Sleep disturbance and cognitive decline in multiple sclerosis patients with isolated optic neuritis as the first demyelinating event.

PURPOSE: Multiple sclerosis (MS) patients whose first demyelinating event is optic neuritis have been claimed to display a milder disease course and reduced physical disability. Our aim was to investigate the impact of the clinical features of the first clinical episode on cognitive disability and sleep dysfunction in MS. METHODS: A total of 26 (10 with optic neuritis as the first clinical event) MS patients were recruited. A comprehensive sleep study was performed, and a panel of tests were administered to examine cognitive and motor performance. Serum levels of sleep-related mediators orexin-A and melatonin were measured by enzyme-linked immunosorbent assay. Subjective sleep quality was evaluated by Pittsburgh sleep quality test, and daytime excessive sleepiness was tested by Epworth sleepiness scale. RESULTS: MS patients with the first clinical episode of optic neuritis and patients with at least one optic neuritis attack exhibited increased daytime sleepiness, higher sleep efficiency and NREM duration and lower total wake time. Patients with a history of optic neuritis obtained more favorable scores in neuropsychological tests measuring executive functions and complex attention as compared to those who had never experienced optic neuritis. Melatonin and orexin-A levels were lower in patients with optic neuritis onset. The higher no. of optic neuritis attacks was associated with reduced wake time and higher symbol digit modalities test scores. CONCLUSIONS: Having a history of optic neuritis is associated with improved sleep quality and executive functions but increased daytime sleepiness. Reduction of orexin-A and melatonin levels might be one of the underlying mechanisms.

Evaluation of incidence and clinical features of antibody-associated autoimmune encephalitis mimicking dementia.

BACKGROUND: Anti-neuronal autoimmunity may cause cognitive impairment that meets the criteria for dementia. Objective. Our aim was to detect the incidence and clinical features of autoimmune encephalitis imitating clinical findings of primary dementia disorders and to delineate the validity of anti-neuronal antibody screening in dementia patients. METHODS: Fifty consecutive patients fulfilling the clinical criteria for primary dementia, 130 control patients, and 50 healthy controls were included. Their sera were investigated for several ion channel and glutamic acid decarboxylase (GAD) antibodies by a cell-based assay, radioimmunoassay, and ELISA, as required. RESULTS: Sixteen patients satisfying dementia criteria had atypical findings or findings suggestive of autoimmune encephalitis. N-methyl-D-aspartate receptor (NMDAR) antibody was detected in a patient with dementia, Parkinsonism, and REM sleep behavior disorder (RBD) fulfilling the criteria for dementia with Lewy bodies (DLB). One control patient with bipolar disease displayed low anti-GAD antibody levels. CONCLUSIONS: Our study showed for the first time the presence of parkinsonism and RBD in an anti-NMDAR encephalitis patient mimicking DLB. Although autoimmune encephalitis patients may occasionally present with cognitive decline, most dementia patients do not exhibit anti-neuronal antibodies, suggesting that routine analysis of these antibodies in dementia is not mandatory, even though they display atypical features.

Preferential production of IgG1, IL-4 and IL-10 in MuSK-immunized mice.

Myasthenia gravis (MG) is an autoimmune disease characterized by muscle weakness associated with acetylcholine receptor (AChR), muscle-specific receptor kinase (MuSK) or low-density lipoprotein receptor-related protein 4 (LRP4)-antibodies. MuSK-antibodies are predominantly of the non-complement fixing IgG4 isotype. The MuSK associated experimental autoimmune myasthenia gravis (EAMG) model was established in mice to investigate immunoglobulin (Ig) and cytokine responses related with MuSK immunity. C57BL/6 (B6) mice immunized with 30µg of recombinant human MuSK in incomplete or complete Freund's adjuvant (CFA) showed significant EAMG susceptibility (>80% incidence). Although mice immunized with 10µg of MuSK had lower EAMG incidence (14.3%), serum MuSK-antibody levels were comparable to mice immunized with 30µg MuSK. While MuSK immunization stimulated production of all antibody isotypes, non-complement fixing IgG1 was the dominant anti-MuSK Ig isotype in both sera and neuromuscular junctions. Moreover, MuSK immunized IgG1 knockout mice showed very low serum MuSK-antibody levels. Sera and MuSK-stimulated lymph node cell supernatants of MuSK immunized mice showed significantly higher levels of IL-4 and IL-10 (but not IFN-γ and IL-12), than those of CFA immunized mice. Our results suggest that through activation of Th2-type cells, anti-MuSK immunity promotes production of IL-4, which in turn activates anti-MuSK IgG1, the mouse analog of human IgG4. These findings might provide clues for the pathogenesis of other IgG4-related diseases as well as development of disease specific treatment methods (e.g. specific IgG4 inhibitors) for MuSK-related MG.

Switch-associated protein 70 antibodies in multiple sclerosis: possible association with disease progression.

OBJECTIVE: This study was conducted to identify a biomarker for multiple sclerosis (MS) that can be used as a predictor of relapse and disability. MATERIALS AND METHODS: Sera of 26 consecutive relapsing-remitting MS (RRMS) patients were screened for switch-associated protein 70 (SWAP-70) antibody, which was previously identified by protein macroarray. The serum levels of several cytokines, chemokines and soluble adhesion molecules related to MS attacks were measured by enzyme-linked immunosorbent assay (ELISA). A possible correlation was sought among levels of SWAP-70 antibody, measured humoral factors and disability scores. RESULTS: ELISA studies showed high-titre SWAP-70 antibodies in 16 (61.5%) RRMS sera obtained during the attack period and 9 (34.6%) sera obtained during remission. There was a significant inverse correlation between SWAP-70 antibody levels and expanded disability status scale scores, CXCL10, soluble VCAM-1, CXCL13 and soluble VLA-4 levels. CONCLUSION: Our results showed that SWAP-70 antibodies could potentially be utilized as relapse and prognostic biomarkers in MS. Whether or not SWAP-70 antibodies have any effect on disease mechanisms requires further investigation.

Mitochondrial carrier homolog 1 (Mtch1) antibodies in neuro-Behçet's disease.

Efforts for the identification of diagnostic autoantibodies for neuro-Behcet's disease (NBD) have failed. Screening of NBD patients' sera with protein macroarray identified mitochondrial carrier homolog 1 (Mtch1), an apoptosis-related protein, as a potential autoantigen. ELISA studies showed serum Mtch1 antibodies in 68 of 144 BD patients with or without neurological involvement and in 4 of 168 controls corresponding to a sensitivity of 47.2% and specificity of 97.6%. Mtch1 antibody positive NBD patients had more attacks, increased disability and lower serum nucleosome levels. Mtch1 antibody might be involved in pathogenic mechanisms of NBD rather than being a coincidental byproduct of autoinflammation.

Non-convulsive status epilepticus associated with glutamic acid decarboxylase antibody.

Autoimmune encephalitis associated with glutamic acid decarboxylase antibodies (GAD-Ab) often presents with treatment-resistant partial seizures, as well as other central nervous system symptoms. In contrast to several other well-characterized autoantibodies, GAD-Ab has very rarely been associated with status epilepticus. We report a 63-year-old woman initially admitted with somnolence and psychiatric findings. The EEG findings, of generalized and rhythmical slow spike-wave activity over the posterior regions of both hemispheres, together with the clinical deterioration in responsiveness, led to the diagnosis of non-convulsive status epilepticus. Investigation of a broad panel of autoantibodies, revealed only increased serum GAD-Ab levels. Following methylprednisolone and intravenous immunoglobulin treatments, the patient's neurological symptoms improved, EEG findings disappeared and GAD-Ab levels significantly decreased. GAD-Ab should be added to the list of anti-neuronal antibodies associated with non-convulsive status epilepticus. Disappearance of clinical findings and seroreversion after immunotherapy suggest that GAD-Ab might be involved in seizure pathogenesis. 

Serum anti-neuronal antibodies in amyotrophic lateral sclerosis.

We aimed to investigate various anti-neuronal antibodies in sera of amyotrophic lateral sclerosis (ALS) patients to detect possible autoimmune encephalitis patients imitating ALS findings and to delineate the validity of routine screening of well-characterized anti-neuronal antibodies in ALS. The patients fulfilling the revised El Escorial diagnostic criteria for definite ALS were included. Their serum samples were investigated for antiganglioside (IgM/IgG) and onconeural (IgG) antibodies by immunoblotting, for ion channel antibodies (IgG) by a cell-based assay and for IgG binding patterns to the rat brain by indirect immunohistochemistry. Thirty-five patients with definite ALS and 30 healthy individuals were included. Ganglioside antibodies were detected in 2 out of 35 (5.7%) patients with ALS. The onconeural and ion channel antibodies were negative in our series. Varied serum IgG binding patterns were identified in eight (22.9%) patients. Although autoimmune encephalitis patients may occasionally present with atypical motor neuron disease findings, definite ALS patients do not appear to exhibit onconeural or ion channel antibodies, suggesting that routine analysis of these antibodies in typical ALS is not mandatory. By contrast, some ALS patients display anti-neuronal antibodies against undetermined target antigens, prompting investigation of these novel antibodies with more advanced methods.