J Neurol DOI 10.1007/s00415-015-7707-6
ORIGINAL COMMUNICATION
Dalfampridine in hereditary spastic paraplegia: a prospective, open study Matthieu Be´reau1 • Mathieu Anheim2,3,4 • Jean-Baptiste Chanson2 • Gre´gory Tio5 • Andoni Echaniz-Laguna2 • Christel Depienne6 • Nicolas Collongues2,7 Je´roˆme de Se`ze2,7
•
Received: 20 January 2015 / Revised: 10 March 2015 / Accepted: 11 March 2015 Ó Springer-Verlag Berlin Heidelberg 2015
Abstract Our aim was to support the use of dalfampridine as a treatment for patients affected with hereditary spastic paraplegia (HSP). We performed a prospective, uncontrolled, proof of concept, open trial. We included 12 HSP patients defining the total group (TG) who received dalfampridine 10 mg twice daily for 2 weeks. Efficacy assessment was based on walking ability improvement. The Timed-25-Foot Walk Test, the Spastic Paraplegia Rating Scale (SPRS), and the 12-item Multiple Sclerosis Walking Scale (MSWS-12) were performed before and after treatment. Safety assessment was based on adverse events occurrence. A significant improvement in SPRS (p = 0.0195) and MSWS-12 (p = 0.0429) was noted after treatment in the TG. No serious adverse events were noted. M. Be´reau and M. Anheim contributed equally to this work. & Mathieu Anheim [email protected] 1
De´partement de Neurologie, CHRU de Besanc¸on, Besanc¸on, France
2
De´partement de Neurologie, Hoˆpital Civil de Strasbourg, 1, place de L’hoˆpital BP 426, 67091 Strasbourg Cedex, France
3
Fe´de´ration de Me´decine Translationnelle de Strasbourg (FMTS), Universite´ de Strasbourg, Strasbourg, France
4
Institut de Ge´ne´tique et de Biologie Mole´culaire et Cellulaire (IGBMC), INSERM-U964/CNRS-UMR7104/Universite´ de Strasbourg, 67404 Strasbourg, Illkirch, France
5
De´partement de Statistiques, Centre d’Investigation Clinique et d’Innovations Technologiques, INSERM CIT-808, CHRU de Besanc¸on, Besanc¸on, France
6
De´partement de Ge´ne´tique, Cytoge´ne´tique et Embryologie, Groupe hospitalier Pitie´-Salpeˆtrie`re, Paris, France
7
Centre d’Investigation Clinique Plurithe´matique, INSERM CIC-P1002, Hoˆpital Civil de Strasbourg, Strasbourg, France
This interventional study provides encouraging results supporting the use of dalfampridine in HSP. Keywords Hereditary spastic paraplegia Genetics Pharmacology Gait Walking ability Clinical trial
Introduction Dalfampridine (4-aminopyridine) is a class of therapy for spinal cord injuries (SCI) and multiple sclerosis (MS) that directly targets the nervous system and improves action potential conduction in demyelinated axons by blocking voltage-gated K? channels [1, 2]. Previous clinical studies have indicated that administration of dalfampridine improves motor function and reduces spasticity in subjects with spinal cord injury (SCI) [3–5]. An interventional study provided class 1 evidence that dalfampridine extended-release tablets produced clinically meaningful improvement in walking ability in a subset of people with MS [6]. Hereditary spastic paraplegia (HSP) consists in a heterogeneous group of complex inherited disorders in which the main clinical feature is progressive spasticity and weakness of the lower limbs. These symptoms are frequently encountered in MS. The main pathological finding in HSP is axonal degeneration of the terminal portions of the corticospinal tract of the spinal cord [7]. Several forms of HSP are also characterized by a demyelinating component. As in MS, limitation of walking ability is one of the main disabilities of patients with HSP and the most important handicap in the disease. Few treatments (e.g., baclofen and botulinum toxin) are available for HSP symptoms whereas neurological rehabilitation may be of interest. In this open study, we assessed the use of dalfampridine as a treatment of HSP patients.
123
J Neurol
Methods Patients Patients affected with HSP were eligible for the study. They were recruited among the latest patients successively diagnosed with HSP in the University Hospital of Strasbourg (France). Patients were excluded if they had prior exposure to dalfampridine, a history of seizures, renal injury, or any change in the treatment of spasticity within the last 6 months. This trial was performed in accordance with the Declaration of Helsinki and its subsequent amendments, good clinical practice and all applicable regulatory requirements. The study was approved by the local ethics committee. All patients signed an informed consent. Protocol This was a prospective, single-center, uncontrolled, proof of concept, open trial. The patients included defining the total group (TG) received dalfampridine 10 mg twice daily for 2 weeks. All patients underwent a comprehensive clinical examination. By analogy with the studies done in MS, efficacy was based on walking speed and gait improvement [6, 8]. We performed in all patients the Timed25-Foot Walk Test (TWT) in order to assess walking speed (according to the instructions for the Multiple sclerosis Functional Composite) [9] as well as the Spastic Paraplegia Rating Scale (SPRS) [10] and the 12-item Multiple Sclerosis Walking Scale (MSWS-12) [11] in order to evaluate gait improvement. The first clinical evaluation was done before receiving treatment and retest evaluations were performed 15 days after the treatment was started. Performances in TWT, SPRS and MSWS-12 in the TG before and after treatment were compared. Adverse events were reported as the basis for assessing the safety of dalfampridine in HSP patients. In accordance with results obtained in MS studies, two groups were defined at the later stage: a responder group (RG) and a non-responder group (NRG). A responder was defined by an improvement of C20 % in any of the three tests (TWT, SPRS, and MSWS-12); a non-responder was defined by an improvement of \20 % in all three tests. The characteristics of TG, RG and NRG groups and their performance in TWT, SPRS and MSWS-12 were also compared.
cross-table statistics, performing v2 tests of independence, and Fisher’s exact tests when appropriate. Between-group differences in post and pre-test values were examined using an analysis of covariance (ANCOVA) for each outcome variable. Differences between pre-test and 2-week followup scores were treated as dependent variables, responder condition as a fixed factor, and pre-treatment scores as covariates. Continuous variables were compared using the Student’s t test or Wilcoxon test across time for each group.
Results Characteristics of HSP patients Twelve patients were included. The molecular defect could be identified in eleven patients [SPG4 (n = 6), SPG7 (n = 1), SPG10 (n = 2), adrenomyeloneuropathy (ADMN) (n = 2)]. One patient from North Africa had a personal history of childhood onset, sporadic, pure spastic paraplegia and consanguinity. Six patients were included in the RG and six patients in the NRG. There was no significant difference between TG, RG and NRG groups in terms of socio-demographic data, disease characteristics or genetic results (Table 1). Considering retest evaluations in the TG, a significant improvement in SPRS (J0 = 21 ± 9.6; J15 = 19.1 ± 9.6; t = -2.73; p = 0.0195) and MSWS-12 (J0 = 70.3 ± 19.6; J15 = 61 ± 22.7; t = -2.29; p = 0.0429) was noted after treatment. No serious adverse events were observed. Minor adverse events were noted. Asthenia was the most frequent side effect (n = 5). Two patients stopped the treatment because of minor adverse events (insomnia and asthenia, respectively). Considering retest evaluations in the RG, mean improvement in SPRS was 20.7 % (95 % CI 7.2–34.2 %); mean improvement in TWT was 21.1 % (95 % CI 12.2–30 %); mean improvement in MSWS-12 was 31.6 % (95 % CI 23.7–39.5 %) after treatment. Analysis of covariance (ANCOVA) showed significant difference after treatment in SPRS between baseline and endpoint in the RG compared to the NRG (F1.10 = 12.1, p = 0.0069). Similarly, TWT and MSWS-12 showed a significant difference (F1.10 = 8.2, p = 0.0185 and F1.10 = 36.5, p \ 0.001, respectively) after treatment between baseline and endpoint in the RG compared to the NRG.
Statistical analysis All computations were performed using the statistical software Stata/SE 10.1 for Windows (Stata Corp LP, College Station, TX). All statistical tests were two-tailed and significance was set at the 0.05 level. Assessment of group differences on nominal variables was undertaken through
123
Discussion The objective of this proof of concept open study was to support the use of dalfampridine as a treatment of patients affected with HSP. No serious adverse events were noted,
J Neurol Table 1 Characteristics of HSP patients
Characteristics of HSP patients
Total group (n = 12)
Responder group (n = 6)
Non-responder group (n = 6)
p
51.8 ± 10.5
50.5 ± 7.3
53.0 ± 13.3
0.75
Males
7
3
4
1.0
Females
5
3
2
Sex ratio (F/M)
5/7
1
1/2
SPG4
6
3
3
SPG10
2
1
1
ADMN SPG7
2 1
1 1
1 0
Unknown
1
0
1
Socio-demographic data Age, mean ± SD Sex, n
Disease characteristics SPG subtype, n 1.0
Disease duration, mean ± SD
15.7 ± 7.9
14.7 ± 7.0
16.7 ± 8.9
0.87
Concomitant treatment with baclofen, n
7
3
4
0.75
0.55
Gait disturbance, n Autonomous
5
2
3
1 stick
4
3
1
2 sticks
1
0
1
Wheelchair
1
0
1
HSP hereditary spastic paraplegia, SPG spastic paraplegia, ADMN adrenomyeloneuropathy
which argues for the relative safety of this drug in HSP patients. Furthermore, our trial provides encouraging results supporting the use of dalfampridine in HSP: a significant improvement in SPRS (p = 0.0195) and MSWS12 (p = 0.0429) was noted in the TG. Thus, dalfampridine could be considered as an additional option in the currently limited set of classical treatments for spastic paraplegia. By analogy with the studies done in MS [6, 8], we defined two other groups at the later stage: the RG and the NRG groups. The improvement was significant for the three scores (SPRS, TWT, MSWS-12) in the RG, whereas no significant improvement was noted in the NRG. Moreover, the percentage of patients who met the responder criterion in this study in the RG (50 %) was similar to that observed in MS patients (35 % [8] and 42.9 % [6], respectively). However, our results must be interpreted with caution because no control group was included. As such, it cannot be excluded that NRG and RG groups do correspond to groups of patients with and without placebo effect, respectively. In phase III clinical trials conducted in MS, the percentage of patients who met the responder criterion in the placebo group was 8 % [8] and 9.3 % [6], respectively, suggesting a weak effect. In any case, such results, and whether they can be sustained, need to be further confirmed by larger, placebo-controlled, double-blind, randomized
studies comparing the percentage of responder and nonresponder patients between the placebo and non placebo groups. The factors that determine which patients will be responders or non-responders remain unknown. There could be environmental factors and/or genetic factors, especially modifier genes in the case of HSP. In our series, there were no significant differences between the two groups in terms of socio-demographic data and disease characteristics, including molecular diagnosis. The major neuropathological feature of HSP is axonal degeneration, but demyelination and gliosis have also been described [12]. The therapeutic effect of dalfampridine observed in the RG could be related to prolonged depolarization resulting from blocking voltage-gated K? channels in demyelinated nerve fibers in HSP patients. ADMN is known to be associated with demyelination, which is in accordance with the efficacy of dalfampridine. On the other hand, the other type of HSP investigated here is known rather to be characterized by endoplasmic reticulum morphogenesis, endosomal traffic and cytokinesis (SPG4), mitochondrial protease dysfunction (SPG7) and microtubule-based motor protein (SPG10) [13]. The question of whether dalfampridine could also be effective in other forms of HSP dominated by demyelination, such as SPG2 and SPG35 (or FA2H), should be addressed in further studies.
123
J Neurol
Conclusion This interventional study provides encouraging results supporting further research on the use of dalfampridine in HSP. Conflicts of interest Dr. Matthieu Be´reau, Prof. Mathieu Anheim, Dr. Jean-Baptiste Chanson, Mr. Gregory Tio, Dr. Andoni EchanizLaguna, Dr. Christel Depienne, report no disclosures. Dr. Nicolas Collongues serves on scientific advisory boards for and has received honoraria from Biogen Idec, Merck Serono, sanofi-aventis, LFB, Almirall and Bayer Schering Pharma. Prof. Je´rome De Se`ze serves on scientific advisory boards for and has received honoraria from Biogen Idec. Study sponsorship
This study is not industry-sponsored
Ethical standard The study was approved by the local ethics committee. All patients signed an inform consent.
5.
6.
7. 8.
9.
10.
References 11. 1. Judge SI, Bever CT Jr (2006) Potassium channel blockers in multiple sclerosis: neuronal Kv channels and effects of symptomatic treatment. Pharmacol Ther 111:224–259 2. Blight AR (1989) Effect of 4-aminopyridine on axonal conduction-block in chronic spinal cord injury. Brain Res Bull 22:47–52 3. Hansebout RR, Blight AR, Fawcett S, Reddy K (1993) 4-Aminopyridine in chronic spinal cord injury: a controlled, double-blind, crossover study in eight patients. J Neurotrauma 110:1–18 4. Hayes KC, Blight AR, Potter PJ, Allatt RD, Hsieh JT, Wolfe DL, Lam S, Hamilton JT (1993) Preclinical trial of 4-aminopyridine
123
12.
13.
in patients with chronic spinal cord injury. Paraplegia 31:216–224 Potter PJ, Hayes KC, Segal JL, Hsieh JT, Brunnemann SR, Delaney GA, Tiernay DS, Mason D (1998) Randomized doubleblind crossover trial of fampridine-SR (sustained release 4-aminopyridine) in patients with incomplete spinal cord injury. J Neurotrauma 15:837–849 Goodman AD, Brown TR, Edwards KR, Krupp LB, Schapiro RT, Cohen R, Marinucci LN, Blight AR, MSF204 Investigators (2010) A phase 3 trial of extended release oral dalfampridine in multiple sclerosis. Ann Neurol 68:494–502 Bruyn RP (1992) The neuropathology of hereditary spastic paraparesis. Clin Neurol Neurosurg 94(Suppl):S16–S18 Goodman AD, Brown TR, Krupp LB, Schapiro RT, Schwid SR, Cohen R, Marinucci LN, Blight AR, Fampridine MS-F203 (2009) Sustained-release oral fampridine in multiple sclerosis: a randomised, double-blind, controlled trial. Lancet 373:732–738 Fischer JS, Jak AJ, Kniler JE, Cutter G (2001) Multiple sclerosis functional composite (MSFC): administration and scoring manual. National Multiple Sclerosis Society, New York Schule R, Holland-Letz T, Klimpe S, Kassubek J, Klopstock T, Mall V, Otto S, Winner B, Scho¨ls L (2006) The Spastic Paraplegia Rating Scale (SPRS): a reliable and valid measure of disease severity. Neurology 67:430–434 Hobart JC, Riazi A, Lamping DL, Fitzpatrick R, Thompson AJ (2003) Measuring the impact of MS on walking ability: the 12-Item MS Walking Scale (MSWS-12). Neurology 60:31–36 McDermott C, White K, Bushby K, Shaw P (2000) Hereditary spastic paraparesis: a review of new developments. J Neurol Neurosurg Psychiatry 69:150–160 Blackstone C, O’Kane CJ, Reid E (2011) Hereditary spastic paraplegias: membrane traffic and the motor pathway. Nat Rev Neurosci 12:31–42
ORIGINAL COMMUNICATION
Dalfampridine in hereditary spastic paraplegia: a prospective, open study Matthieu Be´reau1 • Mathieu Anheim2,3,4 • Jean-Baptiste Chanson2 • Gre´gory Tio5 • Andoni Echaniz-Laguna2 • Christel Depienne6 • Nicolas Collongues2,7 Je´roˆme de Se`ze2,7
•
Received: 20 January 2015 / Revised: 10 March 2015 / Accepted: 11 March 2015 Ó Springer-Verlag Berlin Heidelberg 2015
Abstract Our aim was to support the use of dalfampridine as a treatment for patients affected with hereditary spastic paraplegia (HSP). We performed a prospective, uncontrolled, proof of concept, open trial. We included 12 HSP patients defining the total group (TG) who received dalfampridine 10 mg twice daily for 2 weeks. Efficacy assessment was based on walking ability improvement. The Timed-25-Foot Walk Test, the Spastic Paraplegia Rating Scale (SPRS), and the 12-item Multiple Sclerosis Walking Scale (MSWS-12) were performed before and after treatment. Safety assessment was based on adverse events occurrence. A significant improvement in SPRS (p = 0.0195) and MSWS-12 (p = 0.0429) was noted after treatment in the TG. No serious adverse events were noted. M. Be´reau and M. Anheim contributed equally to this work. & Mathieu Anheim [email protected] 1
De´partement de Neurologie, CHRU de Besanc¸on, Besanc¸on, France
2
De´partement de Neurologie, Hoˆpital Civil de Strasbourg, 1, place de L’hoˆpital BP 426, 67091 Strasbourg Cedex, France
3
Fe´de´ration de Me´decine Translationnelle de Strasbourg (FMTS), Universite´ de Strasbourg, Strasbourg, France
4
Institut de Ge´ne´tique et de Biologie Mole´culaire et Cellulaire (IGBMC), INSERM-U964/CNRS-UMR7104/Universite´ de Strasbourg, 67404 Strasbourg, Illkirch, France
5
De´partement de Statistiques, Centre d’Investigation Clinique et d’Innovations Technologiques, INSERM CIT-808, CHRU de Besanc¸on, Besanc¸on, France
6
De´partement de Ge´ne´tique, Cytoge´ne´tique et Embryologie, Groupe hospitalier Pitie´-Salpeˆtrie`re, Paris, France
7
Centre d’Investigation Clinique Plurithe´matique, INSERM CIC-P1002, Hoˆpital Civil de Strasbourg, Strasbourg, France
This interventional study provides encouraging results supporting the use of dalfampridine in HSP. Keywords Hereditary spastic paraplegia Genetics Pharmacology Gait Walking ability Clinical trial
Introduction Dalfampridine (4-aminopyridine) is a class of therapy for spinal cord injuries (SCI) and multiple sclerosis (MS) that directly targets the nervous system and improves action potential conduction in demyelinated axons by blocking voltage-gated K? channels [1, 2]. Previous clinical studies have indicated that administration of dalfampridine improves motor function and reduces spasticity in subjects with spinal cord injury (SCI) [3–5]. An interventional study provided class 1 evidence that dalfampridine extended-release tablets produced clinically meaningful improvement in walking ability in a subset of people with MS [6]. Hereditary spastic paraplegia (HSP) consists in a heterogeneous group of complex inherited disorders in which the main clinical feature is progressive spasticity and weakness of the lower limbs. These symptoms are frequently encountered in MS. The main pathological finding in HSP is axonal degeneration of the terminal portions of the corticospinal tract of the spinal cord [7]. Several forms of HSP are also characterized by a demyelinating component. As in MS, limitation of walking ability is one of the main disabilities of patients with HSP and the most important handicap in the disease. Few treatments (e.g., baclofen and botulinum toxin) are available for HSP symptoms whereas neurological rehabilitation may be of interest. In this open study, we assessed the use of dalfampridine as a treatment of HSP patients.
123
J Neurol
Methods Patients Patients affected with HSP were eligible for the study. They were recruited among the latest patients successively diagnosed with HSP in the University Hospital of Strasbourg (France). Patients were excluded if they had prior exposure to dalfampridine, a history of seizures, renal injury, or any change in the treatment of spasticity within the last 6 months. This trial was performed in accordance with the Declaration of Helsinki and its subsequent amendments, good clinical practice and all applicable regulatory requirements. The study was approved by the local ethics committee. All patients signed an informed consent. Protocol This was a prospective, single-center, uncontrolled, proof of concept, open trial. The patients included defining the total group (TG) received dalfampridine 10 mg twice daily for 2 weeks. All patients underwent a comprehensive clinical examination. By analogy with the studies done in MS, efficacy was based on walking speed and gait improvement [6, 8]. We performed in all patients the Timed25-Foot Walk Test (TWT) in order to assess walking speed (according to the instructions for the Multiple sclerosis Functional Composite) [9] as well as the Spastic Paraplegia Rating Scale (SPRS) [10] and the 12-item Multiple Sclerosis Walking Scale (MSWS-12) [11] in order to evaluate gait improvement. The first clinical evaluation was done before receiving treatment and retest evaluations were performed 15 days after the treatment was started. Performances in TWT, SPRS and MSWS-12 in the TG before and after treatment were compared. Adverse events were reported as the basis for assessing the safety of dalfampridine in HSP patients. In accordance with results obtained in MS studies, two groups were defined at the later stage: a responder group (RG) and a non-responder group (NRG). A responder was defined by an improvement of C20 % in any of the three tests (TWT, SPRS, and MSWS-12); a non-responder was defined by an improvement of \20 % in all three tests. The characteristics of TG, RG and NRG groups and their performance in TWT, SPRS and MSWS-12 were also compared.
cross-table statistics, performing v2 tests of independence, and Fisher’s exact tests when appropriate. Between-group differences in post and pre-test values were examined using an analysis of covariance (ANCOVA) for each outcome variable. Differences between pre-test and 2-week followup scores were treated as dependent variables, responder condition as a fixed factor, and pre-treatment scores as covariates. Continuous variables were compared using the Student’s t test or Wilcoxon test across time for each group.
Results Characteristics of HSP patients Twelve patients were included. The molecular defect could be identified in eleven patients [SPG4 (n = 6), SPG7 (n = 1), SPG10 (n = 2), adrenomyeloneuropathy (ADMN) (n = 2)]. One patient from North Africa had a personal history of childhood onset, sporadic, pure spastic paraplegia and consanguinity. Six patients were included in the RG and six patients in the NRG. There was no significant difference between TG, RG and NRG groups in terms of socio-demographic data, disease characteristics or genetic results (Table 1). Considering retest evaluations in the TG, a significant improvement in SPRS (J0 = 21 ± 9.6; J15 = 19.1 ± 9.6; t = -2.73; p = 0.0195) and MSWS-12 (J0 = 70.3 ± 19.6; J15 = 61 ± 22.7; t = -2.29; p = 0.0429) was noted after treatment. No serious adverse events were observed. Minor adverse events were noted. Asthenia was the most frequent side effect (n = 5). Two patients stopped the treatment because of minor adverse events (insomnia and asthenia, respectively). Considering retest evaluations in the RG, mean improvement in SPRS was 20.7 % (95 % CI 7.2–34.2 %); mean improvement in TWT was 21.1 % (95 % CI 12.2–30 %); mean improvement in MSWS-12 was 31.6 % (95 % CI 23.7–39.5 %) after treatment. Analysis of covariance (ANCOVA) showed significant difference after treatment in SPRS between baseline and endpoint in the RG compared to the NRG (F1.10 = 12.1, p = 0.0069). Similarly, TWT and MSWS-12 showed a significant difference (F1.10 = 8.2, p = 0.0185 and F1.10 = 36.5, p \ 0.001, respectively) after treatment between baseline and endpoint in the RG compared to the NRG.
Statistical analysis All computations were performed using the statistical software Stata/SE 10.1 for Windows (Stata Corp LP, College Station, TX). All statistical tests were two-tailed and significance was set at the 0.05 level. Assessment of group differences on nominal variables was undertaken through
123
Discussion The objective of this proof of concept open study was to support the use of dalfampridine as a treatment of patients affected with HSP. No serious adverse events were noted,
J Neurol Table 1 Characteristics of HSP patients
Characteristics of HSP patients
Total group (n = 12)
Responder group (n = 6)
Non-responder group (n = 6)
p
51.8 ± 10.5
50.5 ± 7.3
53.0 ± 13.3
0.75
Males
7
3
4
1.0
Females
5
3
2
Sex ratio (F/M)
5/7
1
1/2
SPG4
6
3
3
SPG10
2
1
1
ADMN SPG7
2 1
1 1
1 0
Unknown
1
0
1
Socio-demographic data Age, mean ± SD Sex, n
Disease characteristics SPG subtype, n 1.0
Disease duration, mean ± SD
15.7 ± 7.9
14.7 ± 7.0
16.7 ± 8.9
0.87
Concomitant treatment with baclofen, n
7
3
4
0.75
0.55
Gait disturbance, n Autonomous
5
2
3
1 stick
4
3
1
2 sticks
1
0
1
Wheelchair
1
0
1
HSP hereditary spastic paraplegia, SPG spastic paraplegia, ADMN adrenomyeloneuropathy
which argues for the relative safety of this drug in HSP patients. Furthermore, our trial provides encouraging results supporting the use of dalfampridine in HSP: a significant improvement in SPRS (p = 0.0195) and MSWS12 (p = 0.0429) was noted in the TG. Thus, dalfampridine could be considered as an additional option in the currently limited set of classical treatments for spastic paraplegia. By analogy with the studies done in MS [6, 8], we defined two other groups at the later stage: the RG and the NRG groups. The improvement was significant for the three scores (SPRS, TWT, MSWS-12) in the RG, whereas no significant improvement was noted in the NRG. Moreover, the percentage of patients who met the responder criterion in this study in the RG (50 %) was similar to that observed in MS patients (35 % [8] and 42.9 % [6], respectively). However, our results must be interpreted with caution because no control group was included. As such, it cannot be excluded that NRG and RG groups do correspond to groups of patients with and without placebo effect, respectively. In phase III clinical trials conducted in MS, the percentage of patients who met the responder criterion in the placebo group was 8 % [8] and 9.3 % [6], respectively, suggesting a weak effect. In any case, such results, and whether they can be sustained, need to be further confirmed by larger, placebo-controlled, double-blind, randomized
studies comparing the percentage of responder and nonresponder patients between the placebo and non placebo groups. The factors that determine which patients will be responders or non-responders remain unknown. There could be environmental factors and/or genetic factors, especially modifier genes in the case of HSP. In our series, there were no significant differences between the two groups in terms of socio-demographic data and disease characteristics, including molecular diagnosis. The major neuropathological feature of HSP is axonal degeneration, but demyelination and gliosis have also been described [12]. The therapeutic effect of dalfampridine observed in the RG could be related to prolonged depolarization resulting from blocking voltage-gated K? channels in demyelinated nerve fibers in HSP patients. ADMN is known to be associated with demyelination, which is in accordance with the efficacy of dalfampridine. On the other hand, the other type of HSP investigated here is known rather to be characterized by endoplasmic reticulum morphogenesis, endosomal traffic and cytokinesis (SPG4), mitochondrial protease dysfunction (SPG7) and microtubule-based motor protein (SPG10) [13]. The question of whether dalfampridine could also be effective in other forms of HSP dominated by demyelination, such as SPG2 and SPG35 (or FA2H), should be addressed in further studies.
123
J Neurol
Conclusion This interventional study provides encouraging results supporting further research on the use of dalfampridine in HSP. Conflicts of interest Dr. Matthieu Be´reau, Prof. Mathieu Anheim, Dr. Jean-Baptiste Chanson, Mr. Gregory Tio, Dr. Andoni EchanizLaguna, Dr. Christel Depienne, report no disclosures. Dr. Nicolas Collongues serves on scientific advisory boards for and has received honoraria from Biogen Idec, Merck Serono, sanofi-aventis, LFB, Almirall and Bayer Schering Pharma. Prof. Je´rome De Se`ze serves on scientific advisory boards for and has received honoraria from Biogen Idec. Study sponsorship
This study is not industry-sponsored
Ethical standard The study was approved by the local ethics committee. All patients signed an inform consent.
5.
6.
7. 8.
9.
10.
References 11. 1. Judge SI, Bever CT Jr (2006) Potassium channel blockers in multiple sclerosis: neuronal Kv channels and effects of symptomatic treatment. Pharmacol Ther 111:224–259 2. Blight AR (1989) Effect of 4-aminopyridine on axonal conduction-block in chronic spinal cord injury. Brain Res Bull 22:47–52 3. Hansebout RR, Blight AR, Fawcett S, Reddy K (1993) 4-Aminopyridine in chronic spinal cord injury: a controlled, double-blind, crossover study in eight patients. J Neurotrauma 110:1–18 4. Hayes KC, Blight AR, Potter PJ, Allatt RD, Hsieh JT, Wolfe DL, Lam S, Hamilton JT (1993) Preclinical trial of 4-aminopyridine
123
12.
13.
in patients with chronic spinal cord injury. Paraplegia 31:216–224 Potter PJ, Hayes KC, Segal JL, Hsieh JT, Brunnemann SR, Delaney GA, Tiernay DS, Mason D (1998) Randomized doubleblind crossover trial of fampridine-SR (sustained release 4-aminopyridine) in patients with incomplete spinal cord injury. J Neurotrauma 15:837–849 Goodman AD, Brown TR, Edwards KR, Krupp LB, Schapiro RT, Cohen R, Marinucci LN, Blight AR, MSF204 Investigators (2010) A phase 3 trial of extended release oral dalfampridine in multiple sclerosis. Ann Neurol 68:494–502 Bruyn RP (1992) The neuropathology of hereditary spastic paraparesis. Clin Neurol Neurosurg 94(Suppl):S16–S18 Goodman AD, Brown TR, Krupp LB, Schapiro RT, Schwid SR, Cohen R, Marinucci LN, Blight AR, Fampridine MS-F203 (2009) Sustained-release oral fampridine in multiple sclerosis: a randomised, double-blind, controlled trial. Lancet 373:732–738 Fischer JS, Jak AJ, Kniler JE, Cutter G (2001) Multiple sclerosis functional composite (MSFC): administration and scoring manual. National Multiple Sclerosis Society, New York Schule R, Holland-Letz T, Klimpe S, Kassubek J, Klopstock T, Mall V, Otto S, Winner B, Scho¨ls L (2006) The Spastic Paraplegia Rating Scale (SPRS): a reliable and valid measure of disease severity. Neurology 67:430–434 Hobart JC, Riazi A, Lamping DL, Fitzpatrick R, Thompson AJ (2003) Measuring the impact of MS on walking ability: the 12-Item MS Walking Scale (MSWS-12). Neurology 60:31–36 McDermott C, White K, Bushby K, Shaw P (2000) Hereditary spastic paraparesis: a review of new developments. J Neurol Neurosurg Psychiatry 69:150–160 Blackstone C, O’Kane CJ, Reid E (2011) Hereditary spastic paraplegias: membrane traffic and the motor pathway. Nat Rev Neurosci 12:31–42
