Medical treatment of Rasmussen's Encephalitis: A systematic review.

Rasmussen's encephalitis (RE) is a severe, rare, chronic inflammatory brain disease resulting in drug-resistant epilepsy and progressive destruction of one hemisphere with loss of neurological function. RE is associated with a deterioration of background electroencephalography (EEG) activity, a progressive atrophy on magnetic resonance imaging (MRI) imaging and an extensive positron emission tomography hypometabolism over the affected hemisphere. RE is an immune-mediated disease, with a predominant role of CD8+ T cytotoxic cells, microglial cells, and activation of inflammasome pathway. The diagnosis of RE is based on clinical (intractable epilepsy and neurological deterioration), electrophysiological (unilateral EEG slowing) and MRI (hemiatrophy) criteria. Antiseizure medications are generally unable to stop seizures. The most effective procedure is hemispherotomy (surgical disconnection of one cerebral hemisphere), but this is associated with permanent motor and neurological deficits. Treatments targeting the immune system are recommended especially in the early stages of the disease or in patients with slow disease progression and mild deficits and/or not eligible for surgery. Based on the pathophysiology, several immunotherapies have been tried in RE (none exhaustively: corticosteroid, intravenous immunoglobulins, tacrolimus, azathioprine, adalimumab, mycophenolate mofetil, natalizumab). However, only small cohorts have been reported without comparative study. In this review, we will summarise some pathophysiological mechanisms of RE, before reporting the literature data concerning immunotherapies. We then discuss the limitations of these studies and the prospects for further research.

Native versus deglycosylated IgM in anti-MAG neuropathy: Correlation with clinical status - Study of 10 cases.

BACKGROUND/PURPOSE: In anti-myelin associated glycoprotein (anti-MAG) neuropathies, there is evidence that anti-MAG antibodies are pathogenic but numerous studies report the absence or a weak correlation between the titers of these antibodies and disease course. In this study we assessed the relationships between MAG and glycosylated moieties located on Fc fragment of IgM anti-MAG. MATERIAL AND METHODS: IgM were extracted from the serum of 8 patients with anti-MAG neuropathy and in 2 patients with anti-MAG antibodies without anti-MAG neuropathy. Anti-MAG activity was performed with pre- and post-deglycosylated IgM extracts using indirect immunofluorescence (IIF) and ELISA. Sera from 49 patients with IgM monoclonal gammopathy without neurological disease were tested as control group (CG). Results were compared to clinical scores. For 4 patients the affinity constant of IgM with MAG was analyzed pre- and post-deglycosylated, using surface plasmon resonance technology (SPR). RESULTS: The relationships between MAG and glycosylated moieties of IgM anti-MAG were confirmed by kinetic and immunological assays. Deglycosylation resulted in a decrease in anti-MAG titers. Post-deglycosylation anti-MAG titers trended with changes in IgM titers and allowed quantifying anti-MAG antibodies without a saturation of the testing method. After deglycosylation, the titers better represented pathogenic activity and help to follow a given patient's clinical status prospectively. Six patients from CG (12.2%) had anti-MAG antibody titers over positive threshold: 1000 Bühlmann-Titer-Units (BTU) supporting the hypothesis of neutral intermolecular interactions between IgM and MAG. Deglycosylation allowed distinguishing infra clinical forms from neutral relationships forms, when the titers are weak but this assay remains essentially a diagnostic tool.

[Abdominal pain in progressive encephalomyelitis with rigidity]. / Encéphalomyélite progressive avec rigidité révélée par une douleur abdominale.

INTRODUCTION: Stiff-person syndrome is rare neurological disease, associating trunk rigidity and painful muscular spasms. A clinical variant of stiff person syndrome is the progressive encephalomyelitis with rigidity and myoclonus (PERM), which includes neurological cognitive disturbances. CASE REPORT: We report a 73-year-old woman initially addressed for abdominal pain, anorexia and severe weight-loss, for whom diagnosis of PERM was made. CONCLUSION: Because of its various clinical presentations, sometimes without evidence for neurological disease, the diagnosis of PERM is delayed. The presence of antineuropile antibodies associated with muscular spasms at electromyogram are strong evidence for this diagnosis.

[Neuromyelitis optica in children. Two case reports]. / Neuromyélite optique chez l'enfant. À propos de deux cas.

Devic neuromyelitis optica (NMO) is an inflammatory demyelinating disease of the central nervous system associating acute transverse myelitis and optic neuritis. This is a different disease from multiple sclerosis for which the presence of the NMO antibody directed against aquaporin 4 is a specific marker. Brain damage on MRI does not exclude the diagnosis; the location is superposable in the brain zones rich in aquaporin 4 channels. We report 2 cases of NMO with anti-aquaporin 4. One patient was not symptomatic of brain damage. In this patient, the affinity of anti-NMO for aquaporin 4, studied by flow cytometry, was particularly high. Both patients were treated with immunosuppressive agents (rituximab) due to the failure of or dependence on high-dose corticosteroids.

Alteration of CD1 expression in multiple sclerosis.

Studies of multiple sclerosis (MS) have concentrated mainly on antigen presentation of peptides derived from the myelin sheath, while the implication of lipid antigen has been less explored in this pathology. As the extracellular environment regulates expression of the lipid antigen-presenting molecule CD1, we have examined whether sera from patients alters CD1 surface expression in monocyte-derived dendritic cells. We have shown that: (i) CD1 group 1 proteins were highly expressed in the presence of MS sera; (ii) sera from MS patients differentially regulated CD1 group 1 versus CD1 group 2 molecular expression; and (iii) CD1 was expressed strongly in monocytes from MS patients under immunosuppressive treatment. Overall, these results reveal that CD1 expression is modified in MS and provide novel information on the regulation of lipid antigen presentation in myeloid cells.

Normalization of serum-free light chains in patients with systemic lupus erythematosus upon rituximab treatment and correlation with biological disease activity.

Increased free light chain (FLC) levels have been reported as useful in various autoimmune conditions. We investigated how FLC concentrations change upon B cell targeted therapy in systemic lupus erythematosus (SLE) patients and if they correlate with disease activity. We retrospectively studied 11 SLE patients without renal failure, whom were treated with rituximab. Quantitative determination of IgG, IgA, IgM, and serum FLC was performed before and after rituximab. At baseline, 70% had abnormal serum FLC levels, including increased kappa and lambda levels, while the kappa/lambda ratio was normal for all. A strong correlation was observed between complement C3 fraction and kappa levels (r = -0.929, P < 0.001) or lambda levels (r = -0.854, P = 0.003), but not with IgG, IgA, or IgM levels. After rituximab treatment, kappa and lambda FLC concentrations decreased significantly whilst total concentrations of IgG, IgA, and IgM also decreased but remained within the normal range. There was a strong correlation only between kappa FLC levels and complement C3 fraction consumption (r = -0.543, P = 0.003). In SLE patients without renal failure, increased FLC levels (mainly kappa) with normal kappa/lambda ratios are a common feature, and in contrast to total IgG levels, FLC concentrations correlate with biological disease activity.

Successful treatment with rituximab of one patient with CANOMAD neuropathy.

We report a successful treatment with rituximab in a patient with CANOMAD neuropathy resistant to previous therapy. The titers of anti-disialosyl antibodies were decreased 3 months after the beginning of the treatment and the sensory ataxia clearly improved after 9 months of therapy.

Chronic ataxic neuropathies associated with anti-GD1b IgM antibodies: response to IVIg therapy.

OBJECTIVE: To determine the responses to treatment of patients with chronic sensory ataxic neuropathy associated with anti-GD1b IgM antibodies. METHODS: Patients with chronic sensory ataxic neuropathy associated with anti-GD1b IgM antibodies followed in our department for at least 12 months between 2001 and 2008 were identified and studied retrospectively. Patients were tested at regular intervals using the INCAT disability score. Patients whose disability scores improved by at least one point were taken to have responded to the treatment. Intravenous immunoglobulin (IVIg; 2 g/kg) was administered for 3 to 5 days once every 6 weeks or corticosteroids at an initial daily dose of 1 mg/kg. RESULTS: 13 patients treated during the 8-year period of interest were included in this study. Seven of 13 patients displayed IgM anti-GQ1b, GT1b and GD3 antibodies suggesting reactivity against disialosyl epitope. IgM gammopathy was detected in four of six of serum with anti-disialosyl antibodies and two of the seven other sera. Nine of the 13 patients improved in response to IVIg. Oral corticosteroid treatment was attempted on four patients prior to IVIg treatment, and partial recovery occurred in one, who became steroid-dependent and showed little benefit in the long term. CONCLUSIONS: Screening for anti-GD1b IgM antibodies should be carried out on all patients with chronic ataxic sensory neuropathies. In 69% of the cases studied, the patients' condition improved in response to IVIg. This study shows the short-term efficiency of this treatment. Sustained responses were obtained in the long term by continuing the infusions.

GQ1b ganglioside antibody-related disorders: a case with a complex phenotype.

We described an overlap syndrome associating Miller Fisher syndrome (MFS) and acute inflammatory demyelinating polyradiculoneuropathy (AIDP). Furthermore, the patient presented unusual neurological manifestations including headache, T10 sensory level, urinary urgency, and gadolinium enhancement of the spinal roots. One year follow-up was characterized by clinical recovery and persistent high rates of anti-GQ1b, -GD1b and -GT1b antibodies. Our case suggests broad phenotype of persistent antigangliosides antibodies.

Chronic plasminogen activator inhibitor-1 (PAI-1) overexpression dampens CD25+ lymphocyte recruitment after lipopolysaccharide endotoxemia in mouse lung.

BACKGROUND: Plasma plasminogen activator inhibitor-1 (PAI-1) level rises during sepsis and confers a worse prognosis. PAI-1 participation to sepsis has been poorly documented and was mainly associated with fibrin deposits. Beside fibrin deposits, increased tissue PAI-1 expression may contribute to the poor outcome of endotoxemia through other mechanisms. OBJECTIVE AND METHODS: During lipopolysaccharide (LPS) challenge, the role of PAI-1 in the early phase of inflammation was examined in the lungs of transgenic mice that either overexpress or lack the PAI-1 gene (PAI-1Tg or PAI-1(-/-)). RESULTS: Analysis of leukocytes revealed that neutrophil and macrophage infiltrations did not differ for PAI-1Tg and wild-type (WT) mice. Remarkably, CD25+ lymphocyte infiltration was totally blunted in PAI-1Tg lungs and inversely correlated with fibrin depositions. In parallel, mRNA levels of the regulatory T cell (Treg) markers FoxP3, CTLA-4, and GITR were significantly lower in PAI-1Tg than in WT lungs after LPS challenge. These data are supported by opposite results in PAI-1(-/-) lungs. The systemic compartments (spleen and peripheral blood) showed no decrease in CD25+, CD4+ CD25+ lymphocytes, and Treg markers in PAI-1Tg mice after LPS injection compared with WT mice. In addition, plasma and lung concentrations of interleukin-6 (IL-6) and macrophage inflammatory protein-1alpha (MIP-1alpha) were significantly higher in PAI-1Tg mice than WT mice. CONCLUSION: Our results suggest that chronic tissue PAI-1 overexpression influences the early phase of the inflammatory response during endotoxemia through the control of T lymphocyte traffic.

[Stiff man syndrome: clinical forms, treatment and clinical course]. / Le syndrome de l'homme raide: formes cliniques, traitement et profil évolutif.

INTRODUCTION: Stiff-Man syndrome (SMS) is a rare neurological disease first described fifty years ago. There are several clinical forms, which are frequently misdiagnosed. The aim of this study is to review three of the main clinical forms. MATERIAL AND METHODS: Case reports concerning three women suffering from different forms of SMS are presented, giving the main clinical features, their associations with other diseases, and the biological and electrophysiological findings. RESULTS: The first patient presented a symmetric axial muscle rigidity, painful spasms and contractions of the trunk and limbs associated with anti-GAD antibodies. The common form of SMS was diagnosed and the patient was improved by intravenous immunoglobulin (IVIg). The second patient suffered from contractions and spasms localized to the lower limbs. In this patient, anti-GAD antibodies were absent. The Stiff-Leg syndrome was diagnosed and the patient was improved by intrathecal baclofen. The third patient presented rigidity of limb and trunk muscles associated with signs of encephalitis. In this patient, only anti-amphiphysin antibodies were present. The progressive encephalomyelitis with rigidity was diagnosed and the patient was improved by IVIg associated with corticosteroid. CONCLUSION: Identifying patients with SMS makes it possible to propose appropriate medical management. There are several forms of the disease, and the severity of the evolution differs in each case. Treatment with GABA-ergic inhibitory drugs, IVIg and corticosteroid improve both the symptomatology and the quality of life of these patients.

[Peripheral nerve repair: 30 centuries of scientific research]. / La réparation nerveuse périphérique: 30 siècles de recherche.

INTRODUCTION: Nerve injury compromises sensory and motor functions. Techniques of peripheral nerve repair are based on our knowledge regarding regeneration. Microsurgical techniques introduced in the late 1950s and widely developed for the past 20 years have improved repairs. However, functional recovery following a peripheral mixed nerve injury is still incomplete. STATE OF ART: Good motor and sensory function after nerve injury depends on the reinnervation of the motor end plates and sensory receptors. Nerve regeneration does not begin if the cell body has not survived the initial injury or if it is unable to initiate regeneration. The regenerated axons must reach and reinnervate the appropriate target end-organs in a timely fashion. Recovery of motor function requires a critical number of motor axons reinnervating the muscle fibers. Sensory recovery is possible if the delay in reinnervation is short. Many additional factors influence the success of nerve repair or reconstruction. The timing of the repair, the level of injury, the extent of the zone of injury, the technical skill of the surgeon, and the method of repair and reconstruction contribute to the functional outcome after nerve injury. CONCLUSION: This review presents the recent advances in understanding of neural regeneration and their application to the management of primary repairs and nerve gaps.

[Cutaneous vasculitis with renal impairment complicating interferon-beta 1a therapy for multiple sclerosis]. / Vascularite cutanée avec atteinte rénale compliquant un traitement par interféron bêta-1a pour une sclérose en plaques.

INTRODUCTION: Cutaneous tolerance of the interferon beta used in the treatment of relapsing-remitting multiple sclerosis is good. However, among the rare adverse effects, vasculitis and glomerular impairment have been described for interferon beta-1b. CASE REPORT: A 36-year-old woman had been given subcutaneous injections of interferon beta 1-1a (Rebif, Serono) three times a week for ten weeks. A local transient cutaneous erythema was observed at the injection's sites. A few days after a new injection a erythematous plaques developed at the injection sites followed by pruritus, then purpura with edema on the leg in addition to an increase in body weight of 3 kg. Biological data showed proteinuria and hematuria. The histology study of skin specimens suggested non-specific lymphocytic vasculitis. Outcome was favorable after discontinuing interferon beta-1a. CONCLUSION: The etiology of the cutaneous and renal impairment is not formally established but the drug-induced hypothesis is proposed for interferon beta-1a.

Neonatal lower motor neuron syndrome associated with maternal neuropathy with anti-GM1 IgG.

The authors report a newborn with motor neuropathy associated with anti-GM1 antibodies from an affected mother. This finding suggests that the disorder was due to transplacental transfer of pathogenic antibodies.

Terminal latency index and modified F ratio in distinction of chronic demyelinating neuropathies.

OBJECTIVE: To evaluate indexes calculated from standard electrophysiological data in differentiating chronic demyelinating polyneuropathy (CDP). METHODS: Nerve conduction study of upper limbs was investigated in 19 chronic inflammatory demyelinating polyneuropathy (CIDP) patients, 25 anti-myelin-associated glycoprotein/sulfated glucuronyl paragloboside antibodies (MAG/SGPG) CDP patients, 13 Charcot-Marie-Tooth disease type 1A (CMT1A) patients and 22 controls. Terminal latency index (TLI) was used to compare the wrist-to-thenar muscle segment with the elbow-to-wrist conduction velocity. Modified F ratio (MFR) was used to compare the spinal cord-to-elbow segment latency with that of the wrist-to-thenar muscle segment. RESULTS: Compared with controls, TLI was decreased in 21 anti-MAG/SGPG CDP patients while MFR was either decreased or was normal. In 16 CIDP patients, MFR was increased while TLI was either normal or increased. In CMT1A both TLI and MFR were in normal ranges. The sensitivity of MFR as a supportive finding in CIDP was found to be 84% and its specificity 89%. The sensitivity of TLI as a mean of diagnosis of anti-MAG/SGPG CDP was found to be 93% and its specificity 90%. CONCLUSIONS: The results of TLI and MFR facilitates distinction between different types of CDP. In CIDP, MFR was significantly higher and TLI showed no change; in the anti-MAG/SGPG CDP, TLI and MFR were significantly lower; in CMT1A, TLI and MFR showed no change in comparison with the controls.

Lithostathine and pancreatitis-associated protein are involved in the very early stages of Alzheimer's disease.

According to one of the theories formulated to explain the etiology of Alzheimer's disease (AD), amylosis may reflect a specific inflammatory response. Two inflammatory proteins, lithostathine and PAP, were evidenced by immunohistochemistry in senile plaques and neurofibrillary tangles of patients with AD. In addition, lithostathine and PAP were significantly increased in the cerebrospinal fluid of patients with AD when compared to patients with multiple sclerosis, another inflammatory disease, and to normal control subjects. However, no correlation was observed with age of occurrence. Furthermore, lithostathine and PAP were increased even at the very early stages of AD, and their level remained elevated during the course of the AD unlike TNFalpha whose level, very high at very early stages, regularly decreased. Finally, if part of lithostathine and PAP are synthesized in the brain, a large part comes from serum by passage over the blood-brain barrier. These results indicate (i) the existence of an acute phase response followed by a chronic inflammation in AD, and (ii) that lithostathine and PAP are involved even at the first pre-clinical biochemical events of AD. In addition, because lithostathine undergoes an autolytic cleavage leading to its precipitation and the formation of fibrils, we believe that it may be involved in amyloidosis and tangles by allowing heterogeneous precipitation of other proteins.

[Sensitized immunofixation: a new technique for analyzing the oligoclonal pattern of CSF immunoglobulins]. / L'immunofixation sensibilisée: nouvelle technique d'analyse du profil oligoclonal des immunoglobulines du LCR.

Intrathecal immunoglobulin synthesis is observed in more than 90% of all cases of multiple sclerosis, producing a specific CSF IgG oligoclonal electrophoretic pattern. The consensual method used as reference is isoelectric focusing (IEF). We developed a new CSF Ig analysis method by immunofixation (IF). The method includes an immunoenzymatic detection step performed directly on the gel allowing the use of unconcentrated CSF and avoiding the blotting step. The reliability of this method was established by the analysis of 210 CSF/serum pairs including defined, probable and possible MS, other inflammatory CNS diseases and controls (noninflammatory CNS diseases and peripheral nervous system diseases). Intrathecal IgG synthesis was detected in 95.5% of defined MS cases. The specificity for CNS inflammatory diseases including MS diagnosis, evaluated by comparison with controls, was 98.8%. This new method is quicker and visual interpretation is easier than with IEF. It is a semi-automated method that should be considered for standardization of CSF IgG analysis.