Epitope spreading as an early pathogenic event in pediatric multiple sclerosis

Quintana, Francisco J.; Patel, Bonny; Yeste, Ada; Nyirenda, Mukanthu; Kenison, Jessica E.; Rahbari, Roya; Fetco, Dumitru; Hussain, Mohammad Asif; O’Mahony, Julia; Magalhaes, Sandra; McGowan, Melissa; Johnson, Trina; Rajasekharan, Sathyanath; Narayanan, Sridar; Arnold, Douglas L.; Weiner, Howard L.; Banwell, Brenda; Bar‐Or, Amit

doi:10.1212/wnl.0000000000001066

Cited by 63 publications

(38 citation statements)

References 28 publications

(41 reference statements)

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“…There is a possibility that the humoral response might be caused secondary to CNS damage during the course of relapsing–remitting MS. This is supported by a report that children with relapsing MS more often show autoantibodies against a broader range of CNS antigens compared with children with monophasic demyelinating disorders . In the present case and the case described by Kasaaslan et al ,.…”

Section: Discussionsupporting

confidence: 89%

Diffuse lesions in the limbic system with short‐term memory loss in a patient with multiple sclerosis

Takai

Warabi

Norioka

et al. 2018

Clinical & Exp Neuroim

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Background The role of B cells in the pathogenesis of multiple sclerosis (MS) is a subject of much research. We report a case of a MS patient who presented with subacute diffuse lesions in the limbic system and short‐term memory loss. Case presentation A male patient had experienced numbness in the left upper extremity at the age of 17 years, but this disappeared without treatment. At 19 years‐of‐age, he developed subacute short‐term memory loss followed by paralysis and sensory disturbance in the left upper and lower extremities. Magnetic resonance brain fluid‐attenuated/T2‐weighted imaging showed diffuse high‐intensity lesions in the medial parts of both temporal lobes, and spotty multiple lesions in the periventricular and subcortical white matter. Twenty days later, a new lesion was observed around the right putamen, and the temporal lesions had disappeared. A symptomatic cervical lesion with gadolinium enhancement was observed at C3. This lesion involved just one vertebral segment. Cerebrospinal fluid analysis showed no pleocytosis or elevated protein levels, but did show oligoclonal immunoglobulin G bands. No antibodies against aquaporin‐4 or myelin oligodendrocyte glycoprotein were detected in the serum, and anti‐N‐methyl‐D‐aspartate receptor was not detected in the cerebrospinal fluid. We diagnosed the patient with MS despite the atypical diffuse lesions in the limbic system and the short‐term memory loss. Corticosteroid medication effectively treated the symptoms in his extremities and his impaired memory. Conclusions The present case shows that cortical lesions can occur in MS patients and might be induced by B cell‐mediated mechanisms.

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Section: Discussionsupporting

confidence: 89%

Diffuse lesions in the limbic system with short‐term memory loss in a patient with multiple sclerosis

Takai

Warabi

Norioka

et al. 2018

Clinical & Exp Neuroim

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“…Many alterations of the immune response have been documented in ped-MS, with findings not so far different from those observed in adult MS in spite of the more immature immune system [2,[118][119][120].…”

Section: Mri: a True Distinctive Pattern In Ped-ms?mentioning

confidence: 97%

Pediatric versus adult MS: similar or different?

Ghezzi

Baroncini

Zaffaroni

et al. 2017

Mult Scler Demyelinating Disord

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In this review the most important aspects of pediatric multiple sclerosis are presented and compared with the adult form. Some findings appear peculiar of pediatric MS: a. Clinical manifestations are similar in adolescents and adults with MS, however in very young subjects MS frequency at onset is similar in males and females, with a higher frequency of brainstem/cerebellar involvement and acute polysymptomatic/ADEM like onset; b. The course is relapsing-remitting in the large majority of patients, with a high relapse rate; c. Mild or severe disability is reached after a longer interval, but at a lower age compared to adult MS; d. The frequency of cognitive dysfunction is relatively high, with a quick deterioration but also the capability to partially recover with time; e. MRI is fundamental for diagnosis and prognosis: the pattern of MRI has some peculiar aspects in pediatric MS patients: i) the classic diagnostic criteria cannot be fulfilled, ii) lesion load is more relevant, iii) lesions are less destructive, have a more pronounced inflammatory pattern and have enhanced capability to recover with time; f. Diagnostic criteria of adults can be applied to patients with less than 18 years, but with limitations for subjects with less than 12 years and ADEM-like onset; g. The approach in differential diagnosis is particular complex and many disorders with clinical manifestations in the pediatric age must be considered: in this context it is important to pay attention to clinical, MRI and CSF red flags. Anti-MOG abs syndrome has been recently identified and should be carefully considered in patients with Acquired Demyelinating Syndrome; h. CSF oligoclonal bands are less frequent in pediatric MS patients, their presence in patients with Acquired Demyelinating Syndrome is strongly correlated to the risk of MS; i. The interplay between genetic and environmental factors determine the risk of developing MS; j. MS has a more pronounced inflammatory pattern (as suggested by the high relapse rate and the most relevant inflammatory pattern at brain MRI); k. The treatment is based on the approach used for adults: as MS has a strong impact on patients and their family the model of care should involve a team with specialized neurologists, pediatricians and neuro-pediatricians, nurses, psychologists, social workers and specialists of rehabilitative medicine.

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“…50 Another study applied an antigen array to samples obtained from children at time of presentation with incident episodes of CNS inflammatory demyelination as well as 3 months later. 51 Children were subsequently diagnosed with either MS or monophasic disease. Although some differences were again noted in serum antibody patterns between children with MS and controls, of particular note was the observation that the range of CNS-directed antibodies detected in the children with MS increased substantially between the 2 time points, whereas the range decreased in children with monophasic disease.…”

Section: Cns-directed Antibodies In Pediatricmentioning

confidence: 99%

Immunopathophysiology of pediatric CNS inflammatory demyelinating diseases

et al. 2016

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Elucidating pathophysiologic mechanisms underlying the spectrum of pediatric-onset CNS demyelinating diseases, particularly those that may distinguish multiple sclerosis (MS) from other entities, promises to both improve diagnostics and guide more-informed therapeutic decisions. Observations that pediatric-and adult-onset MS share the same genetic and environmental risk factors support the view that these conditions represent essentially the same illness manifesting at different ages. Nonetheless, special consideration must be given when CNS inflammation manifests in early life, at a time when multiple organs (including immune and nervous systems) are actively maturing. CSF analysis in pediatric-onset MS points to chronic CNS inflammation, supported by observations from limited pathologic material available for study. Emerging results implicate abnormalities in both effector and regulatory T cell subsets, and potentially immune senescence, in children with MS. Although CNS-directed antibodies (including antibodies recognizing myelin antigens; Kir4.1) can be documented in pediatric-onset MS, their pathophysiologic significance (as in adults) remains unclear. This is in contrast to the presence of serum and/or CSF antibodies recognizing aquaporin-4, which, when measured using validated cell-based assays, supports the diagnosis of a neuromyelitis optica spectrum disorder, distinct from MS. Presence of anti-myelin oligodendrocyte glycoprotein antibodies documented with similar cell-based assays may also be associated with pathophysiologically distinct disease phenotypes in children. The substantial impact of pediatriconset MS on normal brain development and function underscores the importance of elucidating both the immunobiology and neurobiology of disease. Ongoing efforts are aimed at developing and validating biological measures that define pathophysiologically distinct monophasic and chronic forms of pediatric CNS demyelination. Neurology ® 2016;87 (Suppl 2):S12-S19 GLOSSARY ADEM 5 acute disseminated encephalomyelitis; AQP4 5 aquaporin-4; BBB 5 blood-brain barrier; CBA 5 cell-based assay; EDSS 5 Expanded Disability Status Scale; MBP 5 myelin basic protein; MOG 5 myelin oligodendrocyte glycoprotein; MS 5 multiple sclerosis; NMO 5 neuromyelitis optica; NMOSD 5 NMO spectrum disorder; OCB 5 oligoclonal band; ON 5 optic neuritis; OPC 5 oligodendrocyte precursor cell; TM 5 transverse myelitis.There is presently limited insight into the pathophysiologic mechanisms underlying childhoodonset inflammatory demyelinating diseases. Because these disorders occur in the context of the developing immune and nervous systems, understanding the implications to both disease mechanisms and efficacy and safety profiles of potential therapeutics will help guide optimal management approaches for these children and adolescents. Elucidating the biology of pediatric-onset multiple sclerosis (MS) may provide key insights into earliest targets and processes involved in disease pathogenesis as well as into the broader spectrum of CNS...

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Epitope spreading as an early pathogenic event in pediatric multiple sclerosis

Cited by 63 publications

References 28 publications

Diffuse lesions in the limbic system with short‐term memory loss in a patient with multiple sclerosis

Diffuse lesions in the limbic system with short‐term memory loss in a patient with multiple sclerosis

Pediatric versus adult MS: similar or different?

Immunopathophysiology of pediatric CNS inflammatory demyelinating diseases

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