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Experimental autoimmune neuritis (EAN) serves as an animal model for human Gullain-Barre syndrome (GBS), an autoimmune disease causing demyelination and inflammation of peripheral nerves. Macrophages, which play a major role in this autoimmune inflammatory process, can be selectively targeted by high doses of bisphophonates. The goal of this study was to examine the effect of the bisphosphonate, clodronate, on the severity of the EAN model. EAN was induced in female adult rats by immunization with bovine peripheral myelin. A number of treatment protocols with clodronate were used based on the common dosage regimen of 20 mg/kg in humans starting with the appearance of clinical signs on day 10 post-immunization. The clinical parameters measured included a clinical score, a motor performance test performed on a Rotarod and body weight. The expression of the matrix metaloprotease (MMP-9) in the sciatic nerves was measured as a marker of inflammatory macrophages. Treatment with clodronate, 20 mg/kg daily and 40 mg/kg every 2 days, significantly reduced the disease severity (a 75% decrease in severity, p < 0.01 by ANOVA) as measured by the clinical score compared to controls. Performance on the Rotarod test and body weight confirmed the clinical score findings. MMP-9 expression levels were significantly lower in the sciatic nerves of clodronate-treated rats. The present findings support the efficiency of clodronate in inflammatory diseases of the peripheral nervous system. The mechanism of action includes inhibition of inflammatory macrophages. The results suggest the use of bisphosphonates be considered in humans with GBS.

Oxidation of cerebrospinal fluid (CSF) causes differential unmasking of autoantibodies in control CSF vs. that obtained from postmortem CSF samples from autopsy confirmed Alzheimer's disease (AD) cases. This study demonstrates that normal CSF from both living patients and from non-demented autopsy cases contains redox-reactive autoantibodies with specificities that include antiphospholipid antibodies (aPL). In contrast, CSF from autopsy confirmed AD subjects contained little or no redox-reactive aPL autoantibodies. Tests using an in vitro rat synaptosome model showed that the oxidized CSF autoantibodies from a normal individual can cause ERK1/2 phosphorylation at a level consistent with reports of pathogenic changes found in brain tissues from AD patients. The decrease or absence of redox-reactive antibodies in CSF from Alzheimer's patients suggests that these antibodies may have been previously unmasked by the oxidative conditions that exist in the CNS in AD patients. These unmasked autoantibodies could then bind to neuronal tissues and possibly participate in the initial cascade leading to the dementia in Alzheimer's. To our knowledge, this is the first description of resident autoantibodies with the potential to cause brain cell damage documented in CSF without a breech in the blood-brain barrier. The untimely and inappropriate physiological unmasking of these redox-reactive autoantibodies in AD patients CSF may represent a valuable biomarker for diagnosis and progression of this and perhaps other neurodegenerative diseases which also have oxidative stress components. These novel autoantibody observations may stimulate thoughts about additional therapeutic approaches and warrant similar studies for other neurodegenerative diseases.

Although many neurological deficits have been described in the antiphospholipid syndrome (APS), only stroke is well established and accepted as a diagnostic criterion in the disease. We presently review clinical data obtained from large series of cases regarding stroke, dementia, epilepsy, chorea, migraine, white-matter disease, and behavioral changes in APS, or linked-to-laboratory criteria such as antiphospholipid antibodies (aPL). The contribution of animal models to our understanding of these manifestations of APS is stressed, especially regarding the cognitive and behavioral aspects for which we have established model systems in the mouse. These models utilize immunization of mice with beta(2)-glycoprotein1, a central autoantigen in APS, which induces persistent high levels of aPLs. These mice develop hyperactive behavior after a period of four months, as well as deficits in learning and memory, and are potentially valuable as a system in which to study the pathogenesis and treatment of cognitive and behavioral aspects of APS. We have developed another model, in which IgGs from APS patients induce depolarization of brain synaptoneurosomes, and which may serve as a model for the pathogenesis of epilepsy in APS. Hormonal changes are another potential CNS manifestation of APS and this may be potentially linked to the systemic and central effects of cytokines such as interleukin-3. Better understanding of the link between APS and neurological or neuroendocrine manifestations other than stroke will reveal whether they can be used as clinical criteria for the diagnosis of APS and, it is hoped, lead to better treatment.

The assessment of experimental autoimmune neuritis (EAN) by electrophysiological studies of the sciatic innervation of the plantar muscle may be complicated by local inflammation. We therefore utilized the tail nerve-muscle system to monitor disease progression in 20 rats with EAN and 10 control rats. Early changes were detected in motor nerve conduction velocity (32.06 +/- 1.85 m/s versus 43.57 +/- 3.98 m/s in controls, P < 0.001) at 15 days postimmunization (DPI), and conduction block (70.6 +/- 9.4% compared to 12.4 +/- 3.4%, P < 0.001) at 22 DPI. No consistent conduction block (22.4 +/- 10.4%) was found in the plantar muscle measurements. The tail nerve response of EAN rats demonstrated severe temporal dispersion at 43 DPI, which returned to normal at 135 DPI, although motor nerve conduction velocity values were still lower than in controls (24.4 +/- 0.9 m/s, P < 0.001). The tail nerve may be a useful addition to electrophysiological studies in this model of the Guillain-Barré syndrome., (Copyright 2002 John Wiley & Sons, Inc.)

Abstract: Immune mediated neuropathies are uncommon but important to diagnose because they are potentially treatable. This chapter summarizes the clinical approach to diagnosis of Guillain Barré syndrome (GBS), chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), and related neuropathies which are thought to be caused by direct autoimmune attack on peripheral nerves. [Copyright &y& Elsevier]

Background/Aims: Large-scale population studies measuring rates and dynamics of cognitive decline in multiple sclerosis (MS) are lacking. In the current cross-sectional study we evaluated the patterns of cognitive impairment in MS patients with disease duration of up to 30 years. Methods: 1,500 patients with MS were assessed by a computerized cognitive battery measuring verbal and non-verbal memory, executive function, visual spatial perception, verbal function, attention, information processing speed and motor skills. Cognitive impairment was defined as below one standard deviation (SD) and severe cognitive impairment as below 2SD for age and education matched healthy population norms. Results: Cognitive performance in our cohort was poorer than healthy population norms. The most frequently impaired domains were information processing speed and executive function. MS patients with secondary-progressive disease course performed poorly compared with clinically isolated syndrome, relapsing-remitting and primary progressive MS patients. By the fifth year from disease onset, 20.9% of patients performed below the 1SD cutoff for impairment, p = 0.005, and 6.0% performed below the 2SD cutoff for severe cognitive impairment, p = 0.002. By 10 years from onset 29.3% and 9.0% of patients performed below the 1SD and 2SD cutoffs, respectively, p = 0.0001. Regression modeling suggested that cognitive impairment may precede MS onset by 1.2 years. Conclusions: The rates of cognitive impairment in this large sample of MS patients were lower than previously reported and severe cognitive impairment was evident only in a relatively small group of patients. Cognitive impairment differed significantly from expected normal distribution only at five years from onset, suggesting the existence of a therapeutic window during which patients may benefit from interventions to maintain cognitive health. [ABSTRACT FROM AUTHOR]

Antiphospholipid syndrome (APS) is a multisystem disorder characterized by arterial and venous thrombosis, pregnancy morbidity, and neuropsychiatric manifestations. Antiphospholipid IgG injected intracerebro-ventricularly (ICV) cause behavioral hyperactivity in mice. In the present study we investigated the effects of APS whole-serum ICV administration in female Balb/C mice. Control mice were injected with serum derived from healthy subjects or saline solution. Behavior was assessed by the staircase apparatus which combines locomotor (stair-climbing) exploratory activities and rearing as a measure of anxiety. Mice injected with serum from APS patients or serum from normal subjects showed a trend to an increase in the number of stairs climbed in the APS group. The results suggest a differential effect of specific IgG and other serum components in the CNS manifestations of APS. [ABSTRACT FROM AUTHOR]

Abstract: Inflammatory brain diseases such as multiple sclerosis (MS) include hyperactivation of the coagulation pathway which includes thrombin. In the experimental autoimmune encephalomyelitis (EAE) model we have found significantly higher levels of thrombin inhibitors which include the very early elevation of protease nexin 1. The physiological importance of excess thrombin in neural tissue is demonstrated by recent experiments which link thrombin with conduction block in the sciatic nerve. [Copyright &y& Elsevier]

Abstract: We report a 36-year-old woman with the occurrence of painful focal seizures of her left hand and the left leg. She also had focal motor seizures at the left corner of her mouth. The duration and frequency of the episodes increased over four days from a few seconds once a day to frequent intervals lasting more than four hours at a time. The symptoms appeared one day after start of the treatment with fluvastatin (40 mg) administered in order to diminish the endothelial activation induced by antiphospholipid antibodies (aPL). The patient suffered from severe manifestations of the antiphospholipid syndrome (APS) including Catastrophic Antiphospholipid Syndrome (CAPS, Asherson''s syndrome). In this case a single 40 mg dose of oral fluvastatin was linked to seizures. After discontinuation of this treatment, the seizures immediately disappeared and the patient fully recovered without evidence of permanent neurological damage. This data links statins to seizures in patients with compromised blood brain barrier such as APS. [Copyright &y& Elsevier]

Hepatitis-B vaccine (HBVv) can prevent HBV-infection and associated liver diseases. However, concerns regarding its safety, particularly among patients with autoimmune diseases (i.e. SLE) were raised. Moreover, the aluminum adjuvant in HBVv was related to immune mediated adverse events. Therefore, we examined the effects of immunization with HBVv or alum on SLE-like disease in a murine model. NZBWF1 mice were immunized with HBVv (Engerix), or aluminum hydroxide (alum) or phosphate buffered saline (PBS) at 8 and 12 weeks of age. Mice were followed for weight, autoantibodies titers, blood counts, proteinuria, kidney histology, neurocognitive functions (novel object recognition, staircase, Y-maze and the forced swimming tests) and brain histology. Immunization with HBVv induced acceleration of kidney disease manifested by high anti-dsDNA antibodies ( p < 0.01), early onset of proteinuria ( p < 0.05), histological damage and deposition of HBs antigen in the kidney. Mice immunized with HBVv and/or alum had decreased cells counts mainly of the red cell lineage ( p < 0.001), memory deficits ( p < 0.01), and increased activated microglia in different areas of the brain compare with mice immunized with PBS. Anxiety-like behavior was more pronounced among mice immunized with alum. In conclusion, herein we report that immunization with the HBVv aggravated kidney disease in an animal model of SLE. Immunization with either HBVv or alum affected blood counts, neurocognitive functions and brain gliosis. Our data support the concept that different component of vaccines may be linked with immune and autoimmune mediated adverse events. [ABSTRACT FROM AUTHOR]

Abstract: The antiphospholipid syndrome (APS) is an autoimmune disease where the presence of high titers of circulating autoantibodies causes thrombosis with consecutive infarcts. In experimental APS (eAPS), a mouse model of APS, behavioral abnormalities develop in the absence of vessel occlusion or infarcts. Using brain hemispheres of control and eAPS mice with documented neurological and cognitive deficits, we checked for lymphocytic infiltration, activation of glia and macrophages, as well as alterations of ligand binding densities of various neurotransmitter receptors to unravel the molecular basis of this abnormal behavior. Lymphocytic infiltrates were immunohistochemically characterized using antibodies against CD3, CD4, CD8 and forkhead box P3 (Foxp3), respectively. GFAP, Iba1 and CD68-immunohistochemistry was performed, to check for activation of astrocytes, microglia and macrophages. Ligand binding densities of NMDA, AMPA, GABAA and 5-HT1A receptors were analyzed by in vitro receptor autoradiography. No significant inflammatory reaction occurred in eAPS mice. There was neither activation of astrocytes or microglia nor accumulation of macrophages. Binding values of excitatory and inhibitory neurotransmitter receptors were largely unchanged. However, ligand binding densities of the modulatory serotonergic 5-HT1A receptors in the hippocampus and in the primary somatosensory cortex of eAPS mice were significantly upregulated which is suggested to induce the behavioral abnormalities observed. [Copyright &y& Elsevier]

Abstract: The antiphospholipid syndrome (APS) includes systemic and central nervous system (CNS) pathology associated with antibodies to a complex of phospholipids and β2-glycoprotein I (β2-GPI). We have recently reported the induction of APS associated with behavioral and cognitive deficits in BALB/c female mice that developed 4–5 months after immunization with β2-GPI. In the present study, we examined the influence of genetic factors on the ability to induce experimental APS with CNS involvement by testing several mouse strains immunized with β2-GPI. Female mice from five strains were immunized once with β2-GPI in complete Freund''s adjuvant (CFA) or with CFA alone (controls). Autoantibody levels were examined at 1 and 5 months after immunization. Neurological assessment in a staircase test was performed 4–5 months following the immunization. Induction of APS resulted in elevated levels of antibodies against negatively charged phospholipids and β2-GPI in all five mouse strains. Autoantibody levels were significantly higher in Balb/c, ICR, and C57BL/6 mouse strains compared to AKR and C3H. aPL levels dropped significantly more in the C57BL/6 compared to Balb/c mice over a period of 4 months. Hyperactivity reflected by higher number of stairs climbed in 3min, was induced by APS in the Balb/c and ICR, mouse strains. Exploratory behavior reflected by more frequent rears, was seen in the APS-Balb/c and AKR mice. Hypoactivity and less exploration were seen in the APS-C57BL/6 and C3H mice. The study supports a link between high levels of aPL and behavioral changes in a mouse APS model. Qualitative differences in behavioral patterns may be due to nervous system as well as immune genetic factors. The minimal effect of APS in C57BL/6 mice may provide a suitable background for the study of transgenes in these mice. [Copyright &y& Elsevier]

Abstract: Background: The antiphospholipid syndrome (APS) commonly affects the central nervous system through mechanisms that may include small vessel pathology and activation of thrombin. Antiphospholipid antibodies (aPL) activate endothelial cells but the specific activation of brain vascular endothelial cells (BVEC) and the receptors and signaling pathways involved have not been fully characterized. Objective: To examine whether aPL, the inflammatory stimulant lipopolysacharide (LPS) and thrombin activate BVECs through a Ras-dependent pathway. Methods: Rat BVEC (G8) were grown to confluence on 24-well plates. IgG was purified from 8 APS patients on a protein G column. Phosphorylation of ERK in the BVEC was measured by immunoblot utilizing a specific antibody. Results: Significant phosphorylation of ERK was measured following exposure of the cells to LPS and thrombin and this was blocked by the Ras inhibitor farnesylthiosalicylate (FTS). aPL IgG (1:100 relative to serum) from 7/8 patients also induced phosphorylation of ERK. Conclusions: Activation of the Ras-ERK pathway is an effect of both APS IgG and thrombin. This pathway is potentially amenable to drugs such as FTS and may serve as a therapeutic target in APS. [Copyright &y& Elsevier]