Early Immunotherapy and Longer Corticosteroid Treatment Are Associated With Lower Risk of Relapsing Disease Course in Pediatric MOGAD.

BACKGROUND AND OBJECTIVES: We sought to identify early factors associated with relapse and outcome in paediatric-onset myelin oligodendrocyte glycoprotein antibody-associated disorders (MOGAD). METHODS: In a multicenter retrospective cohort of pediatric MOGAD (≤18 years), onset features and treatment were compared in patients with monophasic vs relapsing disease (including cases with follow-up ≥12 months after onset or relapse at any time) and in patients with final Expanded Disability Status Scale (EDSS) 0 vs ≥1 at last follow-up (including cases with follow-up >3 months after last event or EDSS0 at any time). Multivariable logistic regression models were used to evaluate factors associated with relapsing disease course and EDSS ≥ 1 at final follow-up. RESULTS: Seventy-five children were included (median onset age 7 years; median 30 months of follow-up). Presentation with acute disseminated encephalomyelitis was more frequent in children aged 8 years or younger (66.7%, 28/42) than in older patients (30.3%, 10/33) (p = 0.002), whereas presentation with optic neuritis was more common in children older than 8 years (57.6%, 19/33) than in younger patients (21.4%, 9/42) (p = 0.001). 40.0% (26/65) of patients relapsed. Time to first relapse was longer in children aged 8 years or younger than in older patients (median 18 vs 4 months) (p = 0.013). Factors at first event independently associated with lower risk of relapsing disease course were immunotherapy <7 days from onset (6.7-fold reduced odds of relapsing course, OR 0.15, 95% CI 0.03-0.61, p = 0.009), corticosteroid treatment for ≥5 weeks (6.7-fold reduced odds of relapse, OR 0.15, 95% CI 0.03-0.80, p = 0.026), and abnormal optic nerves on onset MRI (12.5-fold reduced odds of relapse, OR 0.08, 95% CI 0.01-0.50, p = 0.007). 21.1% (15/71) had EDSS ≥ 1 at final follow-up. Patients with a relapsing course had a higher proportion of final EDSS ≥ 1 (37.5%, 9/24) than children with monophasic disease (12.8%, 5/39) (p = 0.022, univariate analysis). Each 1-point increment in worst EDSS at onset was independently associated with 6.7-fold increased odds of final EDSS ≥ 1 (OR 6.65, 95% CI 1.33-33.26, p = 0.021). DISCUSSION: At first attack of pediatric MOGAD, early immunotherapy, longer duration of corticosteroid treatment, and abnormal optic nerves on MRI seem associated with lower risk of relapse, whereas higher disease severity is associated with greater risk of final disability (EDSS ≥ 1).

Prognostic relevance of quantitative and longitudinal MOG antibody testing in patients with MOGAD: a multicentre retrospective study.

BACKGROUND: IgG antibodies against myelin oligodendrocyte glycoprotein (MOG-IgG) define a subset of associated disorders (myelin oligodendrocyte glycoprotein associated disorders (MOGAD)) that can have a relapsing course. However, information on relapse predictors is scarce. The utility of retesting MOG-IgG over time and measuring their titres is uncertain. We aimed to evaluate the clinical relevance of longitudinal MOG-IgG titre measurement to predict relapses in patients with MOGAD. METHODS: In this retrospective multicentre Italian cohort study, we recruited patients with MOGAD and available longitudinal samples (at least one >3 months after disease onset) and tested them with a live cell-based assay with endpoint titration (1:160 cut-off). Samples were classified as 'attack' (within 30 days since a disease attack (n=59, 17%)) and 'remission' (≥31 days after attack (n=295, 83%)). RESULTS: We included 102 patients with MOGAD (57% adult and 43% paediatric) with a total of 354 samples (83% from remission and 17% from attack). Median titres were higher during attacks (1:1280 vs 1:640, p=0.001). Median onset titres did not correlate with attack-related disability, age or relapses. Remission titres were higher in relapsing patients (p=0.02). When considering the first remission sample available for each patient, titres >1:2560 were predictors of relapsing course in survival (log rank, p<0.001) and multivariate analysis (p<0.001, HR: 10.9, 95% CI 3.4 to 35.2). MOG-IgG seroconversion to negative was associated with a 95% relapse incidence rate reduction (incidence rate ratio: 0.05, p<0.001). CONCLUSIONS: Persistent MOG-IgG positivity and high remission titres are associated with an increased relapse risk. Longitudinal MOG-IgG titres could be useful to stratify patients to be treated with long term immunosuppression.

Atypical Clinical and Neuroradiological Findings in a Child With Bifacial Weakness With Paresthesias.

BACKGROUND: Guillain-Barré syndrome (GBS) is the broad term used to describe a number of related acute autoimmune neuropathies, which together form a continuous spectrum of variable and overlapping syndromes. Bifacial weakness with paresthesias (BFP) is a rare variant of GBS, characterized by isolated facial diplegia in the absence of ophthalmoplegia, ataxia, or limb weakness, and it is usually associated with distal limb paresthesias. CASE DESCRIPTION: An 8-year-old boy was brought to our attention; because 5 days before coming to the hospital, he noticed he could no longer smile. Bilateral facial droop and inability to close both eyes were evident along with slight paresthesias at the hands and feet and gait disturbances. He progressively developed hypophonia, dysarthria, dysphagia associated with dysmetria, and limb ataxia. Nerve conduction studies showed a demyelinating polyneuropathy. Brain and spine magnetic resonance imaging (MRI) revealed contrast enhancement of both facial nerves and cauda equina nerve roots along with a hyperintense signal of the periaqueductal gray matter, superior cerebellar peduncles, and pontine tegmentum. Because BFP is not typically associated with other cranial neuropathies or ataxia, these clinical features along with peculiar MRI findings supported the diagnosis of "BFP plus." Finally, it can be speculated that this case configures a rare overlap between BFP and the other GBS variants, such as Bickerstaff encephalitis. CONCLUSIONS: This atypical case underlines the potential role of MRI in contributing to refining the nosological classification of GBS spectrum and optimizing individual treatment, especially in children where unusual manifestations are not infrequent and neurological examination is more challenging.

Acute disseminated encephalomyelitis in a patient with Noonan syndrome: A rare autoinflammatory complication or coincidence?

We describe a 13-years-old girl, previously diagnosed with PTPN11-associated Noonan Syndrome (NS), who presented to the pediatric emergency department for fever and drowsiness, which gradually worsened within 48 h. On admission, brain magnetic resonance imaging (MRI) scan showed diffuse, symmetric, multiple, poorly demarcated, confluent hyperintense lesions on MRI T2w-images, located in the Central Nervous System (CNS). In the absence of a better explanation and according to the current diagnostic criteria, a diagnosis of Acute Disseminated Encephalomyelitis (ADEM) was performed. The patient was first treated with intravenous methylprednisolone, then with intravenous immunoglobulin (IVIG). Owing to the poor clinical response, three sessions of therapeutic plasma exchange (TPE) were finally performed, with a progressive improvement. Follow-up MRI performed after three months from the onset revealed a considerable reduction in brain lesions, while cervical and dorsal ones were substantially unmodified. Neurological examination showed a full recovery of cognitive function and improved strength and tone of the upper limbs, while tetrahyporeflexia and proximal weakness of lower limbs were still appreciable. To date, this is the first described case of ADEM occurring in a patient with NS.

Gait abnormalities in minimally disabled people with Multiple Sclerosis: A 3D-motion analysis study.

BACKGROUND: People with Relapsing-Remitting Multiple Sclerosis (pwRR-MS), may be affected by subclinical gait impairment. The Expanded Disability Status Scale, the most used scale to assess MS related disability, may be insensitive to subclinical gait disability. Minor gait abnormalities may be detected by three Dimensional-Gait Analysis (3D-GA). OBJECTIVES: To investigate gait pattern in minimally disabled pwRR-MS by 3D-GA during walking (single task, SinT), and cognitive dual tasks (CogDT) and to evaluate correlations between altered gait parameters, cognitive scores, lesion load (LL) and brain atrophy measures. METHODS: Twenty-two pwRR-MS and twenty-one healthy controls (HCs), underwent neuropsychological (NP) evaluation, and brain MRI to assess brain volumes and lesion load (only in pwRR-MS) and 3D-GA. RESULTS: Both pwRR-MS and HCs were considered cognitively preserved (CP). During SinT pwRR-MS, compared to HCs, showed an impairment of velocity (increase of cycle time), stability (increase of stance time, swing time and coefficients of variability (CV) of swing time) and kinematic (increase of ankle dorsiflexion) parameters. During CogDT, the changes of velocity and stability parameters observed in SinT were confirmed. Moreover, a statistically significant increase of the double limb support was observed. Regarding the kinematic parameters, during CogDT, an increase of ankle dorsiflexion during mid and terminal stance phases of gait cycle was observed. No significant correlations were found between gait abnormalities and cognitive status or MRI structural damage in both groups. CONCLUSIONS: The subclinical abnormal gait in asymptomatic and CP pwRR-MS, may be detected by 3D-GA.

Cognitive performance in multiple sclerosis: the contribution of intellectual enrichment and brain MRI measures.

Cognitive reserve (CR) is a construct that originates from the observation of poor correspondence between brain damage and clinical symptoms. The aim of the study was to investigate the association between cognitive reserve (CR), brain reserve (BR) and cognitive functions and to evaluate whether CR might attenuate/moderate the negative impact of brain atrophy and lesion load on cognitive functions in multiple sclerosis (MS). To achieve these aims, ninety-eight relapsing-remitting MS patients underwent the brief repeatable battery of neuropsychological tests and Stroop test (ST). CR was assessed by vocabulary-based estimate of lifetime intellectual enrichment. All patients underwent a 3T MRI to assess T2-lesion load and atrophy measures, including normalized gray matter and white matter (nWMV) volumes. The BR was evaluated by maximal lifetime brain volume expressed by intracranial volume (ICV). Hierarchical regressions were used to investigate whether higher BR and/or CR is related to better cognitive performances after controlling for potentially confounding factors. The ICV was not associated with any cognitive tests. Intellectual enrichment was positively associated with performance on tests assessing memory, attention and information processing speed, verbal fluency and inhibitory control. Significant relationship between nWMV and ST was moderated by intellectual enrichment. In conclusion, the findings suggested that CR seems to mitigate cognitive dysfunction in MS patients and can reduce the negative impact of brain atrophy on inhibitory control, relevant for integrity of instrumental activities of daily living.

A simple measure of cognitive reserve is relevant for cognitive performance in MS patients.

Cognitive reserve (CR) contributes to preserve cognition despite brain damage. This theory has been applied to multiple sclerosis (MS) to explain the partial relationship between cognition and MRI markers of brain pathology. Our aim was to determine the relationship between two measures of CR and cognition in MS. One hundred and forty-seven MS patients were enrolled. Cognition was assessed using the Rao's Brief Repeatable Battery and the Stroop Test. CR was measured as the vocabulary subtest of the WAIS-R score (VOC) and the number of years of formal education (EDU). Regression analysis included raw score data on each neuropsychological (NP) test as dependent variables and demographic/clinical parameters, VOC, and EDU as independent predictors. A binary logistic regression analysis including clinical/CR parameters as covariates and absence/presence of cognitive deficits as dependent variables was performed too. VOC, but not EDU, was strongly correlated with performances at all ten NP tests. EDU was correlated with executive performances. The binary logistic regression showed that only the Expanded Disability Status Scale (EDSS) and VOC were independently correlated with the presence/absence of CD. The lower the VOC and/or the higher the EDSS, the higher the frequency of CD. In conclusion, our study supports the relevance of CR in subtending cognitive performances and the presence of CD in MS patients.

Longitudinal assessment of immuno-metabolic parameters in multiple sclerosis patients during treatment with glatiramer acetate.

OBJECTIVE: We investigated the effect of glatiramer acetate (GA) on the modulation of immune cell subpopulations and serum levels of multiple immune/metabolic markers in patients with relapsing-remitting multiple sclerosis (RRMS) to understand whether the treatment with GA could induce a specific change in the immunometabolic asset of patients with RRMS. MATERIAL AND METHODS: We performed an extensive peripheral blood immunophenotyping and measured serum levels of several parameters involved in the pathogenesis of RRMS and also relevant in the pathogenesis of metabolic syndrome and obesity such as leptin, soluble leptin-receptor (sLep-R), myeloperoxidase (MPO), soluble CD40 ligand (sCD40-L), soluble tumor necrosis factor-receptor (sTNF-R), monocyte chemoattractant protein 1 (MCP-1), soluble Inter-Cellular Adhesion Molecule-1 (sICAM-1) and osteoprotegerin (OPG), in 20 naïve-to-treatment RRMS patients and 20 healthy controls. We repeated these analyses over time at 6 and 12 months after starting GA treatment. RESULTS: Our analysis showed that naïve-to-treatment RRMS patients had a lower number of CD16(+)CD56(+) NK cells, CD19(+) B cells, CD4(+) T cells co-expressing the MHC class II activation marker HLA-DR (CD4(+)DR(+)) and naïve CD4(+)CD45RA(+) T cells in basal conditions. GA treatment induced a specific and significant decrease of circulating CD19(+) B cells. Naïve-to-treatment RRMS patients also showed a significantly higher number of CD4(+) T cells with a memory phenotype (CD4(+)CD45RO(+)) whose peripheral frequency was not affected by GA treatment. These changes over time associated with a higher serum concentration of leptin and lower levels of MPO. GA treatment also reduced significantly the circulating levels of sCD40-L and sTNF-R overtime. CONCLUSIONS: Our data suggest that the clinical outcome of GA treatment is associated with changes in immune cell subpopulations and modulation of specific immunometabolic markers. These data add substantial evidence of the immune modulating effect of GA during RRMS and could be of relevance in understanding the pathogenesis of disease and its follow-up.

Visual resting-state network in relapsing-remitting MS with and without previous optic neuritis.

OBJECTIVE: To investigate functional connectivity of the visual resting-state network (V-RSN) in normal-sighted relapsing-remitting multiple sclerosis (RRMS) patients with and without previous optic neuritis (ON). METHODS: Thirty normal-sighted RRMS patients, 16 without (nON-MS) and 14 with (ON-MS) previous ON, and 15 age- and sex-matched healthy controls (HCs) underwent a neuro-ophthalmologic evaluation, including automated perimetry and retinal nerve fiber layer (RNFL) measurement, as well as an MRI protocol, including structural and resting-state fMRI (RS-fMRI) sequences. Functional connectivity of the V-RSN was evaluated by independent component analysis (ICA). Regional gray matter atrophy was assessed by voxel-based morphometry (VBM). A correlation analysis was performed between RS-fMRI results and clinical, neuro-ophthalmologic, and structural MRI variables. RESULTS: Compared to HCs, patients with RRMS showed a reduced functional connectivity in the peristriate visual cortex, bilaterally. Compared to nON-MS, ON-MS patients revealed a region of stronger functional connectivity in the extrastriate cortex, at the level of right lateral middle occipital gyrus, as well as a region of reduced functional connectivity at the level of right inferior peristriate cortex. These latter changes correlated with the number of previous ON. All detected V-RSN changes did not colocalize with regional gray matter atrophy. CONCLUSIONS: Normal-sighted RRMS patients show a significant functional disconnection in the V-RSN. RRMS patients recovered from a previous ON show a complex reorganization of the V-RSN, including an increased functional connectivity at the level of extrastriate visual areas.

Infratentorial progressive multifocal leukoencephalopathy in a patient treated with fludarabine and rituximab.

Progressive multifocal leukoencephalopathy (PML) is a rare demyelinating disease of the central nervous system caused by the JC papovavirus, and is a well known complication in patients with lymphoproliferative diseases (LPDs) during chemotherapy. We report the case of a 59-year-old woman affected by B-cell LPD who underwent three cycles of chemotherapy with fludarabine and rituximab and developed atypical PML six months after the last cycle of chemotherapy. Our patient showed the following peculiarities: chemotherapy regimen was neither heavy nor prolonged; the onset of neurological symptoms was unexpectedly late; the MRI lesion was atypical for non-HIV-related PML, being monofocal and infratentorial with early gadolinium (Gd) enhancement and mass effect; survival was rather prolonged despite the lack of treatment. These data suggest that in patients with LPDs, the occurrence of progressive neurological deficits should induce the suspicion of PML even when clinical onset is late (with respect to chemotherapy) and in the presence of a single infratentorial lesion, with Gd enhancement and mass effect.