IL-2, IL-6 and chitinase 3-like 2 might predict early relapse activity in multiple sclerosis.

BACKGROUND: The possibility to better predict the severity of the disease in a patient newly diagnosed with multiple sclerosis would allow the treatment strategy to be personalized and lead to better clinical outcomes. Prognostic biomarkers are highly needed. OBJECTIVE: To assess the prognostic value of intrathecal IgM synthesis, cerebrospinal fluid and serum IL-2, IL-6, IL-10, chitinase 3-like 2 and neurofilament heavy chains obtained early after the onset of the disease. METHODS: 58 patients after the first manifestation of multiple sclerosis were included. After the initial diagnostic assessment including serum and cerebrospinal fluid biomarkers, all patients initiated therapy with either glatiramer acetate, teriflunomide, or interferon beta. To assess the evolution of the disease, we followed the patients clinically and with MRI for two years. RESULTS: The IL-2:IL-6 ratio (both in cerebrospinal fluid) <0.48 (p = 0.0028), IL-2 in cerebrospinal fluid ≥1.23pg/ml (p = 0.026), and chitinase 3-like 2 in cerebrospinal fluid ≥7900pg/ml (p = 0.033), as well as baseline EDSS ≥1.5 (p = 0.0481) and age <22 (p = 0.0312), proved to be independent markers associated with shorter relapse free intervals. CONCLUSION: The IL-2:IL-6 ratio, IL-2, and chitinase 3-like 2 (all in cerebrospinal fluid) might be of value as prognostic biomarkers in early phases of multiple sclerosis.

An immunotherapy effect analysis in Rasmussen encephalitis.

BACKGROUND: Immune-mediated mechanisms substantially contribute to the Rasmussen encephalitis (RE) pathology, but for unknown reasons, immunotherapy is generally ineffective in patients who have already developed intractable epilepsy; overall laboratory data regarding the effect of immunotherapy on patients with RE are limited. We analyzed multiple samples from seven differently treated children with RE and evaluated the effects of immunotherapies on neuroinflammation. Immunotherapy was introduced to all patients at the time of intractable epilepsy and they all had to undergo hemispherothomy. METHODS: Immunohistochemistry, flow cytometry, Luminex multiplex bead and enzyme-linked immunosorbent assay techniques were combined to determine: 1) inflammatory changes and lymphocyte subpopulations in 45 brain tissues; 2) lymphocyte subpopulations and the levels of 12 chemokines/cytokines in 24 cerebrospinal fluid (CSF) samples and 30 blood samples; and 3) the dynamics of these parameters in four RE patients from whom multiple samples were collected. RESULTS: Sustained T cell-targeted therapy with cyclophosphamide, natalizumab, alemtuzumab, and intrathecal methotrexate (ITMTX), but not with azathioprine, substantially reduced inflammation in brain tissues. Despite the therapy, the distributions of CD8+ T cells and the levels of C-X-C motif ligand (CXCL) 10, CXCL13, and B cell activating factor (BAFF) in patients' CSF remained increased compared to controls. A therapeutic approach combining alemtuzumab and ITMTX was the most effective in producing simultaneous reductions in histopathological inflammatory findings and in the numbers of activated CD8+ T cells in the brain tissue, as well as in the overall CD8+ T cell population and chemokine/cytokine production in the CSF. CONCLUSIONS: We provide evidence that various T cell-targeted immunotherapies reduced inflammation in the brains of RE patients. The observation that intractable epilepsy persisted in all of the patients suggests a relative independence of seizure activity on the presence of T cells in the brain later in the disease course. Thus, new therapeutic targets must be identified. CXCL10, CXCL13 and BAFF levels were substantially increased in CSF from all patients and their significance in RE pathology remains to be addressed.

Diffusion Tensor Imaging And Tractography In Autistic, Dysphasic, And Healthy Control Children.

BACKGROUND: Diffusion tensor imaging (DTI) is a powerful tool for investigating brain anatomical connectivity. The aim of our study was to compare brain connectivity among children with autism spectrum disorders (ASD), developmental dysphasia (DD), and healthy controls (HC) in the following tracts: the arcuate fasciculus (AF), inferior frontal occipital fasciculus (IFOF), inferior longitudinal fasciculus (ILF), and uncinate fasciculus (UF). METHODS: Our sample consisted of 113 children with a mean age 8.7±2.2 years (77 boys, 36 girls), divided into three subgroups: ASD (n=39), DD (n=36), and HC (n=38). The International Classification of Diseases, 10th ed. was used to make clinical diagnoses. DTI images were collected using a 1.5 T Phillips Achieva MR imaging system. RESULTS: Detailed analyses of fractional anisotropy (FA) revealed significant differences among the ASD, DD, and HC groups in the left AF (p=0.014) and right AF (p=0.001), the left IFOF (p<0.001) and right IFOF (p<0.001), the left ILF (p<0.001) and right ILF (p<0.001), but not in the UF. Post-hoc analyses revealed three patterns of FA differences among the groups: (1) in the right AF, right IFOF, and right ILF, FA was significantly lower in the ASD group compared to the DD and HC groups; however, there was no difference in FA between DD and HC; (2) in the left AF and left IFOF, FA was significantly lower in the ASD than in the HC group, but there were no differences between DD vs HC nor DD vs ASD; and (3) in the left ILF, no difference in FA was seen between ASD and DD, but FA in both was significantly lower than in the HC. CONCLUSION: Microstructural white matter properties differed between ASD vs DD and HC subjects. The tract where FA impairment in ASD and DD subjects was the most similar was the left ILF.

Structural alterations of the language connectome in children with specific language impairment.

We evaluated brain white matter pathways associated with language processing in 37 children with specific language impairment aged 6-12 years and 34 controls, matched for age, sex and handedness. Arcuate fascicle (AF), inferior fronto-occipital fascicle (IFOF), inferior longitudinal fascicle (ILF) and uncinate fascicle (UF) were identified using magnetic resonance diffusion tensor imaging (DTI). Diffusivity parameters and volume of the tracts were compared between the SLI and control group. Children with SLI showed decreased fractional anisotropy in all investigated tracts, increased mean diffusivity and radial diffusivity component in arcuate fascicle bilaterally, left IFOF and left ILF. Further, bilaterally increased volume of the ILF in children with SLI was found. We confirmed previous findings indicating deficient connectivity of the arcuate fascicle and as a novel finding, demonstrate abnormal development of the ventral language stream in patients with SLI.

SISCOM and FDG-PET in patients with non-lesional extratemporal epilepsy: correlation with intracranial EEG, histology, and seizure outcome.

AIMS: To assess the practical localising value of subtraction ictal single-photon emission computed tomography (SISCOM) coregistered with MRI and (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET) in patients with extratemporal epilepsy and normal MRI. METHODS: We retrospectively studied a group of 14 patients who received surgery due to intractable epilepsy and who were shown to have focal cortical dysplasia, undetected by MRI, based on histological investigation. We coregistered preoperative SISCOM and PET images with postoperative MRI and visually determined whether the SISCOM focus, PET hypometabolic area, and cerebral cortex, exhibiting prominent abnormalities on intracranial EEG, were removed completely, incompletely, or not at all. These results and histopathological findings were compared with postoperative seizure outcome. RESULTS: Two patients underwent one-stage multimodal image-guided surgery and the remaining 12 underwent long-term invasive EEG. SISCOM findings were localised for all but 1 patient. FDG-PET was normal in 3 subjects, 2 of whom had favourable postsurgical outcome (Engel class I and II). Complete resection of the SISCOM focus (n=3), the area of PET hypometabolism (n=2), or the cortical regions with intracranial EEG abnormalities (n=7) were predictive of favourable postsurgical outcome. Favourable outcome was also encountered in: 4 of 8 patients with incomplete resection and 1 of 2 with no resection of the SISCOM focus; 4 of 7 patients with incomplete resection and 1 of 2 with no resection of the PET hypometabolic area; and 2 of 7 patients with incomplete resection of the area corresponding to intracranial EEG abnormality. No correlation between histopathological FCD subtype and seizure outcome was observed. CONCLUSION: Complete resection of the dysplastic cortex localised by SISCOM, FDG-PET or intracranial EEG is a reliable predictor of favourable postoperative seizure outcome in patients with non-lesional extratemporal epilepsy.

Postural function of the diaphragm in persons with and without chronic low back pain.

STUDY DESIGN: A case-control study. OBJECTIVES: To examine the function of the diaphragm during postural limb activities in patients with chronic low back pain and healthy controls. BACKGROUND: Abnormal stabilizing function of the diaphragm may be an etiological factor in spinal disorders. However, a study designed specifically to test the dynamics of the diaphragm in chronic spinal disorders is lacking. METHODS: Eighteen patients with chronic low back pain due to chronic overloading, as ascertained via clinical assessment and magnetic resonance imaging, and 29 healthy subjects were examined. Both groups presented with normal pulmonary function test results. A dynamic magnetic resonance imaging system and specialized spirometric readings were used with subjects in the supine position. Measurements during tidal breathing (TB) and isometric flexion of the upper and lower extremities against external resistance with TB were performed. Standard pulmonary function tests, including respiratory muscle drive (PI(max) and PE(max)), were also assessed. RESULTS: Using multivariate analysis of covariance, smaller diaphragm excursions and higher diaphragm position were found in the patient group (P<.05) during the upper extremity TB and lower extremity TB conditions. Maximum changes were found in costal and middle points of the diaphragm. A 1-way analysis of covariance showed a steeper slope in the middle-posterior diaphragm in the patient group both in the upper extremity TB and lower extremity TB conditions (P<.05). CONCLUSION: Patients with chronic low back pain appear to have both abnormal position and a steeper slope of the diaphragm, which may contribute to the etiology of the disorder.