Pre- and Postictal Changes in the Innate Immune System: Cause or Effect?

INTRODUCTION: Recent studies have shown that inflammatory processes might play a role in epileptogenesis. Their role in ictogenesis is much less clear. The aim of this study was to investigate peri-ictal changes of the innate immune system by analyzing changes of immune cells, as well as pro- and anti-inflammatory cytokines. METHODS: Patients with active epilepsy admitted for video-EEG monitoring for presurgical evaluation were included. Blood was sampled every 20 min for 5 h on 3 consecutive days until a seizure occurred. After a seizure, additional samples were drawn immediately, as well as 1 and 24 h later. To analyze the different populations of peripheral blood mononuclear cells, all samples underwent FACS for CD3, CD4, CD8, CD56, CD14, CD16, and CD19. For cytokine analysis, we used a custom bead-based multiplex immunoassay for IFN-γ, IL-1ß, IL-1RA, IL-4, IL-6, IL-10, IL-12, IL-17, MCP-1, MIP-1α, and TNFα. RESULTS: Fourteen patients with focal seizures during the sampling period were included. Natural killer (NK) cells showed a negative correlation (ρ = -0.3362, p = 0.0195) before seizure onset and an immediate increase to 1.95-fold afterward. T helper (TH) and B cells decreased by 2 and 8%, respectively, in the immediate postictal interval. Nonclassical and intermediate monocytes decreased not until 1 day after the seizures, and cytotoxic T (TC) cells showed a long-lasting postictal increase by 4%. IL-10 and MCP-1 increased significantly after seizures, and IL-12 decreased in the postictal phase. DISCUSSION/CONCLUSION: Our study argues for a role of the innate immune system in the pre- and postictal phases. NK cells might be involved in preictal changes or be altered as an epiphenomenon in the immediate preictal interval.

Psychological long-term outcome in patients with psychogenic nonepileptic seizures.

OBJECTIVE: To examine the long-term outcome of psychological status, personality, and health-related quality of life (HRQoL) in patients with psychogenic nonepileptic seizures (PNES) and to define predictors of favorable outcome of cessation of PNES. METHOD: Patients diagnosed with PNES during video-electroencephalography (EEG) monitoring at the Erlangen Epilepsy Center were contacted 1-16 years after communicating the diagnosis. Follow-up information from each participant was obtained by interview (PNES outcome) and by self-reported questionnaires of psychological symptoms (Beck Depression Inventory-II, Symptom Checklist-90-Standard, Dissociative Symptoms questionnaire), personality traits (Freiburg Personality Inventory-Revised), and HRQoL (36-Item Short Form Health Survey). RESULTS: Fifty-two patients participated in the study (mean age ± standard deviation [SD] 40.5 ± 14.0 years; 75% female, follow-up: 5.3 ± 4.2 years). Nineteen patients (37%) were free of PNES for the past 12 months. Patients with persisting PNES were older at disease onset (32.9 vs 22.3 years, P < 0.01) and diagnosis (40.5 vs 27.2 years, P < 0.001), and showed worse psychological functioning, lower extraversion and life satisfaction, and higher inhibitedness and worse HRQoL than PNES-free patients. Patients with cessation of PNES were within the normal range in all dimensions. Cessation of PNES was best predicted by younger age at PNES onset and higher extraversion. SIGNIFICANCE: Outcome of PNES is poor, psychopathology is high, and HRQoL is low in patients with persistent PNES but may normalize with PNES cessation. High introversion and older age at PNES onset are risk factors for persistent PNES.

Psychosocial outcome in epilepsy after extratemporal surgery.

OBJECTIVE: Only limited data exist on psychosocial long-term outcome after epilepsy surgery in patients with extratemporal epilepsy. The aim of this study was to investigate psychosocial outcome after extratemporal epilepsy surgery and to assess factors predicting favorable outcome. METHOD: Sixty-five out of 104 eligible patients who had undergone extratemporal epilepsy surgery at our epilepsy center between 1990 and 2015 (mean age: 42.2. years; 75% of the resections in the frontal lobe) completed a questionnaire asking about seizure status, employment status, marital and living situation, driving status, depressive symptoms, and quality of life (QOL). Follow-up was on average 9.2years after surgery (range: 1-26years). RESULTS: Thirty-eight (58%) patients were free of disabling seizures (Engel class I), and 28 (43%) have not experienced any seizures after surgery (Engel class IA). Employment rate in the primary labor market remained at 45%, but more patients lost employment (14%) than gained employment (8%). Postoperative employment was predicted by preoperative employment (p=.007), seizure freedom (p=.025), older age at seizure onset (p=.018), younger age at follow-up (p=.035), and female gender (p=.048). Seizure-free patients were more likely to be driving; have a partner, particularly in males; and have lower depressive scores. Quality of life at follow-up was best predicted by employment (p=.012), partnership (p=.025), and seizure freedom (p=.025). In contrast, recurrence of seizures and early seizure onset were associated with poor psychosocial outcome, particularly in men. CONCLUSION: The study provides support that extratemporal surgery can lead to improved QOL and favorable psychosocial outcome. Seizure freedom is important but not the only determinant of good psychosocial outcome.

Creutzfeldt-Jakob disease mimicking autoimmune encephalitis with CASPR2 antibodies.

BACKGROUND: Differential diagnosis of severe progressive dementia includes a wide spectrum of inflammatory and neurodegenerative diseases. Particularly challenging is the differentiation of potentially treatable autoimmune encephalitis and Creutzfeldt-Jakob disease. Such a coincidence may indeed complicate the correct diagnosis and influence subsequent treatment. CASE PRESENTATION: A 75-year-old woman was admitted due to rapid progressive cognitive impairment. Her husband observed a temporal disorientation and confusion. The initial neurological examination and an extensive neuropsychological evaluation showed significant impairments in almost all tested cognitive domains. All other neurological functions including motor, sensory and coordinative function were intact. Initial diagnostics included EEG, MRI and lumbar puncture with unspecific results. Complementary blood testing revealed a positive result for antineural antibodies to Contactin-associated protein 2 (CASPR2) and the patient received treatment for CASPR2 autoimmune encephalitis. Further symptoms and results, including 14-3-3 proteins, led to suspected Creutzfeldt-Jakob disease. The postmortem examination supported the diagnosis of a definitive Creutzfeldt-Jakob disease. CONCLUSION: One could argue that global screening for antineural antibodies may lead to a false diagnosis triggering intense and potentially dangerous procedures. We believe, however, that potentially treatable causes of dementia should aggressively sought out and subsequently treated in an attempt to curtail the course of disease and ultimately reduce the rate of mortality.

Psychogenic nonepileptic seizures: clinical characteristics and outcome.

BACKGROUND: Clinical characteristics, outpatient situation, and outcome in patients with psychogenic nonepileptic seizures (PNES) remain to be elucidated. METHODS: Patients diagnosed with PNES after video-electroencephalography (EEG) monitoring (VEM) 03/2000-01/2016 at the Erlangen Epilepsy Center were surveyed between June 2016 and February 2017. Primary outcome was PNES cessation defined as no PNES episodes within > = 12 months prior to the interview. Secondary outcome variables included quality of life (QoL) and dependency. Sensitivity analysis included patients with proven PNES during VEM without comorbid epilepsy. RESULTS: Ninety-nine patients were included (median age 38 (interquartile range (IQR 29-52)) years; 68 (69%) females, follow-up 4 (IQR 2.1-7.7) years). Twenty-eight (28%) patients suffered from comorbid epilepsy. Twenty-five (25%) patients reported PNES cessation. Older age at symptom onset (odds ratio (OR) related to PNES cessation: 0.95 (95% CI 0.90-0.99)), comorbid epilepsy (OR 0.16 (95% CI 0.03-0.83)), anxiety disorder (OR 0.15 (95% CI 0.04-0.61)), and tongue biting (OR 0.22 (95% CI 0.03-0.91)) remained independently associated with ongoing PNES activity after adjustment. Sensitivity analysis (n = 63) revealed depressive disorder (OR 0.03 (95% CI 0.003-0.34)) instead of anxiety as independent predictor, while this seemed relevant only in patients older than 26 years at onset (OR 0.04 (95% CI 0.002-0.78) versus OR 0.21 (95% CI 0.02-1.84) in patients  younger than 26 years). PNES cessation was associated with increased median QoL (8 (IQR 7-9) versus 5.5 (IQR 4-7); p < .001) and an increased frequency of financial independency (14 (56%) versus 21 (28%); p = .01). CONCLUSIONS: We found poor outcomes in PNES especially in older patients at onset with comorbid depressive disorder. Comorbid epilepsy also seems to be a major risk factor of ongoing PNES activity, which in turn affects patients' daily living.

Alpha power decrease in quantitative EEG detects development of cerebral infarction after subarachnoid hemorrhage early.

OBJECTIVE: In subarachnoid hemorrhage (SAH), transcranial Doppler/color-coded-duplex sonography (TCD/TCCS) is used to detect delayed cerebral ischemia (DCI). In previous studies, quantitative electroencephalography (qEEG) also predicted imminent DCI. This study aimed to compare and analyse the ability of qEEG and TCD/TCCS to early identify patients who will develop later manifest cerebral infarction. METHODS: We analysed cohorts of two previous qEEG studies. Continuous six-channel-EEG with artefact rejection and a detrending procedure was applied. Alpha power decline of ≥ 40% for ≥ 5 hours compared to a 6-hour-baseline was defined as significant EEG event. Median reduction and duration of alpha power decrease in each channel was determined. Vasospasm was diagnosed by TCD/TCCS, identifying the maximum frequency and days of vasospasm in each territory. RESULTS: 34 patients were included (17 male, mean age 56 ± 11 years, Hunt and Hess grade: I-V, cerebral infarction: 9). Maximum frequencies in TCD/TCCS and alpha power reduction in qEEG were correlated (r = 0.43; p = 0.015). Patients with and without infarction significantly differed in qEEG parameters (maximum alpha power decrease: 78% vs 64%, p = 0.019; summed hours of alpha power decline: 236 hours vs 39 hours, p = 0.006) but showed no significant differences in TCD/TCCS parameters. CONCLUSIONS: There was a moderate correlation of TCD/TCCS frequencies and qEEG alpha power reduction but only qEEG differentiated between patients with and without cerebral infarction. SIGNIFICANCE: qEEG represents a non-invasive, continuous tool to identify patients at risk of cerebral infarction.

Correction to: Routine diagnostics for neural antibodies, clinical correlates, treatment and functional outcome.

The original version of this article unfortunately contained a mistake.

Routine diagnostics for neural antibodies, clinical correlates, treatment and functional outcome.

OBJECTIVE: To determine frequencies, interlaboratory reproducibility, clinical ratings, and prognostic implications of neural antibodies in a routine laboratory setting in patients with suspected neuropsychiatric autoimmune conditions. METHODS: Earliest available samples from 10,919 patients were tested for a broad panel of neural antibodies. Sera that reacted with leucine-rich glioma-inactivated protein 1 (LGI1), contactin-associated protein-2 (CASPR2), or the voltage-gated potassium channel (VGKC) complex were retested for LGI1 and CASPR2 antibodies by another laboratory. Physicians in charge of patients with positive antibody results retrospectively reported on clinical, treatment, and outcome parameters. RESULTS: Positive results were obtained for 576 patients (5.3%). Median disease duration was 6 months (interquartile range 0.6-46 months). In most patients, antibodies were detected both in CSF and serum. However, in 16 (28%) patients with N-methyl-D-aspartate receptor (NMDAR) antibodies, this diagnosis could be made only in cerebrospinal fluid (CSF). The two laboratories agreed largely on LGI1 and CASPR2 antibody diagnoses (κ = 0.95). The clinicians (413 responses, 71.7%) rated two-thirds of the antibody-positive patients as autoimmune. Antibodies against the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR), NMDAR (CSF or high serum titer), γ-aminobutyric acid-B receptor (GABABR), and LGI1 had ≥ 90% positive ratings, whereas antibodies against the glycine receptor, VGKC complex, or otherwise unspecified neuropil had ≤ 40% positive ratings. Of the patients with surface antibodies, 64% improved after ≥ 3 months, mostly with ≥ 1 immunotherapy intervention. CONCLUSIONS: This novel approach starting from routine diagnostics in a dedicated laboratory provides reliable and useful results with therapeutic implications. Counseling should consider clinical presentation, demographic features, and antibody titers of the individual patient.

Immunoadsorption therapy in autoimmune encephalitides.

OBJECTIVE: It was hypothesized that in encephalitides with autoantibodies directed to CNS surface antigens an antibody-removing intervention might speed up recovery. METHODS: The outcome of autoimmune encephalitis in 19 patients with antibodies against surface antigens (leucine-rich, glioma inactivated 1 [LGI1], n = 3; contactin-associated protein-2 [CASPR2], n = 4; NMDA receptor [NMDAR], n = 7) and intracellular antigens (glutamic acid decarboxylase [GAD], n = 5) after immunoadsorption in addition to corticosteroid therapy was evaluated retrospectively. Modified Rankin scale (mRS) scores and data on seizures, memory, and antibody titers directly after immunoadsorption (early follow-up) and after a median of 4 months (late follow-up) were compiled. RESULTS: Immediately after immunoadsorption, 9 of 14 patients with antibodies against LGI1, CASPR2, or NMDAR (64%), but none with GAD antibodies, had improved by at least one mRS point. Five of the 7 patients with LGI1 or CASRP2 antibodies had become seizure-free, and 2 patients with NMDAR antibodies had a memory improvement of more than 1 SD of a normal control population. At late follow-up, 12 of 14 patients with surface antibodies had improved (86%), and none of the patients with GAD antibodies. CONCLUSIONS: It is suggested that addition of immunoadsorption to immunosuppression therapy in patients with surface antibodies may accelerate recovery. This supports the pathogenic role of surface antibodies. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that immunoadsorption combined with immunosuppression therapy is effective in patients with autoimmune encephalitis with surface antibodies.

Conjoint occurrence of GABAB receptor antibodies in Lambert-Eaton myasthenic syndrome with antibodies to the voltage gated calcium channel.

Antibodies (abs) to the GABAB receptor have been recently found to be responsible for immune-mediated encephalitis with dominant seizures. They are in approximately 50% of cases associated with small-cell lung cancer (SCLC). GABAB receptors are mainly located in the hippocampus, thalamus and cerebellum in the presynaptic and postsynaptic regions of synapses. The main function of these receptors is to reduce activity states of neurons. In some instances, GABAB receptor abs in these patients were accompanied by other antibodies, among them VGCC abs (Lancaster et al., 2010, Boronat et al., 2011). VGCC abs cause paraneoplastic Lambert Eaton myasthenic syndrome (LEMS) by reduction of presynaptic VGCCs (Titulaer et al., 2011). In the domain of CNS disease, VGCC abs have been found in association with paraneoplastic cerebellar ataxia (Mason et al., 1997) and rarely and at low titres also in other paraneoplastic encephalopathies together with Hu abs (Lennon et al., 1995). It has been a long-standing debate if abs in paraneoplastic conditions associate rather with the neurological syndrome or the tumour. Here, we describe the conjoint occurrence of abs to the GABAB receptor and to the VGCC in a patient with SCLC presenting only symptoms of the peripheral nervous system giving another example of the latter hypothesis.