Is a preserved functional reserve a mechanism limiting clinical impairment in pediatric MS patients?

Rocca, Maria A.; Absinta, Martina; Ghezzi, Angelo; Moiola, Lucia; Comı, Gıancarlo; Filippi, Massimo

doi:10.1002/hbm.20712

Cited by 64 publications

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“…1,3 Recent volumetric MRI data have demonstrated that pediatric patients with MS have a smaller overall brain volume than would be expected for age, 13 in spite of the purported higher capability to compensate for brain damage, 14 suggesting that demyelinating lesions can also affect overall brain growth and development. It is also important to note that cognitive dysfunction occurs in about 1/3 of children and adolescents with MS.…”

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Pediatric multiple sclerosis

et al. 2016

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Many disease-modifying therapies are currently available for adults with relapsing-remitting multiple sclerosis (MS) but none of them has been tested in pediatric MS in randomized placebo-controlled trials. At present, as suggested by observational studies and experts' guidelines, interferon-b and glatiramer acetate continue to be the standard first-line treatments for pediatric MS. Observational studies and some controlled unblinded trials have shown a positive effect of these meditations in reducing relapse rate and delaying disease progression, with an acceptable safety profile. The goal of this article is to provide an overview of current knowledge with regard to safety, tolerability, and efficacy of first-line treatment options for MS in the pediatric age group, with the aim of providing guidance for planning first-line treatment of MS in children and adolescents. Neurology ® 2016;87 (Suppl 2):S97-S102 GLOSSARY DMT 5 disease-modifying therapies; GA 5 glatiramer acetate; IFN-b 5 interferon-b; MS 5 multiple sclerosis; NAb 5 neutralizing antibodies; RRMS 5 relapsing-remitting multiple sclerosis.Many disease-modifying therapies (DMT) are currently available for adults with relapsing-remitting multiple sclerosis (RRMS), including interferon-b (IFN-b) 1a/1b, glatiramer acetate (GA), teriflunomide, dimethyl fumarate, natalizumab, fingolimod, and alemtuzumab. Their effectiveness has been demonstrated by phase 3 studies and by observational postmarketing studies for some. [1][2][3][4][5] IFN-b, GA, and teriflunomide have also been tested in patients with clinically isolated syndrome (CIS), and have been found to reduce the risk of a subsequent attack. [6][7][8][9][10] Results are disappointing in the treatment of secondary progressive multiple sclerosis (MS) as only IFN-b was shown to reduce the progression if administered to patients with a residual inflammatory component. 11,12 No medication currently approved for adults with RRMS has completed testing for pediatric MS in randomized placebo-controlled trials, although several pediatric MS trials have recently been launched. Use of DMT in pediatric MS remains off-label in many countries, especially in patients younger than 12 years; nevertheless, these medications are widely used.The high frequency of relapses in pediatric MS, especially in the first years, with a relapse rate higher than that of adults, and the pattern of MRI lesions, with more pronounced inflammatory aspects, support the use of DMT in the pediatric population as they mainly target the inflammatory component. 1,3 Recent volumetric MRI data have demonstrated that pediatric patients with MS have a smaller overall brain volume than would be expected for age, 13 in spite of the purported higher capability to compensate for brain damage, 14 suggesting that demyelinating lesions can also affect overall brain growth and development. It is also important to note that cognitive dysfunction occurs in about 1/3 of children and adolescents with MS. These findings additionally support the view that ped...

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Pediatric multiple sclerosis

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“…25 Using resting-state fMRI, Rocca et al 26 showed that patients with POMS as compared with controls demonstrated decreased functional connectivity (FC), mainly in posterior brain regions, suggesting an impaired maturation of large-scale brain connectivity. In addition, increased FC of the medial frontal gyrus (implicating the attention network) was also observed.…”

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confidence: 99%

Pediatric multiple sclerosis

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In comparison with the large body of evidence on cognitive functioning in adults with multiple sclerosis (MS), there is limited information on cognition in pediatric-onset MS (POMS). Unique vulnerabilities in POMS can derive from having a disease that occurs during key periods of ageexpected brain growth, active myelination in the CNS, and maturation of neural networks during the learning curve and key formative years in the academic career of the patient. Therefore, the consequences of MS on developing cognitive faculties can be assessed only in the pediatric population and cannot be simply extrapolated from studies carried on in the adult population. Until the last decade, research in the pediatric population was mainly represented by small clinical series, often limited by the narrow scope of neuropsychological assessment and lack of adequate control groups. Over the last decade, however, cognitive functioning and mood-related difficulties have become an increasing concern as awareness of this population has grown. A few specialized MS centers have begun performing more systematic research in the field in order to assess the prevalence of cognitive impairments and mood-related difficulties in patients with POMS, to better characterize the neuropsychological pattern and determine the functional consequences of these problems. This chapter summarizes our current understanding of cognitive and moodrelated difficulties in POMS and highlights perceived gaps in knowledge and priorities for future research. Neurology ® 2016;87 (Suppl 2):S82-S87 GLOSSARY BNBC 5 Brief Neuropsychological Battery for Children; CIS 5 clinically isolated syndrome; CL 5 cortical lesions; EDSS 5 Expanded Disability Status Scale; FC 5 functional connectivity; fMRI 5 functional MRI; GM 5 gray matter; MS 5 multiple sclerosis; POMS 5 pediatric-onset multiple sclerosis; SDMT 5 Symbol Digit Modalities Test; WM 5 white matter.Patients with pediatric-onset multiple sclerosis (POMS) may be particularly vulnerable to inflammation, demyelination, and axonal damage associated with multiple sclerosis (MS). 1The concurrence of these changes with myelination in the developing CNS that can go on through the third decade of life can damage networks involved in cognition.2 Research suggests loss of myelin in POMS can adversely affect cognition and academic skills.2,3 Whether brain plasticity and compensatory abilities can mitigate against disease-related pathologic changes remains unclear: answers will ultimately emerge through careful long-term studies of cognitive outcomes in POMS.PREVALENCE, NEUROPSYCHOLOGICAL PROFILE, AND CLINICAL CORRELATES Across differing test batteries and definitions of cognitive impairment, cognitive impairment is consistently reported in approximately one-third of patients with POMS (table 1). In interpreting different thresholds used to classify cognitive impairment, it is useful to note that the 5th percentile equates to 1.67 SD.In a US study of 37 POMS cases, 4 35.1% of the patients showed cognitive impairment, defined ...

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“…Nevertheless, in spite of this severity, the brain of pediatric patients exibits an high capability to compensate the damage: this finding is supported by the possibility to partially reduce the extent of CD in the long-term, and by studies with functional and nonconventional MRI demonstrating an higher plasticity of the brain. It has been demonstrated that the activation of brain areas after a simple movement of the hand, that is progressively more widespread with progression of MS, is more restricted in pediatric compared to adult MS [59], indicating a relatively preserved functional organization of the brain; moreover the pattern of connectivity among brain areas is more efficient in children, compared to adults (see also Differential diagnosis: can clinical manifestations and ancillary investigations make the difference? section).…”

Section: Clinical Aspects: How Similar To Adult Ms?mentioning

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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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Is a preserved functional reserve a mechanism limiting clinical impairment in pediatric MS patients?

Cited by 64 publications

References 35 publications

Pediatric multiple sclerosis

Pediatric multiple sclerosis

Pediatric multiple sclerosis

Pediatric versus adult MS: similar or different?

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