Cerebrospinal fluid examinations in cryptogenic West and Lennox-Gastaut syndrome before and after intravenous immunoglobulin administration

Engelen, B.G.M. van; Renier, W.O.; Weemaes, C.M.R.; Lamers, K.J.B.; Gabreëls, F.J.M.; Meinardi, H.

doi:10.1016/0920-1211(94)90006-x

Cited by 9 publications

(3 citation statements)

References 35 publications

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“…At first glance, the lack of a BBB in our experimental model seems to limit the interpretation of our findings with regards to a therapeutic in vivo situation. We found few data on the actual amount of systemically administered IVIG reaching the CNS compartment: van Engelen detected a mean increase of 44% in cerebrospinal fluid (CSF) IgG concentration in epilepsy patients after systemic IVIG delivery, with the extent of increase correlating with Q albumin, a measure of blood CSF permeability . Wurster and Haas measured an intrathecal Ig concentration reaching close to 1% of the serum Ig concentration (0.317 g/L vs. 32.1 g/L) in a patient with polyradiculitis after infusion of 30 g IVIG .…”

Section: Discussionmentioning

confidence: 99%

Dose‐dependent inhibition of demyelination and microglia activation by IVIG

Winter

Baksmeier

Steckel

et al. 2016

Ann Clin Transl Neurol

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ObjectiveIntravenous immunoglobulin (IVIG) is an established treatment for numerous autoimmune conditions. Clinical trials of IVIG for multiple sclerosis, using diverse dose regimens, yielded controversial results. The aim of this study is to dissect IVIG effector mechanisms on demyelination in an ex vivo model of the central nervous system (CNS)‐immune interface.MethodsUsing organotypic cerebellar slice cultures (OSC) from transgenic mice expressing green fluorescent protein (GFP) in oligodendrocytes/myelin, we induced extensive immune‐mediated demyelination and oligodendrocyte loss with an antibody specific for myelin oligodendrocyte glycoprotein (MOG) and complement. Protective IVIG effects were assessed by live imaging of GFP expression, confocal microscopy, immunohistochemistry, gene expression analysis and flow cytometry.Results IVIG protected OSC from demyelination in a dose‐dependent manner, which was at least partly attributed to interference with complement‐mediated oligodendroglia damage, while binding of the anti‐MOG antibody was not prevented. Staining with anti‐CD68 antibodies and flow cytometry confirmed that IVIG prevented microglia activation and oligodendrocyte death, respectively. Equimolar IVIG‐derived Fab fragments or monoclonal IgG did not protect OSC, while Fc fragments derived from a polyclonal mixture of human IgG were at least as potent as intact IVIG.InterpretationBoth intact IVIG and Fc fragments exert a dose‐dependent protective effect on antibody‐mediated CNS demyelination and microglia activation by interfering with the complement cascade and, presumably, interacting with local immune cells. Although this experimental model lacks blood–brain barrier and peripheral immune components, our findings warrant further studies on optimal dose finding and alternative modes of application to enhance local IVIG concentrations at the site of tissue damage.

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Section: Discussionmentioning

confidence: 99%

Dose‐dependent inhibition of demyelination and microglia activation by IVIG

Winter

Baksmeier

Steckel

et al. 2016

Ann Clin Transl Neurol

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“…The mode of action of IVIG in epilepsy is not understood, but it is generally thought that IVIG reach the brain and act centrally (van Engelen et al, 1994a). van Engelen et al (1994c) documented a positive correlation between Q albumin and CSF IgG increase in cryptogenic West or Lennox–Gastaut syndrome patients, suggestive of IVIG transport across the normal BBB. Several possible transport mechanisms have been proposed, including passive, active, and retrograde axonal transport (Wurster and Haas, 1994).…”

Section: Discussionmentioning

confidence: 99%

“…Q albumin indices in our patients correlated with Q IgG indices, and as the Q albumin and the Q IgG fit well in the function relating the CSF/serum concentration quotients to the radius of the protein (Felgenhauer, 1974), this observation supports the possibility of passive transport of IgG across the BBB. Our data failed to show a significant increase in CSF IgG concentration following IVIG, and, in contrast to van Engelen et al (1994c), CSF IgG changes did not correlate with Q albumin or Q IgG indices. We hypothesize that the absence of demonstrable changes in CSF IgG is the net effect of intrathecally transported exogenous IVIG and their consumption during their biological activity.…”

Section: Discussionmentioning

confidence: 99%

Intravenous Immunoglobulins in Refractory Childhood‐Onset Epilepsy: Effects on Seizure Frequency, EEG Activity, and Cerebrospinal Fluid Cytokine Profile

Billiau

Witters²,

Ceulemans³

et al. 2007

Epilepsia

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Summary:Purpose: Several studies have reported favorable effects of intravenous immunoglobulins (IVIG) in refractory epilepsy. Evidence substantiating an immunomodulatory action is scarce. In an open-label study, we prospectively investigated the effect of IVIG on clinical, EEG and serum/CSF immunological parameters in patients with refractory childhood-onset epilepsy.Methods: Thirteen patients (median age 6.9 years; range 1.6-25.8) with refractory seizures despite 3-4 antiepileptic drug regimens were given IVIG (Sandoglobulin, ZLB-Behring, add-on, 4 × 400 mg/kg/3 weeks). Seizure frequency, 24-h video-EEG, and CSF/serum immunological parameters and cytokine profiles (IL-6/IL-8/IL-12/IL-10) were documented before and after completion of the course.Results: Seizure frequency was reduced by ≥50% in four, and by 25%-50% in three patients. In contrast, variation in automatically recorded spike counts (1-h-wake and -sleep) did not correlate with clinical improvement. Serum immunological parameters showed variable deviations in eight patients (e.g., IgG 2 deficiency) and CSF immunoblotting showed oligoclonal bands in two patients. Blood-brain barrier permeability was normal in 12 patients. IL-6 and IL-8 were clearly detectable in CSF of all patients; the levels were significantly higher than those in plasma but remained unaffected by IVIG treatment.Conclusions: Despite unchanged EEG spike counts, substantial reductions in seizure frequency occurred in 7 of 13 patients, suggesting that IVIG hinder progression of central epileptic activity into clinical seizures. Intrathecal presence of IL-8 and IL-6 was documented in all patients, but was unaffected by IVIG, suggesting that their production is directly related to electrical seizure activity and that IVIG may act through interference with immune pathways downstream to IL-6 and IL-8.

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High-dose intravenous immunoglobulin treatment in cryptogenic West and Lennox-Gastaut syndrome; an add-on study

et al. 1994

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In an add-on pilot study, a group of 15 children with cryptogenic and intractable West syndrome (3) and Lennox-Gastaut syndrome (12) received intravenous immunoglobulin (IVIg, 0.4 g/kg body weight per day for 5 consecutive days, followed by the same dose once every 2 weeks for 3 months). Five patients had been treated previously with ACTH without success. The reduction in clinical seizures averaged 70%. Electroencephalographic (EEG) recordings revealed a mean reduction in epileptic discharges of 40%. In all 15 patients, acceleration of EEG background activity occurred, and psychomotor development improved. Prior to IVIg administration, CSF examinations were normal. After IVIg administration, the serum total IgG concentration increased by an average of 76%, and the CSF IgG concentration by 44%. According to our data, IVIg crosses the blood-CSF barrier, and might be effective in the treatment of West syndrome and Lennox-Gastaut syndrome. We suggest it should be considered when other treatments, such as ACTH, have failed.

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Cerebrospinal fluid examinations in cryptogenic West and Lennox-Gastaut syndrome before and after intravenous immunoglobulin administration

Cited by 9 publications

References 35 publications

Dose‐dependent inhibition of demyelination and microglia activation by IVIG

Dose‐dependent inhibition of demyelination and microglia activation by IVIG

Intravenous Immunoglobulins in Refractory Childhood‐Onset Epilepsy: Effects on Seizure Frequency, EEG Activity, and Cerebrospinal Fluid Cytokine Profile

High-dose intravenous immunoglobulin treatment in cryptogenic West and Lennox-Gastaut syndrome; an add-on study

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