Abstract
Objective: To identify clinical, radiologic, or CSF factors that predict conversion to multiple sclerosis (MS) after a first attack of inflammatory demyelination in children.
Methods: In this nationwide retrospective multicenter study in the Netherlands, 117 children below age 16 were included. Fifty-four children presented with a monofocal clinically isolated syndrome (CIS) and 63 children with a polyfocal CIS (PCIS).
Results: A second MS-defining attack occurred in 43% of the CIS cases, compared to 21% of the patients with PCIS onset (p < 0.006). Basal ganglia and thalamic lesions and lesions larger than 2 cm on MRI (considered typical of ADEM) were observed during PCIS, irrespective of the presence of encephalopathy. No significant difference in developing MS was found in children with PCIS with or without encephalopathy. Elevated IgG index and presence of oligoclonal CSF bands were more often observed in children who developed MS. Both Barkhof and KIDMUS MRI criteria shared a high specificity and had a high positive predictive value for conversion to MS. In children under the age of 10, the Barkhof criteria had a higher sensitivity than the KIDMUS criteria, but still lower than in older children.
Conclusions: Barkhof and KIDMUS MRI criteria share a high specificity and positive prognostic value for conversion to multiple sclerosis (MS). Sensitivity of these criteria is poor, especially in children below 10 years of age. Basal ganglia lesions can occur in patients who later develop MS. A substantial number of patients presenting with polyfocal onset and no encephalopathy remained monophasic.
Glossary
- ADEM=
- acute disseminated encephalomyelitis;
- CIS=
- clinically isolated syndrome;
- MS=
- multiple sclerosis;
- OCB=
- oligoclonal bands;
- PCIS=
- polyfocal CIS.
Onset of multiple sclerosis (MS) before the age of 16 years is reported in 2.2–5.0% of the total MS population and before the age of 10 years is observed in 0.2–0.6%.1–5 Diagnosis of MS in children can be more difficult than in adults. More frequently than in adults, the first attack of inflammation cannot be distinguished from acute disseminated encephalomyelitis (ADEM).6–9
Predicting development of MS after a first demyelinating attack is useful because of uncertainty of caregivers about prognosis and possible future therapeutic options. A cross-sectional study in children with MS showed that half of the children with MS fulfilled the Barkhof MRI criteria, which are widely accepted as prognostic for developing MS after a first clinical attack in adults.10,11 A French study in children with a broad clinical spectrum of first demyelinating attacks showed that next to the Barkhof criteria the presence of lesions perpendicular to the corpus callosum and only well-defined lesions on MRI (KIDMUS criteria) were prognostic for developing MS.8,12 A recent review on MRI abnormalities in children with MS stressed the problem of implementing the adult criteria to children and especially to the very young, aged under 10 years.13 The aim of this nationwide study was to identify clinical, radiologic, or CSF factors predicting development of MS after a first inflammatory demyelinating attack in children.
METHODS
Patients.
Patients were identified by members of the Dutch study group on childhood MS and ADEM. Eleven major neuropediatric centers in hospitals in nine large cities participated with complete geographic covering of the Netherlands. Children under the age of 16 with an attack, in the period 1990–2007, compatible with a demyelinating disease of the CNS, based on clinical features, were included. No other diagnosis than demyelinating disease of the CNS, like bacterial or viral infection of the CNS or a vasculitis, was allowed. Neuromyelitis optica (Devic disease) was also excluded. Length of follow-up time was determined by the last visit or telephone contact with a neurologist or pediatrician.
Definitions.
A clinically isolated syndrome (CIS) was defined as a monofocal attack of CNS demyelination (in optic nerve, brainstem, hemisphere, cerebellum, or spinal cord). A polyfocal clinically isolated syndrome (PCIS) was defined as a polyregional attack, implicating multiple CNS lesions. The term ADEM was avoided because of the incomplete consensus on diagnosis, especially considering the diagnostic weight of presentation with encephalopathy and findings on MRI, which are studied here as independent variables.14,15 This enabled us to dissect patients with PCIS into subgroups with and without encephalopathy at onset, without discussion whether they should be labeled as ADEM. Encephalopathy was defined as altered consciousness or evident change of behavior at time of debut of the attack (3 days before or after the first contact with the treating physician) not related to seizures or antiepileptic treatment. We considered a second attack within 1 month after the first attack or a second attack while on steroids or a second attack within 1 month after steroid discontinuation to be part of the initial first attack. Thus such cases were still labeled as monophasic.
A multiphasic disease course with at least 1 month between two attacks was considered MS when there was also dissemination in space, according to the revised McDonald criteria.11
Demographic data.
Demographic, clinical, and laboratory data were collected from chart records by a trained researcher using standardized recording sheets and kept in a database. Collected patient characteristics were age at onset and gender. Furthermore we scored the presence of a preceding infection or vaccination in the 4 weeks before onset, meningism, seizures, fever, headache, and the occurrence of a second and third attack.
MRI data.
Available scans were done at 1.0 or 1.5 Tesla and typically consisted of transverse T1, T2, and proton density 3–5 mm images. In most cases T2-weighted fast-fluid-attenuated-inversion recovery scans were available. Gadolinium was not administered routinely. To avoid reader bias, available MRI scans at baseline were centrally re-evaluated using a standardized MRI record form in consensus by two experienced MRI assessors (R.F.N. and R.Q.H.), blinded to clinical symptoms, disease evolution, and initial MRI analysis of the local neuroradiologist. Lesions were scored on transverse proton density and T2-weighted images. Periventricular lesions were defined as lesions in direct contact with the ventricular system. Juxtacortical lesions were defined as lesions in direct contact with the cortical gray matter with no intervening white matter. Infratentorial locations consisted of brainstem and cerebellar lesions. We assessed the fulfillment (at least three out of four) of the Barkhof criteria: 1) at least nine lesions on the T2-weighted images; 2) presence of at least three periventricular lesions; 3) presence of at least one juxtacortical lesion; 4) presence of at least one infratentorial lesion.16 Additional variables tested for prediction of MS conversion were white matter lesions perpendicular to the corpus callosum, gray matter lesions in the thalamus or basal ganglia, and T2 lesion size (large lesions were defined as lesions with a maximal diameter over 2 cm, small lesions had a maximal diameter below 2 cm). We also scored the sole presence of well-defined lesions, which were defined by clear lesions borders; an abrupt decrease in intensity of T2-weighted signal at the borderline between lesion and surrounding brain tissue.12
CSF data.
Data on CSF were collected from the period during or soon after the first clinical attack. IgG index upper cutoff value of 0.68 was selected.17 CSF oligoclonal bands (OCB) detected with immunoelectric focusing were positive in case of two or more bands present in CSF, but not in serum.
Statistical analysis.
Descriptive data were compared by means of the χ2 test and Fisher exact test for proportions and the t test and Mann-Whitney test for continuous measures. Survival curves were estimated using the Kaplan-Meier method. Time zero for the survival analysis was taken as the date of the first attack. The primary endpoint was conversion to MS. Time to conversion to MS was defined by the time between the first and second attack. For event-free subjects the follow-up period ended on the date of the last known visit, at which point the time was censored. p Value below 0.05 was considered significant. Statistical analysis was performed using SPSS version 11.0.
RESULTS
A total of 117 children were included in the study with a mean follow-up of 54 months (median 43 months, range 5–201 months). Clinical characteristics are depicted in table 1. Sixty-five (56%) children had a first presentation below the age of 10 years and 40 (34%) below the age of 6. In total, 37 of the 117 patients were diagnosed with MS, fulfilling the clinical McDonald criteria.
Table 1 Clinical and MRI features at baseline in patients with a diagnosis of CIS and PCIS at onset
PCIS was seen in 63 children. Thirteen of them (21%) had a second MS defining attack. The mean time to this second attack was 24.7 months (median: 10 months, range: 2–79 months). In 5 (38%) children this second attack was again a polyfocal attack. Children with PCIS and encephalopathy, fulfilling the proposed international criteria for ADEM,14 had a lower age at onset and a higher prevalence of seizures than children with PCIS without encephalopathy, but showed no significant difference in the other clinical features. Children with PCIS without encephalopathy progressed to MS more frequently then children with PCIS with encephalopathy, but this difference was not significant (table 1). Basal ganglia or thalamic lesions and large lesions on MRI were both seen in children with PCIS with and without encephalopathy (table 1). Using the definitions from the international pediatric MS study group,14 we found only two cases of multiphasic ADEM and no cases of recurrent ADEM.
Fifty-four children presented with CIS. Of these 54 children, 12 had optic neuritis, 17 isolated transverse myelitis, 18 brainstem symptoms, 4 hemispheric symptoms, and 3 had cerebellar symptoms. Twenty-four (44%) children with a CIS had a second, MS defining, attack. The mean time to conversion to MS after a CIS was 17.7 months (median: 12 months, range: 2–75 months).
Children with a final diagnosis of PCIS were younger, had significantly more often encephalopathy, headache, fever, and seizures, as well as a preceding infectious episode within the 4 weeks preceding the onset of initial attack (table 2). Mean time to MS diagnosis in the total group was 18.6 months (median: 11 months, range: 2–79). This was significantly shorter than the duration of follow-up of both the groups with a final diagnosis of CIS (mean: 52.7 months, median: 42.5 months, range: 12–162 months) and PCIS (mean: 44.8 months, median: 32 months, range: 5–201 months).
Table 2 Clinical and CSF features at baseline of children with a final diagnosis of CIS, PCIS, and MS
CSF was obtained in all but one patient. IgG index was tested in 72 children within 1 month and in one child within 5 months after onset. An elevated IgG index was significantly more frequently seen in children with MS. OCB were tested in 61 children within 1 month and in two children within 5 months after onset. OCB was significantly more often seen in children with MS (table 2).
A total of 110 brain MRIs at baseline were available. Five children had only a spinal cord MRI and two baseline MRI scans were not available. MRI data are shown in table 3. Each of the four individual Barkhof criteria was significantly more often observed with children with MS. This was not the case for juxtacortical lesions in children younger than 10 years. Presence of at least three Barkhof criteria was significantly more frequently found in children with diagnosed MS in both age groups.
Table 3 MRI features of children with MS and monophasic disease (CIS and PCIS) younger and older than 10 years at onset of symptoms
Survival analysis of the children scoring at least three Barkhof criteria showed a shorter mean time to the second attack of 45 months (95% CI: 18–73) vs 123 months (95% CI: 103–142) (log-rank test p value < 0.0001) in the other children (figure, A). When stratified for age below and above 10 years, difference in time to second attack remained significant.
Figure Survival curves of the time preceding the second attack
(A) Survival curves of the time preceding the second attack according to the presence of 0–2 and 3–4 Barkhof criteria on baseline MRI. Log-rank test p < 0.0001. (B) Survival curves of the time preceding the second attack according to the presence of both lesions perpendicular to the corpus callosum and the presence of only well-defined lesions (KIDMUS criteria) on baseline MRI. Log-rank test p < 0.0001.
Lesions perpendicular to the corpus callosum and only well-defined lesions (the KIDMUS criteria) and small lesions were significantly more often found in children with MS. Large lesions and basal ganglia lesions were significantly less frequently observed in children with MS. This difference was not seen in children aged under 10. Positivity of both KIDMUS criteria was observed significantly more often in children with MS in the total group but not in the group younger than 10 years.
Survival analysis of the children with the KIDMUS criteria showed a shorter mean time to the second attack of 22 months (95% CI: 10–33) vs 143 months (95% CI: 119–168) (log-rank test p value: <0.0001) in the children without (figure, B). When stratified for age below and over 10 years, difference in time to second attack remained significant. The test properties of the Barkhof and KIDMUS criteria are described in table 4.
Table 4 Test properties of the Barkhof and KIDMUS criteria
DISCUSSION
This nationwide study in the Netherlands focused solely on patients from neuropediatric clinics. Due to the retrospective nature of this study, follow-up time of children with a monophasic course was shorter than those with MS (table 2). Nevertheless, the time to conversion to MS in the MS group was significantly shorter than the duration of follow-up of the children who remained monophasic. This indicates that follow-up even in the monophasic patients was likely sufficient to detect the occurrence of a second attack. It is not excluded that children who are now monophasic during follow-up still can have a second MS defining attack in the future.
A diagnosis of ADEM frequently incorporates ADEM-like MRI lesions. These typically large lesions are often related to encephalopathy, making it difficult to independently assess the contribution of such MRI abnormalities and encephalopathy to further conversion into MS. Therefore we avoided the term ADEM, but split the polyfocal onset group into subgroups with and without encephalopathy, regardless of MRI findings. The obligatory presence of encephalopathy for ADEM diagnosis, as proposed by the international pediatric MS study group,14 may carry the risk of underestimation of ADEM cases. In a recent study, not all children with a brain MRI typical of ADEM had encephalopathy.8 The definition of encephalopathy deserves further specification in future studies. It has been proposed to include in the definition of encephalopathy the presence of irritability and lethargy.14 These two features were not part of our definition of encephalopathy, because they may also be observed in any generally sick child.
We also found the presence of large lesions and basal ganglia or thalamic lesions, considered typical of ADEM, in children who had a second MS defining attack and even in children without encephalopathy. Furthermore, we found no statistical difference in progression to MS in the children with PCIS with or without encephalopathy, although there was a trend that children with encephalopathy remained more often monophasic. The 21% of children developing MS in the whole PCIS group was in line with results reported before.8 Also time to a third attack during follow-up of children with MS was not related to either CIS or PCIS onset type (not shown). An interesting finding was that seizures almost exclusively occurred in the group with a monophasic PCIS, which makes seizures a possible relevant prognostic factor. Using the definitions from the international pediatric MS study group,14 we found only two cases of multiphasic ADEM and no cases of recurrent ADEM, indicating that these, at least in our study group, constitute a small subgroup of total numbers of children with multiphasic demyelinating diseases.
In adults it is suggested that an elevated CSF IgG index is predictive of MS.18 In children this has been studied in less detail. We found elevated IgG indices in the majority of cases tested. This sign of intrathecal IgG production was significantly more often found in children with MS. OCB in adults is more sensitive and specific than IgG index in the CSF.18 OCB, when tested, was found significantly more frequently in the group diagnosed with MS than in the group with a final diagnosis of monophasic CIS or PCIS, as has been reported before.19
Three points should be taken into account in respect to the CSF data. First, we did not have information on CSF IgG index and OCB in all patients. Second, some samples were not taken within 1 month after onset of symptoms, although this only occurred in less than 5% of the children. Finally, data were collected in multiple laboratories in a period of more than 10 years, so OCB were not tested uniformly. However, the main technical variance of OCB testing lies in sensitivity. Perhaps future testing in a more optimized and protocolized fashion may even improve the predictive power of this test.
A prognostic factor for progression to MS was the presence of at least three positive Barkhof criteria in children aged above and below 10 years at onset. In the French study it was observed that lesions perpendicular to the corpus callosum as well as only well-defined lesions were prognostic factors for developing MS.10 We confirm this finding, although not in the group with age at onset below 10 years.
Comparison of test qualities of the Barkhof and KIDMUS criteria showed a low sensitivity, but high specificity for both sets of criteria. Especially in children below 10 years, sensitivity was low. In adults the sensitivity of the Barkhof criteria is 49–74%.16 The low sensitivity of the KIDMUS criteria in children under age 10 (18%) has been reported earlier and is confirmed here.10 It should be noted that both our and the other available retrospective studies did not use standardized MRI protocols.
Better tools to predict development of MS are needed. The recent worldwide collaborative efforts will provide longer follow-up data on disease course and disability.20 Such studies will include the assessment of the possible extra value of scoring dissemination in time by MRI, the validation of novel MRI variables, and novel biomarkers. The possibility of a subgroup remaining monophasic after presentation with polyfocal CIS, reminiscent of ADEM but without encephalopathy, deserves further study.
ACKNOWLEDGMENT
The authors thank W.C. Hop, PhD, biostatistician, for assistance with statistics.
Footnotes
-
Editorial, page 962.
e-Pub ahead of print on July 30, 2008, at www.neurology.org.
MS Center ErasMS received financial support for this study from the Netherlands MS Research Foundation. R.Q.H. is supported by a grant from the Dutch Society for Research NWO.
Disclosure: The authors report no disclosures.
Received October 2, 2007. Accepted in final form February 29, 2008.
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