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Interferon-β treatment in patients with childhood-onset multiple sclerosis
Interferon-β treatment in patients with childhoodonset multiple sclerosis Yann Mikaeloff, MD, Thibault Moreau, MD, Marc Debouverie, MD, Jean Pelletier, MD, Christine Lebrun, MD, Olivier Gout, MD, Jean-Michel Pedespan, MD, Catherine Van Hulle, MD, Patrick Vermersch, MD, and Gérard Ponsot, MD
We present a report of the use of interferon-β before 18 years of age in 16 patients with childhood-onset multiple sclerosis. This study demonstrated that the treatment is safe and well tolerated. (J Pediatr 2001;139:443-6)
Multiple sclerosis (MS) is the most common neurologic demyelinating disease affecting adults from 20 to 40 years of age. Occurrence is rare before 16 years of age, accounting for only 3% to 5% of total cases.1,2 In comparison with adult-onset MS, brainstem dysfunction is more frequent in childhood MS at the first attack. Moreover, the relapsing-remitting course is preponderant. Clinical outcome seems comparable to that of adult-onset MS.3 No controlled studies of the treatment of childhood MS have been performed. Attacks are treated with intravenous high-dose steroids; and intravenous immunoglobulin and cyclophosphamide or oral azathioprine have been used in severe cases.4 Supportive care must be adapted to children. Both types of recombinant interferon-β (IFN-β), 1a and 1b, have been reported to be of therapeutic benefit in clini-
cal trials in patients >18 years with relapsing-remitting forms.5-8 We present a case series of IFN-β treatment initiated before 18 years of age in patients with onset of MS before 16 years of age.
METHODS All patients had clinically defined MS according to Poser’s criteria.9 Data before treatment with IFN-β were recorded; 16 patients <18 years old were treated with IFN-β (1a: Avonex for 13, Rebif for 2; 1b: Betaferon for 1) subsequent to frequent or severe relapses. Patients fulfilled criteria for IFN-β treatment specified by French regulatory authorities, namely, being ambulatory with expanded Kurtzke disability status score (EDSS)10 <5.5 and having expe-
From the Department of Neuropediatrics, Saint-Vincent de Paul Hospital, Paris, France; Bordeaux University Hospital, Bordeaux, France; Rouen University Hospital, Rouen, France; Department of Neurology, Dijon University Hospital, Dijon, France; Nancy University Hospital, Nancy, France; University Hospital, Marseille, France; Nice University Hospital, Nice, France; Pitié-Salpétrière Hospital, Paris, France; Lille University Hospital, Lille, France.
Submitted for publication Oct 10, 2000; revision received Feb 13, 2001; accepted May 1, 2001. Reprints not available from author. Correspondence: Yann Mikaeloff, MD, Service de Neurologie Pédiatrique, Hôpital Saint-Vincent de Paul, 82 avenue Denfert-Rochereau, 75674 Paris Cedex 14, France. Copyright © 2001 by Mosby, Inc. 0022-3476/2001/$35.00 + 0 9/22/117004 doi:10.1067/mpd.2001.117004
rienced a minimum of 2 attacks during the past 2 (Rebif, Betaferon) or 3 years (Avonex). The use of IFN-β is permitted by the French regulatory authorities (ie, it has market authorization) only for paCSF EDSS IFN-β MRI MS
Cerebrospinal fluid Expanded Kurtzke disability status score Interferon-β Magnetic resonance imaging Multiple sclerosis
tients 16 years of age or older, which was the case for 7 patients. The 9 younger patients were treated in accordance with protocol, and informed consent was obtained from the parents or guardians of the children. All patients were of expected weight and size for their age. In all but one case, they were treated with adult doses, initiated progressively: Avonex, 6 × 106 IU = 30 µg given intramuscularly every week; Rebif, 6 × 106 IU = 22 µg given subcutaneously 3 times per week; Betaferon, 8 × 106 IU given subcutaneously every 2 days. The youngest patient, 10.5 years old, was treated with a half dose of Avonex. Oral contraceptives were prescribed to female patients of childbearing age. We performed prospective follow-up with visits scheduled at 1, 2, and 3 months and every 6 months thereafter. At each visit, clinical status was defined with EDSS, and blood count and hepatic enzymes were monitored. Magnetic resonance imaging (MRI) was performed before initiation of treatment and twice in the 2 following years for most patients. Injection of 443
THE JOURNAL OF PEDIATRICS SEPTEMBER 2001
MIKAELOFF ET AL
Table. Patient characteristics
Patient No.
Sex
Age at beginning of IFN-β (y)
Duration of disease (y)
No. of relapses before IFN-β treatment
8.5 14.5 12 12.5
M F M F
10.5 15.5 15.5 15
3 2 5.5 4.5
3 4 3 10
Motor, CN Diplopia, vestibular Diplopia, cerebellar, CN Cerebellar, CN Sensory, ON Motor, sensory, CN ON Motor, ON, CN, diplopia Motor, cerebellar ON
13 12 14 14 11 15 12 13 12 15.5
F F F F F F F F F F
14 14.5 15 15 15 16 16 16 17 17
3 3 1.5 3 4.5 3 6.5 5.5 6 2.5
5 6 4 2 3 3 7 10 6 3
Diplopia Diplopia
15.8 14
F F
17 16
3 5
Initial symptoms
Age at onset of MS (y)
Motor Motor Motor Motor, sensory, ON, CN cerebellar
5 6 7 8 9 10 11 12 13 14
15 16
1 2 3 4
3 3
CN, Cranial nerves; erythema, erythema at injection site; FLS, flu-like syndrome; IDD, insulin-dependent diabetes; ON, optic neuritis.
gadolinium was not systematically administered.
RESULTS The group of patients included 14 girls and 2 boys. Two girls had an autoimmune disorder, either type 1 diabetes or thyroiditis, before treatment. In the month before the first attack, 2 patients had been vaccinated against hepatitis B. There was no familial antecedent of MS or other autoimmune diseases. Median age at the first attack was 13 years (range, 8.5-15.8 years). Only one boy developed MS before 10 years of age (8.5 years). The initial clinical manifestations are reported in the Table. Median age at the time of diagnosis of clinically definite MS was 14 years (range, 9.5-17 years). Twelve patients had biologic markers: oligoclonal bands on cerebrospinal fluid (CSF) isoelectric focus444
ing for 9 patients or increased IgG index in 3 cases without oligoclonal bands. Analysis of CSF was not performed in 2 cases. Median value of CSF cell count was 7 cells/mm3 (range, 1-35 cells/mm3). Initial MRI revealed increased multiple and periventricular T2-weighted signals in all 16 cases, with subcortical white-matter lesions in 15 cases. In some cases, increased signals were located in the brainstem (10 cases), cerebellum (7 cases), or spinal cord (5 cases) (spinal cord MRI was performed initially in 9 cases). All patients had a relapsing-remitting course. Median interval between first and second attacks was 0.9 year (range, 0.2-4 years). Complete recovery after the first attack was achieved in 12 cases (8 treated with intravenous high-dose steroids), whereas sequelae were observed in 4 patients (3 treated with intravenous high-dose steroids). Before administration of IFN-β was initiated, median duration of the dis-
ease was 1.7 years (range, 0.5-5 years) and median number of attacks was 3.5 (range, 2-10), most of which had been treated with intravenous high-dose steroids, followed by a tapering dose of oral steroids. Median age at beginning of IFN-β treatment was 15.5 years (range, 10.517 years). Nine patients were treated before 16 years of age. Median EDSS when beginning treatment was 2.25 (range, 0-4.5). Median duration of IFN-β treatment was 1 year (range, 0.5-2.5 years). Median EDSS was stable during treatment. No significant differences were observed between patients treated before 16 years of age with the special procedure and patients treated at 16 years of age or older for initial and follow-up results (Table). MRI follow-up with IFN-β treatment was evaluated by T2-weighted sequences for 9 patients. According to these analyses, disease was stable for 3 patients but worsened in 6 cases.
MIKAELOFF ET AL
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VOLUME 139, NUMBER 3
EDSS at initiation of IFN-β
EDSS at end of IFN-β treatment period
Duration of IFN-β treatment
No. of relapses during IFN-β treatment
3 2.5 1 2.5
3 2.5 0 4
1 0.5 1.5 1.6
0 0 1 3
1.5 3 4 2.5 0 2 4.5 2 0 2.5
1.5 3.5 1 3.5 0 5.5 5.5 1 0 2.5
1 1.5 0.5 0.5 0.8 0.7 1.4 2 1 0.5
5 1 1 3 0 5 5 5 0 0
0 0
0 0
2 2.5
1 1
Intensity of side effects was mild. A flu-like syndrome was observed in 11 cases, and isolated myalgia, in 3 patients. Medications were given to control flu-like symptoms with good efficacy as follows: acetaminophen for 6 (associated with ibuprofen for one), ibuprofen for 4, and nurofen for 1 patient. There was a rotation of injection sites, and the injection technique was reviewed periodically as recommended. Injection site reactions were moderate: 3 patients had localized erythema (Betaferon 1, Avonex 2). No skin breakdown was observed. There were no hematologic or hepatic side effects, except in one patient who had a moderate but transient increase in transaminase levels at initiation of treatment with spontaneous normalization. One patient with type 1 diabetes developed transient hyperglycemia after injection of IFN-β, which was controlled by an increase in insulin dose. IFN-β (Avonex) administration was inter-
Continuing initial IFN-β treatment
Reason for discontinuation
Myalgia FLS FLS Myalgia, erythema
Yes Yes Yes No
— — — Frequent attacks
No FLS FLS FLS FLS Erythema FLS FLS FLS FLS, hyperglycemia with stable IDD Myalgia FLS, erythema
Yes Yes Yes No Yes No No Yes Yes Yes
— — — Frequent attacks — Frequent attacks Frequent attacks — — —
Yes Yes
— —
Side effects
rupted in 4 cases because of frequent attacks (3, 5, 5, and 3 attacks in 0.5, 0.7, 1.4, and 1.6 years of treatment, respectively), but never because of adverse effects. In these cases, an alternative higher dose of IFN-β was prescribed (Rebif). Tolerance was the same as that observed for the initial product.
DISCUSSION Few studies with immunomodulatory drugs have been performed in childhood MS. To date, there is no published report of treatment of childhood MS with recombinant IFN-β. In light of the well-documented efficacy of such treatment in adult MS, it was of considerable interest to evaluate its use in childhood MS. In our study, the high frequency of treatment failure (4/16, 25%) relative to that observed in any of the other trials5-8 may be attributable to the selection of severe forms
of childhood-onset MS with numerous polysymptomatic onsets (9/16). IFN-β is a well-tolerated treatment in children and adolescents. In our small study group, efficacy was variable without worsening of EDSS status. There were no significant differences between patients treated before 16 years of age and other patients. We conclude that IFN-β is well tolerated in patients younger than 16 years and consider that such treatment should be made accessible to this age group. Larger studies with prolonged follow-up will be necessary to determine whether therapeutic benefit is long-lasting, particularly because in adults early treatment with IFN-β is recommended.11
REFERENCES 1. Duquette P, Murray TJ, Pleines J, Ebers GC, Sadovnick D, Weldon P, et al. Multiple sclerosis in childhood: clini445
THE JOURNAL OF PEDIATRICS SEPTEMBER 2001
MIKAELOFF ET AL
2.
3.
4. 5.
446
cal profile in 125 patients. J Pediatr 1987;111:359-63. Ruggieri M, Polizzi A, Pavone L, Grimaldi LME. Multiple sclerosis in children under 6 years of age. Neurology 1999;53:478-84. Ghezzi A, Deplano V, Faroni J, Grasso MG, Liguori M, Marrosu G, et al. Multiple sclerosis in childhood: clinical features of 149 cases. Multiple sclerosis 1997;3:43-6. Hanefeld FA. Characteristics of childhood multiple sclerosis. Int MS J 1995;1:91-7. IFNB Multiple Sclerosis Study Group. Interferon beta-1b is effective in relaps-
ing-remitting multiple sclerosis. I. Clinical results of a multicenter, randomized, double-blind, placebo-controlled trial. Neurology 1993;43:655-61. 6. Jacobs LD, Cookfair DL, Rudick RA, Herndon R, Richert JR, Salazar AM, et al. Intramuscular interferon beta-1a for disease progression in relapsing multiple sclerosis. Ann Neurol 1996;39:285-94. 7. PRISMS (Prevention of Relapses and Disability by Interferon β-1A Subcutaneously in Multiple Sclerosis) Study Group. Lancet 1998;352:1498-504. 8. Goodkin DE. Interferon β therapy for multiple sclerosis. Lancet 1998;352:1486-7.
9. Poser CM, Paty DW, Scheinberg L, McDonald WI, Davis FA, Ebers GC, et al. New-diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol 1983;13:227-31. 10. Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology 1983;33:1444-52. 11. Jacobs LD, Beck RW, Simon JH, Kinkel RP, Brownscheidle CM, Murray TJ, et al. Intramuscular interferon beta-1a therapy initiated during a first demyelinating event in multiple sclerosis. N Engl J Med 2000;343:898-904.
We present a report of the use of interferon-β before 18 years of age in 16 patients with childhood-onset multiple sclerosis. This study demonstrated that the treatment is safe and well tolerated. (J Pediatr 2001;139:443-6)
Multiple sclerosis (MS) is the most common neurologic demyelinating disease affecting adults from 20 to 40 years of age. Occurrence is rare before 16 years of age, accounting for only 3% to 5% of total cases.1,2 In comparison with adult-onset MS, brainstem dysfunction is more frequent in childhood MS at the first attack. Moreover, the relapsing-remitting course is preponderant. Clinical outcome seems comparable to that of adult-onset MS.3 No controlled studies of the treatment of childhood MS have been performed. Attacks are treated with intravenous high-dose steroids; and intravenous immunoglobulin and cyclophosphamide or oral azathioprine have been used in severe cases.4 Supportive care must be adapted to children. Both types of recombinant interferon-β (IFN-β), 1a and 1b, have been reported to be of therapeutic benefit in clini-
cal trials in patients >18 years with relapsing-remitting forms.5-8 We present a case series of IFN-β treatment initiated before 18 years of age in patients with onset of MS before 16 years of age.
METHODS All patients had clinically defined MS according to Poser’s criteria.9 Data before treatment with IFN-β were recorded; 16 patients <18 years old were treated with IFN-β (1a: Avonex for 13, Rebif for 2; 1b: Betaferon for 1) subsequent to frequent or severe relapses. Patients fulfilled criteria for IFN-β treatment specified by French regulatory authorities, namely, being ambulatory with expanded Kurtzke disability status score (EDSS)10 <5.5 and having expe-
From the Department of Neuropediatrics, Saint-Vincent de Paul Hospital, Paris, France; Bordeaux University Hospital, Bordeaux, France; Rouen University Hospital, Rouen, France; Department of Neurology, Dijon University Hospital, Dijon, France; Nancy University Hospital, Nancy, France; University Hospital, Marseille, France; Nice University Hospital, Nice, France; Pitié-Salpétrière Hospital, Paris, France; Lille University Hospital, Lille, France.
Submitted for publication Oct 10, 2000; revision received Feb 13, 2001; accepted May 1, 2001. Reprints not available from author. Correspondence: Yann Mikaeloff, MD, Service de Neurologie Pédiatrique, Hôpital Saint-Vincent de Paul, 82 avenue Denfert-Rochereau, 75674 Paris Cedex 14, France. Copyright © 2001 by Mosby, Inc. 0022-3476/2001/$35.00 + 0 9/22/117004 doi:10.1067/mpd.2001.117004
rienced a minimum of 2 attacks during the past 2 (Rebif, Betaferon) or 3 years (Avonex). The use of IFN-β is permitted by the French regulatory authorities (ie, it has market authorization) only for paCSF EDSS IFN-β MRI MS
Cerebrospinal fluid Expanded Kurtzke disability status score Interferon-β Magnetic resonance imaging Multiple sclerosis
tients 16 years of age or older, which was the case for 7 patients. The 9 younger patients were treated in accordance with protocol, and informed consent was obtained from the parents or guardians of the children. All patients were of expected weight and size for their age. In all but one case, they were treated with adult doses, initiated progressively: Avonex, 6 × 106 IU = 30 µg given intramuscularly every week; Rebif, 6 × 106 IU = 22 µg given subcutaneously 3 times per week; Betaferon, 8 × 106 IU given subcutaneously every 2 days. The youngest patient, 10.5 years old, was treated with a half dose of Avonex. Oral contraceptives were prescribed to female patients of childbearing age. We performed prospective follow-up with visits scheduled at 1, 2, and 3 months and every 6 months thereafter. At each visit, clinical status was defined with EDSS, and blood count and hepatic enzymes were monitored. Magnetic resonance imaging (MRI) was performed before initiation of treatment and twice in the 2 following years for most patients. Injection of 443
THE JOURNAL OF PEDIATRICS SEPTEMBER 2001
MIKAELOFF ET AL
Table. Patient characteristics
Patient No.
Sex
Age at beginning of IFN-β (y)
Duration of disease (y)
No. of relapses before IFN-β treatment
8.5 14.5 12 12.5
M F M F
10.5 15.5 15.5 15
3 2 5.5 4.5
3 4 3 10
Motor, CN Diplopia, vestibular Diplopia, cerebellar, CN Cerebellar, CN Sensory, ON Motor, sensory, CN ON Motor, ON, CN, diplopia Motor, cerebellar ON
13 12 14 14 11 15 12 13 12 15.5
F F F F F F F F F F
14 14.5 15 15 15 16 16 16 17 17
3 3 1.5 3 4.5 3 6.5 5.5 6 2.5
5 6 4 2 3 3 7 10 6 3
Diplopia Diplopia
15.8 14
F F
17 16
3 5
Initial symptoms
Age at onset of MS (y)
Motor Motor Motor Motor, sensory, ON, CN cerebellar
5 6 7 8 9 10 11 12 13 14
15 16
1 2 3 4
3 3
CN, Cranial nerves; erythema, erythema at injection site; FLS, flu-like syndrome; IDD, insulin-dependent diabetes; ON, optic neuritis.
gadolinium was not systematically administered.
RESULTS The group of patients included 14 girls and 2 boys. Two girls had an autoimmune disorder, either type 1 diabetes or thyroiditis, before treatment. In the month before the first attack, 2 patients had been vaccinated against hepatitis B. There was no familial antecedent of MS or other autoimmune diseases. Median age at the first attack was 13 years (range, 8.5-15.8 years). Only one boy developed MS before 10 years of age (8.5 years). The initial clinical manifestations are reported in the Table. Median age at the time of diagnosis of clinically definite MS was 14 years (range, 9.5-17 years). Twelve patients had biologic markers: oligoclonal bands on cerebrospinal fluid (CSF) isoelectric focus444
ing for 9 patients or increased IgG index in 3 cases without oligoclonal bands. Analysis of CSF was not performed in 2 cases. Median value of CSF cell count was 7 cells/mm3 (range, 1-35 cells/mm3). Initial MRI revealed increased multiple and periventricular T2-weighted signals in all 16 cases, with subcortical white-matter lesions in 15 cases. In some cases, increased signals were located in the brainstem (10 cases), cerebellum (7 cases), or spinal cord (5 cases) (spinal cord MRI was performed initially in 9 cases). All patients had a relapsing-remitting course. Median interval between first and second attacks was 0.9 year (range, 0.2-4 years). Complete recovery after the first attack was achieved in 12 cases (8 treated with intravenous high-dose steroids), whereas sequelae were observed in 4 patients (3 treated with intravenous high-dose steroids). Before administration of IFN-β was initiated, median duration of the dis-
ease was 1.7 years (range, 0.5-5 years) and median number of attacks was 3.5 (range, 2-10), most of which had been treated with intravenous high-dose steroids, followed by a tapering dose of oral steroids. Median age at beginning of IFN-β treatment was 15.5 years (range, 10.517 years). Nine patients were treated before 16 years of age. Median EDSS when beginning treatment was 2.25 (range, 0-4.5). Median duration of IFN-β treatment was 1 year (range, 0.5-2.5 years). Median EDSS was stable during treatment. No significant differences were observed between patients treated before 16 years of age with the special procedure and patients treated at 16 years of age or older for initial and follow-up results (Table). MRI follow-up with IFN-β treatment was evaluated by T2-weighted sequences for 9 patients. According to these analyses, disease was stable for 3 patients but worsened in 6 cases.
MIKAELOFF ET AL
THE JOURNAL OF PEDIATRICS
VOLUME 139, NUMBER 3
EDSS at initiation of IFN-β
EDSS at end of IFN-β treatment period
Duration of IFN-β treatment
No. of relapses during IFN-β treatment
3 2.5 1 2.5
3 2.5 0 4
1 0.5 1.5 1.6
0 0 1 3
1.5 3 4 2.5 0 2 4.5 2 0 2.5
1.5 3.5 1 3.5 0 5.5 5.5 1 0 2.5
1 1.5 0.5 0.5 0.8 0.7 1.4 2 1 0.5
5 1 1 3 0 5 5 5 0 0
0 0
0 0
2 2.5
1 1
Intensity of side effects was mild. A flu-like syndrome was observed in 11 cases, and isolated myalgia, in 3 patients. Medications were given to control flu-like symptoms with good efficacy as follows: acetaminophen for 6 (associated with ibuprofen for one), ibuprofen for 4, and nurofen for 1 patient. There was a rotation of injection sites, and the injection technique was reviewed periodically as recommended. Injection site reactions were moderate: 3 patients had localized erythema (Betaferon 1, Avonex 2). No skin breakdown was observed. There were no hematologic or hepatic side effects, except in one patient who had a moderate but transient increase in transaminase levels at initiation of treatment with spontaneous normalization. One patient with type 1 diabetes developed transient hyperglycemia after injection of IFN-β, which was controlled by an increase in insulin dose. IFN-β (Avonex) administration was inter-
Continuing initial IFN-β treatment
Reason for discontinuation
Myalgia FLS FLS Myalgia, erythema
Yes Yes Yes No
— — — Frequent attacks
No FLS FLS FLS FLS Erythema FLS FLS FLS FLS, hyperglycemia with stable IDD Myalgia FLS, erythema
Yes Yes Yes No Yes No No Yes Yes Yes
— — — Frequent attacks — Frequent attacks Frequent attacks — — —
Yes Yes
— —
Side effects
rupted in 4 cases because of frequent attacks (3, 5, 5, and 3 attacks in 0.5, 0.7, 1.4, and 1.6 years of treatment, respectively), but never because of adverse effects. In these cases, an alternative higher dose of IFN-β was prescribed (Rebif). Tolerance was the same as that observed for the initial product.
DISCUSSION Few studies with immunomodulatory drugs have been performed in childhood MS. To date, there is no published report of treatment of childhood MS with recombinant IFN-β. In light of the well-documented efficacy of such treatment in adult MS, it was of considerable interest to evaluate its use in childhood MS. In our study, the high frequency of treatment failure (4/16, 25%) relative to that observed in any of the other trials5-8 may be attributable to the selection of severe forms
of childhood-onset MS with numerous polysymptomatic onsets (9/16). IFN-β is a well-tolerated treatment in children and adolescents. In our small study group, efficacy was variable without worsening of EDSS status. There were no significant differences between patients treated before 16 years of age and other patients. We conclude that IFN-β is well tolerated in patients younger than 16 years and consider that such treatment should be made accessible to this age group. Larger studies with prolonged follow-up will be necessary to determine whether therapeutic benefit is long-lasting, particularly because in adults early treatment with IFN-β is recommended.11
REFERENCES 1. Duquette P, Murray TJ, Pleines J, Ebers GC, Sadovnick D, Weldon P, et al. Multiple sclerosis in childhood: clini445
THE JOURNAL OF PEDIATRICS SEPTEMBER 2001
MIKAELOFF ET AL
2.
3.
4. 5.
446
cal profile in 125 patients. J Pediatr 1987;111:359-63. Ruggieri M, Polizzi A, Pavone L, Grimaldi LME. Multiple sclerosis in children under 6 years of age. Neurology 1999;53:478-84. Ghezzi A, Deplano V, Faroni J, Grasso MG, Liguori M, Marrosu G, et al. Multiple sclerosis in childhood: clinical features of 149 cases. Multiple sclerosis 1997;3:43-6. Hanefeld FA. Characteristics of childhood multiple sclerosis. Int MS J 1995;1:91-7. IFNB Multiple Sclerosis Study Group. Interferon beta-1b is effective in relaps-
ing-remitting multiple sclerosis. I. Clinical results of a multicenter, randomized, double-blind, placebo-controlled trial. Neurology 1993;43:655-61. 6. Jacobs LD, Cookfair DL, Rudick RA, Herndon R, Richert JR, Salazar AM, et al. Intramuscular interferon beta-1a for disease progression in relapsing multiple sclerosis. Ann Neurol 1996;39:285-94. 7. PRISMS (Prevention of Relapses and Disability by Interferon β-1A Subcutaneously in Multiple Sclerosis) Study Group. Lancet 1998;352:1498-504. 8. Goodkin DE. Interferon β therapy for multiple sclerosis. Lancet 1998;352:1486-7.
9. Poser CM, Paty DW, Scheinberg L, McDonald WI, Davis FA, Ebers GC, et al. New-diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol 1983;13:227-31. 10. Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology 1983;33:1444-52. 11. Jacobs LD, Beck RW, Simon JH, Kinkel RP, Brownscheidle CM, Murray TJ, et al. Intramuscular interferon beta-1a therapy initiated during a first demyelinating event in multiple sclerosis. N Engl J Med 2000;343:898-904.