Immune system's role in viral encephalitis.

Viral infections can be a major thread for the central nervous system (CNS), therefore, the immune system must be able to mount a highly proportionate immune response, not too weak, which would allow the virus to proliferate, but not too strong either, to avoid collateral damages. Here, we aim at reviewing the immunological mechanisms involved in the host defense in viral CNS infections. First, we review the specificities of the innate as well as the adaptive immune responses in the CNS, using several examples of various viral encephalitis. Then, we focus on three different modes of interactions between viruses and immune responses, namely human Herpes virus-1 encephalitis with the defect in innate immune response which favors this disease; JC virus-caused progressive multifocal leukoencephalopathy and the crucial role of adaptive immune response in this example; and finally, HIV infection with the accompanying low grade chronic inflammation in the CNS in some patients, which may be an explanation for the presence of cognitive disorders, even in some well-treated HIV-infected patients. We also emphasize that, although the immune response is generally associated with viral replication control and limited cellular death, an exaggerated inflammatory reaction can lead to tissue damage and can be detrimental for the host, a feature of the immune reconstitution inflammatory syndrome (IRIS). We will briefly address the indication of steroids in this situation.

[Anti-neuronal antibodies: a rapidly developing field]. / Anticorps antineuronaux: un domaine en plein développement.

Anti-neuronal antibodies are implicated in various neurological syndromes that are sometimes associated with tumors. Depending on the antigenic target (nuclear, cytoplasmic or extracellular cell-surface or synaptic) the clinical presentation is different. In neurological syndromes associated with antibodies specific for intracellular antigens, the T-cell mediated immunological response predominates as pathogenic effector and the response to treatment is typically poor. In contrast, in syndromes related to antibodies against extracellular targets, the role of the antibodies is pathogenic and the neurological syndrome often responds better to immunomodulatory treatment, associated or not with an anti-tumoral treatment. We review the spectrum of anti-neuronal antibodies and their corresponding clinical and therapeutic characteristics.

[Dysimmune neuromuscular disorders: diagnostic challenges and new ways of management]. / Maladies auto-immunes neuromusculaires: diagnostic et prise en charge.

This review describes some dysimmune neuromuscular disorders and their recent management: syndrome of peripheral nerve hyperexcitability (treatment of cramps, immunosuppressors); Guillain-Barré syndrome (new mechanisms and consensus treatment); chronic inflammatory demyelinating polyradiculoneuropathy (new indication for the use of pulse dexamethasone, new scores of activity); importance of subcutaneous immunoglobulin in multifocal motor neuropathy and of infusions of rituximab in myasthenia gravis; new entities in myositis and their treatment.

[New treatment options in multiple sclerosis and their complications]. / Traitement de tla sclérose en plaques: nouveautés et complications.

A new therapeutic era opened for multiple sclerosis (MS) with the appearance of molecules given p.o. and/or molecules with greater efficiency. Early diagnosis is critical, as the time and the choice of therapeutic intervention. The initiation of treatments must be personalized, including the risks associated with MS and those potentially related to the treatment chosen, answering the question >. Monitoring tools that allow to objectively evaluate: I) MS activity and aggressiveness for each patient and 2) the safety of treatments and their risks of complications, must be further investigated.

Fatal PML associated with efalizumab therapy: insights into integrin αLß2 in JC virus control.

OBJECTIVES: Progressive multifocal leukoencephalopathy (PML) has become much more common with monoclonal antibody treatment for multiple sclerosis and other immune-mediated disorders. METHODS: We report 2 patients with severe psoriasis and fatal PML treated for ≥3 years with efalizumab, a neutralizing antibody to αLß2-leukointegrin (LFA-1). In one patient, we conducted serial studies of peripheral blood and CSF including analyses of leukocyte phenotypes, migration ex vivo, and CDR3 spectratypes with controls coming from HIV-infected patients with PML. Extensive pathologic and histologic analysis was done on autopsy CNS tissue of both patients. RESULTS: Both patients developed progressive cognitive and motor deficits, and JC virus was identified in CSF. Despite treatment including plasma exchange (PE) and signs of immune reconstitution, both died of PML 2 and 6 months after disease onset. Neuropathologic examination confirmed PML. Efalizumab treatment was associated with reduced transendothelial migration by peripheral T cells in vitro. As expression levels of LFA-1 on peripheral T cells gradually rose after PE, in vitro migration increased. Peripheral and CSF T-cell spectratyping showed CD8+ T-cell clonal expansion but blunted activation, which was restored after PE. CONCLUSIONS: From these data we propose that inhibition of peripheral and intrathecal T-cell activation and suppression of CNS effector-phase migration both characterize efalizumab-associated PML. LFA-1 may be a crucial factor in homeostatic JC virus control.

[Neurology]. / Neurologie.

In 2011, new oral anticoagulants for atrial fibrillation are available and the ABCD3-I score predicting stroke after TIA updates the ABCD2 score. New McDonald criteria allow faster MS diagnosis and the first oral treatment (fingolimod) for MS can be prescribed. A new anti-antiepileptic drug (retigabine) is available and sodium valproate has long term neurological adverse effects after in utero exposure. Among Parkinson disease treatments, deep brain stimulation is extending applications and dopamine agonists with extended release are as efficient and well tolerated as standard forms at long term scale. Monoclonal antibodies and immunosuppressant agents are proposed as good alternatives in the treatment of chronic dysimmune polyneuropathies. Gene therapy for the treatment of genetic myopathies is progressing.

[Therapeutic advances in neurology]. / Neurologie.

This article summarizes the main therapeutic advances of 2010 in the field of neurology. It focuses on aspects that are likely to change the care of patients in clinical practice. Among these, we discuss the new oral treatments that have proved to be effective in multiple sclerosis, the results of two large studies comparing endarterectomy and stenting in carotid stenosis, novel therapeutic approaches for the treatment of non-motor symptoms in Parkinson's disease as well as the results of several pharmacological studies in the field of epilepsy.

EFNS guidelines on diagnosis and management of neuromyelitis optica.

BACKGROUND AND PURPOSE: Neuromyelitis optica (NMO) or Devic's disease is a rare inflammatory and demyelinating autoimmune disorder of the central nervous system (CNS) characterized by recurrent attacks of optic neuritis (ON) and longitudinally extensive transverse myelitis (LETM), which is distinct from multiple sclerosis (MS). The guidelines are designed to provide guidance for best clinical practice based on the current state of clinical and scientific knowledge. SEARCH STRATEGY: Evidence for this guideline was collected by searches for original articles, case reports and meta-analyses in the MEDLINE and Cochrane databases. In addition, clinical practice guidelines of professional neurological and rheumatological organizations were studied. RESULTS: Different diagnostic criteria for NMO diagnosis [Wingerchuk et al. Revised NMO criteria, 2006 and Miller et al. National Multiple Sclerosis Society (NMSS) task force criteria, 2008] and features potentially indicative of NMO facilitate the diagnosis. In addition, guidance for the work-up and diagnosis of spatially limited NMO spectrum disorders is provided by the task force. Due to lack of studies fulfilling requirement for the highest levels of evidence, the task force suggests concepts for treatment of acute exacerbations and attack prevention based on expert opinion. CONCLUSIONS: Studies on diagnosis and management of NMO fulfilling requirements for the highest levels of evidence (class I-III rating) are limited, and diagnostic and therapeutic concepts based on expert opinion and consensus of the task force members were assembled for this guideline.

[Autoantibodies in neurological diseases: clinical implications]. / Autoanticorps en neurologie: implications cliniques.

Autoantibodies are defined as antibodies directed against self antigens, i.e., against a normal antigenic endogenous tissue constituent. They can be the immediate cause of the neurological syndrome or be detected as an epiphenomenon of the pathogenic process. Autoantibodies are often considered useful biomarkers for the improvement of diagnostic accuracy, for the staging of disease progression or for the follow up of a biological response to a therapeutic intervention. The purpose of this article is to review the autoantibodies that are available to investigate immune-mediated neurological conditions. The detection of some of these autoantibodies may help the clinician to establish a definite diagnosis which may further facilitate the therapeutic decision.

Chimeric immune receptors (CIRs) specific to JC virus for immunotherapy in progressive multifocal leukoencephalopathy (PML).

Progressive multifocal leukoencephalopathy (PML) is a deadly brain disease caused by the polyomavirus JC (JCV). The aim of this study is to develop 'designer T cells' armed with anti-JCV TCR-based chimeric immune receptors (CIRs) by gene modification for PML immunotherapy. Two T cell lines specific to two dominant CTL epitopes derived from JCV VP1 protein (termed p36 and p100) from an HLA-A0201+ PML survivor were generated for TCR cloning. Two distinct dominant TCR alpha chains (Valpha6 and Valpha12) and a unique TCR beta chain (Vbeta5.1) were cloned from the p36-specific cell line, while only one alpha (Valpha8.6) and one beta (Vbeta2) chains were dominant in the p100-specific line. Retroviral constructs encoding CIRs were created with the extracellular domains of TCR alpha and beta chains fused to the transmembrane and cytoplasmic portions of CD3zeta (ValphaCalphaCD3zeta or VbetaCbetaCD3zeta). Cellular expression and screening for binding specific peptide-HLA-A0201 tetramer confirmed the reactivity of the p100 TCRalphabeta and of one of the two pairs of p36 TCRalphabeta (Valpha12 and Vbeta5.1). Functional tests confirmed CIR-expressing T cells secreted cytokines and expressed potent cytotoxicity on contact with A0201+ B-lymphoblastoid line loaded with peptides and/or with HLA-A0201+ cells expressing native JCV VP1 protein. In conclusion, anti-JCV designer T cells were generated.

Neuromyelitis optica following CMV primo-infection.

We report the case of an acute optic neuromyelitis with rhabdomyolysis in a 34-year-old immunocompetent transsexual patient following a recent cytomegalovirus (CMV) infection. The combination of optic neuropathy and myelopathy is recognized as Devic's syndrome. Clinical presentation was unusual as the recent CMV infection induced rhabdomyolysis and was the suspected trigger of neuromyelitis.

Favourable outcome of progressive multifocal leucoencephalopathy in two patients with dermatomyositis.

Progressive multifocal leucoencephalopathy (PML), a demyelinating disease caused by the JC virus (JCV), occurs in immunosuppressed patients and carries a poor prognosis. A favourable outcome is reported in two patients with PML and dermatomyositis. Immunosuppressive drugs were stopped in patient 1 but could only be partially tapered in patient 2. The JCV-specific CD8+ T cell response was strong in patient 1 and weak in patient 2. Both were treated with cytosine-arabinoside, and patient 2 was also treated with mirtazapine, a 5HT2A receptor antagonist. Combination of these drugs might be helpful to treat HIV-negative patients with PML.

Detection of JC virus-specific cytotoxic T lymphocytes in healthy individuals.

The polyomavirus JC (JCV) infects 85% of healthy individuals, and its reactivation in a limited number of immunosuppressed people causes progressive multifocal leukoencephalopathy (PML), a severe demyelinating disease of the central nervous system. We hypothesized that JCV-specific cytotoxic T lymphocytes (CTLs) might control JCV replication in healthy individuals, blocking the evolution of PML. Using 51Cr release and tetramer staining assays, we show that 8 of 11 HLA-A*0201+ healthy subjects (73%) harbor detectable JCV-specific CD8+ CTLs that recognize one or two epitopes of JCV VP1 protein, the HLA-A*0201-restricted VP1p36 and VPp1100 epitopes. We determined that the frequency of JCV VP1 epitope-specific CTLs varied from less than 1/100,000 to 1/2,494 peripheral blood mononuclear cells. More individuals had JCV VP1-specific than cytomegalovirus-specific CTLs (8 of 11 subjects [73%] versus 2 of 10 subjects [20%], respectively). These results show that a CD8+-T-cell response against JCV is commonly found in immunocompetent people and suggest that these cells might protect against the development of PML.

The effect of aging on postural stability: a cross sectional and longitudinal study.

AIMS OF THE STUDY: Only a good knowledge of the effects of age on postural stability allows differentiating between physiological aging and pathologies leading to its impairment. The aims of this study were to define the posturographic parameters which best reflected the effects of aging on postural stability and to determine the slope of postural stability impairment related to aging. PATIENTS AND METHODS: Postural stability of 50 normal volunteers aged 25-83 years (55.4) was studied with one Kistler force plate. Subjects were asked to stand for 30 s on two-legged stance, eyes open then closed. The center of pressure displacement (COPd) and velocities (COPv), in the antero-posterior (x) and the medio-lateral (z) axis, the sway axis, and the integral of COP displacement vs. time were computed. Eleven subjects were retested at 3 and 6 months to estimate the reliability of posturographic measurements. In addition, 28 subjects aged 25-83 years (60.2) were retested 2.2 years after their first posturographic assessment. RESULTS: COPxv best reflected postural stability impairment with aging. Closure of the eyes increased the variance of the results. This change was higher in subjects more than 60 years old: 0.019-0.157 cm2 s(-2) than in younger ones: 0.011-0.043 cm2 s(-2). Retesting at 3 and 6 months showed a reliability of 79%. According to the cross-sectional part of the study, the slope of postural stability impairment with aging was estimated at 0.0038 cm/s/year. These results were confirmed by the longitudinal part of the study, which showed that COPxv increased from 0.66-0.75 cm/s/year (P = 0.0001) (slope = 0.0041 cm/s/year). CONCLUSION: (1) Measurement of COPxv, on two-legged stance, is a simple and reliable way to assess postural stability. (2) Thanks to both a cross sectional and a longitudinal study, the rate of postural stability impairment due to aging was precisely estimated, which will be useful to help distinguishing between the part of postural stability impairment attributable to aging from the one due to neuro-degenerative diseases.

Productive infection of cerebellar granule cell neurons by JC virus in an HIV+ individual.

BACKGROUND: In the setting of severe immunosuppression, the polyomavirus JC (JCV) can cause a lytic infection of oligodendrocytes. This demyelinating disease of the CNS white matter (WM) is called progressive multifocal leukoencephalopathy (PML). JCV has a very narrow host-cell range and productive infection of neurons has never been demonstrated. Patient, methods, and results: An HIV-1-infected patient presented with signs of pyramidal tract and cerebellar dysfunction. Brain MRI revealed T2 hyperintensities in the WM of both frontal lobes and cerebellar atrophy. His disease progressed despite therapy and he died 6 months later. In addition to classic PML findings in the frontal lobe WM, autopsy revealed scattered foci of tissue destruction in the internal granule cell layer (IGCL) of the cerebellum. In these foci, enlarged granule cell neurons identified by the neuronal markers MAP-2 and NeuN reacted with antibodies specific for the polyomavirus VP1 capsid protein. Electron microscopy showed 40 nm viral particles, consistent with polyomaviruses, in these granule cell neurons. In addition, JCV DNA was detected by PCR after laser capture microdissection of cells from the areas of focal cell loss. Finally, in situ hybridization studies demonstrated that many granule cell neurons were infected with JCV but did not contain viral proteins. Sequence analysis of the JCV regulatory region from cerebellar virions showed a tandem repeat pattern also found in PML lesions of the frontal lobe WM. CONCLUSION: JCV can productively infect granule cell neurons of the IGCL of the cerebellum. This suggests a role for JCV infection of neurons in cerebellar atrophy occurring in HIV-infected individuals.