Multiple sclerosis: Moroccan children
clinical characteristics and disability progression in
Elhachmia Ait Ben Haddou, Mounia Alhyan, Jehanne Aasfara, Wafa Regragui, Azeddine Ibrahimi, Rachid Razine, Redouane Abouqal, Ali Benomar, Mohamed Yahyaoui PII: DOI: Reference:
S0022-510X(14)00521-8 doi: 10.1016/j.jns.2014.08.008 JNS 13375
To appear in:
Journal of the Neurological Sciences
Received date: Revised date: Accepted date:
13 April 2014 4 July 2014 6 August 2014
Please cite this article as: Ait Ben Haddou Elhachmia, Alhyan Mounia, Aasfara Jehanne, Regragui Wafa, Ibrahimi Azeddine, Razine Rachid, Abouqal Redouane, Benomar Ali, Yahyaoui Mohamed, Multiple sclerosis: clinical characteristics and disability progression in Moroccan children, Journal of the Neurological Sciences (2014), doi: 10.1016/j.jns.2014.08.008
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Multiple sclerosis: children
clinical characteristics and disability progression in Moroccan
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Elhachmia Ait Ben Haddou a,b,f*, Mounia Alhyan a,f, Jehanne Aasfara a,f, Wafa Regragui a, Azeddine Ibrahimi c, Rachid Razine d,e, Redouane Abouqal d, Ali Benomar a,b and Mohamed Yahyaoui a a
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: Department of Neurology B and Neurogenetics, Hôpital des Spécialités Rabat, Faculté de Médecine et de Pharmacie Rabat, Mohammed V University Souissi, Rabat, Morocco. b
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: Medical Center of Clinical Trials and Epidemiological Study (CRECET), Faculté de Médecine et de Pharmacie Rabat, Mohammed V University Souissi, Rabat, Morocco. c
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: Biotech Lab. (MedBiotech), Faculté de Médecine et de Pharmacie Rabat, Mohammed V University Souissi, Rabat, Morocco. d
: Laboratory of Biostatistics and clinical epidemiological research (LBRCE), Faculté de Médecine et de Pharmacie Rabat, Mohammed V University Souissi, Rabat, Morocco. e
: These three authors contributed equally to this work.
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f
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: Laboratoire de santé publique, Faculté de Médecine et de Pharmacie Rabat, Mohammed V University Souissi, Rabat, Morocco.
* Corresponding author: Ait Ben Haddou Elhachmia
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Tel.: +212 6 72860 980
E-mail address: [email protected] Alhyan Mounia: [email protected] Aasfara Jehanne: [email protected] Regragui Wafa: [email protected] Ibrahimi Azeddine: [email protected] Razine Rachid: [email protected] Abouqal Redouane: [email protected] Benomar Ali: [email protected] Yahyaoui Mohamed: [email protected]
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ACCEPTED MANUSCRIPT Abstract:
Background: 5% of Multiple sclerosis have their onset in childhood.
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Objectives: We aim to show the clinical features and follow-up of Moroccan pediatric MS
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patients.
Methods: 25 pediatric MS records were analyzed between 2005 and 2013 at the Neurology B
disorder of Rabat Mohammed V University Souissi.
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department of Rabat Ibn sina University Hospital and medical school group of Neurogenetic
Results: The median duration of follow up was 4 years [1.5 - 6]. The median age at disease
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onset was 14 years. Clinical symptoms were described. At the last evaluation, the median EDSS score was 3.0 [0- 7.5]. The median time between disease onset and diagnosis was 2
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years [1-9] and the median time from MS onset to second neurological episode was 1 year [0.9-3] with an average of 2 relapses in the first 2 years. The median time to reach EDSS 3.0 was 4.5 years [2- 17] and the median time to go from EDSS 3.0 to 6.0 was 4 years [2.5-6].
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The majority of cases at the last follow-up were; relapsing-remitting (17 patients: 68%),
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although 8 patients (32%) developed secondary progressive MS after median disease duration of 5 years [4-19]. None of the patients had a primary progressive MS.
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Conclusion: Time EDSS 3.0 and to secondary progression was shorter in our cohort than previously reported in others series.
Keywords: Multiple sclerosis; Age of onset; Children; Clinical features; Outcome
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measurement; Treatment.
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ACCEPTED MANUSCRIPT 1. Introduction:
Multiple sclerosis (MS) is a demyelinating disease of the central nervous system, often
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starting in the third or fourth decade of life [1]. However, it can be identified in children and
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adolescents as well. The first MS case in childhood is believed to have been described by Pierre Marie in 1893 [2]. Between 0.4 and 5.7% of all MS cases have their onset before the
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age of 18. A single study reported 10.5% of patients with an onset before the age of 16 [3]. Relapsing-remitting forms are, by far, the most common presentation at onset in children [4]. Pediatric MS diagnosis is challenging and many questions remain unanswered about its
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clinical course, etiology and relationship with other childhood demyelinating diseases [5]. Muller R et al and Leibowitz U et al described a better prognosis for patients with low age of
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onset[6,7], while Lazarte JA et al reported more favorable prognosis for older patients [8] and Poser S et al could not find any influence of age of onset on the clinical features [9]. Morocco is one of the areas of low MS prevalence, although a recent increase has been observed [10].
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The demographic and clinical profile of Moroccan MS pediatric patients is still unknown.
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In this study, we present the clinical characteristics and disability progression in a cohort of MS patients presenting with their first symptoms under the age of 18 years, seen at Neurology
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B department of the Rabat University hospital.
2. Material and methods:
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2.1 Material:
This is a retrospective study. We identified patients with pediatric onset (before age 18) among all MS patients admitted between 2005 and 2013 at the Neurology B department of Rabat Ibn sina University Hospital and medical school group of neurogenetic disorder of Rabat Med V university. The department is a national referral center for patients with MS onset before the age of 18 years.
2.2 Clinical definitions: The 2012 revised criteria of the International Paediatric Multiple Sclerosis Study Group (IPMSSG) for pediatric cases (CIS, ADEM, MS and NMO) were used to analyze the data [11]. 3
ACCEPTED MANUSCRIPT Disability status was assessed by a neurologist with the Expanded Disability Status Scale (EDSS) [12].
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2.3 Epidemiological data:
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The following information was collected for all patients:
- Demographic data: date of birth, age at follow-up, gender, geographical origin.
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- Clinical data: age of MS onset, age of MS diagnosis, symptoms at disease onset, relapse history (frequency, duration of first and second remissions), age at the onset of secondary progression, Expanded Disability Status Scale score (EDSS) at time of admission,
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time to reach EDSS 3.0, time from EDSS 3.0 to EDSS 6.0, ongoing treatment, dosage, age at treatment initiation, EDSS before treatment and treatment duration.
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- We have used the consensus definitions published by the international pediatric MS study Group in 2007, which defines pediatric MS as having an onset below 18 years of age. EDSS 3.0 and 6.0, and secondary progression were the major chosen outcomes as they are
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widely used in natural history studies of MS and reflect clear steps in disability and
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2.4 Statistical analysis:
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unfavorable changes in the course of MS.
Categorical variables were expressed as frequencies and continuous variables were expressed as median (interquartile range).Tests used included Chi-square and Mann- Whitney tests. A p value of 0.05 or less was considered to be statistically significant. Data were analyzed
3. Results:
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using the statistical software SPSS version 13.0 (spss, Inc., Chicago, IL, USA).
3.1 Sociodemographics data: We identified 25 patients with pediatric-onset MS out of 232 MS patients admitted during the study period (14 girls, 56%). The female/male ratio was respectively 1.2 and 1.3 before and after the age of 12. Demographic characteristics are shown in table I. The median age at onset of the disease was 14 years [range 11-16 years]. Age of onset was similar for males (14 years [range 11-16]) and females (14 years [range 11-16.5], p=0.956). None of our pediatric MS patients reported a history of MS in first degree relatives.
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ACCEPTED MANUSCRIPT 3.2 Clinical data: Figure 1 illustrates the initial symptoms in our patients. At the time of onset, motor disturbances occurred in 9 patients (53%), brainstem symptoms in 6 (35.3%) and optic
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neuritis in 5 (29.4%). One case (5.9%) experienced unilateral optic neuritis while 4 (23.6%)
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had bilateral optic neuritis at onset. None of our patients had bilateral optic neuritis concurrent with transverse myelitis. Sensory symptoms occurred in 2 patients (11.7%), cerebellar ataxia
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and s p h i n c t e r d i s o r d e r s i n 4 p a t i e n t s r e s p e c t i v e l y ( 23.5%).
Monofocal
b r a i n s t e m a n d cerebellar symptoms were occurred respectively in 3 (17.6%) and 2 (11.8%) patients.
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We found 9 patients (36%) with monosymptomatic presentation, while others had polysymptomatic onset.
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No patient had an acute, fulminant, multifocal or monofocal neurological disturbances associated with meningoencephalitic symptoms and signs such as fever, headache, consciousness alteration, convulsions or meningism.
3.3 Clinical course:
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infection before symptom onset.
None of the patients had signs of
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The median time between disease onset and time of diagnosis was 2 years [range 1- 9]. Relapsing-remitting (RR) course was more common (17 patients: 68%), of whom 9 female (52.9%).
Among the 25 patients with relapsing-remitting MS at the beginning of their illness; 8 (32%)
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had progression; their median age at disease onset was 15 years [10.3 - 16], and their median duration of transition to progression was 5 years [4 -19]. One patient had progression before the age of 18.
The time between onset and diagnosis in SPMS patients was 1 years [0 – 3.5]. No primary progressive MS was reported (table I). The median time between the first and second attacks was1 year [range 0.9-3] with a median of 2 relapses in the first 2 years (range: 1 to 4). The median time to secondary progression was 5 years (range: 4 to 19). At the time of the last evaluation, the median time follow up was 4 years [1.5 - 6] and the median EDSS score was 3.0 [range 0-7.5]. The median time to reach EDSS 3.0 was 4.5 years [range 2-17 years]. Median time to transition from EDSS 3.0 to 6.0 was 4 years [range 2.5-6 years].
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ACCEPTED MANUSCRIPT 3.4 Treatment: The use of medication for MS is represented in figure 2 showing that the most commonly prescribed treatment was methylprednisolone (60%) and cyclophosphamide (32%).
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For patients treated with cyclophosphamide, the median age of onset of treatment was 21.5
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years [18-32 years] showing that over 75% of these patients began their treatment beyond the age of 18.
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All patients with secondary progressive MS were treated by cyclophosphamide. They have been treated according to the same protocol by an intravenous infusion of 600mg/m2 body surface administrated every 2 months for a period of 24 months [13].
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Two patients were on Interferon B1a weekly (one for 1 year and the other for 4 years) both had an EDSS score of 1.0.
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The MS patients, hospitalized before 2002 received a basic therapy of methylprednisolone bolus bimonthly or quarterly.
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4. Discussion:
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This is the first report of Moroccan pediatric-onset MS. Our data suggest that some patients progress early to a secondary progressive form of MS with substantial disability (5 years).The
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female predominance in our study is in line with previous literature (sex ratio ranging from 2.2 to 3) [14,15]. The most common symptoms at onset were motor deficit (52.4%) in the absence of signs encephalitic ADEM. 32% of patients were treated with cyclophosphamide and 75% of them began their treatment beyond the age of 18. Other patients diagnosed
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before the age of 18 were treated with methylprednisolone boluses. Childhood onset MS is defined in some studies as MS that starts before 16 years of age. More recent definitions have used a cut-off of 18 years [3]. The incidence of pediatric-onset MS cases among the MS in-patient admissions in our department was 10.7%, consistent with the series of Simone et al which estimated a prevalence of pediatric onset MS of 10.5% [16]. However, some other series have reported lower incidence in the outpatient setting [14,15,17]. The median age of onset in our cohort (14 years) was somewhat older than in some previously published series. In the series of Gusev et al, it was 11.7 years, 2 and 9.3 years in the three groups [18]. The youngest published onset of MS was in a 24 month-old patient [19].The earliest onset in the Bauer and Hanefeld’s cohort was in a 4 year-old boy [20]. In our series, the earliest onset was in an 8 year-old girl. This difference could be explained by the differences in referral to the studies.
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ACCEPTED MANUSCRIPT In our cohort, more than half of the children who were eventually diagnosed with MS presented with polyfocal symptoms (16 patients, 64%), about a third with monofocal features (9 patients 36%), contrary to what is reported in others series in which the initial presentation
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is predominantly monosymptomatic (56.2 to 87.9%) [15,16,17]. This difference could be
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related to our patients having a more severe presentation leading to admission as in-patients, while most of the other published series were reported in out-patient setting. The most
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common initial clinical symptoms in our patients were motor deficits (53%), followed by the brainstem symptoms (35.3%) and optic neuritis (29.4%). The predominance of motor symptoms at onset was also reported in two other series (53.6% and 36.1%of the patients)
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[16,21]. This is also in line with others series reporting isolated optic neuritis in approximately 20 – 25% of the patients, brainstem dysfunction in 10 – 25%, and long tract
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dysfunction (including motor and sensory changes) in 40 – 50% (3). In two other series, sensory disturbance was more common at onset (26.4% and 25.9%) [14,15]. The 3 patients with onset before 10 years had respectively monoplegia and optic neuritis,
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cerebellar syndrome with monoplegia and hemiplegia with convergent strabismus. ADEM
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was ruled out because they presented additional relapses during their follow-up. According to the literature, in 15-35% of patients who present with an initial suspected diagnosis of ADEM
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further follow-up reveals a final diagnosis of MS [22,23,24]. Thus, clinical features consistent with ADEM at presentation do not exclude a future diagnosis of MS, especially in children. In our study, time from MS onset to the second neurological event was 12 months. This is in line with some published studies although some had a longer duration up to 71.3 months [2,
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15,25,26,27]. In the multicenter French and Belgian KIDMUS study, the estimated median time was 2 years, similar to the duration of 2.2 years in the adults onset Lyon cohort with relapsing–remitting MS [28]. The referral bias, ethnicity and demographic characteristics of our cohort may contribute to a higher risk of second event during the first year of onset. Eight (32%) of our pediatric patients experienced secondary progression after a mean of 5 years after disease onset. In our cases, this progression is more severe than those reported in other series [15,16,26]. Indeed, the proportion of patients reaching the secondary progressive phase varies with the duration of follow-up and the MS cases entering the progressive phase increase in quasi – linear manner with duration of the follow-up [29,30]. Therefore, the proportion of patients reaching the secondary progressive phase is highly variable from 0 in studies with the shortest follow-up to more than 50% in some other series. Different reports, showed that secondary progressive could be seen in 53% [15], 42%[31], 14% [16], 4% [26], respectively, after mean 7
ACCEPTED MANUSCRIPT disease durations of 17.7 years, 12.9 years, 10 years, 4.8 years demonstrating that the follow up duration is the key determinant of entry into secondary progressive MS. However in our series, we found that 32% of our patients entering secondary progressive phase after a median
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disease duration of 5 years. This raises the hypothesis that a genetic factor could impact this
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percentage; however more studies are needed to determine this MS genetic predisposition. Patients with childhood-onset MS convert to secondary progression on average 10 years later
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than patients with adult’s onset, but they are on average 10 years younger when reaching this phase of the disease [2]. The median time from onset of MS to the secondary progressive phase was estimated at 23 years, in a cohort of 113 patients, compared to 10 years for a
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comparison cohort of adult-onset MS [15]. The risk of secondary progressive MS was associated with a high frequency of relapse and shorter intervals between attacks in the first 2
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years of the disease [16]. In our patients, the median time between the first and second attacks was short, 1 year, with an average of 2 relapses in the first 2 years. In the various published case series, between 24% and 60% of pediatric patients experienced a second clinical attack
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within one year [5]. It is possible that younger children tend to have a longer interval from
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first to second attack (median 6 years), in contrast with adolescent patients with MS, who have their second attack within 12 months [32]. However, this needs to be confirmed as series
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typically have very few patients under 10. Disability progression in our cohort was more severe than in most published series; the median time to reach EDSS 3.0 was 4.5 years, and median time between EDSS 3.0 and 6.0 was 4 years compared with18 years in Moroccan adult-onset MS [33]. In a Canadian cohort,
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the median time from pediatric MS onset to the assignment of a score of 3.0 was 23 years compared with10 years in the adult-onset group. The median time to EDSS 6.0 was 28 years compared with18 years for the adult group [3]. One of the major limitations of our study is the small sample size related to the fact that our centre mostly treats adults-onset MS patients. In addition, it is possible that pediatric cases referred to our hospital were more severe and that milder cases were not referred to us. Other limitations of our study include the retrospective design, and the use of recall data regarding the nature of first symptoms at onset. Mono- and polysymptomatic onset as well as ADEMlike onset may have been misclassified because patients were not examined at the time of first symptoms.
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ACCEPTED MANUSCRIPT 5. Conclusion: These results should help initiate early treatment for Moroccan children and adolescents with MS. A multicenter study including all the neuropediatric and neurologic departments in
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Morocco, using standardized diagnostic criteria for pediatric MS and standardized follow-up
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with MRI assessment after a first demyelinating event in childhood is needed.
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ACCEPTED MANUSCRIPT References: 1. Serkan O, Egemen I, Baris B, et al: Childhood and juvenile onset multiple sclerosis:clinical and paraclinical features. Brain and Development 2003;25:233-236.
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2. Gusev E, Boiko A and Olga B. The natural history of early onset multiple sclerosis:
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3. Christel R, Sandra V and Christian C: The natural history of multiple sclerosis with childhood onset, clinical Neurology and Neurosurgery 2008;110:897-904. 4. Kazuhiro S, Yoshihisa H, Kyoko O et al: Clinical course and prognosis of 27 patients with
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6. Müller R. Studies on disseminated sclerosis. Acta Med Scand 1949;22:211–214. 7. Leibowitz U, Halpern L and Alter M. Clinical studies of MS in Israel. Arch Neurol
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8. Lazarte JA. MS: prognosis ambulatory and nonambulatory patients. Assoc Res Nerv Dis
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9. Poser S, Raun NE and Poser W. Age at onset, initial symptomatology and the course of multiple sclerosis. Acta Neurol Scand 1982;66:355–362. 10. Atlas Multiple Sclerosis Resources in the World, 2008, p.15. 11. Krupp LB, Tardieu M, Pia Amato M, et al. International Pediatric Multiple Sclerosis
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ACCEPTED MANUSCRIPT 17. Ghezzi A, Deplano V, Faroni J, et al. Multiple sclerosis in childhood: clinical features of 149 cases. Multiple sclerosis 1997;3:43-6. 18. Torisu H, Kira R and Ishizaki Y. Clinical study of childhood acute disseminated
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20. Bauer HJ and Hanefeld F. Multiple Sklerose imKindesalter. In: Hanefeld F, editor. Aktuelle Neuropädiatri 1989, Berlin: Springer, 1990: 285–295.
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21. Cole GF and Stuart CA. A long perspective on childhood multiple sclerosis.Dev Med Child Neurol 1995;37:661-6.
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study: prognostic factors for relapse. Eur J Paediatr Neurol 2007; 11: 90–95. 25. Selcen D, Anlar B and Renda Y. Multiple sclerosis in childhood: report of 16 cases. Eur Neurol 1996; 36: 79-84.
26. Mikaeloff Y, Caridade G, Assi S, et al. Prognostic factors for early severity in a childhood
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onset multiple sclerosis cohort. Pediatrics 2006; 118: 1133-9. 27. Banwell B, Krupp L, Kennedy J, et al. Clinical features and viral serologies in children with multiple sclerosis: a multinational observational study. Lancet Neurol 2007; 6: 773-781. 28. Renoux C, Vukusic S and Confavreux C. Natural history of multiple sclerosis with childhood onset. N Engl J Med 2007; 356: 2603-13 29. Confavreux C and Compston A. The natural history of multiple sclerosis. In: Compston A, editor. McAlpine’s multiple sclerosis. 4th ed. London: Churchill Livingstone Elsevier 2006:183-272. 30. Vukusic S, Confavreux C. Prognostic factors for progression of disability in the secondary progressive phase of multiple sclerosis. J Neurol Sci 2003; 206: 135-137.
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ACCEPTED MANUSCRIPT 31. Deryck O, Ketelaer P, Dubois B. Clinical characteristics and long term prognosis in early onset multiple sclerosis. J Neurol. 2006 Jun;253(6):720-3. Epub 2006 Mar 6. 32. Araqi-Houssaini A, Lahlou I, Benkadmir Y, et al. Multiple sclerosis severity score in a
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33. Banwell B, Ghezzi A, Bar-Or A. Multiple sclerosis in children: clinical diagnosis,
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ACCEPTED MANUSCRIPT
Initial symptoms
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11.7
Sensitive symptoms
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23.5
Sphincter disorders
23.5
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Cerebellar ataxia
29.4
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Optic neuritis
Brainstem symptoms
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10
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Motor disorders Motors desorders 20
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Figure 1: Frequencies of initial clinical symptoms.
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35.3
53
% 30
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50
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Patient's treatment Cyclophosphamide
Metylprednisolone
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8%
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Interferon
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60%
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Figure 2: Patient’s treatment.
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32%
ACCEPTED MANUSCRIPT Table I: Comparative demographic and disease-related characteristics of relapsing– remitting and secondary progressive cases
Secondary progressive multiple sclerosis n=8 5 (62.5%)
P-value
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Relapsing-remitting multiple sclerosis n = 17 9 (52.9%)
Age at MS onset ¶ (years)
14 [12-16]
15 [10.25-16]
0.56
Age at MS diagnosis ¶ (years)
16.3±5.3
18.5±7.1
0.43
Time between onset of disease and diagnosis (years)
1 [0-2.5]
1.5 [0-8]
0.55
EDSS ¶
1 (0.38-2)
6.5 (4.75-7)
0.001
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Females*
* Expressed with Number and %
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¶ Expressed with median and interquartile range
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ACCEPTED MANUSCRIPT Highlights (for review)
We report the first MS study on Moroccan pediatric-onset (25 patients).
Epidemiological, clinical characteristics and disability progression was studied.
Early progression to secondary form of MS with substantial disability was found.
The early starting of adequate and recommended treatment is important.
Genetic factors may explain the made observations and need to be explored.
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clinical characteristics and disability progression in
Elhachmia Ait Ben Haddou, Mounia Alhyan, Jehanne Aasfara, Wafa Regragui, Azeddine Ibrahimi, Rachid Razine, Redouane Abouqal, Ali Benomar, Mohamed Yahyaoui PII: DOI: Reference:
S0022-510X(14)00521-8 doi: 10.1016/j.jns.2014.08.008 JNS 13375
To appear in:
Journal of the Neurological Sciences
Received date: Revised date: Accepted date:
13 April 2014 4 July 2014 6 August 2014
Please cite this article as: Ait Ben Haddou Elhachmia, Alhyan Mounia, Aasfara Jehanne, Regragui Wafa, Ibrahimi Azeddine, Razine Rachid, Abouqal Redouane, Benomar Ali, Yahyaoui Mohamed, Multiple sclerosis: clinical characteristics and disability progression in Moroccan children, Journal of the Neurological Sciences (2014), doi: 10.1016/j.jns.2014.08.008
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Multiple sclerosis: children
clinical characteristics and disability progression in Moroccan
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Elhachmia Ait Ben Haddou a,b,f*, Mounia Alhyan a,f, Jehanne Aasfara a,f, Wafa Regragui a, Azeddine Ibrahimi c, Rachid Razine d,e, Redouane Abouqal d, Ali Benomar a,b and Mohamed Yahyaoui a a
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: Department of Neurology B and Neurogenetics, Hôpital des Spécialités Rabat, Faculté de Médecine et de Pharmacie Rabat, Mohammed V University Souissi, Rabat, Morocco. b
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: Medical Center of Clinical Trials and Epidemiological Study (CRECET), Faculté de Médecine et de Pharmacie Rabat, Mohammed V University Souissi, Rabat, Morocco. c
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: Biotech Lab. (MedBiotech), Faculté de Médecine et de Pharmacie Rabat, Mohammed V University Souissi, Rabat, Morocco. d
: Laboratory of Biostatistics and clinical epidemiological research (LBRCE), Faculté de Médecine et de Pharmacie Rabat, Mohammed V University Souissi, Rabat, Morocco. e
: These three authors contributed equally to this work.
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f
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: Laboratoire de santé publique, Faculté de Médecine et de Pharmacie Rabat, Mohammed V University Souissi, Rabat, Morocco.
* Corresponding author: Ait Ben Haddou Elhachmia
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Tel.: +212 6 72860 980
E-mail address: [email protected] Alhyan Mounia: [email protected] Aasfara Jehanne: [email protected] Regragui Wafa: [email protected] Ibrahimi Azeddine: [email protected] Razine Rachid: [email protected] Abouqal Redouane: [email protected] Benomar Ali: [email protected] Yahyaoui Mohamed: [email protected]
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ACCEPTED MANUSCRIPT Abstract:
Background: 5% of Multiple sclerosis have their onset in childhood.
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Objectives: We aim to show the clinical features and follow-up of Moroccan pediatric MS
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patients.
Methods: 25 pediatric MS records were analyzed between 2005 and 2013 at the Neurology B
disorder of Rabat Mohammed V University Souissi.
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department of Rabat Ibn sina University Hospital and medical school group of Neurogenetic
Results: The median duration of follow up was 4 years [1.5 - 6]. The median age at disease
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onset was 14 years. Clinical symptoms were described. At the last evaluation, the median EDSS score was 3.0 [0- 7.5]. The median time between disease onset and diagnosis was 2
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years [1-9] and the median time from MS onset to second neurological episode was 1 year [0.9-3] with an average of 2 relapses in the first 2 years. The median time to reach EDSS 3.0 was 4.5 years [2- 17] and the median time to go from EDSS 3.0 to 6.0 was 4 years [2.5-6].
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The majority of cases at the last follow-up were; relapsing-remitting (17 patients: 68%),
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although 8 patients (32%) developed secondary progressive MS after median disease duration of 5 years [4-19]. None of the patients had a primary progressive MS.
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Conclusion: Time EDSS 3.0 and to secondary progression was shorter in our cohort than previously reported in others series.
Keywords: Multiple sclerosis; Age of onset; Children; Clinical features; Outcome
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measurement; Treatment.
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ACCEPTED MANUSCRIPT 1. Introduction:
Multiple sclerosis (MS) is a demyelinating disease of the central nervous system, often
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starting in the third or fourth decade of life [1]. However, it can be identified in children and
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adolescents as well. The first MS case in childhood is believed to have been described by Pierre Marie in 1893 [2]. Between 0.4 and 5.7% of all MS cases have their onset before the
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age of 18. A single study reported 10.5% of patients with an onset before the age of 16 [3]. Relapsing-remitting forms are, by far, the most common presentation at onset in children [4]. Pediatric MS diagnosis is challenging and many questions remain unanswered about its
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clinical course, etiology and relationship with other childhood demyelinating diseases [5]. Muller R et al and Leibowitz U et al described a better prognosis for patients with low age of
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onset[6,7], while Lazarte JA et al reported more favorable prognosis for older patients [8] and Poser S et al could not find any influence of age of onset on the clinical features [9]. Morocco is one of the areas of low MS prevalence, although a recent increase has been observed [10].
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The demographic and clinical profile of Moroccan MS pediatric patients is still unknown.
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In this study, we present the clinical characteristics and disability progression in a cohort of MS patients presenting with their first symptoms under the age of 18 years, seen at Neurology
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B department of the Rabat University hospital.
2. Material and methods:
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2.1 Material:
This is a retrospective study. We identified patients with pediatric onset (before age 18) among all MS patients admitted between 2005 and 2013 at the Neurology B department of Rabat Ibn sina University Hospital and medical school group of neurogenetic disorder of Rabat Med V university. The department is a national referral center for patients with MS onset before the age of 18 years.
2.2 Clinical definitions: The 2012 revised criteria of the International Paediatric Multiple Sclerosis Study Group (IPMSSG) for pediatric cases (CIS, ADEM, MS and NMO) were used to analyze the data [11]. 3
ACCEPTED MANUSCRIPT Disability status was assessed by a neurologist with the Expanded Disability Status Scale (EDSS) [12].
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2.3 Epidemiological data:
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The following information was collected for all patients:
- Demographic data: date of birth, age at follow-up, gender, geographical origin.
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- Clinical data: age of MS onset, age of MS diagnosis, symptoms at disease onset, relapse history (frequency, duration of first and second remissions), age at the onset of secondary progression, Expanded Disability Status Scale score (EDSS) at time of admission,
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time to reach EDSS 3.0, time from EDSS 3.0 to EDSS 6.0, ongoing treatment, dosage, age at treatment initiation, EDSS before treatment and treatment duration.
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- We have used the consensus definitions published by the international pediatric MS study Group in 2007, which defines pediatric MS as having an onset below 18 years of age. EDSS 3.0 and 6.0, and secondary progression were the major chosen outcomes as they are
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widely used in natural history studies of MS and reflect clear steps in disability and
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2.4 Statistical analysis:
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unfavorable changes in the course of MS.
Categorical variables were expressed as frequencies and continuous variables were expressed as median (interquartile range).Tests used included Chi-square and Mann- Whitney tests. A p value of 0.05 or less was considered to be statistically significant. Data were analyzed
3. Results:
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using the statistical software SPSS version 13.0 (spss, Inc., Chicago, IL, USA).
3.1 Sociodemographics data: We identified 25 patients with pediatric-onset MS out of 232 MS patients admitted during the study period (14 girls, 56%). The female/male ratio was respectively 1.2 and 1.3 before and after the age of 12. Demographic characteristics are shown in table I. The median age at onset of the disease was 14 years [range 11-16 years]. Age of onset was similar for males (14 years [range 11-16]) and females (14 years [range 11-16.5], p=0.956). None of our pediatric MS patients reported a history of MS in first degree relatives.
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ACCEPTED MANUSCRIPT 3.2 Clinical data: Figure 1 illustrates the initial symptoms in our patients. At the time of onset, motor disturbances occurred in 9 patients (53%), brainstem symptoms in 6 (35.3%) and optic
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neuritis in 5 (29.4%). One case (5.9%) experienced unilateral optic neuritis while 4 (23.6%)
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had bilateral optic neuritis at onset. None of our patients had bilateral optic neuritis concurrent with transverse myelitis. Sensory symptoms occurred in 2 patients (11.7%), cerebellar ataxia
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and s p h i n c t e r d i s o r d e r s i n 4 p a t i e n t s r e s p e c t i v e l y ( 23.5%).
Monofocal
b r a i n s t e m a n d cerebellar symptoms were occurred respectively in 3 (17.6%) and 2 (11.8%) patients.
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We found 9 patients (36%) with monosymptomatic presentation, while others had polysymptomatic onset.
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No patient had an acute, fulminant, multifocal or monofocal neurological disturbances associated with meningoencephalitic symptoms and signs such as fever, headache, consciousness alteration, convulsions or meningism.
3.3 Clinical course:
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infection before symptom onset.
None of the patients had signs of
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The median time between disease onset and time of diagnosis was 2 years [range 1- 9]. Relapsing-remitting (RR) course was more common (17 patients: 68%), of whom 9 female (52.9%).
Among the 25 patients with relapsing-remitting MS at the beginning of their illness; 8 (32%)
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had progression; their median age at disease onset was 15 years [10.3 - 16], and their median duration of transition to progression was 5 years [4 -19]. One patient had progression before the age of 18.
The time between onset and diagnosis in SPMS patients was 1 years [0 – 3.5]. No primary progressive MS was reported (table I). The median time between the first and second attacks was1 year [range 0.9-3] with a median of 2 relapses in the first 2 years (range: 1 to 4). The median time to secondary progression was 5 years (range: 4 to 19). At the time of the last evaluation, the median time follow up was 4 years [1.5 - 6] and the median EDSS score was 3.0 [range 0-7.5]. The median time to reach EDSS 3.0 was 4.5 years [range 2-17 years]. Median time to transition from EDSS 3.0 to 6.0 was 4 years [range 2.5-6 years].
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ACCEPTED MANUSCRIPT 3.4 Treatment: The use of medication for MS is represented in figure 2 showing that the most commonly prescribed treatment was methylprednisolone (60%) and cyclophosphamide (32%).
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For patients treated with cyclophosphamide, the median age of onset of treatment was 21.5
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years [18-32 years] showing that over 75% of these patients began their treatment beyond the age of 18.
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All patients with secondary progressive MS were treated by cyclophosphamide. They have been treated according to the same protocol by an intravenous infusion of 600mg/m2 body surface administrated every 2 months for a period of 24 months [13].
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Two patients were on Interferon B1a weekly (one for 1 year and the other for 4 years) both had an EDSS score of 1.0.
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The MS patients, hospitalized before 2002 received a basic therapy of methylprednisolone bolus bimonthly or quarterly.
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4. Discussion:
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This is the first report of Moroccan pediatric-onset MS. Our data suggest that some patients progress early to a secondary progressive form of MS with substantial disability (5 years).The
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female predominance in our study is in line with previous literature (sex ratio ranging from 2.2 to 3) [14,15]. The most common symptoms at onset were motor deficit (52.4%) in the absence of signs encephalitic ADEM. 32% of patients were treated with cyclophosphamide and 75% of them began their treatment beyond the age of 18. Other patients diagnosed
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before the age of 18 were treated with methylprednisolone boluses. Childhood onset MS is defined in some studies as MS that starts before 16 years of age. More recent definitions have used a cut-off of 18 years [3]. The incidence of pediatric-onset MS cases among the MS in-patient admissions in our department was 10.7%, consistent with the series of Simone et al which estimated a prevalence of pediatric onset MS of 10.5% [16]. However, some other series have reported lower incidence in the outpatient setting [14,15,17]. The median age of onset in our cohort (14 years) was somewhat older than in some previously published series. In the series of Gusev et al, it was 11.7 years, 2 and 9.3 years in the three groups [18]. The youngest published onset of MS was in a 24 month-old patient [19].The earliest onset in the Bauer and Hanefeld’s cohort was in a 4 year-old boy [20]. In our series, the earliest onset was in an 8 year-old girl. This difference could be explained by the differences in referral to the studies.
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ACCEPTED MANUSCRIPT In our cohort, more than half of the children who were eventually diagnosed with MS presented with polyfocal symptoms (16 patients, 64%), about a third with monofocal features (9 patients 36%), contrary to what is reported in others series in which the initial presentation
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is predominantly monosymptomatic (56.2 to 87.9%) [15,16,17]. This difference could be
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related to our patients having a more severe presentation leading to admission as in-patients, while most of the other published series were reported in out-patient setting. The most
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common initial clinical symptoms in our patients were motor deficits (53%), followed by the brainstem symptoms (35.3%) and optic neuritis (29.4%). The predominance of motor symptoms at onset was also reported in two other series (53.6% and 36.1%of the patients)
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[16,21]. This is also in line with others series reporting isolated optic neuritis in approximately 20 – 25% of the patients, brainstem dysfunction in 10 – 25%, and long tract
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dysfunction (including motor and sensory changes) in 40 – 50% (3). In two other series, sensory disturbance was more common at onset (26.4% and 25.9%) [14,15]. The 3 patients with onset before 10 years had respectively monoplegia and optic neuritis,
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cerebellar syndrome with monoplegia and hemiplegia with convergent strabismus. ADEM
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was ruled out because they presented additional relapses during their follow-up. According to the literature, in 15-35% of patients who present with an initial suspected diagnosis of ADEM
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further follow-up reveals a final diagnosis of MS [22,23,24]. Thus, clinical features consistent with ADEM at presentation do not exclude a future diagnosis of MS, especially in children. In our study, time from MS onset to the second neurological event was 12 months. This is in line with some published studies although some had a longer duration up to 71.3 months [2,
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15,25,26,27]. In the multicenter French and Belgian KIDMUS study, the estimated median time was 2 years, similar to the duration of 2.2 years in the adults onset Lyon cohort with relapsing–remitting MS [28]. The referral bias, ethnicity and demographic characteristics of our cohort may contribute to a higher risk of second event during the first year of onset. Eight (32%) of our pediatric patients experienced secondary progression after a mean of 5 years after disease onset. In our cases, this progression is more severe than those reported in other series [15,16,26]. Indeed, the proportion of patients reaching the secondary progressive phase varies with the duration of follow-up and the MS cases entering the progressive phase increase in quasi – linear manner with duration of the follow-up [29,30]. Therefore, the proportion of patients reaching the secondary progressive phase is highly variable from 0 in studies with the shortest follow-up to more than 50% in some other series. Different reports, showed that secondary progressive could be seen in 53% [15], 42%[31], 14% [16], 4% [26], respectively, after mean 7
ACCEPTED MANUSCRIPT disease durations of 17.7 years, 12.9 years, 10 years, 4.8 years demonstrating that the follow up duration is the key determinant of entry into secondary progressive MS. However in our series, we found that 32% of our patients entering secondary progressive phase after a median
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disease duration of 5 years. This raises the hypothesis that a genetic factor could impact this
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percentage; however more studies are needed to determine this MS genetic predisposition. Patients with childhood-onset MS convert to secondary progression on average 10 years later
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than patients with adult’s onset, but they are on average 10 years younger when reaching this phase of the disease [2]. The median time from onset of MS to the secondary progressive phase was estimated at 23 years, in a cohort of 113 patients, compared to 10 years for a
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comparison cohort of adult-onset MS [15]. The risk of secondary progressive MS was associated with a high frequency of relapse and shorter intervals between attacks in the first 2
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years of the disease [16]. In our patients, the median time between the first and second attacks was short, 1 year, with an average of 2 relapses in the first 2 years. In the various published case series, between 24% and 60% of pediatric patients experienced a second clinical attack
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within one year [5]. It is possible that younger children tend to have a longer interval from
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first to second attack (median 6 years), in contrast with adolescent patients with MS, who have their second attack within 12 months [32]. However, this needs to be confirmed as series
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typically have very few patients under 10. Disability progression in our cohort was more severe than in most published series; the median time to reach EDSS 3.0 was 4.5 years, and median time between EDSS 3.0 and 6.0 was 4 years compared with18 years in Moroccan adult-onset MS [33]. In a Canadian cohort,
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the median time from pediatric MS onset to the assignment of a score of 3.0 was 23 years compared with10 years in the adult-onset group. The median time to EDSS 6.0 was 28 years compared with18 years for the adult group [3]. One of the major limitations of our study is the small sample size related to the fact that our centre mostly treats adults-onset MS patients. In addition, it is possible that pediatric cases referred to our hospital were more severe and that milder cases were not referred to us. Other limitations of our study include the retrospective design, and the use of recall data regarding the nature of first symptoms at onset. Mono- and polysymptomatic onset as well as ADEMlike onset may have been misclassified because patients were not examined at the time of first symptoms.
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ACCEPTED MANUSCRIPT 5. Conclusion: These results should help initiate early treatment for Moroccan children and adolescents with MS. A multicenter study including all the neuropediatric and neurologic departments in
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Morocco, using standardized diagnostic criteria for pediatric MS and standardized follow-up
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with MRI assessment after a first demyelinating event in childhood is needed.
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ACCEPTED MANUSCRIPT References: 1. Serkan O, Egemen I, Baris B, et al: Childhood and juvenile onset multiple sclerosis:clinical and paraclinical features. Brain and Development 2003;25:233-236.
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2. Gusev E, Boiko A and Olga B. The natural history of early onset multiple sclerosis:
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3. Christel R, Sandra V and Christian C: The natural history of multiple sclerosis with childhood onset, clinical Neurology and Neurosurgery 2008;110:897-904. 4. Kazuhiro S, Yoshihisa H, Kyoko O et al: Clinical course and prognosis of 27 patients with
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9. Poser S, Raun NE and Poser W. Age at onset, initial symptomatology and the course of multiple sclerosis. Acta Neurol Scand 1982;66:355–362. 10. Atlas Multiple Sclerosis Resources in the World, 2008, p.15. 11. Krupp LB, Tardieu M, Pia Amato M, et al. International Pediatric Multiple Sclerosis
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ACCEPTED MANUSCRIPT 17. Ghezzi A, Deplano V, Faroni J, et al. Multiple sclerosis in childhood: clinical features of 149 cases. Multiple sclerosis 1997;3:43-6. 18. Torisu H, Kira R and Ishizaki Y. Clinical study of childhood acute disseminated
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Japan. Brain and Development 2010;32:454-462.
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20. Bauer HJ and Hanefeld F. Multiple Sklerose imKindesalter. In: Hanefeld F, editor. Aktuelle Neuropädiatri 1989, Berlin: Springer, 1990: 285–295.
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21. Cole GF and Stuart CA. A long perspective on childhood multiple sclerosis.Dev Med Child Neurol 1995;37:661-6.
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22. Rust RS. Multiple sclerosis, acute disseminated encephalomyelitis, and related conditions.
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study: prognostic factors for relapse. Eur J Paediatr Neurol 2007; 11: 90–95. 25. Selcen D, Anlar B and Renda Y. Multiple sclerosis in childhood: report of 16 cases. Eur Neurol 1996; 36: 79-84.
26. Mikaeloff Y, Caridade G, Assi S, et al. Prognostic factors for early severity in a childhood
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onset multiple sclerosis cohort. Pediatrics 2006; 118: 1133-9. 27. Banwell B, Krupp L, Kennedy J, et al. Clinical features and viral serologies in children with multiple sclerosis: a multinational observational study. Lancet Neurol 2007; 6: 773-781. 28. Renoux C, Vukusic S and Confavreux C. Natural history of multiple sclerosis with childhood onset. N Engl J Med 2007; 356: 2603-13 29. Confavreux C and Compston A. The natural history of multiple sclerosis. In: Compston A, editor. McAlpine’s multiple sclerosis. 4th ed. London: Churchill Livingstone Elsevier 2006:183-272. 30. Vukusic S, Confavreux C. Prognostic factors for progression of disability in the secondary progressive phase of multiple sclerosis. J Neurol Sci 2003; 206: 135-137.
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ACCEPTED MANUSCRIPT 31. Deryck O, Ketelaer P, Dubois B. Clinical characteristics and long term prognosis in early onset multiple sclerosis. J Neurol. 2006 Jun;253(6):720-3. Epub 2006 Mar 6. 32. Araqi-Houssaini A, Lahlou I, Benkadmir Y, et al. Multiple sclerosis severity score in a
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33. Banwell B, Ghezzi A, Bar-Or A. Multiple sclerosis in children: clinical diagnosis,
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therapeutic strategies, and future directions. Lancet Neurol 2007;6:887–902.
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ACCEPTED MANUSCRIPT
Initial symptoms
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11.7
Sensitive symptoms
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23.5
Sphincter disorders
23.5
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Cerebellar ataxia
29.4
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Optic neuritis
Brainstem symptoms
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10
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Motor disorders Motors desorders 20
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Figure 1: Frequencies of initial clinical symptoms.
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35.3
53
% 30
40
50
60
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Patient's treatment Cyclophosphamide
Metylprednisolone
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8%
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Interferon
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60%
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Figure 2: Patient’s treatment.
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32%
ACCEPTED MANUSCRIPT Table I: Comparative demographic and disease-related characteristics of relapsing– remitting and secondary progressive cases
Secondary progressive multiple sclerosis n=8 5 (62.5%)
P-value
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Relapsing-remitting multiple sclerosis n = 17 9 (52.9%)
Age at MS onset ¶ (years)
14 [12-16]
15 [10.25-16]
0.56
Age at MS diagnosis ¶ (years)
16.3±5.3
18.5±7.1
0.43
Time between onset of disease and diagnosis (years)
1 [0-2.5]
1.5 [0-8]
0.55
EDSS ¶
1 (0.38-2)
6.5 (4.75-7)
0.001
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Females*
* Expressed with Number and %
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¶ Expressed with median and interquartile range
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ACCEPTED MANUSCRIPT Highlights (for review)
We report the first MS study on Moroccan pediatric-onset (25 patients).
Epidemiological, clinical characteristics and disability progression was studied.
Early progression to secondary form of MS with substantial disability was found.
The early starting of adequate and recommended treatment is important.
Genetic factors may explain the made observations and need to be explored.
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