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Pediatric onset multiple sclerosis
NEUROL-2058; No. of Pages 7 revue neurologique xxx (2018) xxx–xxx
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Neuropediatrics
Pediatric onset multiple sclerosis K. Deiva a,b,1 a
Service de neurologie pe´diatrique, CRMR maladies inflammatoires rares du cerveau et de la moelle (MIRCEM), assistance publique-hoˆpitaux de Paris, hoˆpitaux universitaires Paris-Sud, Site Biceˆtre, 72, rue G-Leclerc, 94275 Le Kremlin Biceˆtre, France b Inserm UMR1184 « Immunology of viral infections and autoimmune diseases », CEA, IDMIT, faculte´ de me´decine Paris Sud–XI, faculte´ de me´decine Paris-Sud, 63, rue Gabriel-Peri 94276 Le Kremlin-Biceˆtre, France
info article
abstract
Article history:
Multiple Sclerosis (MS) is the commonest among inflammatory demyelinating diseases.
Received 15 November 2018
While the disease prevalence is high in adults, frequency of pediatric onset multiple
Received in revised form
sclerosis (POMS) is very low in children and particularities in this population have been
9 February 2019
identified. We will address in this review characteristics of POMS.
Accepted 19 February 2019
# 2019 Published by Elsevier Masson SAS.
Available online xxx Keywords: Pediatric Neurology Neuroimmunology Clinical Neuroscience
1.
Demographic features
1.1.
Incidence
POMS is a rare disease and represents between 3–10% of all MS diagnosis. Its incidence varies according to countries and is estimated around 0.66 to 1.66/100 000 children less than 16 or 18 years old [1–5]. According to our Kidbiosep cohort, we have observed a frequency of 30–35 new cases every year in France.
1.2.
Clinical characteristics
The median age of children with POMS is 12 years (range: 1.6–17). Children less than 10 years old are also affected,
accounting for 17–30% of all POMS [6,7]. Sex-ratio varies according to ages of diagnosis: in children less than 10 years old, there are as many girls as boys, while in older children (> 10 years old) a female predominance of observed. This may suggest hormonal interferences during puberty. An increase of relapses and of MS incidence during puberty was recently observed in Northern American studies [8]. The commonest clinical presentations are: [1] long tract involvement (65%), brainstem symptoms (37%), optic neuritis (ON) (34%) and acute demyelinating encephalomyelitis (ADEM) (15%). Transverse myelitis is rare (7%) and differences in clinical presentations according to the age of onset were again noted. Indeed, the occurrence of an infection in the month preceding the first attack in children under 10 is more
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Please cite this article in press as: Deiva K. Pediatric onset multiple sclerosis. Revue neurologique (2019), https://doi.org/10.1016/ j.neurol.2019.02.002
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Box 1. POMS diagnostic criteria according to Krupp and al, 2013 [9].
Box 2. Definition of Acute Demyelinating Encephalomyelitis according to Krupp and al, 2013 [10].
2 non-ence´phalopathie CNS events: Separated by < 30 days, Involving < 1 arreˆt of the CNS:
A first polysymptomatic demyelinating attack; Alteration of consciousness not explained by fever (ranging from abnormal somnolence to coma, confusional syndrome, behavioral disorders); Abnormal brain MRI during the acute phase (3 months) with diffuse white matter lesions, poorly limited, wide (> 1–2 cm), with rare hypointense T1 lesions, and possible involvement of the gray matter (thalamus, or other basal ganglia), optic nerve pathways, brainstem, cerebellum and spinal cord are also described.
Single clinicat vent and MRI features relying on 2010 re´viser McDonald criteria for DIS and DIT; ADEM followed 3 monte´s laver by: A non-ence´phalopathie clinicat event New le´sions on train MRI consistent witz MS
common than those who are over 10 years old (41% vs. 20%). ADEM presentations at onset are more often in children under 10 years (36% vs. 9%), as well as polysymptomatic presentations (61% vs. 40%). The median time between the first and the second attack is 8 months (range: 1–111 months) and this time is longer for children under 10 [7].
2.
Diagnostic criteria
In 2012, diagnostic criteria for POMS were established by the International Pediatric MS Study Group (IPMSSG) [9] (Box 1). One of the major differences from the previous 2007 criteria was that POMS can be diagnosed after one attack by using MacDonald 2010 criteria for dissemination in space and time. The fact that ADEM presentation (see definition Box 2) can also
be accepted as the inaugural attack of MS is a major particularity of POMS. Recently, the 2017 MS criteria were defined in adults and these criteria can be used in children more than 11 years old and if the first attack is not an ADEM presentation [11]. The 2017 criteria are currently under validation in pediatric cohorts of POMS.
3.
Biological characteristics and markers
Cerebrospinal fluid (CSF) study has again gained importance in recent years following the inclusion of oligoclonal bands in the 2017 MS criteria; their presence would suggest dissemination in time (DIT). In children with MS, the presence of
Fig. 1 – Axial MRI images at onset of a 14 y-old girl with MS showing hyper-T2 periventricular, subcortical lesions (A) as well as brain stem and cerebellar lesions (B) which are also hypto-T1 (C). Axial MRI images at onset of a 12 years old girl with MS showing multiple subcortical well defined, perpendicular to the corpus callosum, periventricular (D) cerebellar peduncle hyper-T2 lesions (E) and some of them are enhanced by gadolinium (F). Please cite this article in press as: Deiva K. Pediatric onset multiple sclerosis. Revue neurologique (2019), https://doi.org/10.1016/ j.neurol.2019.02.002
NEUROL-2058; No. of Pages 7 revue neurologique xxx (2018) xxx–xxx
3
Fig. 2 – Axial MRI images at onset of a 12 years old boy with MS who had an ADEM presentation at onset showing subcortical, periventricular hyper-T2 lesions and some of them are gadolinium enhancing lesions.
Fig. 3 – Axial MRI of a 13-year-old girl presenting tremor, horizontal nystagmus with anti-MOG antibodies seropositivity showing multiple bilateral, periventricular, juxtacortical lesions (A, B). One of the lesions was enhanced by gadolinium (C).
oligoclonal bands (OCB) was found in 50 to 90% of children [7,12,13]. OCB are less commonly found in children who have presented their first attack at an age of less than 10 years than those who presented it after 10 years (27% vs. 52%) [7]. It has also been shown that neutrophil-like pleiocytosis predominates in younger children rather than lymphocytes as in adolescents or adults, suggesting the probable role of the innate immune system in younger children. Recently, other biomarkers of disease progression have been described in POMS. Among them, sCD27, a marker of T cell activation, seems to be a good predictor of clinically definite MS (CDMS) in children as previously shown in adults. In 94 children with an acute demyelinating syndrome (ADS), sCD27 in CSF is significantly increased in children who have CDMS when compared to other non-MS ADS. They have also shown that it is also increased in patients with dissemination in space (DIS) on baseline MRI and correlated with OCB, IgG index and gadolinium enhancement [14]. Light chain neurofilament (Nfl), well known in adult MS, is another interesting marker of POMS: it has been demonstrated that Nfl in CSF in adult and pediatric CDMS is increased and higher Nfl levels in adult and pediatric CIS were associated with a shorter time to CDMS diagnosis. Ongoing studies in serum Nfl seems to show that this marker is increased in POMS when compared to healthy
control patients, is correlated with clinical and MRI disease activity and therapeutical response [15].
4.
Magnetic Resonance Imaging (MRI)
Several MRI studies have been carried out to define diagnostic criteria for POMS [16,17]. The presence of at least one periventricular lesion and/or T1 hyposignal lesion or the absence of bilateral diffuse lesions during the first attack is much more suggestive of POMS (Figs. 1–5]. The revised MacDonald 2010 criteria (Box 3) can be applied in children but with caution in children under 12 years of age given their low specificity and sensitivity [18]. It is interesting to note that the lesion load in T2 seems higher in children than in adults at onset [19]. In addition, cerebral atrophy may be present from the very beginning of the disease, even involving the deep gray matter [20,21].
5.
Evolution
POMS appears to be more active with a higher relapse rate than that observed in adults (annualized relapse rate: 1.12–
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Fig. 4 – Axial flair images of a 4 years old girl presenting lethargia, gait difficulties, paraparesia compatible with an ADEM and anti-MOG seropositivity showing bilateral deep grey matter, peri-ventricular, sub-cortical, brain stem lesions (A, B, C). Spinal MRI revealed spinal lesion extending in more than 3 vertebras.
Fig. 5 – Diagnostic algorithm for POMS.
Box 3. 2010 McDonald MRI criteria for demonstration of dissemination in space (DIS) and time (DIT) according to Polman et al, 2010 *symptomatic brainstem or spinal cord syndrome are excluded from the criteria. DIS if there is 1 T2 lesions in at least 2 of 4 areas of the CNS: Periventicular; Juxtacortical; Infratentorial; Spinal cord*: DIT if: A new T2 and/or gadolinium-enhancing lesions(s) on follow-up MRI, with reference to a baseline scan, irrespective of the timing of the baseline MRI; Simultaneous presence of asymptomatic gadolinium-enhancing and non-enhancing lesions at any time.
2.76 vs. 0.35–1.78, respectively), especially during the first two years [22]. A higher lesion load at the beginning with a higher rate of new MRI lesions was also observed in children compared to adults [19]. Complete recovery without sequelae after the initial attack in children with MS is very common with a lower EDSS score around 1 in the majority of the children. Evolution towards a secondary progressive form is nevertheless possible and it has been shown that patients who had an onset of MS before the age of 18 years take longer time to evolve towards the secondary progressive form (10 years more) but they do so at younger ages (10 years younger in average) than patients who developed MS in adulthood [23]. Primary progressive forms of MS are extremely rare in children (less than 1%) [22].
6.
Genetic and environmental risk factors
MS is a multifactorial disease with genetic, epigenetic and environmental risk factors, and POMS offers a unique
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opportunity to study these factors. Indeed, the time between exposure to these factors and the onset of the disease is shorter and the information will be easier to obtain. As in adults, HLA-DRB1 alleles have been reported to be more common in pediatric MS compared to controls [24]. In particular, the HLA-DRB1*15 allele is more common in children with MS than children with monophasic demyelinating disease [25]. Among environmental factors, vitamin D plays an important role. Indeed, serum vitamin D levels are strongly associated with the risk of relapses in children, and an increase in serum of 10 ng/mL of 25-hydroxy-vitamin D has been associated with a 34% decrease in relapse rate [26]. In addition, previous exposure to certain viral agents such as Epstein-Barr virus is more common in children with MS than in controls [10], unlike cytomegalovirus or VZV infection, which are less common in this group and which would suggest a possible protection by these viruses against the disease [27,28]. Vaccination, in particular against hepatitis B, has often been incriminated in the occurrence of MS but the study of a French cohort of children with MS has demonstrated that there is no increased risk of MS compared to controls [29]. Other health problems are associated with an increased risk of pediatric MS such as passive smoking and obesity [4,30].
7.
Differential diagnosis
Due to the scarcity of POMS, the diagnosis MS should be proposed once all other differential diagnoses are excluded. There are several relapsing inflammatory demyelinating diseases that can mimic POMS and mainly two of them have to be identified earlier such as AQP4-positive neuromyelitis optica spectrum disorders (NMOSD) and antibodies against myelin oligodendrocyte glycoproteins (anti-MOG) associated acute demyelinating diseases (ADS). Anti-MOG antibodies have been found frequently in children ADS [31–33]. Some clinical presentations (ADEM, optic neuritis. . .) may relapse in more than 40% of the cases and mimic POMS but presence of these antibodies would plead against MS diagnosis [32,34,35].
5
A recent European collaborative study on relapsing anti-MOG positive ADS showed that usual MS treatment would not be efficient [36]. Therefore, anti-MOG antibodies should be sought at onset of any ADS and greater caution must be taken regarding the final diagnosis of MS in their presence. Systemic diseases may also present a neurological onset with relapses and need to be differentiated with POMS as well as other genetic, metabolic and tumor disorders [37] (Table 1).
8.
Cognitive and psychological impact
The disability as measured by the EDSS score is not adapted to POMS because it evaluates motor, coordination, visual, brainstem, sphincter and ambulation functions. As previously said, children recover well after their relapses and rarely would present an EDSS score 4 during their follow-up. On the other hand, cognitive difficulties with psychosocial and academic consequences can be observed. Several crosssectional studies have reported cognitive dysfunction in nearly one-third of pediatric MS cases, even in the early stages of the disease, compared with healthy controls [38–40]. The cognitive domains most commonly affected in POMS are: attention, memory, speed of information integration, language, and spatial and visual integration. Fatigue and associated psychological disorders can worsen cognition. Fatigue is reported in 20–50% of pediatric patients [41,42] and when anxiety and mood disorders are associated with it, a decrease in cognitive performance can be observed [43]. These difficulties have a direct impact on level of daily activities and quality of life. Overall scores on quality of life questionnaires are lower compared to siblings, correlated with neurological impairment, duration of illness, MRI findings, and visual acuity [44,45].
9.
Treatment
The treatment of relapses remains high doses of corticosteroids (methylprednisolone) (30 mg/kg/day without exceeding 1 g) for 3 to 5 days. Oral tapering of corticosteroids (prednisone, 1 to 2 mg/kg/day) is empirical.
Table 1 – Mimics of POMS. Inflammatory diseases Acute encephalitis with auto-antibodies Anti-AQP4+, anti-MOG, anti-TPO antibodies CNS Vasculitis Systemic diseases with neurological involvement Neuro-lupus, neuro-Behcet, neuro-sarcoidosis CLIPPERS Secondary hemophagocytic lymphohistiocytosis Genetic, metabolic diseases Mitochondrial diseases (e.g Leigh, Leber diseases, OPA mutations) Peroxisomal diseases (e.g X-Adreno-leucodystrophy), lysosomal diseases (e.g metachromatic leucodystrophy) Genetical inflammatory diseases (e.g Aicardi-Gouttie`res diseases, RANBP2 mutations) Genetical angiopathies (e.g Cadasil, COATS+ syndrome. . .) Primary hemophagocytic lymphohistiocytosis Tumor Oligodendroglioma, astrocytoma, lymphoma
9.1.
Immunomodulators
It has been suggested by the International Pediatric MS Study Group’s working group that once a child is diagnosed with POMS, long-term treatment may be proposed [46]. Immunomodulators such as interferons (Avonex1, Rebif1, Betaferon1) or glatiramer acetate (Copaxone1) have been authorized to be used in children 12 years of age. Although there have been no randomized studies, these immunomodulators have shown similar efficacy and tolerance to those of adults in many retrospective international studies [47–49]. There is no real consensus for the dose of these treatments to be used in children, but as per our experience, for interferons, the recommended dose is the full dose regardless of the age of the child, which will be secondarily adapted depending on the tolerance obtained during the recommended titration of each interferon. Similarly, for Copaxone1, the full dose will be used
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in children regardless of the child’s age and this without titration.
9.2.
Oral treatments
Several oral treatments are available or have recently been approved for patients over 18 years of age, such as fingolimod, teriflunomide and dimethyl fumarate. These treatments have been used to a limited extent in children and recently several clinical trials in patients under 18 years old with MS are ongoing. One of the first randomized studies in pediatric MS with fingolimod (PARADIGMS trial) has demonstrated an efficacy of 82% in the reduction of the annualized relapse rate compared to interferons and a reduction of at least 53% of annualized rate of new/new enlarging T2 hypersignal lesions on MRI [50]. In addition, the tolerance is almost similar to what is observed in adults. Randomized studies with teriflunomide and dimethyl fumarate are currently underway.
9.3.
Natalizumab
In children with a very active and severe disease or resistant to the first line of treatment, natalizumab (Tysabri1) can be used but under certain conditions. The treatment is not approved in POMS but in retrospective Italian, German or Austrian studies [51–53], this treatment appears to be as effective as in adults with similar tolerance. However, it requires long-term monitoring due to the possibility of progressive multifocal leukoencephalopathy following JC virus reactivation.
10.
Conclusion
POMS has particularities when compared to adult MS especially in young and pre-pubertal children. Cognitive impairment is quite common in children with MS, which requires specific management. The study of pediatric MS would help to better understand the pathophysiology of the disease in view of the short time between the likely triggers and the onset of the disease. Many clinical trials are currently underway with results that seems to be more encouraging than in adults, which would allow for better management.
Disclosure of interest The author declares that he has no competing interest.
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Neuropediatrics
Pediatric onset multiple sclerosis K. Deiva a,b,1 a
Service de neurologie pe´diatrique, CRMR maladies inflammatoires rares du cerveau et de la moelle (MIRCEM), assistance publique-hoˆpitaux de Paris, hoˆpitaux universitaires Paris-Sud, Site Biceˆtre, 72, rue G-Leclerc, 94275 Le Kremlin Biceˆtre, France b Inserm UMR1184 « Immunology of viral infections and autoimmune diseases », CEA, IDMIT, faculte´ de me´decine Paris Sud–XI, faculte´ de me´decine Paris-Sud, 63, rue Gabriel-Peri 94276 Le Kremlin-Biceˆtre, France
info article
abstract
Article history:
Multiple Sclerosis (MS) is the commonest among inflammatory demyelinating diseases.
Received 15 November 2018
While the disease prevalence is high in adults, frequency of pediatric onset multiple
Received in revised form
sclerosis (POMS) is very low in children and particularities in this population have been
9 February 2019
identified. We will address in this review characteristics of POMS.
Accepted 19 February 2019
# 2019 Published by Elsevier Masson SAS.
Available online xxx Keywords: Pediatric Neurology Neuroimmunology Clinical Neuroscience
1.
Demographic features
1.1.
Incidence
POMS is a rare disease and represents between 3–10% of all MS diagnosis. Its incidence varies according to countries and is estimated around 0.66 to 1.66/100 000 children less than 16 or 18 years old [1–5]. According to our Kidbiosep cohort, we have observed a frequency of 30–35 new cases every year in France.
1.2.
Clinical characteristics
The median age of children with POMS is 12 years (range: 1.6–17). Children less than 10 years old are also affected,
accounting for 17–30% of all POMS [6,7]. Sex-ratio varies according to ages of diagnosis: in children less than 10 years old, there are as many girls as boys, while in older children (> 10 years old) a female predominance of observed. This may suggest hormonal interferences during puberty. An increase of relapses and of MS incidence during puberty was recently observed in Northern American studies [8]. The commonest clinical presentations are: [1] long tract involvement (65%), brainstem symptoms (37%), optic neuritis (ON) (34%) and acute demyelinating encephalomyelitis (ADEM) (15%). Transverse myelitis is rare (7%) and differences in clinical presentations according to the age of onset were again noted. Indeed, the occurrence of an infection in the month preceding the first attack in children under 10 is more
E-mail address: [email protected]. http://www.nie-enfant.com/ https://doi.org/10.1016/j.neurol.2019.02.002 0035-3787/# 2019 Published by Elsevier Masson SAS. 1
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Box 1. POMS diagnostic criteria according to Krupp and al, 2013 [9].
Box 2. Definition of Acute Demyelinating Encephalomyelitis according to Krupp and al, 2013 [10].
2 non-ence´phalopathie CNS events: Separated by < 30 days, Involving < 1 arreˆt of the CNS:
A first polysymptomatic demyelinating attack; Alteration of consciousness not explained by fever (ranging from abnormal somnolence to coma, confusional syndrome, behavioral disorders); Abnormal brain MRI during the acute phase (3 months) with diffuse white matter lesions, poorly limited, wide (> 1–2 cm), with rare hypointense T1 lesions, and possible involvement of the gray matter (thalamus, or other basal ganglia), optic nerve pathways, brainstem, cerebellum and spinal cord are also described.
Single clinicat vent and MRI features relying on 2010 re´viser McDonald criteria for DIS and DIT; ADEM followed 3 monte´s laver by: A non-ence´phalopathie clinicat event New le´sions on train MRI consistent witz MS
common than those who are over 10 years old (41% vs. 20%). ADEM presentations at onset are more often in children under 10 years (36% vs. 9%), as well as polysymptomatic presentations (61% vs. 40%). The median time between the first and the second attack is 8 months (range: 1–111 months) and this time is longer for children under 10 [7].
2.
Diagnostic criteria
In 2012, diagnostic criteria for POMS were established by the International Pediatric MS Study Group (IPMSSG) [9] (Box 1). One of the major differences from the previous 2007 criteria was that POMS can be diagnosed after one attack by using MacDonald 2010 criteria for dissemination in space and time. The fact that ADEM presentation (see definition Box 2) can also
be accepted as the inaugural attack of MS is a major particularity of POMS. Recently, the 2017 MS criteria were defined in adults and these criteria can be used in children more than 11 years old and if the first attack is not an ADEM presentation [11]. The 2017 criteria are currently under validation in pediatric cohorts of POMS.
3.
Biological characteristics and markers
Cerebrospinal fluid (CSF) study has again gained importance in recent years following the inclusion of oligoclonal bands in the 2017 MS criteria; their presence would suggest dissemination in time (DIT). In children with MS, the presence of
Fig. 1 – Axial MRI images at onset of a 14 y-old girl with MS showing hyper-T2 periventricular, subcortical lesions (A) as well as brain stem and cerebellar lesions (B) which are also hypto-T1 (C). Axial MRI images at onset of a 12 years old girl with MS showing multiple subcortical well defined, perpendicular to the corpus callosum, periventricular (D) cerebellar peduncle hyper-T2 lesions (E) and some of them are enhanced by gadolinium (F). Please cite this article in press as: Deiva K. Pediatric onset multiple sclerosis. Revue neurologique (2019), https://doi.org/10.1016/ j.neurol.2019.02.002
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Fig. 2 – Axial MRI images at onset of a 12 years old boy with MS who had an ADEM presentation at onset showing subcortical, periventricular hyper-T2 lesions and some of them are gadolinium enhancing lesions.
Fig. 3 – Axial MRI of a 13-year-old girl presenting tremor, horizontal nystagmus with anti-MOG antibodies seropositivity showing multiple bilateral, periventricular, juxtacortical lesions (A, B). One of the lesions was enhanced by gadolinium (C).
oligoclonal bands (OCB) was found in 50 to 90% of children [7,12,13]. OCB are less commonly found in children who have presented their first attack at an age of less than 10 years than those who presented it after 10 years (27% vs. 52%) [7]. It has also been shown that neutrophil-like pleiocytosis predominates in younger children rather than lymphocytes as in adolescents or adults, suggesting the probable role of the innate immune system in younger children. Recently, other biomarkers of disease progression have been described in POMS. Among them, sCD27, a marker of T cell activation, seems to be a good predictor of clinically definite MS (CDMS) in children as previously shown in adults. In 94 children with an acute demyelinating syndrome (ADS), sCD27 in CSF is significantly increased in children who have CDMS when compared to other non-MS ADS. They have also shown that it is also increased in patients with dissemination in space (DIS) on baseline MRI and correlated with OCB, IgG index and gadolinium enhancement [14]. Light chain neurofilament (Nfl), well known in adult MS, is another interesting marker of POMS: it has been demonstrated that Nfl in CSF in adult and pediatric CDMS is increased and higher Nfl levels in adult and pediatric CIS were associated with a shorter time to CDMS diagnosis. Ongoing studies in serum Nfl seems to show that this marker is increased in POMS when compared to healthy
control patients, is correlated with clinical and MRI disease activity and therapeutical response [15].
4.
Magnetic Resonance Imaging (MRI)
Several MRI studies have been carried out to define diagnostic criteria for POMS [16,17]. The presence of at least one periventricular lesion and/or T1 hyposignal lesion or the absence of bilateral diffuse lesions during the first attack is much more suggestive of POMS (Figs. 1–5]. The revised MacDonald 2010 criteria (Box 3) can be applied in children but with caution in children under 12 years of age given their low specificity and sensitivity [18]. It is interesting to note that the lesion load in T2 seems higher in children than in adults at onset [19]. In addition, cerebral atrophy may be present from the very beginning of the disease, even involving the deep gray matter [20,21].
5.
Evolution
POMS appears to be more active with a higher relapse rate than that observed in adults (annualized relapse rate: 1.12–
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Fig. 4 – Axial flair images of a 4 years old girl presenting lethargia, gait difficulties, paraparesia compatible with an ADEM and anti-MOG seropositivity showing bilateral deep grey matter, peri-ventricular, sub-cortical, brain stem lesions (A, B, C). Spinal MRI revealed spinal lesion extending in more than 3 vertebras.
Fig. 5 – Diagnostic algorithm for POMS.
Box 3. 2010 McDonald MRI criteria for demonstration of dissemination in space (DIS) and time (DIT) according to Polman et al, 2010 *symptomatic brainstem or spinal cord syndrome are excluded from the criteria. DIS if there is 1 T2 lesions in at least 2 of 4 areas of the CNS: Periventicular; Juxtacortical; Infratentorial; Spinal cord*: DIT if: A new T2 and/or gadolinium-enhancing lesions(s) on follow-up MRI, with reference to a baseline scan, irrespective of the timing of the baseline MRI; Simultaneous presence of asymptomatic gadolinium-enhancing and non-enhancing lesions at any time.
2.76 vs. 0.35–1.78, respectively), especially during the first two years [22]. A higher lesion load at the beginning with a higher rate of new MRI lesions was also observed in children compared to adults [19]. Complete recovery without sequelae after the initial attack in children with MS is very common with a lower EDSS score around 1 in the majority of the children. Evolution towards a secondary progressive form is nevertheless possible and it has been shown that patients who had an onset of MS before the age of 18 years take longer time to evolve towards the secondary progressive form (10 years more) but they do so at younger ages (10 years younger in average) than patients who developed MS in adulthood [23]. Primary progressive forms of MS are extremely rare in children (less than 1%) [22].
6.
Genetic and environmental risk factors
MS is a multifactorial disease with genetic, epigenetic and environmental risk factors, and POMS offers a unique
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opportunity to study these factors. Indeed, the time between exposure to these factors and the onset of the disease is shorter and the information will be easier to obtain. As in adults, HLA-DRB1 alleles have been reported to be more common in pediatric MS compared to controls [24]. In particular, the HLA-DRB1*15 allele is more common in children with MS than children with monophasic demyelinating disease [25]. Among environmental factors, vitamin D plays an important role. Indeed, serum vitamin D levels are strongly associated with the risk of relapses in children, and an increase in serum of 10 ng/mL of 25-hydroxy-vitamin D has been associated with a 34% decrease in relapse rate [26]. In addition, previous exposure to certain viral agents such as Epstein-Barr virus is more common in children with MS than in controls [10], unlike cytomegalovirus or VZV infection, which are less common in this group and which would suggest a possible protection by these viruses against the disease [27,28]. Vaccination, in particular against hepatitis B, has often been incriminated in the occurrence of MS but the study of a French cohort of children with MS has demonstrated that there is no increased risk of MS compared to controls [29]. Other health problems are associated with an increased risk of pediatric MS such as passive smoking and obesity [4,30].
7.
Differential diagnosis
Due to the scarcity of POMS, the diagnosis MS should be proposed once all other differential diagnoses are excluded. There are several relapsing inflammatory demyelinating diseases that can mimic POMS and mainly two of them have to be identified earlier such as AQP4-positive neuromyelitis optica spectrum disorders (NMOSD) and antibodies against myelin oligodendrocyte glycoproteins (anti-MOG) associated acute demyelinating diseases (ADS). Anti-MOG antibodies have been found frequently in children ADS [31–33]. Some clinical presentations (ADEM, optic neuritis. . .) may relapse in more than 40% of the cases and mimic POMS but presence of these antibodies would plead against MS diagnosis [32,34,35].
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A recent European collaborative study on relapsing anti-MOG positive ADS showed that usual MS treatment would not be efficient [36]. Therefore, anti-MOG antibodies should be sought at onset of any ADS and greater caution must be taken regarding the final diagnosis of MS in their presence. Systemic diseases may also present a neurological onset with relapses and need to be differentiated with POMS as well as other genetic, metabolic and tumor disorders [37] (Table 1).
8.
Cognitive and psychological impact
The disability as measured by the EDSS score is not adapted to POMS because it evaluates motor, coordination, visual, brainstem, sphincter and ambulation functions. As previously said, children recover well after their relapses and rarely would present an EDSS score 4 during their follow-up. On the other hand, cognitive difficulties with psychosocial and academic consequences can be observed. Several crosssectional studies have reported cognitive dysfunction in nearly one-third of pediatric MS cases, even in the early stages of the disease, compared with healthy controls [38–40]. The cognitive domains most commonly affected in POMS are: attention, memory, speed of information integration, language, and spatial and visual integration. Fatigue and associated psychological disorders can worsen cognition. Fatigue is reported in 20–50% of pediatric patients [41,42] and when anxiety and mood disorders are associated with it, a decrease in cognitive performance can be observed [43]. These difficulties have a direct impact on level of daily activities and quality of life. Overall scores on quality of life questionnaires are lower compared to siblings, correlated with neurological impairment, duration of illness, MRI findings, and visual acuity [44,45].
9.
Treatment
The treatment of relapses remains high doses of corticosteroids (methylprednisolone) (30 mg/kg/day without exceeding 1 g) for 3 to 5 days. Oral tapering of corticosteroids (prednisone, 1 to 2 mg/kg/day) is empirical.
Table 1 – Mimics of POMS. Inflammatory diseases Acute encephalitis with auto-antibodies Anti-AQP4+, anti-MOG, anti-TPO antibodies CNS Vasculitis Systemic diseases with neurological involvement Neuro-lupus, neuro-Behcet, neuro-sarcoidosis CLIPPERS Secondary hemophagocytic lymphohistiocytosis Genetic, metabolic diseases Mitochondrial diseases (e.g Leigh, Leber diseases, OPA mutations) Peroxisomal diseases (e.g X-Adreno-leucodystrophy), lysosomal diseases (e.g metachromatic leucodystrophy) Genetical inflammatory diseases (e.g Aicardi-Gouttie`res diseases, RANBP2 mutations) Genetical angiopathies (e.g Cadasil, COATS+ syndrome. . .) Primary hemophagocytic lymphohistiocytosis Tumor Oligodendroglioma, astrocytoma, lymphoma
9.1.
Immunomodulators
It has been suggested by the International Pediatric MS Study Group’s working group that once a child is diagnosed with POMS, long-term treatment may be proposed [46]. Immunomodulators such as interferons (Avonex1, Rebif1, Betaferon1) or glatiramer acetate (Copaxone1) have been authorized to be used in children 12 years of age. Although there have been no randomized studies, these immunomodulators have shown similar efficacy and tolerance to those of adults in many retrospective international studies [47–49]. There is no real consensus for the dose of these treatments to be used in children, but as per our experience, for interferons, the recommended dose is the full dose regardless of the age of the child, which will be secondarily adapted depending on the tolerance obtained during the recommended titration of each interferon. Similarly, for Copaxone1, the full dose will be used
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in children regardless of the child’s age and this without titration.
9.2.
Oral treatments
Several oral treatments are available or have recently been approved for patients over 18 years of age, such as fingolimod, teriflunomide and dimethyl fumarate. These treatments have been used to a limited extent in children and recently several clinical trials in patients under 18 years old with MS are ongoing. One of the first randomized studies in pediatric MS with fingolimod (PARADIGMS trial) has demonstrated an efficacy of 82% in the reduction of the annualized relapse rate compared to interferons and a reduction of at least 53% of annualized rate of new/new enlarging T2 hypersignal lesions on MRI [50]. In addition, the tolerance is almost similar to what is observed in adults. Randomized studies with teriflunomide and dimethyl fumarate are currently underway.
9.3.
Natalizumab
In children with a very active and severe disease or resistant to the first line of treatment, natalizumab (Tysabri1) can be used but under certain conditions. The treatment is not approved in POMS but in retrospective Italian, German or Austrian studies [51–53], this treatment appears to be as effective as in adults with similar tolerance. However, it requires long-term monitoring due to the possibility of progressive multifocal leukoencephalopathy following JC virus reactivation.
10.
Conclusion
POMS has particularities when compared to adult MS especially in young and pre-pubertal children. Cognitive impairment is quite common in children with MS, which requires specific management. The study of pediatric MS would help to better understand the pathophysiology of the disease in view of the short time between the likely triggers and the onset of the disease. Many clinical trials are currently underway with results that seems to be more encouraging than in adults, which would allow for better management.
Disclosure of interest The author declares that he has no competing interest.
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