion recovery hyperintensity. Protein levels and cell counts in the CSF were normal in all patients, but numerous oligoclonal bands were observed in 4 patients. All 6 patients received antiepileptic drugs and immunotherapy, but management of epilepsy was difficult in all of them. Five of the children developed cognitive impairments. CONCLUSION: In children, as in adults, Hu-Abs can be a marker of PNS. However, in contrast to adults, Hu-Abs in children are also associated with an aggressive form of autoimmune nonparaneoplastic limbic encephalitis. Future studies should be conducted to determine the incidence of this syndrome and whether earlier diagnosis and T-cell-directed immunotherapies may improve its prognosis.

Disrupted surface cross-talk between NMDA and Ephrin-B2 receptors in anti-NMDA encephalitis.

Autoimmune synaptic encephalitides are recently described human brain diseases leading to psychiatric and neurological syndromes through inappropriate brain-autoantibody interactions. The most frequent synaptic autoimmune encephalitis is associated with autoantibodies against extracellular domains of the glutamatergic N-methyl-d-aspartate receptor, with patients developing psychotic and neurological symptoms in an autoantibody titre-dependent manner. Although N-methyl-d-aspartate receptors are the primary target of these antibodies, the cellular and molecular pathway(s) that rapidly lead to N-methyl-d-aspartate receptor dysfunction remain poorly understood. In this report, we used a unique combination of high-resolution nanoparticle and bulk live imaging approaches to demonstrate that anti-N-methyl-d-aspartate receptor autoantibodies from patients with encephalitis strongly alter, in a time-dependent manner, the surface content and trafficking of GluN2-NMDA receptor subtypes. Autoantibodies laterally displaced surface GluN2A-NMDA receptors out of synapses and completely blocked synaptic plasticity. This loss of extrasynaptic and synaptic N-methyl-d-aspartate receptor is prevented both in vitro and in vivo, by the activation of EPHB2 receptors. Indeed, the anti-N-methyl-d-aspartate receptor autoantibodies weaken the interaction between the extracellular domains of the N-methyl-d-aspartate and Ephrin-B2 receptors. Together, we demonstrate that the anti-N-methyl-d-aspartate receptor autoantibodies from patients with encephalitis alter the dynamic retention of synaptic N-methyl-d-aspartate receptor through extracellular domain-dependent mechanism(s), shedding new light on the pathology of the neurological and psychiatric disorders observed in these patients and opening possible new therapeutic strategies.

Subcontinuous epileptiform activity after failed hippocampal radiosurgery.

PURPOSE: Although gamma-knife radiosurgery (GKS) has proved efficacious in temporal lobe epilepsy (TLE), its antiepileptic mechanism of action remains elusive. Human and experimental data suggest that subnecrotic radiation-induced tissue changes might contribute to the antiepileptic effect of GKS. However, there are no data regarding the evolution of electroencephalography (EEG) activity within GKS-treated hippocampus, information that aid in better understanding both the mechanism of action and the reason for failure of GKS treatment. METHODS: Two patients with disabling seizures 4 and 6 years after mesial temporal GKS with a marginal dose of 24 Gy were investigated with stereotactic intracerebral EEG recordings. Both patients had right TLE with hippocampal atrophy, but with past history of Coxsackie virus meningoencephalitis and congenital toxoplasmosis, respectively. Ten to 12 electrodes were implanted, including seven to eight electrodes within the epileptic temporal lobe. KEY FINDINGS: In both patients, depths electrodes placed within the irradiated mesial temporal structures disclosed a remarkable pattern of subcontinuous spiking activity intermingled with asymptomatic rhythmic discharges up to 1 min in duration. This activity differed from the abnormalities usually captured in mesial TLE (mTLE) and suggested radiosurgery-induced brain changes. Both patients underwent anterior temporal lobectomy and achieved a class I outcome after a follow-up of 18 and 40 months, respectively. Pathologic examination of the surgical specimens showed variable degrees of radiation-effect changes. SIGNIFICANCE: Our study shows that mesial temporal structures previously treated with GKS can demonstrate a persistent high degree of epileptiform activity in patients who failed to respond to that treatment. Although this persistent EEG activity appears likely to reflect GKS-induced brain changes, its relation to GKS seizure outcome remains unclear.

Anti-N-methyl-D-aspartate receptor encephalitis complicating ovarian teratomas: a case report.

Anti-N-methyl-D-aspartate receptor encephalitis is an emerging disease that affects young women. Its diagnosis can be delayed because of the neuropsychiatric symptoms in the foreground, but early removal of the associated teratoma improves the prognosis. We report the treatment of a patient with anti-N-methyl-D-aspartate receptor encephalitis that was related to an ovarian teratoma.

Malignant catatonia due to anti-NMDA-receptor encephalitis in a 17-year-old girl: case report.

Anti-NMDA-Receptor encephalitis is a severe form of encephalitis that was recently identified in the context of acute neuropsychiatric presentation. Here, we describe the case of a 17-year-old girl referred for an acute mania with psychotic features and a clinical picture deteriorated to a catatonic state. Positive diagnosis of anti-NMDA-receptor encephalitis suggested specific treatment. She improved after plasma exchange and immunosuppressive therapy. Post-cognitive sequelae (memory impairment) disappeared within 2-year follow-up and intensive cognitive rehabilitation.

Afferent facilitation of corticomotor responses is increased by IgGs of patients with NMDA-receptor antibodies.

A severe subacute encephalitis associated with auto-antibodies to the NMDA receptor (NMDA-R) has been reported in humans. These antibodies are directed to NR1/NR2 heteromers of the NMDA receptor. We studied the effects of patients' cerebrospinal fluid (CSF) injected in rFr2 (the prefrontal area) on the afferent facilitation in a conditioning paradigm for corticomotor responses. The afferent facilitation was assessed in forelimbs and hindlimbs of rats, before and after application of trains of high-frequency stimulation (HFS) which are known to modulate the excitability of M1. Before HFS, patients' CSF did not modify afferent facilitation. After HFS, the amplitudes of corticomotor responses before conditioning were significantly larger in forelimbs and hindlimbs. There was an increase of the afferent facilitation in forelimbs. The same effect was observed after injection of purified IgGs from patients' sera. Our results highlight that IgGs of patients with NMDA-R antibodies induce a state of corticomotor hyperexcitability following application of HFS over the prefrontal area.

Voxel-based analysis of asymmetry index maps increases the specificity of 18F-MPPF PET abnormalities for localizing the epileptogenic zone in temporal lobe epilepsies.

UNLABELLED: (18)F-4-(2'-methoxyphenyl)-1-[2'-(N-2-pyridinyl)-p-fluorobenzamido]-ethyl-piperazine ((18)F-MPPF) PET has proved to be a sensitive technique in the presurgical evaluation of patients with drug-resistant temporal lobe epilepsy (TLE), but a significant proportion of visually detected abnormalities failed to be detected by standard statistical parametric mapping (SPM) analysis. This study aimed at describing a voxel-based method for computing interhemispheric asymmetric index (AI) using statistical software and applying and validating the clinical relevance of this method for analyzing asymmetries of (18)F-MPPF PET images in patients with drug-resistant TLE. METHODS: (18)F-MPPF PET scans of 24 TLE patients who achieved an Engel class I outcome after epilepsy surgery and of 41 controls were analyzed visually, with standard SPM, and by computing voxel-based AIs. Both SPM methods were assessed using 2 different statistical thresholds (P < 0.05, corrected at the cluster level, and P < 0.05, familywise error (FWE) corrected at the voxel level). Sensitivity and specificity of each method were estimated and compared using McNemar tests. RESULTS: The sensitivity of AI analysis to detect decreases of (18)F-MPPF binding potential ipsilateral to the epileptogenic lobe was 92% (P < 0.05, corrected at the cluster level) and 96% (P < 0.05, familywise error corrected at the voxel level), whereas specificity (defined as the congruence between the localization of the voxel associated with the greatest z score and that of the epileptogenic zone) was 88% at both thresholds. AI analysis was significantly more sensitive (P < 0.05) and specific (P < 0.005) than standard SPM analysis, regardless of the applied threshold. AI analysis also proved to be more sensitive than visual analysis. CONCLUSION: AI analysis of (18)F-MPPF PET was more sensitive and specific than previous methods of analysis. This noninvasive imaging procedure was especially informative for the presurgical assessment of patients presenting with clinical histories atypical of mesial TLE or with normal brain MRI results.

In vivo effects of antibodies from patients with anti-NMDA receptor encephalitis: further evidence of synaptic glutamatergic dysfunction.

BACKGROUND: A severe encephalitis that associates with auto-antibodies to the NR1 subunit of the NMDA receptor (NMDA-R) was recently reported. Patients' antibodies cause a decrease of the density of NMDA-R and synaptic mediated currents, but the in vivo effects on the extracellular glutamate and glutamatergic transmission are unknown. METHODS: We investigated the acute metabolic effects of patients' CSF and purified IgG injected in vivo. Injections were performed in CA1 area of Ammon's horn and in premotor cortex in rats. RESULTS: Patient's CSF increased the concentrations of glutamate in the extracellular space. The increase was dose-dependent and was dramatic with purified IgG. Patients' CSF impaired both the NMDA- and the AMPA-mediated synaptic regulation of glutamate, and did not affect the glial transport of glutamate. Blockade of GABA-A receptors was associated with a marked elevation of extra-cellular levels of glutamate following a pretreatment with patients' CSF. CONCLUSION: These results support a direct role of NMDA-R antibodies upon altering glutamatergic transmission. Furthermore, we provide additional evidence in vivo that NMDA-R antibodies deregulate the glutamatergic pathways and that the encephalitis associated with these antibodies is an auto-immune synaptic disorder.

HLA-DQ2+ individuals are susceptible to Hu-Ab associated paraneoplastic neurological syndromes.

BACKGROUND: Hypothetically, T cells are involved in the pathogenesis of paraneoplastic neurological syndromes associated with Hu-antibodies (Hu-PNS). OBJECTIVE: To identify genetic risk factors for Hu-PNS and investigate the role of T cells. METHODS: HLA-A, B, DRB1 and DQB1 alleles were compared in 53 Hu-PNS patients with 24 small-cell lung-cancer (SCLC) patients and 2440 healthy controls (HC). RESULTS: The frequency of both HLA-DQ2 and HLA-DR3 was significantly higher in Hu-PNS patients than in HC. CONCLUSIONS: This study indicates an association between Hu-PNS and presence of HLA-DQ2 and HLA-DR3, which supports a role for CD4(+) T cells in the pathogenesis of Hu-PNS.

Facial pain as first manifestation of anti-Hu paraneoplastic syndrome.

The diagnosis of anti-Hu-associated encephalomyelitis/sensory neuropathy may be particularly difficult when cranial nerve involvement represents the first clinical manifestation of the disease. We report a case of a patient who presented with facial pain as the first manifestation of an anti-Hu paraneoplastic syndrome, which needs a rapid detection and treatment of the underlying tumour. We suggest that paraneoplastic neuropathy should be considered during the management of trigeminal neuropathic pain, especially when brain imagery is normal.

Initial neuro-ophthalmological manifestations in Churg-Strauss syndrome.

Churg-Strauss syndrome (CSS) is a systemic vasculitis with frequent respiratory tract involvement. It can also affect the nervous system, notably the optic tract. The present work reports the case of a 65-year-old man diagnosed as having CSS in the context of several acute onset neurological symptoms including muscle weakness and signs of temporal arteritis, including bilateral anterior ischaemic optic neuropathy (ON). Electroretinograms (ERGs) and visual evoked potentials (VEPs) were performed. Flash ERGs were normal whereas VEPs were highly abnormal, showing a dramatic voltage reduction, thus confirming the ON. The vision outcome was poor. Ophthalmological presentations of CSS have rarely been reported, but no previous case of sudden blindness documented by combined ERG and VEP investigations were found in the literature. The present case strongly suggests that the occurrence of visual loss in the context of systemic inflammation with hypereosinophilia should lead to considering the diagnosis of CSS.

Expanding spectrum of encephalitis with NMDA receptor antibodies in young children.

The authors report here 2 cases of subacute-onset encephalitis with N-methyl-D-aspartate (NMDA) receptor antibodies. One had a paraneoplastic syndrome associated with a neuroblastoma, whereas the other had no primary tumor. This disease was originally described as a paraneoplastic syndrome in young women with ovarian teratoma. The clinical features of both children resembled the typical symptoms reported for older patients with this disease: psychomotor deterioration, movement disorders, and seizures. One of the reported cases is the first known case of paraneoplastic encephalitis with NMDA antibodies in a child with neuroblastoma. Both cases described here were younger than any of the previously reported cases. Consistent with recently published series, this report suggests that the spectrum of symptoms of encephalitis with NMDA receptor antibodies is probably wider than previously thought.

Update on paraneoplastic neurological syndromes.

PURPOSE OF REVIEW: To describe specificities and new advances in treatment of paraneoplastic neurological syndromes (PNS). RECENT FINDINGS: PNS are defined as neurological syndromes of unknown cause that often antedate the diagnosis of an underlying cancer that is usually not clinically evident. The clinical signs of PNS are accurately described and 'classical' PNS have been established. Within the context of these syndromes, the concept of limbic encephalitis has evolved dramatically in the last 2 years due to the description of new auto-antibodies. The diagnosis and treatment of the associated cancer remains the key goal of the clinical management of PNS. However, the specific treatment of the neurological symptoms primarily depends on the immunological findings. SUMMARY: There is increasing recognition of an extensive array of PNS and of several paraneoplastic antibodies as biological markers of these disorders. Basic immunological studies support the pathogenic role of some of these antibodies. Others are only markers of the disease.

PET imaging of brain 5-HT1A receptors in the preoperative evaluation of temporal lobe epilepsy.

[(18)F]MPPF PET has previously been used to identify the epileptic lobe in temporal lobe epilepsy (TLE) patients at the group level. This study aims to validate the visual analysis of [(18)F]MPPF PET in the assessment of individual TLE patients for their suitability to undergo temporal lobe resection. Forty-two patients suffering from TLE and 18 control subjects matched for age and gender were prospectively enrolled for [(18)F]MPPF PET. Four subtypes were defined according to the presurgical evaluation: mesio-TLE (MTLE, 32 patients), temporal neocortical epilepsy (NC, five patients), temporo-perisylvian epilepsy (T+, three patients) and temporal epilepsy without further information (t, two patients). Parametric binding potential (BP(ND)) images were obtained using a simplified reference tissue model. Three examiners, who were blinded to other data, visually interpreted each scan and delineated areas of decreased [(18)F]MPPF BP(ND). Statistical parametric mapping (SPM) analysis of MPPF BP(ND) images was also performed. Visual analysis showed a low rate of disagreement between the three examiners (7%). PET scans were considered normal in four patients (9.5%). In the remaining 38 patients (90.5%), areas of focal BP(ND) decrease were identified. A specific pattern was encountered in the MTLE subgroup, consisting of a BP(ND) decrease involving hippocampus, amygdala and temporal pole altogether. Combining the results from the presurgical investigations and the surgical outcome, we estimated that the area of BP(ND) decrease coincided with the epileptogenic zone in 40% of patients in the MTLE subgroup and 33% in the other TLE subtypes. This relatively low precision was due to 47% of patients who showed BP(ND) decreases in the insula ipsilateral to the epileptogenic lobe. The SPM analysis had much lower sensitivity (67%) to detect BP(ND) decreases in the epileptogenic temporal lobe, but revealed areas of increased BP(ND) outside the epileptogenic zone and bitemporal BP(ND) decreases of undetermined clinical significance, which were undetectable by visual analysis, in 29% of patients. In conclusion, visual analysis of [(18)F]MPPF BP(ND) images helps in the correct identification of the epileptogenic temporal lobe in all patients showing BP(ND) decreases, with a false negative rate inferior to 10% and no false positives in control subjects. All TLE patients with [(18)F]MPPF BP(ND) decreases involving hippocampus, amygdala and temporal pole together, with or without extension to the ipsilateral insula, were good candidates for anterior temporal lobectomy. All these patients became seizure free after surgery, even when the clinical presentation was not that of a typical MTLE, or when MRI failed to detect hippocampal atrophy.