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Multiple sclerosis in pediatric patients in Slovenia
Author’s Accepted Manuscript Multiple sclerosis in pediatric patients in Slovenia N. Krajnc, J. Oražem, Z. Rener-Primec, M.J. Kržan
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PII: DOI: Reference:
S2211-0348(18)30037-3 https://doi.org/10.1016/j.msard.2018.01.026 MSARD759
To appear in: Multiple Sclerosis and Related Disorders Received date: 20 September 2017 Revised date: 10 January 2018 Accepted date: 28 January 2018 Cite this article as: N. Krajnc, J. Oražem, Z. Rener-Primec and M.J. Kržan, Multiple sclerosis in pediatric patients in Slovenia, Multiple Sclerosis and Related Disorders, https://doi.org/10.1016/j.msard.2018.01.026 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 galley proof before it is published in its final citable 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.
Multiple sclerosis in pediatric patients in Slovenia Krajnc N1,2, Oražem J1, Rener-Primec Z1, Kržan MJ1, 3 Address1: University Children’s Hospital Department of Child, Adolescent & Developmental Neurology Bohoričeva 20 1525 Ljubljana, Slovenia Address2: Department of Pediatrics General Hospital Slovenj Gradec Gosposvetska cesta 1 2380 Slovenj Gradec, Slovenia Address3: Neurology Revita Kidričeva 47a 4000 Kranj, Slovenia Corresponding author: Natalija Krajnc, MD, PhD Department of Pediatrics General Hospital Slovenj Gradec Gosposvetska cesta 1 2380 Slovenj Gradec, Slovenia Tel.: + 386 2 88 23 471 Email: [email protected]
Word count: 2939 (main text) Abstract Aim: The purpose of this study is to review the Slovenian experience with the diagnostics, treatment and outcome in pediatric multiple sclerosis (MS) patients. There has been no nationwide report on outcomes of childhood onset multiple sclerosis in last decades. Methods: Children and adolescent diagnosed with MS and followed by Department of Child, Adolescent and Developmental Neurology, University Childrens' Hospital Ljubljana, between 1 January 2000 and 31 December 2012 were included. Data from patients' documentation were analysed retrospectively to record demographic data, clinical presentation, paraclinical findings, disability progression, relapse rate and treatment strategies. Results: The study includes 38 patients up to 18 years with MS diagnosis, with female:male ratio 2.8:1 and the incidence of 0.81 per 100.000 children of 0-18 years.The mean age at the time of diagnosis was 15 years 4 months. Most frequent presenting symptoms were sensory, motor, brain-stem, visual and ataxia and 65% of patients had a relapse in the first year. The
value of paraclinical findings was asessed. 74 % of patients with definite MS and 36 % of those with clinically isolated syndrome received disease modifyng therapy and 68 % of them was not affected at the follow-up. Interpretation: The characteristics of pediatric MS patients in Slovenia disclose higher annual relapse rates than in adults but also favourable impact of disease modifying treatment on a clinical course. Our data suggest a good treatment tolerance but also the influence of the formulation on a decision to start or switch the treatment.
Keywords: multiple sclerosis; children; epidemiology; evoked potentials; treatment response; outcome.
Running foot: Pediatric multiple sclerosis in Slovenia.
Highlights
Information on nationwide incidence and outcomes of pediatric multiple sclerosis Most frequent presenting symptoms The value of paraclinical findings The clinical course and outcome measurements
Abbreviations MS - multiple sclerosis
MS-RR - relapsing-remitting multiple sclerosis MS-SP - secondary progressive multiple sclerosis MS-PP - primary progressive multiple sclerosis IFN-ß - interferon-beta GA - glatiramer acetate DMT - disease-modifying treatment CIS - clinically isolated syndrome EDSS - Expanded Disability Status Scale CSF - cerebrospinal fluid VEP - visual evoked potentials SSEP - somatosensory evoked potentials ABEP - auditory brainstem evoked potentials MRI - magnetic resonance imaging IVIG - intravenous immunoglobulins MTX - methotrexate
Introduction The majority of MS patients present in early adulthood, but 3-5 % present before 18 years of age, including 0.1 %- 0.7 % before puberty.1-4 The etiology of MS, which causes chronic inflammatory demyelination of the central nervous system, is not known, but is probably multifactorial.5 A family history of MS in relatives is positive in 6-21 %, and geographic differences play a role in the incidence reported worldwide.6 MS is reported to be more prevalent in females, with a female to male ratio of 3:1. The McDonald diagnostic criteria, revised in 2010, are applicable for use in children and permit the diagnosis of multiple sclerosis at the first clinical attack.7-8 A higher relapse rate, an increased T2 lesion burden on MRI and evidence of early cognitive deficit at a younger age suggest a more inflammatory course of MS in the pediatric population than in adults.9 Most pediatric MS is relapsing-remitting (MS-RR), representing more than 90 % of all cases. Secondary progression (MS-SP) is rare and a primary progressive course (MSPP) is extremely rare and should raise the suspicion of an inherited leukodystrophy or a metabolic or mitochondrial etiology.1, 10 The use of interferon-beta (IFN-ß) and glatiramer acetate (GA) is generally accepted as the first-line disease-modifying treatment (DMT) in MS-RR, but there is no consensus on such treatment for the first demyelinating episode or clinically isolated syndrome (CIS).9 There is a lack of global consensus on the definition of an inadequate treatment response for MS in both adults and children to facilitate decision-making on treatment escalation. The proposed working definition of the International Pediatric Multiple Sclerosis Study Group helps to establish a treatment failure.9 Regulatory approval of first-line DMT in Slovenia restricted administration to older adolescents and adult patients during the first years of approval (late 90s to the beginning of 2000), but in the last decade this treatment has become available to patients 12 years and older. The treatment is approved and fully paid for by the National Health Service after approval by a regional Committee for Treatment of MS, comprising a team of adult neurologists. Our department as a part of a University Children’s Hospital Ljubljana is the only pediatric MS referral center in Slovenia and only exceptionally the pediatric patients were first evaluated elsewhere and then referred to us. So the nationwide incidence and clinical characteristics of pediatric MS are fairly representative for Slovenia, which has a population of about 2 million, and could be compared in a context of geographical differences reported in other pediatric studies. The aim of this study was to provide an overview of the Slovenian pediatric MS population which was sistematically followed-up but not reported previously. Materials and methods This study included children and adolescents under 18 years of age who were diagnosed with multiple sclerosis between 1 January 2000 and 31 December 2012 in the Department of Child, Adolescent and Developmental Neurology, University Children’s Hospital Ljubljana. The formal patients consent or ethical approval was not needed for this type of the retrospective data analysis. According to new diagnostic and treatment approaches, and to achieve at least 3 years of follow-up, we included only patients presenting between 2000 and
2012. All patients have been identified by search through a local database of our department. The medical and demographic data were collected from the patients' medical records of their outpatient or hospital visits to our MS team according to the confirmed diagnosis of MS or CIS. CIS was defined as a central nervous system demyelinating event isolated in time, not evolved to definite MS at the time of follow-up. All other patients with demyelinating spectrum disorders were excluded from the study. The patients were included according to the McDonald 2010 criteria. We recorded demographic data such as gender and age at presentation, family history of multiple sclerosis, symptoms at presentation, Expanded Disability Status Scale (EDSS) at presentation and at the last follow-up, paraclinical findings such as cerebrospinal fluid (CSF) analysis, visual evoked potentials (VEP), somatosensory evoked potentials (SSEP), auditory brainstem evoked potentials (ABEP) and magnetic resonance imaging (MRI), relapse rate, and treatment.
Results We included 38 patients over a 13-year period. The female to male ratio was 2.8:1. The incidence was 0.81 per 100,000 children aged 0-18 years in Slovenia. Only the youngest two patients, both aged 10 years, were prepubertal. Definite MS was confirmed in 27 patients, in one patient as secondary progressive MS (MSSP) and, in the remainder, as relapsing-remitting MS (MS-RR). Clinically isolated syndrome (CIS) was confirmed in 11 patients. The mean age at diagnosis was 15 years 4 months (range: 10.0 years – 17 years 11 months) and the mean follow-up was 52 months (range: 1 – 106 months). The family history revealed MS in a first-degree relative in 7 of 37 (19 %) of our patients, including two pairs of sisters. The mean time between the first symptoms and confirmation of the diagnosis was six months (range: 0 – 24 months). The diagnosis was confirmed in a couple of days in 17 (45 %) patients and after 24 months, at the time of a relapse, in a single patient with a previous history of transitory sensory symptoms. We evaluated separately the mean lag time to confirmation of the diagnosis for the patients referred in the last 5-year period. This was 2.5 months (range: 0 – 19 months), with 50 % of patients being diagnosed in less than one month, although one patient with previous paroxysmal motor phenomena was diagnosed 19 months later. The most common presenting symptoms were sensory disturbance (16 patients, 42 %), followed by motor (13 patients, 34 %), brainstem (10 patients, 26 %), visual (9 patients, 24 %), ataxia (8 patients, 21 %) and urinary bladder dysfunction (2 patients, 5 %). Only one system was affected in 22 patients (58 %), most frequently the sensory system (10 patients, 26 %), followed by visual (6 patients, 16 %), motor and brainstem (3 patients, 8 %, respectively). (Table 1) The mean time between diagnosis and the first relapse was 12 months, with 65 % of patients relapsing within the first year. The annual relapse rate was calculated in 22 of 27 MS patients who were followed long enough and revealed 0.95 relapses per patient per year in the first three years. Cerebrospinal fluid analysis
CSF was analyzed at the time of diagnosis in all patients except one CIS patient who refused the procedure, in 33 of 36 at the time of the acute neurologic presentation. CSF analysis was repeated later in only one patient with MS-RR, but all parameters were negative, even at the time of the second analysis. Pleocytosis, elevated proteins, intrathecal Ig synthesis and oligoclonal bands were evaluated. (Table 2) Pleocytosis was present in 18 of 34 (53 %) patients, in 4 of 10 (40 %) patients with CIS and in 14 of 24 (58 %) MS patients. Mildly elevated proteins (less than 1g /l) were present only in 3 of 34 (9 %) patients, in 2 of 10 (20 %) patients with CIS and 1 of 25 (4 %) with MS. Intrathecal Ig synthesis was present in 23 of 36 (64 %) patients, in 7 of 10 (70 %) patients with CIS and in 16 of 25 (64 %) MS patients. Further data on intrathecal Ig subtype were available for 22 of 23 patients; nine patients (41 %) had isolated IgG synthesis, seven patients (32 %) had isolated IgM synthesis, two patients (9 %) had combined IgG and IgM synthesis, three (14 %) patients had combined IgG, IgM and IgA synthesis, and one patient (4.5 %) had isolated IgA synthesis. Oligoclonal bands present only in the CSF were confirmed in 24 of 36 (67 %) patients, in 9 of 10 (90 %) patients with CIS and 15 of 26 (58 %) MS patients. No patient had positive oligoclonal bands in plasma. Neurophysiological investigations They were performed in 37 patients, in 34 of them in the time of the acute neurologic presentation, and in 3 patients partially in acute or non-acute phase. VEP were assessed in all patients and were abnormal in 19 (50 %), including all six patients (16 %) with isolated unilateral optic neuritis, but also in 13 (34 %) other patients without overt visual disturbance at the time of clinical presentation. SSEP were assessed in 32 (84 %) patients and were abnormal in 20 (62.5 %), including two (6 %) patients with isolated visual disturbance. ABEP were assessed in 14 (37 %) patients and were abnormal in seven (50 %), including four patients with brainstem disturbance and three patients with isolated motor, sensory or combined sensory and visual disturbance. (Table 1) MRI results MRI lesions were typical according to the McDonald criteria in all but four patients (89 %) at the time of presentation. One MS-RR patient had only four non-contrast-enhancing lesions, one CIS patient had only one non-contrast-enhancing lesion, one CIS patient had only two non-contrast-enhancing lesions and one CIS patient had atypical lesions resembling an ischemic etiology. Disability and treatment The median EDSS at the time of diagnosis was 2.0 (range: 1.0 – 6.5) and, at the last followup, 2.5 in 11 patients with residual neurological deficits (range: 1.0 – 6.5), but 26 (68 %) patients had EDSS 0.0. The single patient with MS-SP had EDSS 2.5 after 38 months of follow-up. The cognitive outcome was not assessed in this study.
High-dose intravenous pulse therapy with methylprednisolone was administered to all patients for acute episodes or relapses. In total, 24 patients (63 %) were treated with first-line DMT, including most of the MS-RR group (74 %) and four CIS (36 %) patients. Two MS patients refused all treatment options; one of these with MS-RR evolved to EDSS 6.5 in 55 months of follow-up, but the other remained clinically stable with EDSS 0.0 over a 51-month period. Another three MS-RR patients were not treated; two with EDSS 0.0, a single relapse and low MRI lesion burden without activity at prolonged follow-up (87 and 51 months) and one with EDSS 0.0 and a single relapse who was not treated during a 5-month follow-up after which she was referred to an adult neurologist. Eight patients (33 %) switched to other therapy; six to another first-line treatment, three from IFN-ß to oral treatment with dimethyl fumarate due to needle fatigue, two from low-dose IFN-ß to high-dose IFN-ß, and one patient from IFN-ß to GA due to side effects. One patient switched to a third first-line therapy, from two IFN-ß to GA, due to side effects. One patient switched to second-line treatment with natalizumab at the age of 16 years. All patients who received escalating therapy had negative IFN- ß antibodies. In the first years of our study, between 2000-2005, 10 patients received monthly intravenous immunoglobulin (IVIG) therapy after acute corticosteroid pulse treatment for a mean duration of 22 months (range: 5-60 months). This treatment option was given to three younger patients due to IFN-ß regulatory issues, to one patient with MS-SP and to the other six patients as a short-term (mean: 6 months) treatment option while awaiting approval to start DMT. We have previously reported our positive experience with prolonged first-line IVIG therapy in patients treated in our center between 1992 and 2005, with 0.6 relapses per patient per year and no side effects of treatment.11 Two patients received methotrexate (MTX) before IFN-ß. The first patient received MTX for 13 months as combined first-line treatment in 2000 while he was clinically stable. At the last follow-up at 93 months, EDSS was 1.0. The second patient, diagnosed in 2006, received MTX for 24 months following acute corticosteroid treatment and steroid dependency, with severe relapses at each trial of tapering. MTX was stopped due to evolving hepatopathy. (Table 1) One patient with MS-RR decided on alternative treatment despite being clinically stable on IFN-ß therapy with EDSS 0.0 over 42 months of follow-up, with jugular venous dilatation performed at the time of transition to an adult neurologist.
Discussion We found that the national incidence of pediatric multiple sclerosis in Slovenia and the gender ratio are both comparable with data reported in other pediatric studies.12-14 The incidence of pediatric MS of 0.81 in this study of patients between 2000-2012 compared to an incidence of 0.36 reported previously for the period between 1992-2001, reveals an obvious trend towards a higher incidence.11 Pediatric MS patients were referred to the same pediatric center for the last 25 years, so the possible explanation for higher incidence in the last years is the availability of better diagnostic tools (access to MRI) and the use of revised diagnostic criteria.
We found a predominance of patients with MS-RR and a relatively highly positive family history of multiple sclerosis, the latter being possibly due to the inclusion of two pairs of sisters in our study.10 Other studies found lower prevalence of positive family history of MS being from 2 to 14 %.6, 14 The childhood onset MS, under the age of 12 years, was similar to other pediatric studies.12-14 The mean time between the first symptoms and confirmation of the diagnosis was a more favorable for the last 5-year period but we learned that patients with brief paroxysmal sensory or motor phenomena were at higher risk of a longer delay before seeking medical attention because they neglected their symptoms. The annual relapse rate is comparable to that reported in pediatric MS, which is in a context with higher disease activity in pediatric population.3, 10, 15-17 Pleocytosis and oligoclonal bands were present in comparable proportion of patients reported in other studies but there were no reports on Ig subsets. 2,14 The relatively high representation of IgM or polyclonal Ig in our series could be a reflection of a more inflammatory course of pediatric MS. Higher representation of IgG or oligoclonal bands might be expected with repeated lumbar puncture later in the course of the disease, but we were not able to follow these dynamics as we did not perform repeated CSF analysis when the diagnosis of MS was conclusive according to other criteria.17-18 Neurophysiological investigations added important diagnostic information in particular in those patients who had no specific complaints or symptoms from the visual or sensory system. There have been no systematic neurophysiological studies in pediatric MS patients published. However, in certain patients along with clinical assessment there is a place for neurophysiological tests, to better evaluate and follow the disease activity. MRI lesions were typical according to the McDonald criteria in vast majority of patients at the time of presentation, which suggests a high diagnostic value of this neuroradiological tool in pediatric patients. Stable median EDSS at follow-up in our series suggests the impact of therapy. The majority of MS and one-third of CIS patients were treated with first-line DMT. Two-thirds of patients adhered to the first treatment, which is similar to the outcome reported in the USA group, although they reported more patients on the first treatment with GA.19 There is a trend towards switching from injectable to oral first-line treatment in our patients due to needle fatigue, as first-line oral treatment with dimethyl fumarate has been available in Slovenia since 2015. The daily use of injectable therapy is frequently not tolerated, which was the major reason for not starting first-line therapy with GA or for starting low-dose IFN-ß treatment with weekly applications in some of our patients. Considering the treatment options from the “pre-interferon era”, we were able to confirm positive outcomes in our eight patients treated with prolonged IVIG or MTX first-line therapy. All except one had stable period without relapses for more than 3 years. IVIG can still be used in cases with poor recovery after corticosteroid treatment or when there are contraindications to its use.20 MTX is usually not used nowadays as other second-line treatment options are available and reported to be effective in pediatric patients. We have not used plasma exchange in any of our pediatric MS patients so far.
The weaknesses of our study are the retrospective analysis of a relatively small group of patients and the absence of neuropsychological follow-up in the clinical disability assessment. The positive aspect is that the referral of pediatric patients to a single tertiary center in our country enables a good overview of demographic data, and extensive diagnostic workup and treatment.
Conclusion Our analysis is comparable to existing reports which suggest that the incidence of pediatric multiple sclerosis is relatively low, but the disease activity is higher than in adults. The early recognition of multiple sclerosis enables close follow-up and early implementation of diseasemodifying therapy in those who do not fulfill the criteria for starting treatment at the time of the first presentation. Neurophysiological tools, especially VEP, help to detect disability in patients without overt clinical signs and symptoms, provide a full impression of clinical disability and follow-up of the clinical course. A relapsing-remitting course is expected in the majority of pediatric patients, with favorable improvement after relapses. Treatment escalation is needed in cases of treatment failure, or the switch to another first-line therapy in cases of non-adherence due to treatment fatigue or side effects. Acknowledgement JO contributed to acquisition and analysis of data, ZRP contributed to patient inclusion, MJK performed SSEP and ABEP studies, NK contributed to patient inclusion, interpretation of data, manuscript concept and text revision. The authors thank Neža Župančič, MD, child neurologist, who directed the treatment in the first MS patients in our department and was a great teacher of child neurology to the team.
Conflicts of interests The authors declare that there is no conflict of interest.
References 1. Duquette P, Murray TJ, Pleines J, et al. Multiple sclerosis in childhood: clinical profile in 125 patients. J Paediatr 1987; 111: 359-363. 2. Ghezzi A, Deplano V, Faroni J, et al. Multiple sclerosis in childhood: clinical features of 149 cases. Mult Scler 1997; 3: 43-46. 3. Sandern E, Haas J, Stark E et al. Early onset MS under the age of 16: clinical and paraclinical features. Acta Neurol Scand 1992; 86: 280-284. 4. Chitnis T, Glanz B, Jaffin S, et al. Demographics of pediatric-onset multiple sclerosis in a MS center population from the Northeastern United States. Mult Scler 2009; 15: 627-631. 5. Tenembaum SN. Emerging concepts in pediatric-onset multiple sclerosis and related disorders. Curr Opin Ped 2010; 22: 726-730. 6. Nielsen NM; Westergaard T, Rostgaard K, et al. Familial risk of multiple sclerosis: a nationwide cohort study. Ann J Epidemiol 2005; 162 (8): 774-778. 7. Polman CH, Reingold SC, BanwellB, et al. Diagnostic criteria for multiple sclerosis: 2010 revision of McDonald criteria. Ann Neurol 2011; 69 (2): 292-302.
8. Krupp LB, Tardieu M, Amato MP, et al. International Pediatric Multiple Sclerosis Study Group criteria for pediatric multiple sclerosis and immune-mediated central nervous system demyelinating disorder: revisions to the 2007 definitions. Mult Scler J 2013; 19 (10): 1261-1267. 9. Chitnis T, Tenembaum S, Banwell B, et al. Consensus statement: evaluation of new and existing therapeutics for pediatric multiple sclerosis. Mult Scler J 2012; 18 (1): 116-127. 10. Bigi S, Banwell B. Pediatric multiple sclerosis. J Child Neurol 2012; 27 (11): 13781383. 11. Krajnc N, župančič N, Rener Primec Z. IVIG as a safe and well tolerated treatment option in young multiple sclerosis patients. Eur J Paed Neurol 2005; 3-4: 220-221. 12. Langer-Gould A, Zhang JL, Chung J, et al. Incidence of aquired CNS demyelinating syndromes in a multicentric cohort of children. Neurology 2011; 77: 1145-1148. 13. Banwell B, Kennedy J, Sadovnick D, et al. Incidence of aquired demyelination of the CNS in Canadian children. Neurology 2008; 72: 232-237. 14. Pohl D, Hennemuth I, von Kries R, et al. Pediatric multiple sclerosis and acute dysemminated encephalomyelitis in Germany: results of nationwide survey. Eur J Paediatr 2007; 166; 166: 405-412. 15. Shiraishi K, Higuchi Y, Ozawa K, et al. Clinical course and prognosis of 27 patients with childhood onset multiple sclerosis in Japan. Brain & Dev 2005; 27: 224-227. 16. Gormann MP; Healey BC, Polgar-Turcsanyi M, et al. Increased relapse rate in pediatric-onset compared with adult-onset multiple sclerosis. Arch Neurol 2009; 66: 54-59. 17. Huppke B, Ellenberger D, Rosewich H, et al. Clinical presentation of pediatric multiple sclerosis before puberty. Eur J Neurol 2014; 21: 441-446. 18. Sandvig I, Barlinn J, Nedregaard B, et al. Multiple sclerosis in children and adolescents. An important differential diagnosis of acute neurological disease. Eur J Paed Neurol 2015; 19: 211-217. 19. Yeh AE, Waubant E, Krupp LB, et al. Multiple sclerosis therapies in pediatric patients with refractory multiple sclerosis. Arch Neurol 2011; 68 (4): 437-444. 20. Yeh EA, Weinstock-Guttman B. The management of pediatric multiple sclerosis. J Child Neurol 2012; 27 (1): 1384-1393.
Table 1. Clinical characteristics and evoked potentials studies. No. of Diagnosis patient 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38
MS-RR MS-RR CIS CIS MS-RR CIS CIS CIS MS-RR MS-RR MS-RR CIS CIS CIS MS-RR MS-RR MS-RR MS-RR MS-RR MS-SP CIS MS-RR CIS CIS MS-RR MS-RR MS-RR MS-RR MS-RR MS-RR MS-RR MS-RR MS-RR MS-RR MS-RR MS-RR MS-RR MS-RR
Age (y,m)
First sympt
VEP
ABEP
SSEP
Therapy
EDDS final
16,8 16,4 16,10 15,9 17,11 17,0 17,3 17,3 16,1 16,4 13,11 14,3 13,9 14,1 13,5 14,11 13,9 15,0 16,2 17,11 16,0 15,1 17,6 17,11 10,0 10,3 13,5 15,4 13,9 17,11 14,3 13,6 12,8 15,9 16,4 13,4 16,1 17,11
S, M S B S M, A V S V M B, A M, B, A M S, B V, S S, M, A S V S V, A M, B, A V S, M, A V B, A M, B, U S V M, B M, A, U S V, S S M, B B S M B S
n abn n abn abn abn n abn n n abn n n abn n n abn n abn abn abn abn abn n n n abn n abn n abn n n abn abn abn n
n n n n abn abn n abn abn abn n n abn abn -
n n abn abn abn n abn abn n abn n abn n n abn n abn abn abn abn abn abn abn abn abn n abn n abn abn abn abn abn
IFN-ß, GA 0.0 IFN-ß 0.0 0.0 IFN-ß 0.0 IFN-ß 0.0 0.0 IFN-ß 0.0 IFN-ß, DF 0.0 refused 0.0 IFN-ß, DF 0.0 IFN-ß 0.0 0.0 1.0 IFN-ß 0.0 IFN-ß 0.0 IFN-ß 0.0 IFN-ß 0.0 IFN-ß 0.0 IFN-ß 0.0 IVIG 2.5 3.0 IFN-ß 4.5 0.0 0.0 0.0 IFN-ß, DF 0.0 0.0 0.0 MTX, IFN-ß, NT 2.0 IFN-ß 0.0 refused 6.5 IVIG, IFN-ß 0.0 IVIG, IFN-ß 2.5 IVIG, IFN-ß 2.5 MTX, IVIG, IFN-ß 1.0 IVIG, IFN-ß 3.0 IVIG, IFN-ß 1.0 IVIG 0.0
FU (m) 57 37 7 37 29 36 29 46 51 38 36 36 44 56 65 72 79 42 21 38 1 73 25 5 51 78 87 54 68 7 55 86 77 106 93 78 97 5
No: number, y: years, m: months, VEP: visual evoked potentials, ABEP: auditory brainstem evoked potentials, SSEP: somatosensory evoked potentials, EDSS: expanded dysability status scale, FU: follow-up, MS-RR: ralapsing-remitting multiple sclerosis, MS-SP: secondary progressive multiple sclerosis, CIS: clinically isolated syndrome, V: visual, S: sensory, M: motor, B: brainstem, A: ataxia, U: urinary bladder, n: normal, abn: abnormal, - : not performed / not received, IFN-ß: interferon-beta, GA: glatiramer acetate, DF: dimethyl fumarate, MTX: methotrexate, IVIG: intravenous immunoglobulins.
Table 2. Cerebrospinal fluid analysis. Diagnosis
CIS MS
Cell counts elevated (n, %) 4/10 (40) 14/24 (58)
Proteins elevated (n, %) 2/10 (20) 1/25 (4)
Ig synthesis (n, %) 7/10 (70) 16/25 (64)
OCB synthesis (n, %) 9/10 (90) 15/26 (58)
Total No. (%) 18/34 (53) 3/34 (9) 23/36 (64) 24/36 (67) of positive Ig: immunoglobulins, OCB: oligoclonal bands, n: number, CIS: clinically isolated syndrome, MS: multiple sclerosis, No: number.
www.elsevier.com/locate/msard
PII: DOI: Reference:
S2211-0348(18)30037-3 https://doi.org/10.1016/j.msard.2018.01.026 MSARD759
To appear in: Multiple Sclerosis and Related Disorders Received date: 20 September 2017 Revised date: 10 January 2018 Accepted date: 28 January 2018 Cite this article as: N. Krajnc, J. Oražem, Z. Rener-Primec and M.J. Kržan, Multiple sclerosis in pediatric patients in Slovenia, Multiple Sclerosis and Related Disorders, https://doi.org/10.1016/j.msard.2018.01.026 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 galley proof before it is published in its final citable 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.
Multiple sclerosis in pediatric patients in Slovenia Krajnc N1,2, Oražem J1, Rener-Primec Z1, Kržan MJ1, 3 Address1: University Children’s Hospital Department of Child, Adolescent & Developmental Neurology Bohoričeva 20 1525 Ljubljana, Slovenia Address2: Department of Pediatrics General Hospital Slovenj Gradec Gosposvetska cesta 1 2380 Slovenj Gradec, Slovenia Address3: Neurology Revita Kidričeva 47a 4000 Kranj, Slovenia Corresponding author: Natalija Krajnc, MD, PhD Department of Pediatrics General Hospital Slovenj Gradec Gosposvetska cesta 1 2380 Slovenj Gradec, Slovenia Tel.: + 386 2 88 23 471 Email: [email protected]
Word count: 2939 (main text) Abstract Aim: The purpose of this study is to review the Slovenian experience with the diagnostics, treatment and outcome in pediatric multiple sclerosis (MS) patients. There has been no nationwide report on outcomes of childhood onset multiple sclerosis in last decades. Methods: Children and adolescent diagnosed with MS and followed by Department of Child, Adolescent and Developmental Neurology, University Childrens' Hospital Ljubljana, between 1 January 2000 and 31 December 2012 were included. Data from patients' documentation were analysed retrospectively to record demographic data, clinical presentation, paraclinical findings, disability progression, relapse rate and treatment strategies. Results: The study includes 38 patients up to 18 years with MS diagnosis, with female:male ratio 2.8:1 and the incidence of 0.81 per 100.000 children of 0-18 years.The mean age at the time of diagnosis was 15 years 4 months. Most frequent presenting symptoms were sensory, motor, brain-stem, visual and ataxia and 65% of patients had a relapse in the first year. The
value of paraclinical findings was asessed. 74 % of patients with definite MS and 36 % of those with clinically isolated syndrome received disease modifyng therapy and 68 % of them was not affected at the follow-up. Interpretation: The characteristics of pediatric MS patients in Slovenia disclose higher annual relapse rates than in adults but also favourable impact of disease modifying treatment on a clinical course. Our data suggest a good treatment tolerance but also the influence of the formulation on a decision to start or switch the treatment.
Keywords: multiple sclerosis; children; epidemiology; evoked potentials; treatment response; outcome.
Running foot: Pediatric multiple sclerosis in Slovenia.
Highlights
Information on nationwide incidence and outcomes of pediatric multiple sclerosis Most frequent presenting symptoms The value of paraclinical findings The clinical course and outcome measurements
Abbreviations MS - multiple sclerosis
MS-RR - relapsing-remitting multiple sclerosis MS-SP - secondary progressive multiple sclerosis MS-PP - primary progressive multiple sclerosis IFN-ß - interferon-beta GA - glatiramer acetate DMT - disease-modifying treatment CIS - clinically isolated syndrome EDSS - Expanded Disability Status Scale CSF - cerebrospinal fluid VEP - visual evoked potentials SSEP - somatosensory evoked potentials ABEP - auditory brainstem evoked potentials MRI - magnetic resonance imaging IVIG - intravenous immunoglobulins MTX - methotrexate
Introduction The majority of MS patients present in early adulthood, but 3-5 % present before 18 years of age, including 0.1 %- 0.7 % before puberty.1-4 The etiology of MS, which causes chronic inflammatory demyelination of the central nervous system, is not known, but is probably multifactorial.5 A family history of MS in relatives is positive in 6-21 %, and geographic differences play a role in the incidence reported worldwide.6 MS is reported to be more prevalent in females, with a female to male ratio of 3:1. The McDonald diagnostic criteria, revised in 2010, are applicable for use in children and permit the diagnosis of multiple sclerosis at the first clinical attack.7-8 A higher relapse rate, an increased T2 lesion burden on MRI and evidence of early cognitive deficit at a younger age suggest a more inflammatory course of MS in the pediatric population than in adults.9 Most pediatric MS is relapsing-remitting (MS-RR), representing more than 90 % of all cases. Secondary progression (MS-SP) is rare and a primary progressive course (MSPP) is extremely rare and should raise the suspicion of an inherited leukodystrophy or a metabolic or mitochondrial etiology.1, 10 The use of interferon-beta (IFN-ß) and glatiramer acetate (GA) is generally accepted as the first-line disease-modifying treatment (DMT) in MS-RR, but there is no consensus on such treatment for the first demyelinating episode or clinically isolated syndrome (CIS).9 There is a lack of global consensus on the definition of an inadequate treatment response for MS in both adults and children to facilitate decision-making on treatment escalation. The proposed working definition of the International Pediatric Multiple Sclerosis Study Group helps to establish a treatment failure.9 Regulatory approval of first-line DMT in Slovenia restricted administration to older adolescents and adult patients during the first years of approval (late 90s to the beginning of 2000), but in the last decade this treatment has become available to patients 12 years and older. The treatment is approved and fully paid for by the National Health Service after approval by a regional Committee for Treatment of MS, comprising a team of adult neurologists. Our department as a part of a University Children’s Hospital Ljubljana is the only pediatric MS referral center in Slovenia and only exceptionally the pediatric patients were first evaluated elsewhere and then referred to us. So the nationwide incidence and clinical characteristics of pediatric MS are fairly representative for Slovenia, which has a population of about 2 million, and could be compared in a context of geographical differences reported in other pediatric studies. The aim of this study was to provide an overview of the Slovenian pediatric MS population which was sistematically followed-up but not reported previously. Materials and methods This study included children and adolescents under 18 years of age who were diagnosed with multiple sclerosis between 1 January 2000 and 31 December 2012 in the Department of Child, Adolescent and Developmental Neurology, University Children’s Hospital Ljubljana. The formal patients consent or ethical approval was not needed for this type of the retrospective data analysis. According to new diagnostic and treatment approaches, and to achieve at least 3 years of follow-up, we included only patients presenting between 2000 and
2012. All patients have been identified by search through a local database of our department. The medical and demographic data were collected from the patients' medical records of their outpatient or hospital visits to our MS team according to the confirmed diagnosis of MS or CIS. CIS was defined as a central nervous system demyelinating event isolated in time, not evolved to definite MS at the time of follow-up. All other patients with demyelinating spectrum disorders were excluded from the study. The patients were included according to the McDonald 2010 criteria. We recorded demographic data such as gender and age at presentation, family history of multiple sclerosis, symptoms at presentation, Expanded Disability Status Scale (EDSS) at presentation and at the last follow-up, paraclinical findings such as cerebrospinal fluid (CSF) analysis, visual evoked potentials (VEP), somatosensory evoked potentials (SSEP), auditory brainstem evoked potentials (ABEP) and magnetic resonance imaging (MRI), relapse rate, and treatment.
Results We included 38 patients over a 13-year period. The female to male ratio was 2.8:1. The incidence was 0.81 per 100,000 children aged 0-18 years in Slovenia. Only the youngest two patients, both aged 10 years, were prepubertal. Definite MS was confirmed in 27 patients, in one patient as secondary progressive MS (MSSP) and, in the remainder, as relapsing-remitting MS (MS-RR). Clinically isolated syndrome (CIS) was confirmed in 11 patients. The mean age at diagnosis was 15 years 4 months (range: 10.0 years – 17 years 11 months) and the mean follow-up was 52 months (range: 1 – 106 months). The family history revealed MS in a first-degree relative in 7 of 37 (19 %) of our patients, including two pairs of sisters. The mean time between the first symptoms and confirmation of the diagnosis was six months (range: 0 – 24 months). The diagnosis was confirmed in a couple of days in 17 (45 %) patients and after 24 months, at the time of a relapse, in a single patient with a previous history of transitory sensory symptoms. We evaluated separately the mean lag time to confirmation of the diagnosis for the patients referred in the last 5-year period. This was 2.5 months (range: 0 – 19 months), with 50 % of patients being diagnosed in less than one month, although one patient with previous paroxysmal motor phenomena was diagnosed 19 months later. The most common presenting symptoms were sensory disturbance (16 patients, 42 %), followed by motor (13 patients, 34 %), brainstem (10 patients, 26 %), visual (9 patients, 24 %), ataxia (8 patients, 21 %) and urinary bladder dysfunction (2 patients, 5 %). Only one system was affected in 22 patients (58 %), most frequently the sensory system (10 patients, 26 %), followed by visual (6 patients, 16 %), motor and brainstem (3 patients, 8 %, respectively). (Table 1) The mean time between diagnosis and the first relapse was 12 months, with 65 % of patients relapsing within the first year. The annual relapse rate was calculated in 22 of 27 MS patients who were followed long enough and revealed 0.95 relapses per patient per year in the first three years. Cerebrospinal fluid analysis
CSF was analyzed at the time of diagnosis in all patients except one CIS patient who refused the procedure, in 33 of 36 at the time of the acute neurologic presentation. CSF analysis was repeated later in only one patient with MS-RR, but all parameters were negative, even at the time of the second analysis. Pleocytosis, elevated proteins, intrathecal Ig synthesis and oligoclonal bands were evaluated. (Table 2) Pleocytosis was present in 18 of 34 (53 %) patients, in 4 of 10 (40 %) patients with CIS and in 14 of 24 (58 %) MS patients. Mildly elevated proteins (less than 1g /l) were present only in 3 of 34 (9 %) patients, in 2 of 10 (20 %) patients with CIS and 1 of 25 (4 %) with MS. Intrathecal Ig synthesis was present in 23 of 36 (64 %) patients, in 7 of 10 (70 %) patients with CIS and in 16 of 25 (64 %) MS patients. Further data on intrathecal Ig subtype were available for 22 of 23 patients; nine patients (41 %) had isolated IgG synthesis, seven patients (32 %) had isolated IgM synthesis, two patients (9 %) had combined IgG and IgM synthesis, three (14 %) patients had combined IgG, IgM and IgA synthesis, and one patient (4.5 %) had isolated IgA synthesis. Oligoclonal bands present only in the CSF were confirmed in 24 of 36 (67 %) patients, in 9 of 10 (90 %) patients with CIS and 15 of 26 (58 %) MS patients. No patient had positive oligoclonal bands in plasma. Neurophysiological investigations They were performed in 37 patients, in 34 of them in the time of the acute neurologic presentation, and in 3 patients partially in acute or non-acute phase. VEP were assessed in all patients and were abnormal in 19 (50 %), including all six patients (16 %) with isolated unilateral optic neuritis, but also in 13 (34 %) other patients without overt visual disturbance at the time of clinical presentation. SSEP were assessed in 32 (84 %) patients and were abnormal in 20 (62.5 %), including two (6 %) patients with isolated visual disturbance. ABEP were assessed in 14 (37 %) patients and were abnormal in seven (50 %), including four patients with brainstem disturbance and three patients with isolated motor, sensory or combined sensory and visual disturbance. (Table 1) MRI results MRI lesions were typical according to the McDonald criteria in all but four patients (89 %) at the time of presentation. One MS-RR patient had only four non-contrast-enhancing lesions, one CIS patient had only one non-contrast-enhancing lesion, one CIS patient had only two non-contrast-enhancing lesions and one CIS patient had atypical lesions resembling an ischemic etiology. Disability and treatment The median EDSS at the time of diagnosis was 2.0 (range: 1.0 – 6.5) and, at the last followup, 2.5 in 11 patients with residual neurological deficits (range: 1.0 – 6.5), but 26 (68 %) patients had EDSS 0.0. The single patient with MS-SP had EDSS 2.5 after 38 months of follow-up. The cognitive outcome was not assessed in this study.
High-dose intravenous pulse therapy with methylprednisolone was administered to all patients for acute episodes or relapses. In total, 24 patients (63 %) were treated with first-line DMT, including most of the MS-RR group (74 %) and four CIS (36 %) patients. Two MS patients refused all treatment options; one of these with MS-RR evolved to EDSS 6.5 in 55 months of follow-up, but the other remained clinically stable with EDSS 0.0 over a 51-month period. Another three MS-RR patients were not treated; two with EDSS 0.0, a single relapse and low MRI lesion burden without activity at prolonged follow-up (87 and 51 months) and one with EDSS 0.0 and a single relapse who was not treated during a 5-month follow-up after which she was referred to an adult neurologist. Eight patients (33 %) switched to other therapy; six to another first-line treatment, three from IFN-ß to oral treatment with dimethyl fumarate due to needle fatigue, two from low-dose IFN-ß to high-dose IFN-ß, and one patient from IFN-ß to GA due to side effects. One patient switched to a third first-line therapy, from two IFN-ß to GA, due to side effects. One patient switched to second-line treatment with natalizumab at the age of 16 years. All patients who received escalating therapy had negative IFN- ß antibodies. In the first years of our study, between 2000-2005, 10 patients received monthly intravenous immunoglobulin (IVIG) therapy after acute corticosteroid pulse treatment for a mean duration of 22 months (range: 5-60 months). This treatment option was given to three younger patients due to IFN-ß regulatory issues, to one patient with MS-SP and to the other six patients as a short-term (mean: 6 months) treatment option while awaiting approval to start DMT. We have previously reported our positive experience with prolonged first-line IVIG therapy in patients treated in our center between 1992 and 2005, with 0.6 relapses per patient per year and no side effects of treatment.11 Two patients received methotrexate (MTX) before IFN-ß. The first patient received MTX for 13 months as combined first-line treatment in 2000 while he was clinically stable. At the last follow-up at 93 months, EDSS was 1.0. The second patient, diagnosed in 2006, received MTX for 24 months following acute corticosteroid treatment and steroid dependency, with severe relapses at each trial of tapering. MTX was stopped due to evolving hepatopathy. (Table 1) One patient with MS-RR decided on alternative treatment despite being clinically stable on IFN-ß therapy with EDSS 0.0 over 42 months of follow-up, with jugular venous dilatation performed at the time of transition to an adult neurologist.
Discussion We found that the national incidence of pediatric multiple sclerosis in Slovenia and the gender ratio are both comparable with data reported in other pediatric studies.12-14 The incidence of pediatric MS of 0.81 in this study of patients between 2000-2012 compared to an incidence of 0.36 reported previously for the period between 1992-2001, reveals an obvious trend towards a higher incidence.11 Pediatric MS patients were referred to the same pediatric center for the last 25 years, so the possible explanation for higher incidence in the last years is the availability of better diagnostic tools (access to MRI) and the use of revised diagnostic criteria.
We found a predominance of patients with MS-RR and a relatively highly positive family history of multiple sclerosis, the latter being possibly due to the inclusion of two pairs of sisters in our study.10 Other studies found lower prevalence of positive family history of MS being from 2 to 14 %.6, 14 The childhood onset MS, under the age of 12 years, was similar to other pediatric studies.12-14 The mean time between the first symptoms and confirmation of the diagnosis was a more favorable for the last 5-year period but we learned that patients with brief paroxysmal sensory or motor phenomena were at higher risk of a longer delay before seeking medical attention because they neglected their symptoms. The annual relapse rate is comparable to that reported in pediatric MS, which is in a context with higher disease activity in pediatric population.3, 10, 15-17 Pleocytosis and oligoclonal bands were present in comparable proportion of patients reported in other studies but there were no reports on Ig subsets. 2,14 The relatively high representation of IgM or polyclonal Ig in our series could be a reflection of a more inflammatory course of pediatric MS. Higher representation of IgG or oligoclonal bands might be expected with repeated lumbar puncture later in the course of the disease, but we were not able to follow these dynamics as we did not perform repeated CSF analysis when the diagnosis of MS was conclusive according to other criteria.17-18 Neurophysiological investigations added important diagnostic information in particular in those patients who had no specific complaints or symptoms from the visual or sensory system. There have been no systematic neurophysiological studies in pediatric MS patients published. However, in certain patients along with clinical assessment there is a place for neurophysiological tests, to better evaluate and follow the disease activity. MRI lesions were typical according to the McDonald criteria in vast majority of patients at the time of presentation, which suggests a high diagnostic value of this neuroradiological tool in pediatric patients. Stable median EDSS at follow-up in our series suggests the impact of therapy. The majority of MS and one-third of CIS patients were treated with first-line DMT. Two-thirds of patients adhered to the first treatment, which is similar to the outcome reported in the USA group, although they reported more patients on the first treatment with GA.19 There is a trend towards switching from injectable to oral first-line treatment in our patients due to needle fatigue, as first-line oral treatment with dimethyl fumarate has been available in Slovenia since 2015. The daily use of injectable therapy is frequently not tolerated, which was the major reason for not starting first-line therapy with GA or for starting low-dose IFN-ß treatment with weekly applications in some of our patients. Considering the treatment options from the “pre-interferon era”, we were able to confirm positive outcomes in our eight patients treated with prolonged IVIG or MTX first-line therapy. All except one had stable period without relapses for more than 3 years. IVIG can still be used in cases with poor recovery after corticosteroid treatment or when there are contraindications to its use.20 MTX is usually not used nowadays as other second-line treatment options are available and reported to be effective in pediatric patients. We have not used plasma exchange in any of our pediatric MS patients so far.
The weaknesses of our study are the retrospective analysis of a relatively small group of patients and the absence of neuropsychological follow-up in the clinical disability assessment. The positive aspect is that the referral of pediatric patients to a single tertiary center in our country enables a good overview of demographic data, and extensive diagnostic workup and treatment.
Conclusion Our analysis is comparable to existing reports which suggest that the incidence of pediatric multiple sclerosis is relatively low, but the disease activity is higher than in adults. The early recognition of multiple sclerosis enables close follow-up and early implementation of diseasemodifying therapy in those who do not fulfill the criteria for starting treatment at the time of the first presentation. Neurophysiological tools, especially VEP, help to detect disability in patients without overt clinical signs and symptoms, provide a full impression of clinical disability and follow-up of the clinical course. A relapsing-remitting course is expected in the majority of pediatric patients, with favorable improvement after relapses. Treatment escalation is needed in cases of treatment failure, or the switch to another first-line therapy in cases of non-adherence due to treatment fatigue or side effects. Acknowledgement JO contributed to acquisition and analysis of data, ZRP contributed to patient inclusion, MJK performed SSEP and ABEP studies, NK contributed to patient inclusion, interpretation of data, manuscript concept and text revision. The authors thank Neža Župančič, MD, child neurologist, who directed the treatment in the first MS patients in our department and was a great teacher of child neurology to the team.
Conflicts of interests The authors declare that there is no conflict of interest.
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8. Krupp LB, Tardieu M, Amato MP, et al. International Pediatric Multiple Sclerosis Study Group criteria for pediatric multiple sclerosis and immune-mediated central nervous system demyelinating disorder: revisions to the 2007 definitions. Mult Scler J 2013; 19 (10): 1261-1267. 9. Chitnis T, Tenembaum S, Banwell B, et al. Consensus statement: evaluation of new and existing therapeutics for pediatric multiple sclerosis. Mult Scler J 2012; 18 (1): 116-127. 10. Bigi S, Banwell B. Pediatric multiple sclerosis. J Child Neurol 2012; 27 (11): 13781383. 11. Krajnc N, župančič N, Rener Primec Z. IVIG as a safe and well tolerated treatment option in young multiple sclerosis patients. Eur J Paed Neurol 2005; 3-4: 220-221. 12. Langer-Gould A, Zhang JL, Chung J, et al. Incidence of aquired CNS demyelinating syndromes in a multicentric cohort of children. Neurology 2011; 77: 1145-1148. 13. Banwell B, Kennedy J, Sadovnick D, et al. Incidence of aquired demyelination of the CNS in Canadian children. Neurology 2008; 72: 232-237. 14. Pohl D, Hennemuth I, von Kries R, et al. Pediatric multiple sclerosis and acute dysemminated encephalomyelitis in Germany: results of nationwide survey. Eur J Paediatr 2007; 166; 166: 405-412. 15. Shiraishi K, Higuchi Y, Ozawa K, et al. Clinical course and prognosis of 27 patients with childhood onset multiple sclerosis in Japan. Brain & Dev 2005; 27: 224-227. 16. Gormann MP; Healey BC, Polgar-Turcsanyi M, et al. Increased relapse rate in pediatric-onset compared with adult-onset multiple sclerosis. Arch Neurol 2009; 66: 54-59. 17. Huppke B, Ellenberger D, Rosewich H, et al. Clinical presentation of pediatric multiple sclerosis before puberty. Eur J Neurol 2014; 21: 441-446. 18. Sandvig I, Barlinn J, Nedregaard B, et al. Multiple sclerosis in children and adolescents. An important differential diagnosis of acute neurological disease. Eur J Paed Neurol 2015; 19: 211-217. 19. Yeh AE, Waubant E, Krupp LB, et al. Multiple sclerosis therapies in pediatric patients with refractory multiple sclerosis. Arch Neurol 2011; 68 (4): 437-444. 20. Yeh EA, Weinstock-Guttman B. The management of pediatric multiple sclerosis. J Child Neurol 2012; 27 (1): 1384-1393.
Table 1. Clinical characteristics and evoked potentials studies. No. of Diagnosis patient 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38
MS-RR MS-RR CIS CIS MS-RR CIS CIS CIS MS-RR MS-RR MS-RR CIS CIS CIS MS-RR MS-RR MS-RR MS-RR MS-RR MS-SP CIS MS-RR CIS CIS MS-RR MS-RR MS-RR MS-RR MS-RR MS-RR MS-RR MS-RR MS-RR MS-RR MS-RR MS-RR MS-RR MS-RR
Age (y,m)
First sympt
VEP
ABEP
SSEP
Therapy
EDDS final
16,8 16,4 16,10 15,9 17,11 17,0 17,3 17,3 16,1 16,4 13,11 14,3 13,9 14,1 13,5 14,11 13,9 15,0 16,2 17,11 16,0 15,1 17,6 17,11 10,0 10,3 13,5 15,4 13,9 17,11 14,3 13,6 12,8 15,9 16,4 13,4 16,1 17,11
S, M S B S M, A V S V M B, A M, B, A M S, B V, S S, M, A S V S V, A M, B, A V S, M, A V B, A M, B, U S V M, B M, A, U S V, S S M, B B S M B S
n abn n abn abn abn n abn n n abn n n abn n n abn n abn abn abn abn abn n n n abn n abn n abn n n abn abn abn n
n n n n abn abn n abn abn abn n n abn abn -
n n abn abn abn n abn abn n abn n abn n n abn n abn abn abn abn abn abn abn abn abn n abn n abn abn abn abn abn
IFN-ß, GA 0.0 IFN-ß 0.0 0.0 IFN-ß 0.0 IFN-ß 0.0 0.0 IFN-ß 0.0 IFN-ß, DF 0.0 refused 0.0 IFN-ß, DF 0.0 IFN-ß 0.0 0.0 1.0 IFN-ß 0.0 IFN-ß 0.0 IFN-ß 0.0 IFN-ß 0.0 IFN-ß 0.0 IFN-ß 0.0 IVIG 2.5 3.0 IFN-ß 4.5 0.0 0.0 0.0 IFN-ß, DF 0.0 0.0 0.0 MTX, IFN-ß, NT 2.0 IFN-ß 0.0 refused 6.5 IVIG, IFN-ß 0.0 IVIG, IFN-ß 2.5 IVIG, IFN-ß 2.5 MTX, IVIG, IFN-ß 1.0 IVIG, IFN-ß 3.0 IVIG, IFN-ß 1.0 IVIG 0.0
FU (m) 57 37 7 37 29 36 29 46 51 38 36 36 44 56 65 72 79 42 21 38 1 73 25 5 51 78 87 54 68 7 55 86 77 106 93 78 97 5
No: number, y: years, m: months, VEP: visual evoked potentials, ABEP: auditory brainstem evoked potentials, SSEP: somatosensory evoked potentials, EDSS: expanded dysability status scale, FU: follow-up, MS-RR: ralapsing-remitting multiple sclerosis, MS-SP: secondary progressive multiple sclerosis, CIS: clinically isolated syndrome, V: visual, S: sensory, M: motor, B: brainstem, A: ataxia, U: urinary bladder, n: normal, abn: abnormal, - : not performed / not received, IFN-ß: interferon-beta, GA: glatiramer acetate, DF: dimethyl fumarate, MTX: methotrexate, IVIG: intravenous immunoglobulins.
Table 2. Cerebrospinal fluid analysis. Diagnosis
CIS MS
Cell counts elevated (n, %) 4/10 (40) 14/24 (58)
Proteins elevated (n, %) 2/10 (20) 1/25 (4)
Ig synthesis (n, %) 7/10 (70) 16/25 (64)
OCB synthesis (n, %) 9/10 (90) 15/26 (58)
Total No. (%) 18/34 (53) 3/34 (9) 23/36 (64) 24/36 (67) of positive Ig: immunoglobulins, OCB: oligoclonal bands, n: number, CIS: clinically isolated syndrome, MS: multiple sclerosis, No: number.