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.

New onset status epilepticus in older patients: Clinical characteristics and outcome.

PURPOSE: We here evaluated (1) the differential characteristics of status epilepticus (SE) in older (≥60 years) compared to younger adults (18-59 years). In particular, we were interested in (2) the proportion and characteristics of new onset SE in patients with no history of epilepsy (NOSE) in older compared to younger adults, and (3) predictive parameters for clinical outcome in older subjects with NOSE. METHODS: We performed a monocentric retrospective analysis of all adult patients (≥18years) admitted with SE to our tertiary care centre over a period of 10 years (2006-2015) to evaluate clinical characteristics and short-time outcome at discharge. RESULTS: One-hundred-thirty-five patients with SE were included in the study. Mean age at onset was 64 years (range 21-90), eighty-seven of the patients (64%) were older than 60 years. In 76 patients (56%), SE occurred as NOSE, sixty-seven percent of them were aged ≥60 years. There was no age-dependent predominance for NOSE. NOSE was not a relevant outcome predictor, especially regarding age-related subgroups. Older patients with NOSE had less frequently general tonic clonic SE (GTCSE; p=0.001) and were more often female (p=0.01). Regarding outcome parameters and risk factors in older patients with NOSE, unfavourable outcome was associated with infections during in-hospital treatment (0.04), extended stay in ICU (p=0.001), and generally in hospital (p<0.001). CONCLUSION: In our cohort, older patients represented the predominant subgroup in patients with SE. Older patients suffered more often from non-convulsive semiology and had a less favourable short-time outcome. NOSE was not a predictive outcome parameter in older patients. Data suggest that avoiding infections should have a priority because higher infection rates were associated with unfavourable outcome.

Suspected antibody negative autoimmune limbic encephalitis: outcome of immunotherapy.

OBJECTIVES: Whether and when to immunologically treat epilepsy patients with suggested autoantibody (AB)-negative limbic encephalitis (LE) is clinically challenging. Therefore, we evaluated the clinical outcome and eventual outcome predictors of immunotherapy in a group of AB-negative patients with recent-onset temporal lobe epilepsy (TLE), magnetic resonance imaging (MRI) indicators of LE, subjective cognitive decline, and/or psychiatric symptoms. METHODS: This retrospective, observational, uncontrolled study monitored 28 TLE patients with suggested AB-negative LE along with methylprednisolone immunotherapy. RESULTS: All patients had seizures, amygdala and/or -hippocampal enlargement, subjective cognitive decline and/or behavioral problems. Eighty-six percent (24/28) were impaired in executive or memory functions, 39% (10/25) depressed, 81% were on antiepileptic drugs when pulse therapy started. After a median follow-up of 18 months, 46% (13/28) of the patients were seizure free (>2 months), 48% (13/27) showed MRI improvements (amygdala and/or hippocampal volume reduction), cognition improved in 57% (16/28), worsened in 32% (9/28), mood improved in 14% (4/25), and deteriorated in 11% (3/25). Immunotherapy was discontinued in 75% (21/28). Clinical changes did not correlate to each other. Outcomes could not be predicted. CONCLUSION: Immunological treatment of suggested AB-negative LE showed reasonable seizure control, MRI and cognitive improvements. Treatment success was not predictable from clinical features, nor definitely attributable to immunological treatment. Lacking biomarkers for the reliable diagnosis of AB-negative LE, we suggest that in presence of mild manifestations, and after initiating antiepileptic drug therapy, negative dynamics in MRI, seizures, cognition, and behavior should be documented before immunosuppressive treatment is initiated.

[Therapy of Antibody-Associated Autoimmune Encephalitis]. / Therapie von Antikörper-vermittelten Autoimmunenzephalitiden.

The identification of an antibody-associated autoimmune encephalitis underlying diverse syndromes, typically comprising epileptic seizures and neuropsychiatric symptoms, and their favorable prognosis, when treated with immunotherapies, is one of the success stories in neurology in recent years. Here we review current widely used therapy regimens in antibody-associated autoimmune encephalitis and the prognosis of the different antibody-associated sub-forms. The main therapeutic instruments encompass tumor therapy (if tumor is detected) and immunotherapies, though recommendations are mainly based on retrospective data analysis. The primary therapeutic goal is complete remission. The degree to which this can be accomplished depends upon the different sub-forms.

Supratentorial white matter blurring associated with voltage-gated potassium channel-complex limbic encephalitis.

INTRODUCTION: Limbic encephalitis (LE) associated with voltage-gated potassium channel-complex antibodies (VGKC-LE) is frequently non-paraneoplastic and associated with marked improvement following corticosteroid therapy. Mesial temporal lobe abnormalities are present in around 80 % of patients. If associated or preceded by faciobrachial dystonic seizures, basal ganglia signal changes may occur. In some patients, blurring of the supratentorial white matter on T2-weighted images (SWMB) may be seen. The purpose of this study was to evaluate the incidence of SWMB and whether it is specific for VGKC-LE. METHODS: Two experienced neuroradiologists independently evaluated signal abnormalities on FLAIR MRI in 79 patients with LE while unaware on the antibody type. RESULTS: SWMB was independently assessed as present in 10 of 36 (28 %) compared to 2 (5 %) of 43 non-VGKC patients (p = 0.009). It was not related to the presence of LGI1 or CASPR2 proteins of VGKC antibodies. MRI showed increased temporomesial FLAIR signal in 22 (61 %) VGKC compared to 14 (33 %) non-VGKC patients (p = 0.013), and extratemporomesial structures were affected in one VGKC (3 %) compared to 11 (26 %) non-VGKC patients (p = 0.005). CONCLUSION: SWMB is a newly described MRI sign rather specific for VGKC-LE.

Treatment of immune-mediated temporal lobe epilepsy with GAD antibodies.

PURPOSE: Temporal lobe epilepsy with antibodies (abs) against the glutamic acid decarboxylase 65 isoform (GAD-TLE) is known as an immune-mediated neurological syndrome. Here we evaluate the therapy response to various immunotherapies and epilepsy surgery in this syndrome. METHOD: All patients with GAD-TLE and follow-up data and stored serum and CSF samples, identified and treated at the Bonn centre from 2002 to 2010, were studied retrospectively. Seizure freedom for ≥1 year and reduction of ≥50%, i.e. therapy response, were assessed. GAD-ab titres and neuropsychological performances were documented prior and after individual interventions. RESULTS: Thirteen patients with GAD-TLE were identified with the following seizure responses: corticosteroids (5 responders out of 11 treated patients); i.v. immunoglobulins (1/5), apheresis therapy (1/8); and natalizumab (1/1), selective amygdala-hippocampectomy (2/3). None of the patients achieved sustained seizure freedom apart from one patient. This patient was on antiepileptic drug treatment after discontinuation of immunotherapy. CONCLUSION: The seizure response to immunotherapies in patients with GAD-TLE was poor. Corticosteroids were the most effective regarding seizure response. Especially the poor effects of apheresis therapies support the idea that GAD-abs are not directly pathogenic. None of three patients was seizure-free after temporal lobe surgery suggesting that GAD-TLE patients respond worse than others to this type of intervention. Our results reflect the chronic course of the disease with low likelihood for patients with GAD-TLE to attain long-term seizure freedom.

Outcome of limbic encephalitis with VGKC-complex antibodies: relation to antigenic specificity.

In limbic encephalitis (LE) with antibodies (Abs) to the voltage-gated potassium channel complex (VGKC), the Abs are mainly directed to the VGKC-complex proteins, leucine-rich, glioma inactivated 1 protein (LGI1) or contactin-associated protein-like 2 (CASPR-2) or neither. Here, we relate the outcomes of VGKC-LE patients to the presence of Abs to LGI1, CASPR-2 or neither antigen (LGI1/CASPR-2-Ab(-)). Clinical, neuropsychology and MRI data were obtained from patient records for all LE patients from the Bonn Epilepsy Centre positive for VGKC-Abs by radioimmunoprecipitation assay between 2002 and 2011. Eighteen VGKC-LE patients were identified: nine patients (50 %) had LGI1-Abs, three (16 %) had CASPR-2-Abs; and six (33 %) were negative for both LGI1- and CASPR-2-Abs. At first assessment, the groups did not differ clinically or radiologically, but faciobrachial dystonic seizures were only observed in two LGI1-Ab(+) patients. All patients received monthly intravenous methylprednisolone (MP) pulses. At the most recent follow up (median 26 months), thirteen (72 %) were seizure-free, and seizure-freedom rates did not differ between the Ab groups. Hippocampal atrophy had developed in 7/9 LGI1-Ab(+) patients, but in none of the CASPR-2-Ab(+) or LGI/CASPR-2-Ab(-) patients (p = 0.003). While all subgroups improved, memory scores only normalized in six patients (33 %) and LGI1-Ab(+) patients were left with significantly poorer memory than the other two subgroups. Most VGKC-LE patients become seizure-free with pulsed monthly MP, but memory outcome is less favourable. Hippocampal atrophy and poor memory recovery is common in patients with LGI1-Abs and suggests permanent functional damage. More intense immunotherapies could improve outcomes in LGI1-Ab(+)-LE.

Neuropsychological course of voltage-gated potassium channel and glutamic acid decarboxylase antibody related limbic encephalitis.

BACKGROUND AND PURPOSE: Autoantibodies (abs) to glutamic acid decarboxylase (GAD) and to voltage-gated potassium channels (VGKC) induce distinct courses of limbic encephalitis, related to MRI findings, seizure outcome and cognition. METHODS: A detailed analysis of the cognitive course of the two forms is presented, spanning a median time interval of 28 months, including parameters of attention, learning and memory in 15 VGKC-ab-positive and 16 GAD-ab-positive patients. RESULTS: In both groups, the initially significantly impaired attention performance recovered to a putatively premorbid level. In VGKC patients the partially severely impaired learning and memory performance improved under treatment but remained subnormal at last follow-up. By contrast, GAD-ab-positive patients had initially less impaired learning and memory scores but did not show an improvement under treatment. CONCLUSIONS: The results provide evidence of distinct relations between inductive processes and cognitive outcome in VGKC-ab-positive and GAD-ab-positive subforms of limbic encephalitis, which possibly depend on differences in pathogenic molecular mechanisms and affected cerebral loci.

Natural defense systems of fasting rats against tumor cells.

The effect of fasting on naturally cytotoxic cells in rat liver and rat spleen was investigated. Neither fasting 100% (nor 50%) for eight days nor 100% overnight significantly reduced this natural cytotoxicity. Target cells YAC-1, P815, and WEHI-164 cells were used in a chromium release assay. Assuming that YAC-1 cells are preferentially killed by "true" natural killer cells, P815 by macrophages, and WEHI-164 by so-called natural cytotoxic cells, our results indicate that none of these subsets of naturally cytotoxic cells are hampered or stimulated by the fasting regimens used.

Cytotoxic T-cells and antibody-producing cells isolated from liver and spleen of immunized rats.

Liver, strategically positioned within the circulation system, is a major trap for circulating tumor cells. Trapping and killing of tumor cells may be mediated by Kupffer cells and natural killer cells. In addition to these spontaneously cytotoxic cells, we isolated T-killer cells and antibody-producing cells from the liver after immunization with xenogeneic cells. Since tumor surveillance may include T-killer cells and antibody-dependent killer cells, the liver is able to attack tumor cells by "natural" and "induced" cytotoxic mechanisms.

Natural killer cells, vitamins, and other blood components of vegetarian and omnivorous men.

The study population consisted of male vegetarians (aged 28-50 years), who were recruited from the vegetarian cohort being followed by the Department of Epidemiology (German Cancer Research Center, Heidelberg, FRG), and the same number of age- and sex-matched controls from the personnel of the same center. Among the vitamins tested, only the level of carotene was significantly higher in vegetarians; the levels of vitamin A, K, and E were not elevated. Among the other blood parameters tested, only creatinine and glutamine-transferase levels were significantly lower in vegetarians. The natural cytotoxicity of peripheral blood lymphocytes was measured using a chromium-release test. Cytotoxic activity, which is expressed as lytic units, was significantly higher in vegetarians than in their omnivorous controls by a factor of 2. The total number of white blood cells, lymphocytes, and other subpopulations did not differ between vegetarians and nonvegetarians. The enhanced natural cytotoxicity may be one of the factors contributing to the lower cancer risk shown by vegetarians.

Tumoricidal cells increased by pulsating magnetic field.

Repeated applications of pulsed magnetic fields (right-angle waves, 50 Hz = 135 Gauss, 2 Hz = 262 Gauss) significantly enhanced the number and the tumoricidal activity of nonparenchymal liver cells. The transplantable mouse leukemia L1210 used as a tumor model was not significantly influenced, either directly or during Cyclophosphamide treatment.

Natural cytotoxic cells from rat liver and spleen kill human glioma cells.

Natural cytotoxic cells from rat spleen and rat liver, (isolated using the collagenase method) were found to be cytotoxic against different lines of human gliomas: T406, T508, T705, HeRo, HeRoCl 1, HeRoCl 8, and HeRo-SV 7/114. After 18 h the lytic units ranged from 75 to 251 in the liver and from 5 to 24 in the spleen. Analyzing the ratio of lysis at 4 h/18 h, it may be concluded that this natural killing is predominantly macrophage (Kupffer cell)-dependent. Lysis by Kupffer cells cannot be increased by transforming glioma cells with SV40. Experiments with SV40-transformed mouse fibroblasts (3T3) and virus-transformed human cell lines (SV80) suggested a "SV40" receptor on Kupffer cells. Thus Kupffer cells have receptors for glioma cells and SV40-dependent membrane structures.

Liver as a tumor cell killing organ: Kupffer cells and natural killers.

Sinusoidal rat liver cells spontaneously kill tumor cells in vitro. They have the same preferences as do spleen cells for certain types of tumor cells, YAC-1, P815, BSP73Asml, BSP73As, EB, EsB, and L5222. Metastasizing tumor cells are less sensitive than their nonmetastasizing counterparts. Not all effector cells are Kupffer cells. These nonmacrophage killer cells share some features with classical natural killers: (a) fast reactions (4 h); (b) high toxicity against YAC-1 cells; (c) sensitivity to anti-asialo GM1 globulin; (d) similar age dependency; (e) short biological halflife (approximately 1 day) (deduced from radiation experiments); (b) silica particle insensitivity; and (g) nonadherence. The natural killing potency of the liver is higher than that of the spleen. The reduction of tumoricidal capacity of the liver in germ-free animals suggests environmental influences. Tumoricidal capacity (organ capacity) is increased in rats chronically fed thioacetamide, carbon tetrachloride (CC14), dimethylaminoazobenzene, and N-nitrosomorpholin.

Liver as a tumor-cell-killing organ.

Lymphoma cells (Eb and ESb, the metastasizing variant) were injected via a mesenteric vein. 85% to 95% of these cells were trapped in the liver. Most of the Eb cells (81%) were destroyed within 18 hours, ESb cells prove to be more resistant: only 28% of these cells were destroyed within this time. 51-Chromium release assay (4 hours) revealed a similar sensitivity of these two tumor cell strains.