Hypocretin-1/orexin-A, sleep and excessive daytime sleepiness in patients with nonconvulsive status epilepticus: A cross-sectional cohort study.

BACKGROUND AND OBJECTIVES: Nonconvulsive status epilepticus (NCSE) manifests as a change in mental status without a coma (NCSE proper) or comatose NCSE. Hypocretin-1/orexin-A (H/O) is involved in alertness and sleep maintenance. Sleep impairment and excessive daytime sleepiness (EDS) have a negative impact on cognitive functions and activities of daily living (ADL). METHODS: Patients meeting the NCSE criteria underwent cerebrospinal fluid and brain magnetic resonance imaging examinations, polysomnographies (PSG), multiple latency sleep tests (MSLT), and completed Epworth Sleepiness Scale (ESS). Montreal Cognitive Assessment was used to evaluate cognitive functions, and the Barthel Index was used to assess ADL in the acute phase (V1) and three months follow-up (V2). RESULTS: From May 2020 to May 2023, we enrolled 15 patients, eight (53.3 %) women, with a median age of 69 (14) years. The median H/O CSF concentration was 250 (63.6) pg/ml; however, only three CSF samples (20 %) decreased below the borderline concentration of 200 pg/ml. Fourteen out of 15 patients (93.3 %) completed the PSG study. The median of wakefulness after sleep onset was 167 (173.5) min, sleep efficiency (SE) was 62.9 (63) %, sleep latency (SL) was 6 (32) min, REM sleep was 2.85 (7.2) %, and REM first episode latency was 210.5 (196.5) minutes. The medians of the stages N1 NREM were 4.65 (15) %, N2 NREM 68.4 (29.9) %, and N3 NREM 21.8 (35.5) %. MSLT mean latency was 7.7 (12.6) minutes. A significant negative correlation exists between H/O CSF concentrations and the stage N1 NREM (rs = -0.612, p = 0.02), and the proportion of cumulative sleep time with oxygen saturation below 90 % in total sleep time (TST) t90 (rs = -0.57, p = 0.03). MSLT had significant negative correlation with TST (rs = -0.5369, p = 0.0478), with SE (rs = -0.5897, p = 0.0265), with apnea-hypopnea index (rs = -0.7631, p = 0.0002) and with deoxygenation index (rs = -0.8009, p = 0.0006). A positive correlation exists between MSLT and SL (rs = 0.6284, p = 0.0161) and between ESS and t90 (rs = 0.9014, p = 0.0004). The correlation between H/O CSF concentrations and EDS, cognitive performance, and ADL was not proved. CONCLUSIONS: Patients after NCSE exhibited sleep impairment and excessive daytime sleepiness. Hypocretin-1/orexin-A concentrations decreased only in 20 % of these cases.

Clinical presentation of new onset refractory status epilepticus in children (the pSERG cohort).

OBJECTIVE: We aimed to characterize the clinical profile and outcomes of new onset refractory status epilepticus (NORSE) in children, and investigated the relationship between fever onset and status epilepticus (SE). METHODS: Patients with refractory SE (RSE) between June 1, 2011 and October 1, 2016 were prospectively enrolled in the pSERG (Pediatric Status Epilepticus Research Group) cohort. Cases meeting the definition of NORSE were classified as "NORSE of known etiology" or "NORSE of unknown etiology." Subgroup analysis of NORSE of unknown etiology was completed based on the presence and time of fever occurrence relative to RSE onset: fever at onset (≤24 h), previous fever (2 weeks-24 h), and without fever. RESULTS: Of 279 patients with RSE, 46 patients met the criteria for NORSE. The median age was 2.4 years, and 25 (54%) were female. Forty (87%) patients had NORSE of unknown etiology. Nineteen (48%) presented with fever at SE onset, 16 (40%) had a previous fever, and five (12%) had no fever. The patients with preceding fever had more prolonged SE and worse outcomes, and 25% recovered baseline neurological function. The patients with fever at onset were younger and had shorter SE episodes, and 89% recovered baseline function. SIGNIFICANCE: Among pediatric patients with RSE, 16% met diagnostic criteria for NORSE, including the subcategory of febrile infection-related epilepsy syndrome (FIRES). Pediatric NORSE cases may also overlap with refractory febrile SE (FSE). FIRES occurs more frequently in older children, the course is usually prolonged, and outcomes are worse, as compared to refractory FSE. Fever occurring more than 24 h before the onset of seizures differentiates a subgroup of NORSE patients with distinctive clinical characteristics and worse outcomes.

GABAA receptor encephalitis associated with human parvovirus B19 virus infection: Case report.

RATIONALE: Human parvovirus B19 (B19) infection can produce a spectrum of clinical syndromes, including neurological manifestations, most notably encephalitis. Although symptoms suggestive of autoimmune disease in patients with B19 infection have been previously described, a clear association of autoimmune encephalitis with B19 infection has yet to be established. PATIENT CONCERNS: We describe the case of a 6-year-old boy who was hospitalized due to status epilepticus, which evolved to super-refractory status epilepticus that was only mildly responsive to anticonvulsant drugs. DIAGNOSIS: A cerebrospinal fluid study identified slight pleocytosis and B19 positivity. A subsequent autoimmunity cerebrospinal fluid study revealed the presence of anti-γ-aminobutyric acid type A (GABAA) receptor antibodies. INTERVENTIONS: After pulse therapy with methylprednisolone and continuous therapy with prednisolone with cyclosporine, the patient experiencing seizure persistence with disordered motor function manifestations and only minor improvement in consciousness, and so, plasmapheresis was performed. With continued immunosuppressive treatments with cyclosporine and prednisolone, the patient's clinical picture showed progressive improvement, with good control of seizures. Although the patient tolerated withdrawal of the anticonvulsant drugs well, he developed seizures when corticosteroid therapy withdrawal was attempted, so was started on azathioprine. OUTCOMES: After immunosuppressive therapy, the patient evolved with complete remission of symptoms, normal neurological examination and age-appropriate neuropsychomotor development. LESSONS: The present case characteristics, together with previous findings, support the hypothesis that autoimmunity may be triggered by extensive antigen release due to degeneration of infected neurons. This case highlights the importance of early clinical suspicion and treatment.

Super refractory status in a case of Febrile Infection-Related Epilepsy Syndrome due to hemophagocytic lymphocytic histiocytosis.

A 14-year-old boy presented with a prodromal respiratory infection followed by super refractory status epilepticus. A diagnosis of Febrile Infection-Related Epilepsy Syndrome (FIRES) was made. Initial MRI study and CSF analysis were normal. He required multiple anticonvulsants owing to the refractory nature of the seizures. The course of the illness was rather stormy, laced with various medical problems viz. hepatic dysfunction, sepsis, hemodynamic, and hematological abnormalities which posed several challenges in the management. Hemophagocytic lymphocytic histiocytosis (HLH) was identified as the etiology of the illness and was treated but without success. The case report highlights the several immunomodulatory strategies that were employed to treat the disease, despite which the outcome was unfavorable.

First case report of cerebral folate deficiency caused by a novel mutation of FOLR1 gene in a Chinese patient.

BACKGROUND: Cerebral folate deficiency (CFD) is a neurological disease, hallmarked by remarkable low concentrations of 5-methyltetrahydrofolic acid (5-MTHF) in cerebrospinal fluid (CSF). The primary causes of CFD include the presence of folate receptor (FR) autoantibodies, defects of FR encoding gene FOLR1, mitochondrial diseases and congenital abnormalities in folate metabolism. CASE PRESENTATION: Here we first present a Chinese male CFD patient whose seizure onset at 2 years old with convulsive status epilepticus. Magnetic Resonance Imaging (MRI) revealed the development of encephalomalacia, laminar necrosis in multiple lobes of the brain and cerebellar atrophy. Whole Exome Sequencing (WES) uncovered a homozygous missense variant of c.524G > T (p.C175F) in FOLR1 gene. Further laboratory tests demonstrated the extremely low level of 5-MTHF in the CSF from this patient, which was attributed to cerebral folate transport deficiency. Following the intravenous and oral treatment of calcium folinate, the concentrations of 5-MTHF in CSF were recovered to the normal range and seizure symptoms were relieved as well. CONCLUSIONS: One novel variation of FOLR1 was firstly identified from a Chinese male patient with tonic-clonic seizures, developmental delay, and ataxia. The WES and laboratory results elucidated the etiology of the symptoms. Clinical outcomes were improved by early diagnosis and proper treatment.

CSF levels of a set of neurotrophic factors (brain-derived neurotrophic factor, nerve growth factor) and neuropeptides (neuropeptide Y, galanin) in epileptic children.

This paper aims to investigate the possible roles of a set of neurotrophic factors (brain-derived neurotrophic factor-BDNF, nerve growth factor-NGF) and neuropeptides (neuropeptide Y-NPY, and galanin) in children with active epileptogenesis. The cerebrospinal fluid (CSF) levels of BDNF, NPY, NGF and galanin were measured with enzyme-linked immunosorbent assays in epileptic children (n = 73) and controls (n = 64). There were no significant alterations in the CSF levels of BDNF, NPY and NGF in epileptic children with active clinical seizures compared with the levels of controls. However profoundly depressed galanin levels were found in infants with epileptic encephalopathy (mean ± SD:0.63 ± 0.19 pg/ml) and significantly increased galanin levels were measured in children with drug resistant epilepsy during the period of status epilepticus (mean ± SD: 6.92 ± 1.19, pg/ml pg/ml) compared with the levels of controls. Depressed levels of galanin might reflect a defective anti-epileptogenic effect of galanin in infants with epileptic encephalopathy. On the contrary, increased CSF levels of galanin might be a result of anti-epileptogenic effects of this peptide in epileptic children with status epilepticus.

Cerebrospinal fluid and blood biomarkers of status epilepticus.

Status epilepticus is a condition resulting either from the failure of the mechanisms responsible for seizure termination or from the initiation of mechanisms that lead to abnormally prolonged seizures and require urgent administration of antiepileptic drugs. Refractory status epilepticus requires anesthetics drugs and may lead to brain injury with molecular and cellular alterations (eg, inflammation, and neuronal and astroglial injury) that could induce neurologic sequels and further development of epilepsy. Outcome scores based on demographic, clinical, and electroencephalography (EEG) condition are available, allowing prediction of the risk of mortality, but the severity of brain injury in survivors is poorly evaluated. New biomarkers are needed to predict with higher accuracy the outcome of patients admitted with status in an intensive care unit. Here, we summarize the findings of studies from patients and animal models of status epilepticus. Specific protein markers can be detected in the cerebrospinal fluid and the blood. One of the first described markers of neuronal death is the neuron-specific enolase. Gliosis resulting from inflammatory responses after status can be detected through the increase of S100-beta, or some cytokines, like the High Mobility Group Box 1. Other proteins, like progranulin may reflect the neuroprotective mechanisms resulting from the brain adaptation to excitotoxicity. These new biomarkers aim to prospectively identify the severity and development of disability, and subsequent epilepsy of patients with status. We discuss the advantages and disadvantages of each biomarker, by evaluating their brain specificity, stability in the fluids, and sensitivity to external interferences, such as hemolysis. Finally, we emphasize the need for further development and validation of such biomarkers in order to better assess patients with severe status epilepticus.

Etiology is the key determinant of neuroinflammation in epilepsy: Elevation of cerebrospinal fluid cytokines and chemokines in febrile infection-related epilepsy syndrome and febrile status epilepticus.

OBJECTIVE: To investigate intrathecal inflammation using cerebrospinal fluid (CSF) cytokines and chemokines in a subgroup of pediatric epilepsy patients with frequent daily seizures. METHODS: We measured 32 cytokines/chemokines using multiplex immunoassay in CSF collected from pediatric patients with febrile infection-related epilepsy syndrome (FIRES)/FIRES-related disorders (FRD; n = 6), febrile status epilepticus (FSE; n = 8), afebrile status epilepticus (ASE; n = 8), and chronic epilepsy with frequent daily seizures (n = 21) and compared the results with noninflammatory neurological disorders (NIND; n = 20) and encephalitis (n = 43). We also performed longitudinal CSF cytokine/chemokine studies in three cases with FIRES/FRD. RESULTS: The median age of onset of seizures was 2.4 years (range = 0.08-12.5). Median CSF timing from the onset of seizures was longer in chronic epilepsy (540 days), whereas FIRES, FSE, and ASE had CSF tested within 1-2 days of onset of seizures (P < .001). The elevation of cytokines/chemokines was higher in FIRES followed by FSE, when compared to chronic epilepsy and NIND controls. Th1-associated cytokines/chemokines (TNF-α, CXCL9, CXCL10, CXCL11), IL-6, CCL2, CCL19, and CXCL1 (P < .05) were elevated in FIRES, in contrast to the elevation of a broader network of cytokines/chemokines in encephalitis. The cytokines/chemokines (CXCL9, CXCL10, CXCL11, and CCL19) were elevated in FSE when compared to ASE despite the similar median seizure duration and timing of CSF testing in relation to seizures. Chronic epilepsy generally lacked significant elevation of cytokines/chemokines despite frequent daily seizures. The median concentrations of the cytokines/chemokines rapidly declined on serial testing during the course of illness in all three FIRES/FRD cases. SIGNIFICANCE: We identify significant differences in CSF cytokine/chemokine profile between FIRES/FRD and encephalitis. The prominent elevation of CSF cytokines and chemokines in FIRES/FRD and to a lesser extent FSE highlights that the cytokine/chemokine elevation is significantly associated with the etiology of the underlying process rather than purely reactive. However, it is unclear whether the immune activation contributes to the disease process.

Tocilizumab treatment for new onset refractory status epilepticus.

We investigated the therapeutic potential of the interleukin-6 receptor inhibitor tocilizumab in 7 patients with new onset refractory status epilepticus (NORSE) who remained refractory to conventional immunotherapy with rituximab (n = 5) or without rituximab (n = 2). Status epilepticus (SE) was terminated after 1 or 2 doses of tocilizumab in 6 patients with a median interval of 3 days from the initiation. They had no recurrence of SE during the observation. However, 2 patients experienced severe adverse events related to infection during the tocilizumab therapy. Further prospective controlled studies are warranted to validate the efficacy and safety of tocilizumab in patients with NORSE. Ann Neurol 2018;84:940-945.

Low levels of progesterone and derivatives in cerebrospinal fluid of patients affected by status epilepticus.

Neurosteroids such as allopregnanolone may play a role in epilepsy as positive modulators of inhibitory currents mediated by γ-aminobutyric acid type A (GABAA ) receptor. Indeed, these molecules have been consistently shown to be anticonvulsants in animal models, but their role is still unclear in patients. For this reason, we investigated neurosteroids in the cerebrospinal fluid (CSF) of patients with status epilepticus (SE) by liquid chromatography tandem-mass spectrometry. Patients were retrospectively identified within subjects who received a lumbar puncture in the 2007-2017 period. Seventy-three patients (median age 65, ranging from 13 to 94 years; 67% women) with SE were evaluated. Controls (n = 52, median age 53, ranging from 16 to 93 years; 65% women) were patients presenting with symptoms for which a lumbar puncture was required by clinical guidelines, and who were negative at the end of the diagnostic work-up. Progesterone was 64% lower in patients with SE (p < 0.001). With respect to progesterone, upstream pregnenolone sulfate and pregnenolone did not change. Instead, downstream 5α-dihydroprogesterone, pregnanolone and allopregnanolone were, respectively, 49% (p < 0.001), 21% (p < 0.01) and 37% (p < 0.001) lower than in controls. Duration or type of SE, age and sex did not consistently affect CSF neurosteroid levels in the SE cohort. Instead, pregnenolone sulfate (Spearman's ρ = 0.4335, p < 0.01), allopregnanolone (ρ = 0.4121, p < 0.05) and pregnanolone (ρ = 0.592, p < 0.001) levels significantly increased by aging in controls. We conclude that neurosteroidogenesis is defective in patients with SE.

Cerebrospinal fluid findings in non-infectious status epilepticus.

OBJECTIVE: Ictal activity itself can cause pathological cerebrospinal fluid (CSF) findings. However, data regarding pathological CSF findings caused by SE itself to date remain scarce. We here evaluated the frequency and specificity of pathological CSF findings in non-infectious SE. METHODS: We performed a retrospective analysis of CSF samples in adult patients with episodes of non-infectious SE, who had been admitted to the Department of Neurology, University Hospital of Cologne. The following parameters were assessed: cell count, protein, and lactate content, CSF/serum glucose quotient (QGlc), disturbances of blood-brain-barrier function assessed by CSF/serum albumin quotient (QAlb), and qualitative intrathecal IgG synthesis assessed by unmatched oligoclonal bands in CSF. RESULTS: We analysed 54 episodes of non-infectious SE in which CSF had been obtained. CSF pleocytosis was infrequent (6%). Elevated CSF protein content was present in 44% of all cases, whereas elevated CSF lactate content was found in 23% of the cases. A decreased QGlc was present in 9%. Dysfunction of blood-brain-barrier (BBBD) was the most frequent pathological finding, amounting to 55%. Unmatched oligoclonal bands in CSF were seen in 10% of non-infectious SE. Further analysis revealed that elevated CSF protein content was found predominantly in recfractory SE (p = 0.04). Elevated CSF lactate content was associated with shorter latency between onset of SE and CSF retrieval (p = 0.004), positive history of epilepsy (p = 0.02) and an acute symptomatic etiology (p = 0.04). BBBD was also present more often in acute symptomatic SE (p = 0.001) and was the sole pathological CSF parameter associated with clinical outcome: presence of BBBD was associated with a less favorable outcome (p = 0.02). SIGNIFICANCE: Non-infectious SE itself does not commonly cause CSF pleocytosis. Data suggest that the detection of CSF pleocytosis should prompt further diagnostics for an underlying infectious or neoplastic etiology. In contrast, elevation of CSF protein content and BBBD were found frequently in non-infectious SE.

Utility of Lumbar Puncture in Children Presenting With Status Epilepticus.

OBJECTIVES: Because meningitis may trigger seizures, we sought to determine its frequency in children with first-time status epilepticus (SE). METHODS: We performed a retrospective cross-sectional study of children aged 1 month to 21 years who presented to a single pediatric emergency department between 1995 and 2012 with SE and who had a lumbar puncture (LP) performed as part of the diagnostic evaluation. We defined bacterial meningitis as a cerebrospinal fluid (CSF) culture positive for a bacterial pathogen or CSF pleocytosis (CSF white blood cells ≥10 cells/mm) with a blood culture positive for a bacterial pathogen. We defined viral meningitis or encephalitis using a positive enterovirus or herpes simplex virus polymerase chain reaction test. RESULTS: Among 126 children with SE who had an LP performed, 8 (6%) had CSF pleocytosis. Of these, 5 had received antibiotics before performance of a diagnostic LP. One child in the cohort was proven to have bacterial meningitis (0.8%; 95% confidence interval [CI], 0%-6%). Two other children had enteroviral meningitis (2/13 tested, 15%; 95% CI, 3%-51%), and 1 had a herpes simplex virus infection (1/47, 2%; 95% CI, 0%-15%). CONCLUSIONS: Bacterial meningitis is an uncommon cause of SE.

Cerebrospinal fluid microRNAs are potential biomarkers of temporal lobe epilepsy and status epilepticus.

There is a need for diagnostic biomarkers of epilepsy and status epilepticus to support clinical examination, electroencephalography and neuroimaging. Extracellular microRNAs may be potentially ideal biomarkers since some are expressed uniquely within specific brain regions and cell types. Cerebrospinal fluid offers a source of microRNA biomarkers with the advantage of being in close contact with the target tissue and sites of pathology. Here we profiled microRNA levels in cerebrospinal fluid from patients with temporal lobe epilepsy or status epilepticus, and compared findings to matched controls. Differential expression of 20 microRNAs was detected between patient groups and controls. A validation phase included an expanded cohort and samples from patients with other neurological diseases. This identified lower levels of miR-19b in temporal lobe epilepsy compared to controls, status epilepticus and other neurological diseases. Levels of miR-451a were higher in status epilepticus compared to other groups whereas miR-21-5p differed in status epilepticus compared to temporal lobe epilepsy but not to other neurological diseases. Targets of these microRNAs include proteins regulating neuronal death, tissue remodelling, gliosis and inflammation. The present study indicates cerebrospinal fluid contains microRNAs that can support differential diagnosis of temporal lobe epilepsy and status epilepticus from other neurological and non-neurological diseases.

Effectiveness of Electroconvulsive Therapy for Refractory Status Epilepticus in Febrile Infection-Related Epilepsy Syndrome.

Febrile infection-related epilepsy syndrome (FIRES) is a rare condition which evolves into refractory status epilepticus (SE), with poor outcome in most cases. Conventional antiepileptic drugs fail to control SE in FIRES patients. We report the case of a previously healthy 4-year-old boy who was diagnosed with FIRES. One week after pharyngitis and high fever he started seizures, followed by refractory SE. Benzodiazepines, phenytoin, high-dose barbiturates that induce burst suppression, high doses of corticosteroids, plasmapheresis, immunoglobulins, propofol, lidocaine, ketamine, inhaled desflurane, ketogenic diet, lacosamide, and therapeutic hypothermia were tried at different times in a period of 8 weeks, but all of them were ineffective. Electroconvulsive therapy (ECT) has been used in refractory SE in children. We report a case in which ECT was successfully used for treatment of refractory SE in a pediatric patient with FIRES syndrome.

Decreased allopregnanolone levels in cerebrospinal fluid obtained during status epilepticus.

Neuroactive steroids are increasingly considered as relevant modulators of neuronal activity. Especially allopregnanolone (AP) and pregnenolone sulfate (PS) have been shown to possess, respectively, anticonvulsant or proconvulsant properties. In view of the potential role of these steroids, we aimed at evaluating AP and PS levels in cerebrospinal fluid (CSF) and blood samples obtained from patients with status epilepticus (SE). To this purpose, we enrolled 41 patients affected by SE and 41 subjects investigated for nonepileptic neurologic disorders. Liquid chromatographic procedures coupled with electrospray tandem mass spectrometry and routine laboratory investigations were performed. Significantly lower AP levels were found in the CSF of patients affected by SE (-30%; p < 0.05, Mann-Whitney test). Notably, AP was not detectable in 28 of 41 patients affected by SE (p < 0.01 vs. controls, Fisher's exact test). In serum, AP levels did not differ in the two considered groups. Conversely, PS was present at similar levels in the investigated groups. Finally, differences in AP levels could not be explained by a variation in CSF albumin content. These findings indicate that AP is defective in the CSF of patients affected by SE. This phenomenon was not dependent on carriers for steroids, such as albumin.

Febrile infection-related epilepsy syndrome treated with anakinra.

Febrile infection-related epilepsy syndrome (FIRES) is a devastating epileptic encephalopathy with limited treatment options and an unclear etiology. Anakinra is a recombinant version of the human interleukin-1 receptor antagonist used to treat autoinflammatory disorders. This is the first report of anakinra for treatment of a child with super-refractory status epilepticus secondary to FIRES. Anakinra was well tolerated and effective. Cerebral spinal fluid analysis revealed elevated levels of proinflammatory cytokines before treatment that normalized on anakinra, suggesting a potential pathogenic role for neuroinflammation in FIRES. Further studies are required to assess anakinra efficacy and dosing, and to further delineate disease etiology. Ann Neurol 2016;80:939-945.

Progranulin levels in status epilepticus as a marker of neuronal recovery and neuroprotection.

INTRODUCTION: Recently, a mouse model showed that progranulin, a mediator in neuroinflammation and a neuronal growth factor, was elevated in the hippocampus after status epilepticus (SE). This elevated level might mirror compensating neuronal mechanisms after SE. Studies concerning neuronal recovery and neuroprotective mechanisms after SE in humans are scarce, so we tested for progranulinin the cerebrospinal fluid (CSF) after various types of SE. METHOD: We performed a retrospective analysis of progranulin levels in CSF in patients (n = 24) who underwent lumbar puncture as part of diagnostic workup after having SE and in patients after having one single tonic-clonic seizure who comprised the control group (n = 8). RESULTS: In our group with SE, progranulin levels in CSF were not significantly elevated compared to our control group. Furthermore, there was no correlation between progranulin levels and the time interval between lumbar puncture and SE. Additionally, in cases of higher CSF progranulin levels, we found no impact on the clinical outcome after SE. CONCLUSION: Although our cohort is heterogeneous and not fully sufficient, we conclude that progranulin in CSF is not elevated after SE in our cohort. Therefore, our results do not suggest a change in cerebral progranulin metabolism as a possible neuroregenerative or neuroprotective mechanism in humans after SE in acute and subacute phases. A larger cohort study is needed to further strengthen this result. This article is part of a Special Issue entitled "Status Epilepticus".

Effect of epileptic seizures on the cerebrospinal fluid--A systematic retrospective analysis.

OBJECTIVE: Analyses of the cerebrospinal fluid (CSF) are obligatory when epileptic seizures manifest for the first time in order to exclude life-threatening causes or treatable diseases such as acute infections or autoimmune encephalitis. However, there are only few systematic investigations on the effect of seizures themselves on CSF parameters and the significance of these parameters in differential diagnosis. METHODS: CSF samples of 309 patients with epileptic and 10 with psychogenic seizures were retrospectively analyzed. CSF samples were collected between 1999 and 2008. Cell counts, the albumin quotient, lactate and Tau-protein levels were determined. Findings were correlated with seizure types, seizure etiology (symptomatic, cryptogenic, occasional seizure), and seizure duration. RESULTS: Pathological findings were only observed in patients with epileptic but not with psychogenic seizures. The lactate concentration was elevated in 14%, the albumin quotient in 34%, and the Tau protein level in 36% of CSF samples. Cell counts were only slightly elevated in 6% of patients. Different seizure types influenced all parameters except for the cell count: In status epilepticus highest, in simple partial seizures lowest values were seen. Symptomatic partial and generalized epileptic seizures had significantly higher Tau-protein levels than cryptogenic partial seizures. In patients with repetitive and occasional epileptic seizures, higher Tau-protein levels were seen than in those with psychogenic seizures. Duration of epileptic seizures was positively correlated with the albumin quotient, lactate and Tau-protein levels. High variability of investigated CSF parameters within each subgroup rendered a clear separation between epileptic and psychogenic seizures impossible. SIGNIFICANCE: Elevated cell counts are infrequently observed in patients with epileptic seizures and should therefore not uncritically be interpreted as a postictal phenomenon. However, blood-CSF barrier disruption, increased glucose metabolism and elevation of neuronal damage markers are observed in considerable percentages of patients and depend on many factors such as etiology, seizure type and duration.

EEG extreme delta brush: An ictal pattern in patients with anti-NMDA receptor encephalitis.

INTRODUCTION: The anti-NMDA receptor (NMDAr) encephalitis-associated syndrome includes neuropsychiatric symptoms, impaired consciousness, seizures, autonomic instability, and hypoventilation. The electroencephalographic (EEG) activity throughout the course of the disease has still not been well documented. We reviewed electroclinical data of patients with NMDAr encephalitis to characterize their EEG and its clinical correlation. MATERIAL AND METHODS: We retrospectively identified 16 patients with NMDAr encephalitis from 8 Spanish medical centers, 15 of whom underwent video-EEG in the acute phase. RESULTS: In 15 patients (11 females, median age: 37.4, range: 14-87 years), seizures occurred in 9 (60%) and status epilepticus (SE) in 5 (33.3%). Magnetic resonance imaging (MRI) was abnormal in 10 (66.6%), and CSF (cerebrospinal fluid) was normal in 3 and abnormal in 12, with positive PCR (polymerase chain reaction) for Mycoplasma pneumoniae (1/15) and herpes simple virus (1/15). An ovarian teratoma was found in 1 patient and other malignancies (small cell lung carcinoma) in 1 patient. The EEG was abnormal in the acute phase in 14/15 (93.3%). Extreme delta brush (EDB) was observed in 5 (33.3%), and the presence of EDB was associated with SE in all cases. Rhythmic delta activity without EDB was observed in 5 (33.3%), while excessive beta activity was present in 4 (26.6%). Extreme delta brush can follow a pattern of well-characterized electroclinical seizures. CONCLUSIONS: Almost invariably, patients with NMDAr encephalitis had abnormal EEG. The presence of EDB, which can follow a pattern of well-characterized electroclinical seizures, in our patients was associated with seizures and SE. These findings suggest that EDB could be an evolutive pattern of an SE in NMDAr encephalitis. This article is part of a Special Issue entitled "Status Epilepticus".

Cerebrospinal fluid tau proteins in status epilepticus.

Tau protein is a phosphorylated microtubule-associated protein, principally localized at neuronal level in the central nervous system (CNS). Tau levels in the cerebrospinal fluid (CSF) are considered to index both axonal and neuronal damage. To date, however, no study has specifically evaluated the CSF levels of tau proteins in patients with status epilepticus (SE). We evaluated these established biomarkers of neuronal damage in patients with SE who received a lumbar puncture during SE between 2007 and 2014. Status epilepticus cases due to acute structural brain damage, including CNS infection, were excluded. Clinical, biological, therapeutic, and follow-up data were collected. Group comparison between patients stratified according to SE response to antiepileptic drugs (AEDs), disability, and epilepsy outcomes were performed. Twenty-eight patients were considered for the analyses (mean age 56 years): 14 patients had abnormally high CSF t-tau level, six patients had abnormally high CSF p-tau level, and only three patients had abnormally low Aß1-42 level. Cerebrospinal fluid t-tau value was higher in patients who developed a refractory SE compared to patients with seizures controlled by AED. Cerebrospinal fluid t-tau values were positively correlated with SE duration and were higher in patients treated with propofol anesthesia compared to patients that had not received this treatment. Patients with higher CSF t-tau had higher risk of developing disability (OR = 32.5, p = 0.004) and chronic epilepsy (OR = 12; p = 0.016) in comparison with patients with lower CSF t-tau level. Our results suggest that CSF t-tau level might be proposed as a biomarker of SE severity and prognosis. Prospective studies are needed to evaluate the effects of propofol on tau pathology in this setting. This article is part of a Special Issue entitled "Status Epilepticus".