Prognostic indicators in pediatric clinically isolated syndrome

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Patients with pediatric onset (before the age of 18 years) multiple sclerosis (POMS) represent 3 to 10% of the total multiple sclerosis (MS) population.1 An onset before age 10 is even less frequent, accounting probably for <1% of total MS cases.9 The estimated annual incidence of POMS ranges between 0.13 and 0.6 in 100,000 in different countries.10 POMS usually starts with the occurrence of a first attack of demyelination, termed pediatric clinically isolated syndrome (pCIS),19 characterized by a monofocal or multifocal clinical central nervous system event of presumed inflammatory demyelinating cause with acute or subacute onset in the absence of encephalopathy, not explained by fever or systemic illness and that does not meet the 2010 McDonald MS criteria on baseline magnetic resonance imaging (MRI).20 The majority of children with pCIS experience a second clinical attack and consequently convert to clinically definite MS (CDMS) within a variable time ranging between 11 and 71.3 months.6
POMS subjects tend to have higher relapse rate,24 higher MRI lesion accrual,26 and more prominent cognitive deficits27 early in their disease course than adult onset MS (AOMS).
Although time to conversion to a secondary progressive (SP) course is longer in POMS than in AOMS, SP patients' median age is lower in POMS in comparison to AOMS, suggesting that POMS is not a more benign disease7 in comparison to AOMS. Recent MRI data have demonstrated that POMS patients have a smaller overall brain volume than would be expected for age,28 suggesting that demyelinating lesions may impact brain growth and development. For this reason, although the currently available disease‐modifying drugs (DMDs) are not licensed for POMS, their off‐label prescription is increasing in this subpopulation.29
Prognostic demographic, topographic, clinical (age, sex, symptoms at first presentation, relapses after the first attack), MRI (number of brain T2 lesions), and laboratory (cerebrospinal fluid–restricted IgG oligoclonal bands [CSF OB]) factors predicting conversion to CDMS or the risk of disability accumulation over time have been extensively studied in adult CIS.9
As POMS is a rare disease, very few studies on small populations tried to determine which patients with pCIS are at highest risk for CDMS and disability worsening. Predictors for an increased risk of time to second attack in the KIDMUS study,8 the largest prospective series of pCIS to date, included demographic (age > 10 years) and topographic (optic neuritis [ON]) characteristics, and MRI features (multiple well‐defined periventricular or subcortical lesions suggestive of MS) at onset. Myelitis or altered mental status impairment at onset were associated with a decreased risk of conversion to CDMS.8 Abnormal cranial MRI, presence of CSF OB, and age were confirmed as independent predictors of conversion to CDMS in a series of children with isolated ON.48
Occurrence of severe disability and SP course in pCIS8 were more frequently found in children with disability sequelae after the first attack, a short interval between the first 2 demyelinating episodes, a large number of relapses, and progressive onset. However, there was no consistent correlation between gender, age at onset, or a polysymptomatic versus monosymptomatic onset in disease course prognosis,6 so that it is still challenging to identify children who could benefit from very early initiation of a DMD treatment.
Although several randomized clinical trials (RCTs)51 and their extension phases57 demonstrated that early treatment with DMDs can delay conversion to CDMS and accumulation of medium to long‐term disability in adult onset CIS patients, comparable evidence is currently lacking in pCIS.
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