700 research outputs found
Acquired Demyelinating Syndromes and Pediatric Multiple Sclerosis
__Abstract__
Acquired inflammatory demyelinating diseases of the central nervous system (CNS) cause
damage to myelin sheaths and typically result in white matter lesions due to inflammation,
myelin loss and axonal pathology. Clinically, this may result in transient, relapsing or progressive
neurological dysfunction. Multiple sclerosis (MS) is the most common disease within this
spectrum. It typically affects adults between 20 and 40 years old. MS is generally assumed to
be an autoimmune disease, of which the exact etiology remains unknown. Genetic, immunological
and environmental factors each play a role in the pathophysiology of the disease.1
Several other immune-mediated demyelinating diseases of the CNS are known. These
include Acquired Demyelinating Syndrome (ADS) of childhood, Neuromyelitis Optica
(NMO), Acute Disseminated Encephalomyelitis (ADEM), Transverse Myelitis (TM) and Optic
Neuritis (ON).2 3
All these acquired demyelinating syndromes are rare. In general, clinicians encounter
several problems when faced with rare diseases:
- diagnosis is more complex or may be delayed, because a clinician rarely encounters
these diseases and thus may be inexperienced with or unaware of them
- the disease course and future may be hard to predict because of lack of insight into
pathogenesis
- treatment is often based on expert-opinion instead of large randomized controlled trials,
making it difficult to establish the optimal treatment and timing of treatment
- research is challenged by the low number of patients.
For patients, it is more challenging to find the right information or to find fellow sufferers of
the same disease.4
This thesis focuses on pediatric ADS and MS, ADEM and NMO and describes the clinical
features of these diseases. The goal of these studies is to find disease-specific characteristics
that will improve early and accurate diagnosis
Insulin Growth Factor-I in Protein-Energy Malnutrition during Rehabilitation in Two Nutritional Rehabilitation Centres in Burkina Faso
Objective. To investigate the relationship between IGF-I and the nutritional status of West-African children hospitalised for nutritional rehabilitation.
Patients and methods. A cohort study was performed in two centres for nutritional rehabilitation and education (CREN) in Burkina Faso. Children were followed and the anthropometric data as well as the capillary blood samples were taken on the 7th and on the 14th days after their admission. IGF-I levels were determined from dried blood spots on filter paper on IGF-I RIA, after separation of the IGF-I from its binding proteins, using Sep-Pak chromatography.
Results. A total of 59 children was included in the cohort. The IGF-I mean geometric values (SD) were 6.3 (1.4)
μg/L on admission, 8.6 (1.8) μg/L at day 7 and 13.6 (2.0) μg/L at day 14. The differences between these values were statistically significant (P < .001). There is a significant correlation between the changes of IGF-I with the change of weight for height Z-score (P = .01).
Conclusion. These results suggest that IGF-I can be considered as a potential marker to follow the nutritional status of children admitted in hospital for protein and energy malnutrition
Myelin oligodendrocyte glycoprotein and aquaporin-4 antibodies are highly specific in children with acquired demyelinating syndromes
AIM: Our objectives were to evaluate the utility of measuring myelin oligodendrocyte glycoprotein (MOG) and aquaporin-4 (AQP4) antibodies (Ab) in clinical practice and describe their associated neurological phenotypes in children. METHOD: Between 2012 and 2017, 371 children with suspected acquired demyelinating syndromes (ADS) seen in three tertiary centres were tested for MOG-Ab and AQP4-Ab. Medical notes were retrospectively reviewed, and clinical and demographic data compiled. Clinical phenotyping was performed blinded to the antibody results. RESULTS: After review, 237 of the 371 were diagnosed with ADS. Of these, 76 out of 237 (32.1%) were MOG-Ab positive and 14 out of 237 (5.9%) were AQP4-Ab positive. None were positive for both autoantibodies. All 134 patients with non-ADS were negative for MOG-Ab. MOG-Ab were identified in 45 out of 70 (64.3%) patients presenting with acute disseminated encephalomyelitis (ADEM) and in 24 out of 25 patients with relapsing ADEM. Thirty-six out of 75 (48%) MOG-Ab positive patients relapsed. Of the 33 children with neuromyelitis optic spectrum disorder, 14 were AQP4-Ab positive, 13 were MOG-Ab positive, and 6 were seronegative. Of the children with longitudinal samples, 8 out of 13 AQP4-Ab remained positive during the disease course compared to 35 out of 43 MOG-Ab (13/16 monophasic and 22/27 relapsing). INTERPRETATION: Myelin oligodendrocyte glycoprotein antibodies were identified in a third of children with ADS. Almost half of the MOG-Ab positive children relapsed and the majority of them remained antibody positive over 4-years follow-up. WHAT THIS PAPER ADDS: Myelin oligodendrocyte glycoprotein antibodies (MOG-Ab) are highly specific for acquired demyelinating syndromes (ADS). Myelin oligodendrocyte glycoprotein antibodies are not identified in children with peripheral demyelination or genetic leukodystrophies/hypomyelination. Up to 48% of MOG-Ab ADS paediatric patients relapse, higher than previously thought. Seroconversion to MOG-Ab negative status is infrequent; patients may test MOG-Ab positive at follow-up sampling even when asymptomatic. Myelin oligodendrocyte glycoprotein antibodies status should only be used in conjunction with the clinical information to guide maintenance therapy
Grouping of UVCB substances with dose-response transcriptomics data from human cell-based assays
The application of in vitro biological assays as new approach methodologies (NAMs) to support grouping of UVCB (unknown or variable composition, complex reaction products, and biological materials) substances has recently been demonstrated. In addition to cell-based phenotyping as NAMs, in vitro transcriptomic profiling is used to gain deeper mechanistic understanding of biological responses to chemicals and to support grouping and read-across. However, the value of gene expression profiling for characterizing complex substances like UVCBs has not been explored. Using 141 petroleum substance extracts, we performed dose-response transcriptomic profiling in human induced pluripotent stem cell (iPSC)-derived hepatocytes, cardiomyocytes, neurons, and endothelial cells, as well as cell lines MCF7 and A375. The goal was to determine whether transcriptomic data can be used to group these UVCBs and to further characterize the molecular basis for in vitro biological responses. We found distinct transcriptional responses for petroleum substances by manufacturing class. Pathway enrichment informed interpretation of effects of substances and UVCB petroleum-class. Transcriptional activity was strongly correlated with concentration of polycyclic aromatic compounds (PAC), especially in iPSC-derived hepatocytes. Supervised analysis using transcriptomics, alone or in combination with bioactivity data collected on these same substances/cells, suggest that transcriptomics data provide useful mechanistic information, but only modest additional value for grouping. Overall, these results further demonstrate the value of NAMs for grouping of UVCBs, identify informative cell lines, and provide data that could be used for justifying selection of substances for further testing that may be required for registration
T-cell activation marker sCD27 is associated with clinically definite multiple sclerosis in childhood-acquired demyelinating syndromes
Background: Cerebrospinal fluid (CSF) levels of T-cell activation marker soluble CD27 (sCD27) are associated with subsequent disease activity after a first attack of suspected MS in adults. The predictive value for disease course in children with acquired demyelinating syndromes (ADS) is unknown. Objectives: To assess the predictive value of sCD27 levels for clinically definite multiple sclerosis (CDMS) diagnosis in childhood ADS. Methods: Children <18 years with a first demyelinating event were prospectively included and followed. Soluble CD27 was determined in CSF using an enzyme-linked immunosorbent assay (ELISA). Cox regression analyses were used to calculate hazard ratios (HRs) for CDMS. Results: A total of 94 ADS children were included (ADS with encephalopathy (ADS+) n = 33 and ADS without encephalopathy (ADS–) n = 61). Of the 61 ADS– children, 21 (48%) were diagnosed with CDMS during follow-up. At baseline, sCD27 levels were higher in patients with a future CDMS diagnosis (n = 29) than in monophasic ADS+ (n = 30), monophasic ADS– (n = 28) and relapsing non-MS patients (n = 7; p < 0.001). In ADS– patients, sCD27 was associated with CDMS (HR = 1.8 per 100 U/mL increase in sCD27 levels, p = 0.031), after adjustments for age, oligoclonal bands and the presence of dissemination in space on baseline magnetic resonance imaging (MRI). Conclusion: CSF sCD27 levels at first attack of demyelination were associated with CDMS diagnosis in children. This makes sCD27 a potential clinically relevant quantitative marker when performing routine CSF diagnostics
Pancytopenia Due to Vitamin B12 and Folic Acid Deficiency—A Case Report
peer reviewedWe report a case of severe pancytopenia in a 15-year-old patient due to a severe deficiency in vitamin B12 and folic acid, probably of nutritional origin. The clinical and biological course was favorable after vitamin supplementation. With this case, we discuss the diagnostic approach of pancytopenia with megaloblastic anemia in children and adolescents, as well as the mechanisms involved in vitamin B12 and B9 deficiency. Hypovitaminosis B12 is known in its severe form but its diagnosis is often made difficult by insidious signs and symptoms. Traditional intramuscular replacement therapy has now proven to be effective orally. The clinical manifestations of folic acid deficiency are relatively similar to those of vitamin B12 deficiency, reflecting their intricate co-enzymatic functions. Its supplementation is administered orally
'Leukodystrophy‐like' phenotype in children with myelin oligodendrocyte glycoprotein antibody‐associated disease
Aim: To review the demographics and clinical and paraclinical parameters of children with myelin oligodendrocyte glycoprotein (MOG) antibody‐associated relapsing disease. / Method: In this UK‐based, multicentre study, 31 children with MOG antibody‐associated relapsing disease were studied retrospectively. / Results: Of the 31 children studied, 14 presented with acute disseminated encephalomyelitis (ADEM); they were younger (mean 4.1y) than the remainder (mean 8.5y) who presented with optic neuritis and/or transverse myelitis (p<0.001). Similarly, children who had an abnormal brain magnetic resonance imaging (MRI) at onset (n=20) were younger than patients with normal MRI at onset (p=0.001) or at follow‐up (p<0.001). ‘Leukodystrophy‐like’ MRI patterns of confluent largely symmetrical lesions was seen during the course of the disease in 7 out of 14 children with a diagnosis of ADEM, and was only seen in children younger than 7 years of age. Their disability after a 3‐year follow‐up was mild to moderate, and most patients continued to relapse, despite disease‐modifying treatments. / Interpretation: MOG antibody should be tested in children presenting with relapsing neurological disorders associated with confluent, bilateral white matter changes, and distinct enhancement pattern. Children with MOG antibody‐associated disease present with age‐related differences in phenotypes, with a severe leukoencephalopathy phenotype in the very young and normal intracranial MRI in the older children. This finding suggests a susceptibility of the very young and myelinating brain to MOG antibody‐mediated mechanisms of damage. / What this paper adds: Myelin oligodendrocyte glycoprotein (MOG) antibody‐associated demyelination manifest with an age‐related phenotype. / Children with MOG antibody and ‘leukodystrophy‐like’ imaging patterns tend to have poor response to second‐line immunotherapy
Rare brain biopsy findings in a first ADEM-like event of pediatric MS: histopathologic, neuroradiologic and clinical features
Pediatric MS tends to present more often with an acute onset and a polysymptomatic form of the disease, possibly with encephalopathy and large tumefactive lesions similar to those observed in some cases of acute disseminated encephalomyelitis (ADEM), which makes it more difficult to differentiate between an explosive and severe onset of MS vs. ADEM. An ADEM-like first demyelinating event can be the first attack of pediatric MS, but international consensus definitions require two or more non-ADEM demyelinating events for diagnosis of MS. In our patient KIDMUS MRI criteria for MS (Mikaeloff et al. J Pediatr 144:246–252, 2004a; Mikaeloff et al. Brain 127:1942–1947, 2004b) were negative at first attack, but Barkhof criteria for lesion dissemination in space in adults (Barkhof et al. 120:2059–2069, 1997), Callen modified MS-criteria and Callen MS-ADEM criteria for children (Callen et al. Neurology 72:961–967, 2009a; Callen et al. Neurology 72:968–973, 2009b) were positive suggesting pediatric MS. As the clinical course was devastating with non-responsiveness upon high-dose immune modulatory therapy and due to the absence of an alternative diagnosis other than demyelinating disease brain biopsy was performed. Brain biopsy studies or autopsy case reports of fulminant pediatric MS patients are extremely rare. Histopathology revealed an inflammatory demyelinating CNS process with confluent demyelination, indicating the likelihood of a relapsing disease course compatible with an acute to subacute demyelinating inflammatory disease. This pattern was corresponding to the early active multiple sclerosis subtype I of Lucchinetti et al. (Ann Neurol 47(6):707–717, 2000)
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