Risk of multiple sclerosis after a first demyelinating syndrome in an Australian Paediatric cohort : clinical, radiological features and application of the McDonald 2010 MRI criteria

Background: The risk of multiple sclerosis (MS) is dependent on multiple variables, including geographical location. There is increasing interest in the early recognition and treatment of MS in children. Method: Using univariate and multivariate analysis, we determined the clinical and radiological features that were predictive of MS in 88 children from New South Wales, Australia, with a first acute demyelinating syndrome (ADS) who were followed for a minimum of one year. We tested the McDonald, KIDMUS, Callen and Verhey MRI criteria for paediatric MS. Results: After a mean follow-up of 5.2 years, 13/88 (15%) of children had MS. Using multivariate analysis, preceding infection was protective of MS, and corpus callosal lesions, the combined presence of both well and poorly demarcated lesions, and contrast-enhancing lesions on MRI were predictive of MS. The sensitivity and specificity of the respective radiological criteria were McDonald 2005 (69%, 68%), McDonald 2010 (58%, 95%), KIDMUS (8%, 100%), Callen (69%, 85%) and Verhey (62%, 84%). When McDonald 2010 criteria were applied to baseline and serial scans, the sensitivity and specificity was 91% and 93%. Conclusion: Despite the long follow-up, the risk of MS appears lower in New South Wales children compared to previously reported cohorts. Radiological features are more predictive than clinical features in predicting MS. The McDonald 2010 criteria performed well although the dissemination in time criteria on baseline scans is difficult to apply to children with encephalopathy.11 page(s

Failure to thrive potentially secondary to maternal venlafaxine use

2 page(s

B cell, Th17, and neutrophil related cerebrospinal fluid cytokine/chemokines are elevated in MOG antibody associated demyelination

Background: Myelin oligodendrocyte glycoprotein antibody (MOG Ab) associated demyelination represents a subgroup of autoimmune demyelination that is separate from multiple sclerosis and aquaporin 4 IgG-positive NMO, and can have a relapsing course. Unlike NMO and MS, there is a paucity of literature on immunopathology and CSF cytokine/chemokines in MOG Ab associated demyelination. Aim: To study the differences in immunopathogenesis based on cytokine/chemokine profile in MOG Ab-positive (POS) and-negative (NEG) groups. Methods: We measured 34 cytokines/chemokines using multiplex immunoassay in CSF collected from paediatric patients with serum MOG Ab POS [acute disseminated encephalomyelitis (ADEM=8), transverse myelitis (TM=2) n=10] and serum MOG Ab NEG (ADEM=5, TM=4, n=9) demyelination. We generated normative data using CSF from 20 non-inflammatory neurological controls. Results: The CSF cytokine and chemokine levels were higher in both MOG Ab POS and MOG Ab NEG demyelination groups compared to controls. The CSF in MOG Ab POS patients showed predominant elevation of B cell related cytokines/chemokines (CXCL13, APRIL, BAFF and CCL19) as well as some of Th17 related cytokines (IL-6 AND G-CSF) compared to MOG Ab NEG group (all p<0.01). In addition, patients with elevated CSF MOG antibodies had higher CSF CXCL13, CXCL12, CCL19, IL-17A and G-CSF than patients without CSF MOG antibodies. Conclusion: Our findings suggest that MOG Ab POS patients have a more pronounced CNS inflammatory response with elevation of predominant humoral associated cytokines/chemokines, as well as some Th 17 and neutrophil related cytokines/chemokines suggesting a differential inflammatory pathogenesis associated with MOG antibody seropositivity. This cytokine/chemokine profiling provides new insight into disease pathogenesis, and improves our ability to monitor inflammation and response to treatment. In addition, some of these molecules may represent potential immunomodulatory targets.16 page(s

Eye movement disorders are an early manifestation of CACNA1A mutations in children

Aim: The alpha-1 isoform of the calcium channel gene is expressed abundantly in neuronal tissue, especially within the cerebellum. Mutations in this gene may manifest with hemiplegic migraine, spinocerebellar ataxia type 6 (SCA6) and episodic ataxia type 2 (EA2) in adults. There are reports of children with CACAN1A mutations presenting with paroxysmal tonic upgaze, abnormal saccades and congenital nystagmus as well as severe forms of hemiplegic migraine. The aim of this study was to review the clinical presentation and subsequent course of all children with a CACNA1A mutation who presented to a tertiary children's hospital. Method: We reviewed retrospectively nine children with a proven CACNA1A mutation who presented to the Children's Hospital at Westmead between 2005-2015. The initial and subsequent clinical presentation, radiological features and molecular genetic profile of each child was reviewed. Results: Nine children presented to out institute over a 10 year period; six were female and three male. The median age of presentation was 1.2 years. Eye movement disorders were the presenting feature in eight children. Three of these children later presented with severe hemiplegic migraine episodes often requiring ICU care. Affected children also had developmental delay and developed classical hemiplegic migraine, episodic ataxia and seizures. Calcium channel blockers were used with some efficacy in preventing severe HM episodes. Interpretation: Eye movement disorders are an early manifestation of CACNA1A mutations in children. Improved recognition of the CACNA1A phenotype in childhood is important for early diagnosis, counselling and appropriate emergency management. There is some early evidence that calcium channel blockers may be an effective prophylactic agent for the severe hemiplegic migraine episodes.6 page(s

Clinical and laboratory investigations in MOG Ab POS and NEG demyelination syndromes.

<p>Clinical and laboratory investigations in MOG Ab POS and NEG demyelination syndromes.</p

CSF cytokine/ chemokine concentrations in CSF MOG Ab POS patients and CSF MOG Ab NEG patients.

<p>B cell (CXCL13, CCL19, CXCL12,) and Th17 (G-CSF, IL-17A) cytokines/chemokines were elevated in CSF MOG Ab POS patients when compared to CSF MOG Ab NEG patients (P<0.05). Dotted lines represent medians. The statistical analysis was performed using Man Whitney’s test.</p

Correlation between CSF cytokine and chemokine levels in patients with MOG Ab POS demyelination.

<p>This figure shows that the majority of B cell cyto/chemokines correlate with each other and with Th17 molecules (IL-17A, IL-6 and G-CSF) and IL-10, but do not show any association with Th1 (except TNF-α) and Th2 related cytokines/chemokines. The above heat map is graded based on Spearman rank correlation* 0.0 to 0.03, negligible correlation; 0.3 to 0.5, low positive correlation; 0.50 to 0.70, moderate correlation; 0.70 to 0.90, high correlation; 0.9 to 1, very high correlation). *The negative correlations were all moderate or weaker so have been coded the same as the “negligible” correlations.</p

CSF cytokine/ chemokine concentrations in serum MOG Ab POS, serum MOG Ab NEG demyelination groups and controls according to T and B cell subsets.

<p>Th17 (IL-6 & G-CSF), B cell related (CXCL13, CCL19, APRIL & BAFF) and other cytokines and chemokines (TNF-α, IL1ra and IL-10) were elevated in serum MOG Ab POS patients compared to serum MOG Ab NEG group (p<0.05). Dotted lines represent medians. The statistical analysis was performed using Kruskal Wallis test.</p

Antibodies to myelin oligodendrocyte glycoprotein have a demyelination phenotype in children and affect oligodendrocyte cytoskeleton

Objective: To examine the clinical features of paediatric CNS demyelination associated with positive myelin oligodendrocyte glycoprotein (MOG) antibodies, and examine the functional effects of MOG antibody on oligodendrocyte cytoskeleton. Methods: We measured MOG antibody using a flow cytometry live cell-based assay in acute sera of 73 children with CNS demyelination (DEM) (median age 8 years, range 1.3–15.3), followed for a median of 4 years. We used MO3.13 cells to examine IgG effects on oligodendrocyte cytoskeleton using 3-D deconvolution imaging. Results: MOG antibodies were found in 31/73 DEM (42%, n =73), but in 0/24 controls. At first presentation, MOG antibody-positive patients were more likely to have bilateral rather than unilateral optic neuritis (ON) (9/10 vs 1/5, respectively, p= 0.03), less likely to have brainstem findings (2/31 vs 16/42, p= 0.005), more likely to have a raised erythrocyte sedimentation rate N20 mm/h (9/19 vs 3/21, p= 0.05), less likely to have intrathecal oligoclonal band (0/16 v 5/27, p =0.18), and were less likely to be homozygous or heterozygous for HLA-DRB1*1501 (3/18 vs 7/22, p=0.46). MOG antibody positivity varied according to clinical phenotype, with ON and relapsing ON being most likely to be seropositive. Two relapsing MOG antibody-positive patients treated with mycophenolate mofetil remain in remission and have become MOG antibody seronegative. Oligodendrocytes incubated with purified IgG from MOG antibodypositive patients showed a striking loss of organization of the thin filaments and the microtubule cytoskeleton, as evidenced by F-actin and β-tubulin immunolabelings. Conclusions: MOG antibody may define a separate demyelination syndrome which has therapeutic implications. MOG antibody has functional effects on oligodendrocyte cytoskeleton.1 page(s

Antibodies to MOG have a demyelination phenotype and affect oligodendrocyte cytoskeleton

Objective: To examine the clinical features of pediatric CNS demyelination associated with positive myelin oligodendrocyte glycoprotein (MOG) antibodies and to examine the functional effects of MOG antibody on oligodendrocyte cytoskeleton. Methods: We measured MOG antibody using a fluorescence-activated cell sorting live cell-based assay in acute sera of 73 children with CNS demyelination (DEM) (median age 8 years, range 1.3-15.3) followed for a median of 4 years. We used MO3.13 cells to examine immunoglobulin (Ig) G effects on oligodendrocyte cytoskeleton using 3D deconvolution imaging. Results: MOG antibodies were found in 31/73 patients with DEM (42%) but in 0/24 controls. At first presentation, MOG antibody-positive patients were more likely to have bilateral than unilateral optic neuritis (ON) (9/10 vs 1/5, respectively, p = 0.03), less likely to have brainstem findings (2/31 vs 16/42, p = 0.005), more likely to have a raised erythrocyte sedimentation rate >20 mm/h (9/19 vs 3/21, p = 0.05), less likely to have intrathecal oligoclonal bands (0/16 vs 5/27, p = 0.18), and less likely to be homozygous or heterozygous for human leukocyte antigen DRB1*1501 (3/18 vs 7/22, p = 0.46). MOG antibody positivity varied according to clinical phenotype, with ON and relapsing ON most likely to be seropositive. Two relapsing MOG antibody-positive patients treated with mycophenolate mofetil remain in remission and have become MOG antibody seronegative. Oligodendrocytes incubated with purified IgG from MOG antibody-positive patients showed a striking loss of organization of the thin filaments and the microtubule cytoskeleton, as evidenced by F-actin and β-tubulin immunolabelings. Conclusions: MOG antibody may define a separate demyelination syndrome, which has therapeutic implications. MOG antibody has functional effects on oligodendrocyte cytoskeleton.10 page(s