Journal of the Neurological Sciences 337 (2014) 18–24
Contents lists available at ScienceDirect
Journal of the Neurological Sciences journal homepage: www.elsevier.com/locate/jns
Long-term effects of dalfampridine in patients with multiple sclerosis T. Ruck 1, S. Bittner 1, O.J. Simon, K. Göbel, H. Wiendl, M. Schilling 1, S.G. Meuth ⁎,1 Department of Neurology — University of Münster, Albert-Schweitzer-Campus 1, Building A 10, 48149 Münster, Germany
a r t i c l e
i n f o
Article history: Received 2 October 2013 Received in revised form 3 November 2013 Accepted 8 November 2013 Available online 16 November 2013 Keywords: MS Dalfampridine Long-term treatment Mobility Walking ability Fatigue
a b s t r a c t Background/objective: Dalfampridine is the extended-release formulation of 4-aminopyridine and is approved for the symptomatic treatment of impaired mobility in patients with multiple sclerosis. Our aim was to examine the short- and long-term effects of treatment with dalfampridine on motoric and cognitive assessment parameters of multiple sclerosis (MS) patients over 9–12 months. Methods: Fifty-two patients with MS with an EDSS between 4.0 and 7.0 and impaired mobility were evaluated for parameters of walking ability, MSFC, cognitive and motor fatigue and evoked potentials at treatment initiation with dalfampridine as well as 2 weeks and after 9–12 months later. Results: Thirty out of fifty-two patients (~60%) were still on treatment after 9–12 months. Two weeks after treatment initiation, significant ameliorations could be found for T25FW, maximum walking distance as well as motoric and cognitive fatigue which still persisted after 9–12 months. In contrast significant effects for velocity were observed only after 2 weeks, for improvement in PASAT only after 9–12 months. A tendency for improvement of somatosensory evoked potentials was found in a subset of patients. Conclusion: Dalfampridine shows positive short- and long-term effects on motoric and cognitive assessment parameters in an open-label observational study in a cohort of patients with MS. © 2013 Elsevier B.V. All rights reserved.
1. Introduction Multiple sclerosis (MS) is an autoimmune inflammatory disorder of the central nervous system (CNS). Autoreactive immune cells lead to demyelination and axonal damage resulting in acute neuronal deficits and accumulation of disability [1]. MS is the major cause of nontraumatic disability in young adults [2] with severe social and economic consequences. In the later stages of the disease especially reduced mobility and cognitive impairment are among the most important symptoms in MS patients [3]. Current immunomodulatory therapies reduce relapse frequency and aim at delaying disease progression [4]. However, accumulating deficits result in a number of residual symptoms in a large number of patients with relapsing–remitting and later on secondaryprogressive MS. Furthermore, efficient therapies for primaryprogressive MS are still lacking. Therefore, a number of symptomatic treatments aim at reducing disease symptoms (e.g. spasticity, neuropathic pain, bladder dysfunctions or ataxia). Dalfampridine (trade name in Germany: Fampridin; in Great Britain: Fampridine) is an extended-release formulation of 4-aminopyridine with a high bioavailability and almost complete renal clearance. It is the only approved agent for the symptomatic treatment of impaired mobility in patients with MS. Dalfampridine is a broad-spectrum potassium channel blocker which is assumed to block voltage-sensitive potassium channels of nerve fibers exposed upon demyelination. Upon ⁎ Corresponding author. Tel.: +49 251 83 46811; fax: +49 251 83 46812. E-mail address: [email protected] (S.G. Meuth). 1 Equal contribution. 0022-510X/$ – see front matter © 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.jns.2013.11.011
blockade of these channels, dalfampridine decreases abnormal potassium outward currents [5]. This results in an improvement of conduction, prolongation of action-potential duration [6,7] and in a potentiation of synaptic and neuromuscular transmission by increasing the release of neurotransmitters [8,9]. The improvement of walking ability by dalfampridine was demonstrated in two phase III trials, MS-F203 [10] and MS-F204 [11] including 540 patients over a 14-week study period. Compared to placebo, dalfampridine significantly improved the walking speed in approximately one third of MS patients as measured by the timed 25 foot-walk (T25FW). Urinary tract infection, central nervous system excitation and balance disorder were the most common adverse events observed. The most considerable adverse effect was a dose-dependent increase in seizure incidence. Therefore, dalfampridine is generally considered as a safe treatment, when taken as recommended. However, several critical points have repeatedly been raised by different experts, regulatory boards and National Health Service agencies. The costs (approx. 2300 € per year, Germany, 2013; approx. 4700 £, Great Britain, 2013) might influence treatment decisions and a recent document from the NHS Commissioning Board (now named NHS England, a governmental committee in Great Britain) in April 2013 was issued stating: “Fampridine is not considered to be a cost-effective use of NHS resources (http://www.england.nhs.uk/wp-content/uploads/ 2013/04/d04-ps-d.pdf) [12].” As part of the initial European approval in 2011, the conduction of further studies was requested to address the question whether treatment with dalfampridine leads to a long-term clinically meaningful therapeutic benefit.
T. Ruck et al. / Journal of the Neurological Sciences 337 (2014) 18–24
Our present study evaluates the short- and long-term (over nine to twelve months) effects of dalfampridine on several clinical assessment parameters of cognitive and physical functions. Fifty-two patients with relapsing–remitting, primary- or secondary progressive MS with an EDSS (Expanded Disability Status Scale) score between 4.0 and 7.0 were observed for a follow-up period of nine to twelve months under dalfampridine therapy. Favorable effects in the long-term course were observed for measures of walking ability, cognitive and motor fatigue and cognitive function.
2. Patients and methods 2.1. Patients All patients included in this study were seen from 2011 to 2013 in the MS center at the Department of Neurology, University of Münster. Fifty-two patients with clinically definite MS according to McDonald criteria [13] were consecutively included in this study. Eleven patients were classified as relapsing–remitting (RRMS), sixteen as primary progressive (PPMS) and twenty-five as secondary progressive multiple sclerosis (SPMS). See Table 1 for characteristics of the patients enclosed in this study. Patients were included if they fulfilled the following inclusion criteria: They underwent detailed physical and neurological examination including EDSS and had an EDSS of 4.0–7.0 with clinical relevant impairment of ambulation. To minimize the risk for seizures or QTctime prolongations under therapy with dalfampridine, patients had to provide a regular EEG and ECG prior to treatment initiation. Clinical visits were performed prior to treatment initiation, after 14 days and after 9–12 months for long-time measures. Patients received multiple examinations (maximum walking distance, timed 25-foot walk, measurement of motoric and cognitive fatigue and MSFC). A subgroup of randomly selected patients also received multimodal EP, i.e. VEP and/or SEP and/or MEP. All examinations and recordings were done for diagnostic purposes only. Patients, who significantly improved in the timed 25-foot walk after a test period of 14 days, were considered as treatment responders (according to the approval of the EMA). All patients included in this study gave written informed consent in accordance with the Declaration of Helsinki and a protocol approved by the Ethics Committee of the University of Münster.
19
2.3. Timed 25-foot walk (T25FW) The timed 25 foot-walk (T25FW) was carried out according to the instructions for the multiple sclerosis functional composite [14]. The T25FW was performed twice at each visit, allowing a maximum of 5 min rest between tests. Average values were used for analysis. 2.4. Maximum walking distance The maximum walking distance was assessed on a standardized, plain round-course at our MS center. The maximum distance was measured by an accompanying person until the patient needed a break. Measurement was performed at 9 to 11 am at each visit to avoid time-dependent fluctuations, and started after a resting period of 30 min. Patients were allowed to use an assistive device as long as walking was restricted to the usage. 2.5. Fatigue Scale for Motor and Cognitive Functions (FSMC) The Fatigue Scale for Motor and Cognitive Functions was carried out and evaluated as described before [15]. 2.6. Evoked potentials (EP) All electrophysiological examinations were performed on a commercial computer based neurophysiological recording system (VIASYS, Cardinal Health, Germany) as described earlier [16]. Filters and other technical settings were chosen according to established guidelines [17]. For detailed information see Supplementary materials. 2.7. Scoring and analysis of EP data For analysis of EP data an EP score, as published before [18], was used. In summary, we defined an ordinal EP score in which each abnormal result scored one point (e.g. abnormal latency and/or amplitude on either side). Sum scores of each electrophysiological measure were calculated from absolute values, ranging from 0 (no pathological value on both sides), 1 (pathological value on one side, decrease in amplitude or abnormal latency), 2 (pathological value on one side, abnormal amplitude and latency or pathological value on both sides, latency or amplitude), 3 (pathological value on both sides, one side with abnormal latency and amplitude plus one side with abnormal amplitude or latency) to 4 (pathological values on both sides assessed).
2.2. Multiple sclerosis functional composite
2.8. Statistics
The multiple sclerosis functional composite was performed according to the recommendations of the National Multiple Sclerosis Society from 2001 [14].
A Kruskal–Wallis one-way analysis of variance was used in case of multiple comparisons for nonparametric data. All data is presented as mean ± standard error and significance was assumed for p b 0.05. 3. Results
Table 1 Baseline characteristics of MS patients included in the study at the different time-points. (A) The number of patients, the male to female ratio, the proportions of the different disease entities (RRMS: relapsing–remitting MS, SPMS: secondary-progressive MS, PPMS: primary-progressive MS), the mean age and the mean EDSS at the different time points are depicted.
n m/f (%) RRMS (%) SPMS (%) PPMS (%) Age (mean) EDSS (mean)
t=0
t = 2w
t = 9–12 m
52 34.6/65.4 21.2 48 30.8 50 ± 0.17 5.3 ± 0.02
49 34.7/65.3 20.4 49 30.6 50 ± 0.2 5.1 ± 0.02
30 23.3/76.7 20 53.3 26.7 50 ± 0.3 4.9 ± 0.04
Fifty-two patients with relapsing–remitting MS (21.2%), secondary progressive MS (48%) and primary-progressive MS (30.8%) with an EDSS between 4.0 and 7.0 and impaired mobility were evaluated for parameters of walking impairment, MSFC, cognitive and motor fatigue and evoked potentials at initiation of (t = 0), after 2 weeks (t = 2w) and after 9–12 months after treatment (t = 9–12 m) with dalfampridine. After 9–12 months of follow up, thirty out of fifty-two patients were still on dalfampridine medication (57.7%), twenty-two patients were lost to follow up, withdrew medication due to adverse effects or lack of benefit or were excluded due to poor adherence. The proportions of the different disease entities were stable, whereas the male to female ratio was skewed to women over the study period. We did not observe any differences in the mean age and the EDSS at any time point during the period of observation (Table 1). 30.8% of patients received
20
T. Ruck et al. / Journal of the Neurological Sciences 337 (2014) 18–24
immunomodulatory basic therapy (7 interferon, 3 GA) or escalation therapy (3 fingolimod, 2 natalizumab). Dalfampridine has been shown to improve walking ability of MS patients as assessed by the timed 25-foot walk (T25FW) in several previous studies [10,11]. In accordance with the literature we found a significant improvement of the T25FW at 2 weeks after treatment initiation (p b 0.01) compared to baseline values. The positive effect still persisted after 9–12 months under dalfampridine medication
(p = 0.02) (Fig. 1A). The T25FW only measures the walking speed for the initial walking distance. In contrast, the maximum walking distance might be a more relevant parameter for assessing a clinical and everyday relevant benefit. We observed that the maximum walking distance was also significantly improved for both evaluation time-points compared to baseline (p b 0.01 for each time-point) (Fig. 1B), whereas the velocity (as measured by maximum walking distance/time for maximum walking distance) was only significantly faster after 2 weeks (p = 0.02) (Fig. 1C).
Fig. 1. Dalfampridine improves walking of MS patients in the short- and long-term course. (A) Left panel: The line graphs represent the course of the timed 25-foot walk (T25FW) of each individual patient over the different time-points (0: before treatment, 2w: two weeks under treatment, 9–12m: nine to twelve months under treatment). The lower panel magnifies the results between 3 and 11 s. Right panel: The bar graphs depict the mean T25FW of all MS patients at the different time-points. (B) Dalfampridine significantly improves the maximum walking distance after two weeks and in long-term course, whereas (C) the velocity (maximum walking distance/time) is only significantly increased in the short-term course. * p b 0.05; ns, not significant.
T. Ruck et al. / Journal of the Neurological Sciences 337 (2014) 18–24
The timed 25 foot-walk is one of three components of the multiple sclerosis functional composite (MSFC). The MSFC represents one of the most widely used scoring system to assess neurological disability in patients with MS [19,20] and measures leg function/ambulation (assessed by T25FW), arm/hand function (assessed by the 9-hole Peg Test (9HPT)) and cognitive function (as assessed by the Paced Auditory Serial Addition Test (PASAT)). The MSFC overall score showed a tendency to improve over the observational period but did not reach statistical significance (p = 0.17 for each time-point) (Fig. 2A). Cognitive function as assessed by the PASAT was significantly superior to baseline values in the long-term course (p = 0.02) and showed a beneficial trend in the short-term course (p = 0.22) (Fig. 2B). Dalfampridine had no impact on arm/hand function as the results of the 9HPT were similar at 2 weeks and at 9–12 months after treatment initiation (Fig. 2C and Suppl. Fig. 1). Cognitive function is essentially influenced by the capability of attention and concentration, which are markedly affected by fatigue symptoms. Fatigue is reported by approximately 75–95% of patients
21
with multiple sclerosis [15,21] and impacts both cognitive and motor functions. 4-Aminopyridin has shown positive effects on fatigue and cognitive function in previous studies [22,23]. We used the Fatigue Scale for Motor and Cognitive Functions (FSMC) to evaluate the impact of dalfampridine on fatigue symptoms [15]. The FSMC for motor (Fig. 3A, 2 weeks: p b 0.01, 9–12 months: p = 0.01) as well as for cognitive function (Fig. 3B, 2 weeks: p = 0.048, 9–12 months: p = 0.047) showed significantly reduced values in the short- and long-term course compared to baseline. The dalfampridine treatment led to comparable effects among the different disease groups of MS patients (RRMS, SPMS and PPMS) not always reaching significance but with a similar tendency (Suppl. Fig. 2). In animal models dalfampridine improved nerve conduction and action potential generation [6,7]. We measured and analyzed VEP, MEP and SEP data of a subset of fifteen patients at treatment initiation (t = 0) and 9–12 months after treatment (t = 9–12 m) in order to monitor changes and functional relevance in electrophysiological measures of nerve conduction. We used a previously described sum score to
Fig. 2. Dalfampridine shows significant impact on components of the multiple sclerosis functional composite (MSFC). (A) The individual course (left panel) and the mean values of the MSFC (right panel) of MS patients at the different time-points are shown. (B) The results of the PASAT (Paced Auditory Serial Addition Test) are significantly improved in the longterm course. (C) Arm/hand function as assessed by the Nine-hole Peg Test (9HPT) shows no changes in the treatment course, neither for the dominant (left panel) nor for the other hand (right panel). * p b 0.05; ns, not significant.
22
T. Ruck et al. / Journal of the Neurological Sciences 337 (2014) 18–24
Fig. 3. The Fatigue Scale for Motor and Cognitive Functions (FSMC) shows significantly decreased values under dalfampridine treatment. (A) Motor and (B) cognitive fatigue sum scores are depicted for each individual patient (left panels) and as mean values of all MS patients (right panel). * p b 0.05.
quantify the changes observed (for calculation see the Patients and methods section) [18]. We found that VEP sum scores showed an improvement in 13.3% of patients after 9–12 months (from t = 0 to t = 9–12 m) of dalfampridine therapy, 80% remained stable (no changes in the sum scores), and 6.7% deteriorated. For MEP recordings 13.3% showed beneficial effects at 9–12 months, 53.3% showed no changes and 33.3% worsened. The SEP sum score improved in the long-term course in 33.3% of patients, 53.3% remained stable, a worsening was observed in 13.3% of patients (Fig. 4A). Overall, dalfampridine might exhibit a beneficial effect on sensory nerve conductance while larger studies are necessary to confirm our findings. In summary, our results show that treatment with dalfampridine in a clinical setting improves walking ability, fatigue and cognitive function in short-term as well as in long-term course. While larger randomized studies are clearly necessary, our findings underline the clinical
Fig. 4. Development of evoked potential (EP) sum scores under dalfampridine therapy. EP sum scores were assessed on a qualitative scale (0: no pathology on both sides; 4: abnormal latencies and amplitudes on both sides) and change was described as “worsened” (positive change in sum score ≥ 1), “no change” or “improved” (reduction in sum score ≥ 1), before or after nine to twelve months under dalfampridine therapy. (A) Changes in VEP, MEP and SEP sum scores under dalfampridine (n = 15).
benefit of symptomatic treatment with dalfampridine in patients with multiple sclerosis. 4. Discussion Dalfampridine, the extended release formulation of 4-aminopyridine, is the first symptomatic therapy approved for the treatment of walking ability in multiple sclerosis patients with an EDSS between 4.0 and 7.0. Dalfampridine is not considered to have any disease modifying properties [24]. However, two phase III trials have shown that dalfampridine is able to improve walking ability [10,11], one of the most important impairments for MS patients in the later stages of the disease [3]. The positive effect in responding patients was sustained over the observational period of 14 weeks and was completely reversible after discontinuation of medication. However, further knowledge about the long term effects of dalfampridine on walking ability and further outcome parameters like cognition is still missing. We included fifty-two patients with multiple sclerosis in an open-label observational study to evaluate the long term effects of dalfampridine on parameters of walking ability, MSFC, cognitive and motor fatigue and evoked potentials. Thirty out of fifty-two patients (57.7%) were still on treatment after 9–12 months. Previous studies only observed a treatment response in 25–35% [10,11]. This discrepancy might be explained by the smaller sample size, lower average EDSS scores and the different definitions of treatment response (T25FW improved after 2 weeks under treatment vs. Goodman et al.: T25FW improved in three of four visits) of our study. Furthermore, a possible selection bias of more suitable patients might have influenced the response rate. In accordance to previous studies, two weeks after treatment initiation the timed 25-foot walk (T25FW) was significantly improved. In addition, we demonstrated that this effect is sustained over 9–12 months. Moreover, maximum walking distance showed significant improvement, which still persisted after 9–12 months. Maximum walking distance might be a more accurate functional measure compared to
T. Ruck et al. / Journal of the Neurological Sciences 337 (2014) 18–24
T25FW since distance and not speed restrains patients in daily life. As walking velocity showed only a significant improvement at the 2 weeks time point, measures of walking speed seem to be less suitable in the evaluation of long-term effects of dalfampridine. Cognitive and motor fatigue affects approximately 75–95% of all MS patients [21]. 50–60% of patients classify fatigue as one of the most serious symptoms interfering with quality of life [25,26]. Previous studies have shown a beneficial effect of 4-aminopyridine in treatment of fatigue in multiple sclerosis [22]. In our study dalfampridine treatment led to a significant improvement of motor and cognitive fatigue after 2 weeks and after 9–12 months, indicating beneficial properties in short- and long-term treatment of fatigue. Moreover, dalfampridine significantly improved Paced Auditory Serial Addition Test (PASAT) results after 9–12 months. The PASAT measures multiple functional domains as a reliable test of cognitive function. Nevertheless, several issues should be considered in interpreting this test, such as susceptibility to practice effects and dependence on age and low math ability [27]. However, in our study practice effects might be low after 9–12 months without performing the test. Also, age and math ability remain more or less unaltered in the observational period of our study. In this respect dalfampridine might improve cognitive functions in longterm treatment, but neither sample size, study time nor the PASAT is sufficient to draw definite conclusions. In general only 5–10% of MS patients demonstrate a primary progressive disease course. Our study enclosed a relative high proportion of PPMS patients (approx. 30%). This might be due to the inclusion criterion of an EDSS between 4.0 and 7.0, as PPMS patients are more likely to be affected by walking disability compared to RRMS patients, and the specific patient population of our MS center. The dalfampridine treatment led to comparable effects among the different disease groups of multiple sclerosis patients (RRMS, SPMS and PPMS) not always reaching significance but with a similar tendency. Although dalfampridine is a well-known inhibitor of many subtypes of voltage-dependent potassium channels [28], the exact mechanisms of action of therapeutic effects remain unclear. Dalfampridine is assumed to improve nerve conduction, prolongation of action-potential duration [6,7] and to potentiate synaptic and neuromuscular transmission [8,9] by the blockade of above mentioned channels. However, in human subjects average plasma concentrations (therapeutic dose of 10 mg twice daily) are three to four orders of magnitude lower than IC50 values (the concentration at which 50% of the current is blocked) of these channels [28]. In demyelinating axons potassium channels redistribute along the axon and this redistribution in combination with modified expression of potassium channel (and subunits) encoding genes may increase the sensitivity to 4-aminopyridine [29–31]. We tried to evaluate the impact of dalfampridine on nerve conductance by the measurement of evoked potentials. A tendency for improvement was especially found in a subset of patients for somatosensory evoked potentials. A statistical significant change in nerve conductance was not observed. For the adequate interpretation of our study results the immanent shortcomings have to be taken into account. The small sample size of fifty-two patients and the lack of a control group might lessen the significance of our study. Furthermore, the selection of treatment responders in the course of the study might propagate a regression to the mean partially leading to a shift to favorable effects. Patients responding to dalfampridine are less likely affected by drug discontinuation or poor adherence. Hence, the loss of follow up might lead to an overestimation of the dalfampridine effect. In conclusion, our study provides evidence for short- and long-term positive effects of dalfampridine on motoric and cognitive assessment parameters in a significant proportion of MS patients independent of MS disease entity. Regarding expenses and risk-benefit ratio of dalfampridine therapy, MS patients should be carefully evaluated for suitability. Especially for the progressive forms of MS, where sufficient treatment strategies are still pending, dalfampridine can be regarded
23
as an efficient medication to improve functionality in daily living and quality of life. Supplementary data to this article can be found online at http://dx. doi.org/10.1016/j.jns.2013.11.011. Conflict of interest The authors declare no conflict of interest. Acknowledgment We would like to thank Anke Schwabe, Silvia Schubert and Pia Richardt for their excellent technical assistance. References [1] Frohman EM, Racke MK, Raine CS. Multiple sclerosis — the plaque and its pathogenesis. N Engl J Med 2006;354:942–55. [2] Daroff RB, Fenichel GM, Jankovic J, Mazziota J. Bradley's neurology in clinical practice. 6th ed. Philadelphia, Pa: WB Saunders: Elsevier; 2012 92–116. [3] Heesen C, Bohm J, Reich C, Kasper J, Goebel M, Gold SM. Patient perception of bodily functions in multiple sclerosis: gait and visual function are the most valuable. Mult Scler 2008;14:988–91. [4] Miller AE, Rhoades RW. Treatment of relapsing–remitting multiple sclerosis: current approaches and unmet needs. Curr Opin Neurol 2012(25 Suppl.): S4–S10. [5] Dunn J, Blight A. Dalfampridine: a brief review of its mechanism of action and efficacy as a treatment to improve walking in patients with multiple sclerosis. Curr Med Res Opin 2011;27:1415–23. [6] Sherratt RM, Bostock H, Sears TA. Effects of 4-aminopyridine on normal and demyelinated mammalian nerve fibres. Nature 1980;283:570–2. [7] Shi R, Blight AR. Differential effects of low and high concentrations of 4aminopyridine on axonal conduction in normal and injured spinal cord. Neuroscience 1997;77:553–62. [8] Kim YI, Goldner MM, Sanders DB. Facilitatory effects of 4-aminopyridine on normal neuromuscular transmission. Muscle Nerve 1980;3:105–11. [9] Smith KJ, Felts PA, John GR. Effects of 4-aminopyridine on demyelinated axons, synapses and muscle tension. Brain 2000;123(Pt 1):171–84. [10] Goodman AD, Brown TR, Krupp LB, Schapiro RT, Schwid SR, Cohen R, et al. Sustained-release oral fampridine in multiple sclerosis: a randomised, doubleblind, controlled trial. Lancet 2009;373:732–8. [11] Goodman AD, Brown TR, Edwards KR, Krupp LB, Schapiro RT, Cohen R, et al. A phase 3 trial of extended release oral dalfampridine in multiple sclerosis. Ann Neurol 2010;68:494–502. [12] NHS Commisioning Board. Clinical commissioning policy statement: Fampridine for, multiple sclerosis. http://www.england.nhs.uk/wp-content/uploads/2013/04/d04ps-d.pdf2013. [13] Polman CH, Reingold SC, Edan G, Filippi M, Hartung HP, Kappos L, et al. Diagnostic criteria for multiple sclerosis: 2005 revisions to the “McDonald Criteria”. Ann Neurol 2005;58:840–6. [14] Fischer JS, Jak AJ, Kniker JE, Rudick RA, Cutter G. Multiple Sclerosis Functional Composite (MSFC): administration and scoring manual. New York: National Multiple Sclerosis Society; 2001. [15] Penner IK, Raselli C, Stocklin M, Opwis K, Kappos L, Calabrese P. The Fatigue Scale for Motor and Cognitive Functions (FSMC): validation of a new instrument to assess multiple sclerosis-related fatigue. Mult Scler 2009;15:1509–17. [16] Kallmann BA, Fackelmann S, Toyka KV, Rieckmann P, Reiners K. Early abnormalities of evoked potentials and future disability in patients with multiple sclerosis. Mult Scler 2006;12:58–65. [17] Meyer BU, Britton TC, Benecke R, Bischoff C, Machetanz J, Conrad B. Motor responses evoked by magnetic brain stimulation in psychogenic limb weakness: diagnostic value and limitations. J Neurol 1992;239:251–5. [18] Meuth SG, Bittner S, Seiler C, Gobel K, Wiendl H. Natalizumab restores evoked potential abnormalities in patients with relapsing–remitting multiple sclerosis. Mult Scler 2011;17:198–203. [19] Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology 1983;33:1444–52. [20] Amato MP, Portaccio E. Clinical outcome measures in multiple sclerosis. J Neurol Sci 2007;259:118–22. [21] Krupp LB, Coyle PK, Doscher C, Miller A, Cross AH, Jandorf L, et al. Fatigue therapy in multiple sclerosis: results of a double-blind, randomized, parallel trial of amantadine, pemoline, and placebo. Neurology 1995;45:1956–61. [22] Rossini PM, Pasqualetti P, Pozzilli C, Grasso MG, Millefiorini E, Graceffa A, et al. Fatigue in progressive multiple sclerosis: results of a randomized, doubleblind, placebo-controlled, crossover trial of oral 4-aminopyridine. Mult Scler 2001;7:354–8. [23] Smits RC, Emmen HH, Bertelsmann FW, Kulig BM, van Loenen AC, Polman CH. The effects of 4-aminopyridine on cognitive function in patients with multiple sclerosis: a pilot study. Neurology 1994;44:1701–5.
24
T. Ruck et al. / Journal of the Neurological Sciences 337 (2014) 18–24
[24] Gobel K, Wedell JH, Herrmann AM, Wachsmuth L, Pankratz S, Bittner S, et al. 4Aminopyridine ameliorates mobility but not disease course in an animal model of multiple sclerosis. Exp Neurol 2013;248C:62–71. [25] Comi G, Leocani L, Rossi P, Colombo B. Physiopathology and treatment of fatigue in multiple sclerosis. J Neurol 2001;248:174–9. [26] Fisk JD, Pontefract A, Ritvo PG, Archibald CJ, Murray TJ. The impact of fatigue on patients with multiple sclerosis. Can J Neurol Sci 1994;21:9–14. [27] Tombaugh TN. A comprehensive review of the Paced Auditory Serial Addition Test (PASAT). Arch Clin Neuropsychol 2006;21:53–76. [28] Judge SI, Bever Jr CT. Potassium channel blockers in multiple sclerosis: neuronal Kv channels and effects of symptomatic treatment. Pharmacol Ther 2006;111:224–59.
[29] Fehlings MG, Nashmi R. Changes in pharmacological sensitivity of the spinal cord to potassium channel blockers following acute spinal cord injury. Brain Res 1996;736:135–45. [30] Karimi-Abdolrezaee S, Eftekharpour E, Fehlings MG. Temporal and spatial patterns of Kv1.1 and Kv1.2 protein and gene expression in spinal cord white matter after acute and chronic spinal cord injury in rats: implications for axonal pathophysiology after neurotrauma. Eur J Neurosci 2004;19:577–89. [31] Shi R, Kelly TM, Blight AR. Conduction block in acute and chronic spinal cord injury: different dose–response characteristics for reversal by 4-aminopyridine. Exp Neurol 1997;148:495–501.
Contents lists available at ScienceDirect
Journal of the Neurological Sciences journal homepage: www.elsevier.com/locate/jns
Long-term effects of dalfampridine in patients with multiple sclerosis T. Ruck 1, S. Bittner 1, O.J. Simon, K. Göbel, H. Wiendl, M. Schilling 1, S.G. Meuth ⁎,1 Department of Neurology — University of Münster, Albert-Schweitzer-Campus 1, Building A 10, 48149 Münster, Germany
a r t i c l e
i n f o
Article history: Received 2 October 2013 Received in revised form 3 November 2013 Accepted 8 November 2013 Available online 16 November 2013 Keywords: MS Dalfampridine Long-term treatment Mobility Walking ability Fatigue
a b s t r a c t Background/objective: Dalfampridine is the extended-release formulation of 4-aminopyridine and is approved for the symptomatic treatment of impaired mobility in patients with multiple sclerosis. Our aim was to examine the short- and long-term effects of treatment with dalfampridine on motoric and cognitive assessment parameters of multiple sclerosis (MS) patients over 9–12 months. Methods: Fifty-two patients with MS with an EDSS between 4.0 and 7.0 and impaired mobility were evaluated for parameters of walking ability, MSFC, cognitive and motor fatigue and evoked potentials at treatment initiation with dalfampridine as well as 2 weeks and after 9–12 months later. Results: Thirty out of fifty-two patients (~60%) were still on treatment after 9–12 months. Two weeks after treatment initiation, significant ameliorations could be found for T25FW, maximum walking distance as well as motoric and cognitive fatigue which still persisted after 9–12 months. In contrast significant effects for velocity were observed only after 2 weeks, for improvement in PASAT only after 9–12 months. A tendency for improvement of somatosensory evoked potentials was found in a subset of patients. Conclusion: Dalfampridine shows positive short- and long-term effects on motoric and cognitive assessment parameters in an open-label observational study in a cohort of patients with MS. © 2013 Elsevier B.V. All rights reserved.
1. Introduction Multiple sclerosis (MS) is an autoimmune inflammatory disorder of the central nervous system (CNS). Autoreactive immune cells lead to demyelination and axonal damage resulting in acute neuronal deficits and accumulation of disability [1]. MS is the major cause of nontraumatic disability in young adults [2] with severe social and economic consequences. In the later stages of the disease especially reduced mobility and cognitive impairment are among the most important symptoms in MS patients [3]. Current immunomodulatory therapies reduce relapse frequency and aim at delaying disease progression [4]. However, accumulating deficits result in a number of residual symptoms in a large number of patients with relapsing–remitting and later on secondaryprogressive MS. Furthermore, efficient therapies for primaryprogressive MS are still lacking. Therefore, a number of symptomatic treatments aim at reducing disease symptoms (e.g. spasticity, neuropathic pain, bladder dysfunctions or ataxia). Dalfampridine (trade name in Germany: Fampridin; in Great Britain: Fampridine) is an extended-release formulation of 4-aminopyridine with a high bioavailability and almost complete renal clearance. It is the only approved agent for the symptomatic treatment of impaired mobility in patients with MS. Dalfampridine is a broad-spectrum potassium channel blocker which is assumed to block voltage-sensitive potassium channels of nerve fibers exposed upon demyelination. Upon ⁎ Corresponding author. Tel.: +49 251 83 46811; fax: +49 251 83 46812. E-mail address: [email protected] (S.G. Meuth). 1 Equal contribution. 0022-510X/$ – see front matter © 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.jns.2013.11.011
blockade of these channels, dalfampridine decreases abnormal potassium outward currents [5]. This results in an improvement of conduction, prolongation of action-potential duration [6,7] and in a potentiation of synaptic and neuromuscular transmission by increasing the release of neurotransmitters [8,9]. The improvement of walking ability by dalfampridine was demonstrated in two phase III trials, MS-F203 [10] and MS-F204 [11] including 540 patients over a 14-week study period. Compared to placebo, dalfampridine significantly improved the walking speed in approximately one third of MS patients as measured by the timed 25 foot-walk (T25FW). Urinary tract infection, central nervous system excitation and balance disorder were the most common adverse events observed. The most considerable adverse effect was a dose-dependent increase in seizure incidence. Therefore, dalfampridine is generally considered as a safe treatment, when taken as recommended. However, several critical points have repeatedly been raised by different experts, regulatory boards and National Health Service agencies. The costs (approx. 2300 € per year, Germany, 2013; approx. 4700 £, Great Britain, 2013) might influence treatment decisions and a recent document from the NHS Commissioning Board (now named NHS England, a governmental committee in Great Britain) in April 2013 was issued stating: “Fampridine is not considered to be a cost-effective use of NHS resources (http://www.england.nhs.uk/wp-content/uploads/ 2013/04/d04-ps-d.pdf) [12].” As part of the initial European approval in 2011, the conduction of further studies was requested to address the question whether treatment with dalfampridine leads to a long-term clinically meaningful therapeutic benefit.
T. Ruck et al. / Journal of the Neurological Sciences 337 (2014) 18–24
Our present study evaluates the short- and long-term (over nine to twelve months) effects of dalfampridine on several clinical assessment parameters of cognitive and physical functions. Fifty-two patients with relapsing–remitting, primary- or secondary progressive MS with an EDSS (Expanded Disability Status Scale) score between 4.0 and 7.0 were observed for a follow-up period of nine to twelve months under dalfampridine therapy. Favorable effects in the long-term course were observed for measures of walking ability, cognitive and motor fatigue and cognitive function.
2. Patients and methods 2.1. Patients All patients included in this study were seen from 2011 to 2013 in the MS center at the Department of Neurology, University of Münster. Fifty-two patients with clinically definite MS according to McDonald criteria [13] were consecutively included in this study. Eleven patients were classified as relapsing–remitting (RRMS), sixteen as primary progressive (PPMS) and twenty-five as secondary progressive multiple sclerosis (SPMS). See Table 1 for characteristics of the patients enclosed in this study. Patients were included if they fulfilled the following inclusion criteria: They underwent detailed physical and neurological examination including EDSS and had an EDSS of 4.0–7.0 with clinical relevant impairment of ambulation. To minimize the risk for seizures or QTctime prolongations under therapy with dalfampridine, patients had to provide a regular EEG and ECG prior to treatment initiation. Clinical visits were performed prior to treatment initiation, after 14 days and after 9–12 months for long-time measures. Patients received multiple examinations (maximum walking distance, timed 25-foot walk, measurement of motoric and cognitive fatigue and MSFC). A subgroup of randomly selected patients also received multimodal EP, i.e. VEP and/or SEP and/or MEP. All examinations and recordings were done for diagnostic purposes only. Patients, who significantly improved in the timed 25-foot walk after a test period of 14 days, were considered as treatment responders (according to the approval of the EMA). All patients included in this study gave written informed consent in accordance with the Declaration of Helsinki and a protocol approved by the Ethics Committee of the University of Münster.
19
2.3. Timed 25-foot walk (T25FW) The timed 25 foot-walk (T25FW) was carried out according to the instructions for the multiple sclerosis functional composite [14]. The T25FW was performed twice at each visit, allowing a maximum of 5 min rest between tests. Average values were used for analysis. 2.4. Maximum walking distance The maximum walking distance was assessed on a standardized, plain round-course at our MS center. The maximum distance was measured by an accompanying person until the patient needed a break. Measurement was performed at 9 to 11 am at each visit to avoid time-dependent fluctuations, and started after a resting period of 30 min. Patients were allowed to use an assistive device as long as walking was restricted to the usage. 2.5. Fatigue Scale for Motor and Cognitive Functions (FSMC) The Fatigue Scale for Motor and Cognitive Functions was carried out and evaluated as described before [15]. 2.6. Evoked potentials (EP) All electrophysiological examinations were performed on a commercial computer based neurophysiological recording system (VIASYS, Cardinal Health, Germany) as described earlier [16]. Filters and other technical settings were chosen according to established guidelines [17]. For detailed information see Supplementary materials. 2.7. Scoring and analysis of EP data For analysis of EP data an EP score, as published before [18], was used. In summary, we defined an ordinal EP score in which each abnormal result scored one point (e.g. abnormal latency and/or amplitude on either side). Sum scores of each electrophysiological measure were calculated from absolute values, ranging from 0 (no pathological value on both sides), 1 (pathological value on one side, decrease in amplitude or abnormal latency), 2 (pathological value on one side, abnormal amplitude and latency or pathological value on both sides, latency or amplitude), 3 (pathological value on both sides, one side with abnormal latency and amplitude plus one side with abnormal amplitude or latency) to 4 (pathological values on both sides assessed).
2.2. Multiple sclerosis functional composite
2.8. Statistics
The multiple sclerosis functional composite was performed according to the recommendations of the National Multiple Sclerosis Society from 2001 [14].
A Kruskal–Wallis one-way analysis of variance was used in case of multiple comparisons for nonparametric data. All data is presented as mean ± standard error and significance was assumed for p b 0.05. 3. Results
Table 1 Baseline characteristics of MS patients included in the study at the different time-points. (A) The number of patients, the male to female ratio, the proportions of the different disease entities (RRMS: relapsing–remitting MS, SPMS: secondary-progressive MS, PPMS: primary-progressive MS), the mean age and the mean EDSS at the different time points are depicted.
n m/f (%) RRMS (%) SPMS (%) PPMS (%) Age (mean) EDSS (mean)
t=0
t = 2w
t = 9–12 m
52 34.6/65.4 21.2 48 30.8 50 ± 0.17 5.3 ± 0.02
49 34.7/65.3 20.4 49 30.6 50 ± 0.2 5.1 ± 0.02
30 23.3/76.7 20 53.3 26.7 50 ± 0.3 4.9 ± 0.04
Fifty-two patients with relapsing–remitting MS (21.2%), secondary progressive MS (48%) and primary-progressive MS (30.8%) with an EDSS between 4.0 and 7.0 and impaired mobility were evaluated for parameters of walking impairment, MSFC, cognitive and motor fatigue and evoked potentials at initiation of (t = 0), after 2 weeks (t = 2w) and after 9–12 months after treatment (t = 9–12 m) with dalfampridine. After 9–12 months of follow up, thirty out of fifty-two patients were still on dalfampridine medication (57.7%), twenty-two patients were lost to follow up, withdrew medication due to adverse effects or lack of benefit or were excluded due to poor adherence. The proportions of the different disease entities were stable, whereas the male to female ratio was skewed to women over the study period. We did not observe any differences in the mean age and the EDSS at any time point during the period of observation (Table 1). 30.8% of patients received
20
T. Ruck et al. / Journal of the Neurological Sciences 337 (2014) 18–24
immunomodulatory basic therapy (7 interferon, 3 GA) or escalation therapy (3 fingolimod, 2 natalizumab). Dalfampridine has been shown to improve walking ability of MS patients as assessed by the timed 25-foot walk (T25FW) in several previous studies [10,11]. In accordance with the literature we found a significant improvement of the T25FW at 2 weeks after treatment initiation (p b 0.01) compared to baseline values. The positive effect still persisted after 9–12 months under dalfampridine medication
(p = 0.02) (Fig. 1A). The T25FW only measures the walking speed for the initial walking distance. In contrast, the maximum walking distance might be a more relevant parameter for assessing a clinical and everyday relevant benefit. We observed that the maximum walking distance was also significantly improved for both evaluation time-points compared to baseline (p b 0.01 for each time-point) (Fig. 1B), whereas the velocity (as measured by maximum walking distance/time for maximum walking distance) was only significantly faster after 2 weeks (p = 0.02) (Fig. 1C).
Fig. 1. Dalfampridine improves walking of MS patients in the short- and long-term course. (A) Left panel: The line graphs represent the course of the timed 25-foot walk (T25FW) of each individual patient over the different time-points (0: before treatment, 2w: two weeks under treatment, 9–12m: nine to twelve months under treatment). The lower panel magnifies the results between 3 and 11 s. Right panel: The bar graphs depict the mean T25FW of all MS patients at the different time-points. (B) Dalfampridine significantly improves the maximum walking distance after two weeks and in long-term course, whereas (C) the velocity (maximum walking distance/time) is only significantly increased in the short-term course. * p b 0.05; ns, not significant.
T. Ruck et al. / Journal of the Neurological Sciences 337 (2014) 18–24
The timed 25 foot-walk is one of three components of the multiple sclerosis functional composite (MSFC). The MSFC represents one of the most widely used scoring system to assess neurological disability in patients with MS [19,20] and measures leg function/ambulation (assessed by T25FW), arm/hand function (assessed by the 9-hole Peg Test (9HPT)) and cognitive function (as assessed by the Paced Auditory Serial Addition Test (PASAT)). The MSFC overall score showed a tendency to improve over the observational period but did not reach statistical significance (p = 0.17 for each time-point) (Fig. 2A). Cognitive function as assessed by the PASAT was significantly superior to baseline values in the long-term course (p = 0.02) and showed a beneficial trend in the short-term course (p = 0.22) (Fig. 2B). Dalfampridine had no impact on arm/hand function as the results of the 9HPT were similar at 2 weeks and at 9–12 months after treatment initiation (Fig. 2C and Suppl. Fig. 1). Cognitive function is essentially influenced by the capability of attention and concentration, which are markedly affected by fatigue symptoms. Fatigue is reported by approximately 75–95% of patients
21
with multiple sclerosis [15,21] and impacts both cognitive and motor functions. 4-Aminopyridin has shown positive effects on fatigue and cognitive function in previous studies [22,23]. We used the Fatigue Scale for Motor and Cognitive Functions (FSMC) to evaluate the impact of dalfampridine on fatigue symptoms [15]. The FSMC for motor (Fig. 3A, 2 weeks: p b 0.01, 9–12 months: p = 0.01) as well as for cognitive function (Fig. 3B, 2 weeks: p = 0.048, 9–12 months: p = 0.047) showed significantly reduced values in the short- and long-term course compared to baseline. The dalfampridine treatment led to comparable effects among the different disease groups of MS patients (RRMS, SPMS and PPMS) not always reaching significance but with a similar tendency (Suppl. Fig. 2). In animal models dalfampridine improved nerve conduction and action potential generation [6,7]. We measured and analyzed VEP, MEP and SEP data of a subset of fifteen patients at treatment initiation (t = 0) and 9–12 months after treatment (t = 9–12 m) in order to monitor changes and functional relevance in electrophysiological measures of nerve conduction. We used a previously described sum score to
Fig. 2. Dalfampridine shows significant impact on components of the multiple sclerosis functional composite (MSFC). (A) The individual course (left panel) and the mean values of the MSFC (right panel) of MS patients at the different time-points are shown. (B) The results of the PASAT (Paced Auditory Serial Addition Test) are significantly improved in the longterm course. (C) Arm/hand function as assessed by the Nine-hole Peg Test (9HPT) shows no changes in the treatment course, neither for the dominant (left panel) nor for the other hand (right panel). * p b 0.05; ns, not significant.
22
T. Ruck et al. / Journal of the Neurological Sciences 337 (2014) 18–24
Fig. 3. The Fatigue Scale for Motor and Cognitive Functions (FSMC) shows significantly decreased values under dalfampridine treatment. (A) Motor and (B) cognitive fatigue sum scores are depicted for each individual patient (left panels) and as mean values of all MS patients (right panel). * p b 0.05.
quantify the changes observed (for calculation see the Patients and methods section) [18]. We found that VEP sum scores showed an improvement in 13.3% of patients after 9–12 months (from t = 0 to t = 9–12 m) of dalfampridine therapy, 80% remained stable (no changes in the sum scores), and 6.7% deteriorated. For MEP recordings 13.3% showed beneficial effects at 9–12 months, 53.3% showed no changes and 33.3% worsened. The SEP sum score improved in the long-term course in 33.3% of patients, 53.3% remained stable, a worsening was observed in 13.3% of patients (Fig. 4A). Overall, dalfampridine might exhibit a beneficial effect on sensory nerve conductance while larger studies are necessary to confirm our findings. In summary, our results show that treatment with dalfampridine in a clinical setting improves walking ability, fatigue and cognitive function in short-term as well as in long-term course. While larger randomized studies are clearly necessary, our findings underline the clinical
Fig. 4. Development of evoked potential (EP) sum scores under dalfampridine therapy. EP sum scores were assessed on a qualitative scale (0: no pathology on both sides; 4: abnormal latencies and amplitudes on both sides) and change was described as “worsened” (positive change in sum score ≥ 1), “no change” or “improved” (reduction in sum score ≥ 1), before or after nine to twelve months under dalfampridine therapy. (A) Changes in VEP, MEP and SEP sum scores under dalfampridine (n = 15).
benefit of symptomatic treatment with dalfampridine in patients with multiple sclerosis. 4. Discussion Dalfampridine, the extended release formulation of 4-aminopyridine, is the first symptomatic therapy approved for the treatment of walking ability in multiple sclerosis patients with an EDSS between 4.0 and 7.0. Dalfampridine is not considered to have any disease modifying properties [24]. However, two phase III trials have shown that dalfampridine is able to improve walking ability [10,11], one of the most important impairments for MS patients in the later stages of the disease [3]. The positive effect in responding patients was sustained over the observational period of 14 weeks and was completely reversible after discontinuation of medication. However, further knowledge about the long term effects of dalfampridine on walking ability and further outcome parameters like cognition is still missing. We included fifty-two patients with multiple sclerosis in an open-label observational study to evaluate the long term effects of dalfampridine on parameters of walking ability, MSFC, cognitive and motor fatigue and evoked potentials. Thirty out of fifty-two patients (57.7%) were still on treatment after 9–12 months. Previous studies only observed a treatment response in 25–35% [10,11]. This discrepancy might be explained by the smaller sample size, lower average EDSS scores and the different definitions of treatment response (T25FW improved after 2 weeks under treatment vs. Goodman et al.: T25FW improved in three of four visits) of our study. Furthermore, a possible selection bias of more suitable patients might have influenced the response rate. In accordance to previous studies, two weeks after treatment initiation the timed 25-foot walk (T25FW) was significantly improved. In addition, we demonstrated that this effect is sustained over 9–12 months. Moreover, maximum walking distance showed significant improvement, which still persisted after 9–12 months. Maximum walking distance might be a more accurate functional measure compared to
T. Ruck et al. / Journal of the Neurological Sciences 337 (2014) 18–24
T25FW since distance and not speed restrains patients in daily life. As walking velocity showed only a significant improvement at the 2 weeks time point, measures of walking speed seem to be less suitable in the evaluation of long-term effects of dalfampridine. Cognitive and motor fatigue affects approximately 75–95% of all MS patients [21]. 50–60% of patients classify fatigue as one of the most serious symptoms interfering with quality of life [25,26]. Previous studies have shown a beneficial effect of 4-aminopyridine in treatment of fatigue in multiple sclerosis [22]. In our study dalfampridine treatment led to a significant improvement of motor and cognitive fatigue after 2 weeks and after 9–12 months, indicating beneficial properties in short- and long-term treatment of fatigue. Moreover, dalfampridine significantly improved Paced Auditory Serial Addition Test (PASAT) results after 9–12 months. The PASAT measures multiple functional domains as a reliable test of cognitive function. Nevertheless, several issues should be considered in interpreting this test, such as susceptibility to practice effects and dependence on age and low math ability [27]. However, in our study practice effects might be low after 9–12 months without performing the test. Also, age and math ability remain more or less unaltered in the observational period of our study. In this respect dalfampridine might improve cognitive functions in longterm treatment, but neither sample size, study time nor the PASAT is sufficient to draw definite conclusions. In general only 5–10% of MS patients demonstrate a primary progressive disease course. Our study enclosed a relative high proportion of PPMS patients (approx. 30%). This might be due to the inclusion criterion of an EDSS between 4.0 and 7.0, as PPMS patients are more likely to be affected by walking disability compared to RRMS patients, and the specific patient population of our MS center. The dalfampridine treatment led to comparable effects among the different disease groups of multiple sclerosis patients (RRMS, SPMS and PPMS) not always reaching significance but with a similar tendency. Although dalfampridine is a well-known inhibitor of many subtypes of voltage-dependent potassium channels [28], the exact mechanisms of action of therapeutic effects remain unclear. Dalfampridine is assumed to improve nerve conduction, prolongation of action-potential duration [6,7] and to potentiate synaptic and neuromuscular transmission [8,9] by the blockade of above mentioned channels. However, in human subjects average plasma concentrations (therapeutic dose of 10 mg twice daily) are three to four orders of magnitude lower than IC50 values (the concentration at which 50% of the current is blocked) of these channels [28]. In demyelinating axons potassium channels redistribute along the axon and this redistribution in combination with modified expression of potassium channel (and subunits) encoding genes may increase the sensitivity to 4-aminopyridine [29–31]. We tried to evaluate the impact of dalfampridine on nerve conductance by the measurement of evoked potentials. A tendency for improvement was especially found in a subset of patients for somatosensory evoked potentials. A statistical significant change in nerve conductance was not observed. For the adequate interpretation of our study results the immanent shortcomings have to be taken into account. The small sample size of fifty-two patients and the lack of a control group might lessen the significance of our study. Furthermore, the selection of treatment responders in the course of the study might propagate a regression to the mean partially leading to a shift to favorable effects. Patients responding to dalfampridine are less likely affected by drug discontinuation or poor adherence. Hence, the loss of follow up might lead to an overestimation of the dalfampridine effect. In conclusion, our study provides evidence for short- and long-term positive effects of dalfampridine on motoric and cognitive assessment parameters in a significant proportion of MS patients independent of MS disease entity. Regarding expenses and risk-benefit ratio of dalfampridine therapy, MS patients should be carefully evaluated for suitability. Especially for the progressive forms of MS, where sufficient treatment strategies are still pending, dalfampridine can be regarded
23
as an efficient medication to improve functionality in daily living and quality of life. Supplementary data to this article can be found online at http://dx. doi.org/10.1016/j.jns.2013.11.011. Conflict of interest The authors declare no conflict of interest. Acknowledgment We would like to thank Anke Schwabe, Silvia Schubert and Pia Richardt for their excellent technical assistance. References [1] Frohman EM, Racke MK, Raine CS. Multiple sclerosis — the plaque and its pathogenesis. N Engl J Med 2006;354:942–55. [2] Daroff RB, Fenichel GM, Jankovic J, Mazziota J. Bradley's neurology in clinical practice. 6th ed. Philadelphia, Pa: WB Saunders: Elsevier; 2012 92–116. [3] Heesen C, Bohm J, Reich C, Kasper J, Goebel M, Gold SM. Patient perception of bodily functions in multiple sclerosis: gait and visual function are the most valuable. Mult Scler 2008;14:988–91. [4] Miller AE, Rhoades RW. Treatment of relapsing–remitting multiple sclerosis: current approaches and unmet needs. Curr Opin Neurol 2012(25 Suppl.): S4–S10. [5] Dunn J, Blight A. Dalfampridine: a brief review of its mechanism of action and efficacy as a treatment to improve walking in patients with multiple sclerosis. Curr Med Res Opin 2011;27:1415–23. [6] Sherratt RM, Bostock H, Sears TA. Effects of 4-aminopyridine on normal and demyelinated mammalian nerve fibres. Nature 1980;283:570–2. [7] Shi R, Blight AR. Differential effects of low and high concentrations of 4aminopyridine on axonal conduction in normal and injured spinal cord. Neuroscience 1997;77:553–62. [8] Kim YI, Goldner MM, Sanders DB. Facilitatory effects of 4-aminopyridine on normal neuromuscular transmission. Muscle Nerve 1980;3:105–11. [9] Smith KJ, Felts PA, John GR. Effects of 4-aminopyridine on demyelinated axons, synapses and muscle tension. Brain 2000;123(Pt 1):171–84. [10] Goodman AD, Brown TR, Krupp LB, Schapiro RT, Schwid SR, Cohen R, et al. Sustained-release oral fampridine in multiple sclerosis: a randomised, doubleblind, controlled trial. Lancet 2009;373:732–8. [11] Goodman AD, Brown TR, Edwards KR, Krupp LB, Schapiro RT, Cohen R, et al. A phase 3 trial of extended release oral dalfampridine in multiple sclerosis. Ann Neurol 2010;68:494–502. [12] NHS Commisioning Board. Clinical commissioning policy statement: Fampridine for, multiple sclerosis. http://www.england.nhs.uk/wp-content/uploads/2013/04/d04ps-d.pdf2013. [13] Polman CH, Reingold SC, Edan G, Filippi M, Hartung HP, Kappos L, et al. Diagnostic criteria for multiple sclerosis: 2005 revisions to the “McDonald Criteria”. Ann Neurol 2005;58:840–6. [14] Fischer JS, Jak AJ, Kniker JE, Rudick RA, Cutter G. Multiple Sclerosis Functional Composite (MSFC): administration and scoring manual. New York: National Multiple Sclerosis Society; 2001. [15] Penner IK, Raselli C, Stocklin M, Opwis K, Kappos L, Calabrese P. The Fatigue Scale for Motor and Cognitive Functions (FSMC): validation of a new instrument to assess multiple sclerosis-related fatigue. Mult Scler 2009;15:1509–17. [16] Kallmann BA, Fackelmann S, Toyka KV, Rieckmann P, Reiners K. Early abnormalities of evoked potentials and future disability in patients with multiple sclerosis. Mult Scler 2006;12:58–65. [17] Meyer BU, Britton TC, Benecke R, Bischoff C, Machetanz J, Conrad B. Motor responses evoked by magnetic brain stimulation in psychogenic limb weakness: diagnostic value and limitations. J Neurol 1992;239:251–5. [18] Meuth SG, Bittner S, Seiler C, Gobel K, Wiendl H. Natalizumab restores evoked potential abnormalities in patients with relapsing–remitting multiple sclerosis. Mult Scler 2011;17:198–203. [19] Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology 1983;33:1444–52. [20] Amato MP, Portaccio E. Clinical outcome measures in multiple sclerosis. J Neurol Sci 2007;259:118–22. [21] Krupp LB, Coyle PK, Doscher C, Miller A, Cross AH, Jandorf L, et al. Fatigue therapy in multiple sclerosis: results of a double-blind, randomized, parallel trial of amantadine, pemoline, and placebo. Neurology 1995;45:1956–61. [22] Rossini PM, Pasqualetti P, Pozzilli C, Grasso MG, Millefiorini E, Graceffa A, et al. Fatigue in progressive multiple sclerosis: results of a randomized, doubleblind, placebo-controlled, crossover trial of oral 4-aminopyridine. Mult Scler 2001;7:354–8. [23] Smits RC, Emmen HH, Bertelsmann FW, Kulig BM, van Loenen AC, Polman CH. The effects of 4-aminopyridine on cognitive function in patients with multiple sclerosis: a pilot study. Neurology 1994;44:1701–5.
24
T. Ruck et al. / Journal of the Neurological Sciences 337 (2014) 18–24
[24] Gobel K, Wedell JH, Herrmann AM, Wachsmuth L, Pankratz S, Bittner S, et al. 4Aminopyridine ameliorates mobility but not disease course in an animal model of multiple sclerosis. Exp Neurol 2013;248C:62–71. [25] Comi G, Leocani L, Rossi P, Colombo B. Physiopathology and treatment of fatigue in multiple sclerosis. J Neurol 2001;248:174–9. [26] Fisk JD, Pontefract A, Ritvo PG, Archibald CJ, Murray TJ. The impact of fatigue on patients with multiple sclerosis. Can J Neurol Sci 1994;21:9–14. [27] Tombaugh TN. A comprehensive review of the Paced Auditory Serial Addition Test (PASAT). Arch Clin Neuropsychol 2006;21:53–76. [28] Judge SI, Bever Jr CT. Potassium channel blockers in multiple sclerosis: neuronal Kv channels and effects of symptomatic treatment. Pharmacol Ther 2006;111:224–59.
[29] Fehlings MG, Nashmi R. Changes in pharmacological sensitivity of the spinal cord to potassium channel blockers following acute spinal cord injury. Brain Res 1996;736:135–45. [30] Karimi-Abdolrezaee S, Eftekharpour E, Fehlings MG. Temporal and spatial patterns of Kv1.1 and Kv1.2 protein and gene expression in spinal cord white matter after acute and chronic spinal cord injury in rats: implications for axonal pathophysiology after neurotrauma. Eur J Neurosci 2004;19:577–89. [31] Shi R, Kelly TM, Blight AR. Conduction block in acute and chronic spinal cord injury: different dose–response characteristics for reversal by 4-aminopyridine. Exp Neurol 1997;148:495–501.
