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Improvement of multiple sclerosis-associated tremor as a treatment effect of natalizumab
Multiple Sclerosis and Related Disorders (]]]]) ], ]]]–]]]
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Improvement of multiple sclerosis-associated tremor as a treatment effect of natalizumab John R. Rinker IIa,b,n, Amber R. Salterc, Gary R. Cutterc a
Department of Neurology, University of Alabama at Birmingham, 1720 7th Avenue South, SC 440, Birmingham, AL 35294, USA b Birmingham VA Medical Center, 700 19th Street South, Birmingham, AL 35233, USA c Department of Biostatistics, University of Alabama at Birmingham, 1665 University Boulevard, Birmingham, AL 35294, USA Received 3 January 2014; received in revised form 14 March 2014; accepted 2 April 2014
KEYWORDS Multiple sclerosis; Tremor; Neurologic symptoms; Natalizumab; Self-report; Questionnaires
Abstract Background: Tremor is among the most physically disabling symptoms associated with MS. The effect of MS disease modifying therapies (DMTs) on the severity of MS tremor is unclear.
Objective: To compare the change over time in scores reflecting tremor severity between subjects treated with natalizumab and other disease modifying drugs.
Methods: Questionnaires were sent to North American Research Committee on MS registrants reporting mild or greater tremor on semiannual updates. Respondents on natalizumab and other MS therapies completed a survey which included tremor-specific scales to indicate tremor severity both currently and when the current therapy was initiated. Differences between natalizumab and non-natalizumab groups were compared using ANOVA. Results: Surveys were returned by 567 registrants, including 202 taking natalizumab. Subjects on natalizumab were more likely to report tremor improvement (29.6%) than those never (15.2%) or previously (14.8%, p=0.0002) on natalizumab. Over a mean recall period of 6.2 +4.6 years, the Tremor Related Activities of Daily Living score worsened by 1.8 points among natalizumab-treated subjects, 3.3 points among those previously on natalizumab, and 5.3 points among those who never took natalizumab (p=0.009). Conclusion: Respondents taking natalizumab were more likely to experience tremor improvement than those taking other MS disease modifying therapies. & 2014 Published by Elsevier B.V.
1.
Introduction
n
Corresponding author at: Department of Neurology, University of Alabama at Birmingham, 1720 7th Avenue South, SC 440, Birmingham, AL 35294, USA. Tel.: +1 205 996 2092; fax: +1 205 975 6030. E-mail address: [email protected] (J.R. Rinker II).
Tremor ranks among the more physically disabling symptoms caused by multiple sclerosis (MS). Between 25% and 58% of MS patients are affected by tremor (Alusi et al., 2001;
http://dx.doi.org/10.1016/j.msard.2014.04.001 2211-0348/& 2014 Published by Elsevier B.V.
Please cite this article as: Rinker JR II, et al. Improvement of multiple sclerosis-associated tremor as a treatment effect of natalizumab. Multiple Sclerosis and Related Disorders (2014), http://dx.doi.org/10.1016/j.msard.2014.04.001
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J.R. Rinker II et al.
Pittock et al., 2004), and tremor is frequently associated with ataxia, another disabling MS symptom. Since tremor disproportionately affects the upper extremities, it interferes with many routine activities even in the absence of weakness. MS tremor and ataxia have also been shown to correlate with overall disability and dependence on caregivers (Weinshenker et al., 1991), and both are associated with high risk of respiratory impairment (Grasso et al., 2000) and poorer overall prognosis (Weinshenker et al., 1991). A common attribute of MS-associated tremor has been its resistance to symptomatic therapy. Pharmacological interventions such as intrathecal baclofen (Weiss et al., 2003), isoniazid (Bozek et al., 1987; Hallett et al., 1985), levetiracetam (Striano et al., 2006), and cannabis (Fox et al., 2004; Wade et al., 2004; Zajicek et al., 2003) have been studied for their ability to lessen the effects of tremor, but results have been negative, not duplicated, or underpowered to draw clinically meaningful conclusions. Surgical interventions such as thalamotomy have shown benefit in numerous case series (Koch et al., 2007), but the effects are often temporary, and the treatment is expensive, highly specialized, and not practical for many patients. The immune modulating drugs collectively referred to as the MS disease modifying therapies (DMTs) are not intended to reverse established MS symptoms, but rather to slow the accumulation of neurological disability through the prevention of relapses (IFN β Multiple Sclerosis Study Group, 1993; Jacobs et al., 1996; PRISM Study Group, 1998; Johnson et al., 1995; Hartung et al., 2002; Polman et al., 2006; Kappos et al., 2010). However, we observed marked regression of tremor and ataxia in two severely disabled patients after initiation of natalizumab, so we undertook to explore whether natalizumab might be associated with tremor regression across a broad cohort of MS patients. Due to the infrequent presentation of severely ataxic or tremulous patients in a single clinic, we queried the North American Research Committee on Multiple Sclerosis (NARCOMS) registry to identify patients with subjective MS tremor and concurrent use of natalizumab or other MS DMTs. The NARCOMS registry includes more than 36,000 participants (Consortium of Multiple Sclerosis Centers, 2013) who provide demographic information and periodic updates about their treatments and subjective experience of MS symptoms. Participants who indicated the presence of tremor or ataxia were invited to complete a separate survey focused specifically on tremor and its effects on daily life.
2.
Materials and methods
We designed a survey-based, case-control study to compare respondent impression of change in tremor symptoms over time. The primary hypothesis was that natalizumab treatment would be associated with greater likelihood of tremor improvement as measured by the Tremor Related Activities of Daily Living (TRADL) questionnaire (Bain and Findley, 1993). Cases were defined as subjects currently taking natalizumab, and controls were divided into two groups: (1) subjects who had never taken natalizumab and (2) subjects previously on natalizumab but now taking another DMT.
2.1.
Study population
NARCOMS maintains the confidentiality of its registrants by acting as an intermediary between investigators and the registry. Local Internal Review Board approval was obtained prior to data collection. Subjects were identified within NARCOMS according to the following criteria: (1) subjects must have indicated a Tremor and Coordination Scale (TACS) (Marrie and Goldman, 2011) score of 2 or greater (indicating mild or worse impairment) on the Fall 2010, Spring 2011, or Fall 2011 semi-annual updates; and (2) subjects must have reported current use of an approved MS DMT, and have remained on the DMT for at least 6 months. All subjects who indicated current or previous treatment with natalizumab were mailed a survey, as well as a random selection of participants using other MS DMTs. In total, 777 surveys were sent to prospective participants. The surveys did not indicate to participants that their past or current DMT was a criterion for their inclusion in the study. The prior-natalizumab control group was included for two reasons: first, since natalizumab treatment may signify more aggressive or treatment-refractory disease, including this subset would ensure we included respondents with similar disease characteristics to the current natalizumab group. Second, respondents in this group would be able to compare symptom experience between their current DMT and natalizumab.
2.2.
Survey design and outcome measures
All invited participants were mailed a paper survey along with pre-paid return mailing materials. Respondents answered descriptive questions about the natural history of their tremor, parts of the body affected, family history of tremor, current DMT and duration of use, and the use of symptomatic treatments for tremor. Respondents also completed questionnaires assessing various aspects of tremor (Table 1). The TRADL questionnaire was selected to assess the primary endpoint, because it asks about a wide range of functional activities affected by tremor, and lends itself to generation of a summary score to reflect overall tremor severity. Also included in the survey were the Tremor Related Handicap (TRH) (Bain and Findley, 1993) scale, which asks “yes/no” questions about tremor-related physical disability and embarrassment in several common scenarios, and a Visual Analog Scale (VAS) on which respondents report their overall tremor severity. Respondents were asked to complete the TRADL, TRH, and VAS scales twice: once to reflect current symptom experience and a second time to recall their symptoms at the time their current DMT was initiated (a recalled “baseline”). Differences in these questionnaires were used to estimate change in symptom severity over time. Change in the TRADL scale and VAS could be positive or negative: negative scores indicate decreasing symptom burden over time, while positive scores indicate worsening symptoms. For all the tremor-focused outcome measures, lower scores represent less severe tremor or impairment. The survey also adapted a Clinical Ataxia Rating Scale (CARS) (Bain and Findley, 1993), which was intended for use as a physician-administered tool for describing severity of ataxia and tremor, but was adapted for survey respondents using language understandable to non-clinicians. Finally, respondents were asked to draw two Archimedes spirals, one with each hand,
Please cite this article as: Rinker JR II, et al. Improvement of multiple sclerosis-associated tremor as a treatment effect of natalizumab. Multiple Sclerosis and Related Disorders (2014), http://dx.doi.org/10.1016/j.msard.2014.04.001
Improvement of multiple sclerosis-associated tremor as a treatment effect of natalizumab
Table 1
3
Description of Tremor-Focused Rating Scales.
Name of scale
No. of items
Score range per item
Summary score range
Used for before/after comparisons
TRADL TRH VAS TACSb CARS Archimedes spirals
25 9 1 1 4 2
1–4 N/Aa 1–10 0–5 0–4 0–10
25–100 – 1–10 0–5 0–16 0–20
Yes Yes Yes No No No
TRADL: Tremor Related Activities of Daily Living; TRH: Tremor Related Handicap; VAS: Visual Analog Scale; TACS: Tremor and Coordination Scale; CARS: Clinical Ataxia Rating Scale. a Responses are categorical. b Scores retrieved from semi-annual NARCOMS questionnaire (not included as part of tremor survey).
and these were scored by three independent raters using a published rating method (Bain and Findley, 1993). Results of these descriptive measures will be reported separately. Durations of MS, tremor, and DMT usage were derived from the respondents' enrollment and most recent update survey data. Beta-interferon treatment included all subjects on SQ beta-interferon-1b, IM beta-interferon-1a, or SQ beta-interferon-1a.
2.3.
Statistical tests
Statistical analysis was conducted using JMP 10.0.0 (SAS Institute Inc., Cary, NC). Categorical variables were compared using the χ2 test, ordinal variables were compared using the Kruskal–Wallis test, and continuous variables were compared using t-tests or ANOVA, as appropriate. Pairwise comparisons using Tukey's test were used to compare change in TRADL and VAS between cases and control groups. An alpha of 0.05 was considered significant. To adjust for group differences in age, baseline tremor severity, and overall disability (as estimated by the Patient Determined Disease Steps (PDDS)), a multivariate analysis using a least squares regression model was performed including current natalizumab users and those who had never been exposed to natalizumab. Covariates included in the model included DMT (natalizumab or other), subject age, current disability as reported on the PDDS, and TRADL scores at the time of current DMT initiation. In order to assess for demographic or disease characteristics that may be predictive of tremor improvement on the various DMTs, a subgroup analysis was also performed on “responders” and “non-responders” as defined by whether subjects' TRADL scores improved or worsened over time. Subjects whose TRADL scores were unchanged were not included in the subgroup analysis. Chi-square and t-tests were used as appropriate.
3.
Results
Surveys were sent to 777 NARCOMS registrants meeting inclusion criteria, and 567 (73.0%) were returned.
3.1.
Descriptive characteristics
Demographic and clinical characteristics of the cohort are summarized in Table 2. Groups were similar except for several time-based variables: subjects currently or formerly treated with natalizumab were younger, with shorter durations of disease, tremor, and DMT usage than those who had never taken natalizumab. The differences in duration of DMT usage were not unexpected given the more recent commercial availability of natalizumab and the exposurerelated risk of progressive multifocal leukoencephalopathy, which limits treatment duration in some patients. The association of natalizumab use with age and shorter duration of disease and tremor may also be related to a greater likelihood of active, relapsing disease among younger patients, or to other factors which were not captured in this survey (e.g., risk tolerance, increased willingness to change therapies in pursuit of greater efficacy). In both control groups, the majority of respondents were taking either glatiramer acetate or a beta-interferon preparation as their DMT. A small number of subjects who had never taken natalizumab were taking fingolimod, while a larger proportion (29.6%) of subjects who had previously taken natalizumab were taking fingolimod. We do not know from our survey whether subjects switched from natalizumab to fingolimod for reasons of safety, tolerability, or lack of efficacy. Although very few respondents attributed their tremor to a condition other than MS, a higher than expected number of respondents reported a family history of tremor. The population prevalence of essential tremor, the most common form of familial tremor, is estimated to be o1% in the general population (and 4–5% among those 465) (Louis and Ferreira, 2010), so the rates reported here are higher than would be expected of the general population. Fewer than half of respondents took symptomatic medication to suppress tremor (n= 238, 42.0%), with the highest usage rate occurring among those formerly on natalizumab (Table 2). The most commonly utilized class of medications were the anticonvulsants (n =142), with gabapentin the most widely used drug (n= 108). Other tremor-suppressing agents included the benzodiazepines (n = 131), antispasmodic drugs (n= 43), cannabinoids including medical marijuana (n = 32), beta-blockers (n =21), alcohol (n= 17),
Please cite this article as: Rinker JR II, et al. Improvement of multiple sclerosis-associated tremor as a treatment effect of natalizumab. Multiple Sclerosis and Related Disorders (2014), http://dx.doi.org/10.1016/j.msard.2014.04.001
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Table 2
Participant characteristics. Currently on natalizumab (n= 202)
Sex, n (%) Female Male Race, n (%) White Non-White Mean age, years (SD) Employment, n (%) Full time Part time Unemployed Mean age of diagnosis, years (SD) Mean disease duration, years (SD) PDDS, median (IQR) Clinical course, n (%) RRMS SPMS PPMS Unknown Current DMT, n (%) Beta-interferon Glatiramer acetate Fingolimod Mean current DMT duration of use, years (SD) Family history of tremor, n (%) Tremor not attributed to MS, n (%) Mean tremor duration, years (SD) Maximum TACS score, median (IQR) Taking medication to suppress tremor, n (%) Surgical treatment of tremor, n (%)
Never on natalizumab (n = 229)
Previously on natalizumab (n= 136)
p-Value
166 (82.6) 35 (17.4)
170 (74.2) 59 (25.8)
105 (77.8) 30 (22.2)
0.113
170 (96.1) 7 (3.9) 53.5 (9.4)
215 (96.9) 7 (3.1) 58.1 (8.8)
113 (94.2) 7 (5.8) 54.0 (8.9)
0.641
17 (10.1) 16 (9.5) 136 (80.5) 37.2 (9.6) 16.2 (8.4) 4 (3–6)
20 11 169 38.6 19.5 5
(10.0) (5.5) (84.5) (10.0) (8.7) (3–6)
12 13 93 39.1 15.0 5
(10.2) (11.0) (81.7) (8.3) (6.3) (4–6)
94 59 25 20
(47.5) (29.8) (12.6) (10.1)
48 44 15 10
(41.0) (37.6) (12.8) (8.5)
0.385
95 94 5 9.2 34 10 12.5 3 32 5
(49.0) (48.5) (2.6) (4.8) (14.9) (4.4) (7.8) (2–4) (35.8) (2.2)
21 41 26 4.9 18 4 9.7 3 70 2
(23.9) (46.6) (29.6) (3.9) (13.2) (2.9) (7.0) (2–4) (51.5) (1.5)
o0.001
94 46 19 10
(55.6) (27.2) (11.2) (5.9)
– – – 3.5 (1.9) 33 (16.3) 1 (0.5) 11.1 (9.3) 3 (2–3) 86 (42.6) 6 (3.0)
o0.001 0.448
0.154 o0.001 0.180
o0.001 0.681 0.308 0.003 0.388 0.065 0.865
PDDS: Patient Determined Disease Steps; IQR: Interquartile Range; RRMS: Relapsing-Remitting Multiple Sclerosis; SPMS: Secondary Progressive Multiple Sclerosis; PPMS: Primary Progressive Multiple Sclerosis; DMT: Disease Modifying Therapy; TACS: Tremor and Coordination Scale.
and primidone (n = 2). A smaller proportion of respondents felt drugs they were taking worsened their tremor (n= 23), with alcohol (n = 9), medical marijuana (n = 4), pregabalin (n = 3), and gabapentin (n= 3) cited as the most common exacerbating agents.
3.2.
Tremor regression over time
Subjects were asked to report whether they associated their current or any prior DMT with improvement in tremor symptoms. Overall 110 (19.4%) respondents associated one or more DMTs with improvement in tremor, 227 (40.0%) appreciated no improvement, and 204 (36.0%) were unsure. When the question of improvement was linked to subjects' current DMT, natalizumab was significantly more likely to be associated with improvement than the other DMTs (Figure 1a and b). In order to assess the primary endpoint, mean change in TRADL was compared between the natalizumab-treated group and the two control groups (Table 3). Unadjusted,
pairwise comparisons found significant differences between the current natalizumab group and those never treated with natalizumab (p =0.002), while comparisons between prior natalizumab and both current and never natalizumab were not significantly different. Pairwise comparisons of VAS yielded similar results, with current natalizumab users reporting better outcomes in comparison to those who never had never taken natalizumab (p= 0.007). In order to adjust for intergroup differences between cases and controls, we conducted a multi-variable analysis to test whether natalizumab usage was still associated with improved tremor-related outcomes after adjusting for current disability (estimated by PDDS), age, and the TRADL scores at the start of the current DMT. To simplify the comparison, the prior natalizumab control group was excluded from the analysis. Even though all of the included covariates were found to contribute to intergroup differences, the current natalizumab group still experienced less worsening (po0.017) on overall TRADL scores compared to the group that had never taken natalizumab (Table 4).
Please cite this article as: Rinker JR II, et al. Improvement of multiple sclerosis-associated tremor as a treatment effect of natalizumab. Multiple Sclerosis and Related Disorders (2014), http://dx.doi.org/10.1016/j.msard.2014.04.001
Improvement of multiple sclerosis-associated tremor as a treatment effect of natalizumab
5
improvement among “responders” was the same between those currently on natalizumab and those who had never taken natalizumab ( 8.9 points), and was slightly lower among those previously on natalizumab ( 6.1). The same was true for the VAS scale: “responders” among the natalizumab cohort improved by 2.1 points, those never on natalizumab improved by 2.0 points, and those previously on natalizumab improved by 2.1 points. In contrast, among those who worsened on their current DMT, the magnitude of worsening was the least among natalizumab-treated subjects (+8.5 TRADL, +1.6 VAS) and greater in the prior natalizumab (+9.4, +2.2) and never natalizumab (+12.1, +2.1) groups.
3.4.
Predictors of tremor improvement
Due to the baseline differences in age and durations of MS and current DMT usage, we explored whether various demographic or disease characteristics including gender, ethnicity, MS subtype, current age and ages of MS diagnosis and tremor onset, and durations of MS, tremor, and DMT usage were associated with improvement or worsening on the TRADL over time. Among interferon-using subjects (n=91), only gender was associated with responder status. Twelve of 26 males (46.2%) were more likely to report TRADL improvement over time compared to 14 of 65 females (21.5%, p=0.019). Subjects using glatiramer acetate (n=105) did not differ on any of the variables with respect to responder status. Among natalizumab users (n=148), responder status was associated with a younger age of diagnosis (34.6 vs. 38.6, p=0.0081), current age (50.9 vs. 55.0, p=0.005), and longer duration of tremor (14.0 vs. 9.8, p=0.007). Only 21 subjects using fingolimod classified as responders or non-responders, and in this group responders had an older age of diagnosis (41.1 vs. 32.5, p=0.011) and present age (53.4 vs. 46.6, p=0.033) than non-responders. Figure 1 Subjective impression of change in overall tremor severity on current DMT by (a) natalizumab exposure status and (b) current Disease Modifying Therapy. Subjects were asked, “Do you think that any of your current or previous DMTs improved your tremors while you were taking them?” and to then identify which one(s). Answers were matched with current DMT in use so that the figure only depicts perceived change on the current DMT. Panel (a) depicts whether respondents (n =541) reported improvement on their current DMT by natalizumab exposure status, while (b) (n= 469) depicts tremor improvement by the current DMT in use. Chi square tests were performed for both (a) χ2 =25.59, po0.001 and (b) χ2 =28.02, po0.001. DMT: Disease Modifying Therapy.
3.3.
Responders vs. non-responders
Based on the wide distribution of scores in the primary analysis (both improving and worsening over time), we performed a secondary analysis (Figure 2a and b) in which respondents were characterized as “responders” (those who experienced improvement on a DMT), “stable” (those whose scores did not change over time), or “non-responders” (those who worsened over time). The figure illustrates that natalizumab-treated subjects were more likely to experience regression of symptoms over time as measured by both the TRADL and VAS compared to the control groups. However, the magnitude of TRADL
4.
Discussion
These results suggest that for MS patients disabled by tremor, treatment with natalizumab may improve the chances of a reduction in tremor severity over time. While there are several limitations to our study, the results are consistent both with previous descriptions of symptom improvement in natalizumab-treated populations, and also with personal observations in our own clinic. Conventional thinking regards the approved MS DMTs as reducing long-term neurological disability via the prevention of relapses (Hirst et al., 2008). Since relapses are characterized by bouts of inflammatory-mediated demyelination and axonal loss (Prat and Antel, 2005), drugs which prevent or minimize relapses should lessen the accumulation of new injury but have little effect on established symptoms. Nevertheless, subjects enrolled in MS clinical trials can experience improvement in Expanded Disability Status Scale (EDSS)-assessed disability over time, even following a relapse, to scores which are lower than “baseline” levels (Lublin et al., 2003). More recently, natalizumab therapy in particular has been associated with regression of neurological disability in overall EDSS (Phillips et al., 2011), cognition (Lang et al., 2012; Iaffaldano et al., 2012), and visual impairment (Balcer et al., 2012). With demonstration that symptom regression is a possible outcome of DMT
Please cite this article as: Rinker JR II, et al. Improvement of multiple sclerosis-associated tremor as a treatment effect of natalizumab. Multiple Sclerosis and Related Disorders (2014), http://dx.doi.org/10.1016/j.msard.2014.04.001
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Table 3
Measures of change in tremor severity by exposure to natalizumab. Never on natalizumab (n= 229)
Previously on natalizumab (n = 136)
p-Value
45.4 (13.4) 43 (35, 54)
48.2 (15.9) 46 (35, 60)
48.5 (14.7) 48 (37, 58)
0.077
43.7 (15.2) 41 (31, 54)
42.5 (16.9) 37 (27, 54)
44.6 (14.8) 44 (30.5, 55)
0.475
1.8 (10.6) 1 ( 2, 8)
5.3 (13.0) 3 (0, 11)
3.3 (10.6) 0 (0, 4.5)
0.009
4.4 (1.8) 4 (3, 5.25)
4.4 (2.0) 4 (3, 6)
4.6 (2.1) 5 (3, 6)
0.504
4.5 (2.2) 5 (3, 6)
4.1 (2.2) 4 (2, 6)
4.6 (2.4) 5 (2.75, 6)
0.049
0.1 (1.6) 0 ( 1, 1)
0.3 (1.8) 0 (0, 1)
0.1 (1.6) 0 (0, 0)
0.027
Current natalizumab (n= 202) TRADLQ, current Mean (SD) Median (IQR) TRADLQ, at start of DMT Mean (SD) Median (IQR) Change in TRADLQ Mean (SD) Median (IQR) VAS, current Current mean (SD) Median (IQR) VAS, at start of DMT Mean (SD) Median (IQR) Change in VAS Mean (SD) Median (IQR)
TRADLQ: Tremor Related Activities of Daily Living questionnaire; IQR: Interquartile Range; DMT: Disease Modifying Therapy; VAS: Visual Analog Scale.
initiation, at least one group has proposed EDSS improvement be considered as a possible outcome measure for future clinical trials (Phillips et al., 2011). Missing from these encouraging studies on symptom regression have been reports of improved tremor and ataxia among MS patients. Indeed, we have found symptomatic approaches to tremor and ataxia to be of little benefit in most cases of moderate to severe symptoms. Thus, when two patients in our clinic with severe MS-related tremor and ataxia (EDSS Z7.0) experienced marked symptom regression in the months following natalizumab initiation, we questioned whether natalizumab might offer the possibility of improvement for these patients. One of the patients improved to the point of walking unassisted and regaining the ability to drive (EDSS 2.5) while the other regained the ability to walk unaided and complete many household chores which she had been unable to perform (EDSS 4.5). The marked improvement observed in these two patients led to the design of the study reported in this manuscript, questioning whether regression of tremor or ataxia could be observed in the wider MS population. Since the infrequent occurrence of these patients in clinical practice would make a prospective study of tremor regression difficult to conduct, the self-report, retrospective nature of this study was an efficient, cost-effective method to address this particular therapeutic question. However, while the results of this suggest that tremor may improve with natalizumab similar to symptom improvements described elsewhere (Lang et al., 2012; Iaffaldano et al., 2012; Balcer et al., 2012), the strength of our conclusions is limited by the study design. One of the major limitations of this study is the uncontrolled assignment of DMT to each subject. There are many
factors taken into consideration when choosing a DMT for MS, including patient preference, clinician comfort and familiarity with treatments, safety, risk tolerance, convenience, and cost. These factors may influence not only which DMT an individual takes, but also be associated with other disease-related factors such as disability, disease type, and symptom duration. Another important concern in our study design is the reliance on subject recall to demonstrate change in symptom severity over time. We made the decision to base the primary outcome on recalled symptom severity in part to maximize the number of eligible participants, and in part because of the difficulty we would have in using a registry to identify subjects just initiating a DMT and then follow them prospectively over time. In order to minimize the effects of recall bias, we chose as our starting time point the most recent initiation of a DMT (a memorable experience for most patients) instead of a particular time interval. We also omitted any reference to natalizumab as a selection criterion or focus-of-interest for the study in the mailed questionnaire. We also judged that since the tendency of MS is to worsen over time, that there would be an inherent bias against symptom improvement in our data, which would favor the null hypothesis that there was no advantage of one DMT over another for the symptom of MS tremor. There are at least three other limitations to the generalizability of this study. First, the characteristics of the NARCOMS respondents were quite different from those of the author’s two clinic patients whose improvement inspired this investigation. For this study, we set the lower threshold for inclusion at “mild tremor”, which means we included subjects with a wide range of tremor-related impairment. Also, the age of the two clinic responders
Please cite this article as: Rinker JR II, et al. Improvement of multiple sclerosis-associated tremor as a treatment effect of natalizumab. Multiple Sclerosis and Related Disorders (2014), http://dx.doi.org/10.1016/j.msard.2014.04.001
Improvement of multiple sclerosis-associated tremor as a treatment effect of natalizumab
Table 4
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Regression estimates of parameters explaining change in Tremor Related Activities of Daily Living (n =387).
Treatment group Never natalizumab Current natalizumab Current age PDDS Baseline TRADL score
Parameter estimates
95% CI
Reference 1.2 0.2 2.3 0.4
– 2.1 to 0.1–0.3 1.7–2.8 0.5 to
p-Valuea
0.2
0.4
n/a 0.017 0.003 o0.001 o0.001
CI: Confidence Interval; PDDS: Patient Determined Disease Steps; TRADL: Tremor Related Activities of Daily Living. a For the overall model, po0.0001.
Figure 2 Measured change in tremor severity by comparison of pre- and post-Tremor Related Activities of Daily Living (a) and Visual Analog Scale scores (b). For both measures of tremor, a decrease in scores over time from the start of the current DMT to the present was characterized as “improved”, equivalent scores were coded as “stable” and an increase in total scores was coded as “worsened”. For both measures and all treatment categories, respondents were more likely to report worsening over time than improvement; however, subjects taking natalizumab were more likely to document improvement over time than subjects with past or no prior natalizumab exposure. Chi square tests were performed for both panels (a) χ2 =17.19, p=0.002 and (b) χ2 =18.15, p=0.001. DMT: Disease Modifying Therapy.
(mid-1920s and lower 1930s) was much younger than the mean age of participants in this study. Our results suggest that tremor regression might still occur in patients with long-standing symptoms, and not just in younger, more severely affected patients. Second, since this study was based entirely on assessments provided by subjects themselves without objective confirmation, one must acknowledge the potential for bias introduced by relying on subjects to self-categorize their tremor severity. In a subsequent analysis, we hope to partially address the question of validity by correlating subject-drawn Archimedes spirals with the self-report scales of tremor severity. Third, the baseline characteristics of the cohort demonstrate that factors such as current age and duration of DMT usage clearly differ between the groups as they were defined for primary analysis. Certainly the younger average age of natalizumab users could imply a greater resilience to neurological injury compared to older users of other DMTs. From a different vantage point, since natalizumab is often reserved for patients with more aggressive disease, it is also possible these same subjects are disadvantaged by a more debilitating MS course than subjects on other DMTs. The limitations of this study design preclude distinguishing between these two possibilities. However, the multivariable analysis suggests that while age does factor into likelihood of tremor change over time, the use of natalizumab has an independent beneficial effect on reducing tremor severity. Looking to the future, it will be interesting to reproduce these results in a prospective fashion, and also to explore the mechanism by which a drug like natalizumab, which modifies the MS disease process by limiting lymphocyte trafficking into the CNS (Yednock et al., 1992), might influence the generation of tremor.
Conflict of interest Dr. John Rinker is supported by a Department of Veterans Affairs Career Development Award (CDA2) and received no salary support from this work. Dr. Amber Salter received no salary support and reports no conflicts in regards to this work. Dr. Gary Cutter received no salary support and reports no conflicts in regards to this work.
Please cite this article as: Rinker JR II, et al. Improvement of multiple sclerosis-associated tremor as a treatment effect of natalizumab. Multiple Sclerosis and Related Disorders (2014), http://dx.doi.org/10.1016/j.msard.2014.04.001
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Acknowledgments The authors thank the NARCOMS registrants who took the time to complete the surveys and return them in the mail. We also thank Dr. Stacey Cofield for assistance in survey design, and Jeffry Hebert for constructing the database from the returned paper surveys. This study was funded by an Investigator Initiated Grant/ Trial Award from Biogen Idec (US-TYS-11-10238).
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Kappos L, Radue EW, O’Connor P, Polman C, Hohlfield R, Calabresi P, et al. A placebo controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med 2010;362:387–401. Koch M, Mostert J, Heersema D, De Keyser J. Tremor in multiple sclerosis. J Neurol 2007;254:133–45. Lang C, Reiss C, Maeurer M. Natalizumab may improve cognition and mood in multiple sclerosis. Eur Neurol 2012;67:162–6. Louis ED, Ferreira JJ. How common is the most common adult movement disorder? Update on the worldwide prevalence of essential tremor Mov Disord 2010;25:534–41. Lublin FD, Baier M, Cutter G. Effect of relapses on development of residual deficit in multiple sclerosis. Neurology 2003;61:1528–32. Marrie RA, Goldman M. Validation of the NARCOMS registry: tremor and coordination scale. Int J MS Care 2011;13:114–20. Phillips JT, Giovannoni G, Lublin FD, O’Connor PW, Willoughby E, Aschenback W, et al. Sustained improvement in expanded disability status scale as a new efficacy measure of neurological change in multiple sclerosis: treatment effects with natalizumab in patients with relapsing multiple sclerosis. Mult Scler 2011;17:970–9. Pittock S, McClelland R, Mayr W, Rodriguez M, Matsumoto JY. Prevalence of tremor in multiple sclerosis and associated disability in the Olmsted County population. Mov Disord 2004;19:1482–5. Polman CH, O’Connor PW, Havrdova E, Hutchinson M, Kappos L, Miller DH, et al. A randomized placebo-controlled trial of natalizumab for relapsing-remitting multiple sclerosis. N Engl J Med 2006;354:899–910. Prat A, Antel J. Pathogenesis of multiple sclerosis. Curr Opin Neurol 2005;18:225–30. PRISMS Study Group; Randomised double-blind placebo-controlled study of interferon β-1a in relapsing/remitting multiple sclerosis; Lancet; 1998;352;1498–1504. Striano P, Coppola A, Vacca G, Zara F, Brescia Morra V, Orefice G, et al. Levetiracetam for cerebellar tremor in multiple sclerosis. an open-label pilot tolerability and efficacy study. J Neurol 2006;253:762–6. Wade DT, Makela P, Robson P, House H, Bateman C. Do cannabisbased medicinal extracts have general or specific effects on symptoms in multiple sclerosis? A double-blind, randomized, placebo-controlled study on 160 patients Mult Scler 2004;10: 434–41. Weinshenker BG, Rice GP, Noseworthy JH, Carriere W, Baskerville J, Ebers GC. The natural history of multiple sclerosis: a geographically based study. 3. Multivariate analysis of predictive factors and models of outcome. Brain 1991;114:1045–56. Weiss N, North RB, Ohara S, Lenz FA. Attenuation of cerebellar tremor with implantation of an intrathecal baclofen pump: the role of gamma-aminobutyric acidergic pathways. Case report. J Neurosurg 2003;99:768–71. Yednock TA, Cannon C, Fritz LC, Sanchez-Madrid F, Steinman L, Karin N. Prevention of experimental autoimmune encephalomyelitis by antibodies against α4β1 integrin. Nature 1992;356: 63–6. Zajicek J, Fox P, Sanders H, Wright D, Vickery J, Nunn A, et al. Cannabinoids for treatment of spasticity and other symptoms related to multiple sclerosis (CAMS study): multicenter randomized placebo-controlled trial. Lancet 2003;362:1517–26.
Please cite this article as: Rinker JR II, et al. Improvement of multiple sclerosis-associated tremor as a treatment effect of natalizumab. Multiple Sclerosis and Related Disorders (2014), http://dx.doi.org/10.1016/j.msard.2014.04.001
Available online at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/msard
Improvement of multiple sclerosis-associated tremor as a treatment effect of natalizumab John R. Rinker IIa,b,n, Amber R. Salterc, Gary R. Cutterc a
Department of Neurology, University of Alabama at Birmingham, 1720 7th Avenue South, SC 440, Birmingham, AL 35294, USA b Birmingham VA Medical Center, 700 19th Street South, Birmingham, AL 35233, USA c Department of Biostatistics, University of Alabama at Birmingham, 1665 University Boulevard, Birmingham, AL 35294, USA Received 3 January 2014; received in revised form 14 March 2014; accepted 2 April 2014
KEYWORDS Multiple sclerosis; Tremor; Neurologic symptoms; Natalizumab; Self-report; Questionnaires
Abstract Background: Tremor is among the most physically disabling symptoms associated with MS. The effect of MS disease modifying therapies (DMTs) on the severity of MS tremor is unclear.
Objective: To compare the change over time in scores reflecting tremor severity between subjects treated with natalizumab and other disease modifying drugs.
Methods: Questionnaires were sent to North American Research Committee on MS registrants reporting mild or greater tremor on semiannual updates. Respondents on natalizumab and other MS therapies completed a survey which included tremor-specific scales to indicate tremor severity both currently and when the current therapy was initiated. Differences between natalizumab and non-natalizumab groups were compared using ANOVA. Results: Surveys were returned by 567 registrants, including 202 taking natalizumab. Subjects on natalizumab were more likely to report tremor improvement (29.6%) than those never (15.2%) or previously (14.8%, p=0.0002) on natalizumab. Over a mean recall period of 6.2 +4.6 years, the Tremor Related Activities of Daily Living score worsened by 1.8 points among natalizumab-treated subjects, 3.3 points among those previously on natalizumab, and 5.3 points among those who never took natalizumab (p=0.009). Conclusion: Respondents taking natalizumab were more likely to experience tremor improvement than those taking other MS disease modifying therapies. & 2014 Published by Elsevier B.V.
1.
Introduction
n
Corresponding author at: Department of Neurology, University of Alabama at Birmingham, 1720 7th Avenue South, SC 440, Birmingham, AL 35294, USA. Tel.: +1 205 996 2092; fax: +1 205 975 6030. E-mail address: [email protected] (J.R. Rinker II).
Tremor ranks among the more physically disabling symptoms caused by multiple sclerosis (MS). Between 25% and 58% of MS patients are affected by tremor (Alusi et al., 2001;
http://dx.doi.org/10.1016/j.msard.2014.04.001 2211-0348/& 2014 Published by Elsevier B.V.
Please cite this article as: Rinker JR II, et al. Improvement of multiple sclerosis-associated tremor as a treatment effect of natalizumab. Multiple Sclerosis and Related Disorders (2014), http://dx.doi.org/10.1016/j.msard.2014.04.001
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Pittock et al., 2004), and tremor is frequently associated with ataxia, another disabling MS symptom. Since tremor disproportionately affects the upper extremities, it interferes with many routine activities even in the absence of weakness. MS tremor and ataxia have also been shown to correlate with overall disability and dependence on caregivers (Weinshenker et al., 1991), and both are associated with high risk of respiratory impairment (Grasso et al., 2000) and poorer overall prognosis (Weinshenker et al., 1991). A common attribute of MS-associated tremor has been its resistance to symptomatic therapy. Pharmacological interventions such as intrathecal baclofen (Weiss et al., 2003), isoniazid (Bozek et al., 1987; Hallett et al., 1985), levetiracetam (Striano et al., 2006), and cannabis (Fox et al., 2004; Wade et al., 2004; Zajicek et al., 2003) have been studied for their ability to lessen the effects of tremor, but results have been negative, not duplicated, or underpowered to draw clinically meaningful conclusions. Surgical interventions such as thalamotomy have shown benefit in numerous case series (Koch et al., 2007), but the effects are often temporary, and the treatment is expensive, highly specialized, and not practical for many patients. The immune modulating drugs collectively referred to as the MS disease modifying therapies (DMTs) are not intended to reverse established MS symptoms, but rather to slow the accumulation of neurological disability through the prevention of relapses (IFN β Multiple Sclerosis Study Group, 1993; Jacobs et al., 1996; PRISM Study Group, 1998; Johnson et al., 1995; Hartung et al., 2002; Polman et al., 2006; Kappos et al., 2010). However, we observed marked regression of tremor and ataxia in two severely disabled patients after initiation of natalizumab, so we undertook to explore whether natalizumab might be associated with tremor regression across a broad cohort of MS patients. Due to the infrequent presentation of severely ataxic or tremulous patients in a single clinic, we queried the North American Research Committee on Multiple Sclerosis (NARCOMS) registry to identify patients with subjective MS tremor and concurrent use of natalizumab or other MS DMTs. The NARCOMS registry includes more than 36,000 participants (Consortium of Multiple Sclerosis Centers, 2013) who provide demographic information and periodic updates about their treatments and subjective experience of MS symptoms. Participants who indicated the presence of tremor or ataxia were invited to complete a separate survey focused specifically on tremor and its effects on daily life.
2.
Materials and methods
We designed a survey-based, case-control study to compare respondent impression of change in tremor symptoms over time. The primary hypothesis was that natalizumab treatment would be associated with greater likelihood of tremor improvement as measured by the Tremor Related Activities of Daily Living (TRADL) questionnaire (Bain and Findley, 1993). Cases were defined as subjects currently taking natalizumab, and controls were divided into two groups: (1) subjects who had never taken natalizumab and (2) subjects previously on natalizumab but now taking another DMT.
2.1.
Study population
NARCOMS maintains the confidentiality of its registrants by acting as an intermediary between investigators and the registry. Local Internal Review Board approval was obtained prior to data collection. Subjects were identified within NARCOMS according to the following criteria: (1) subjects must have indicated a Tremor and Coordination Scale (TACS) (Marrie and Goldman, 2011) score of 2 or greater (indicating mild or worse impairment) on the Fall 2010, Spring 2011, or Fall 2011 semi-annual updates; and (2) subjects must have reported current use of an approved MS DMT, and have remained on the DMT for at least 6 months. All subjects who indicated current or previous treatment with natalizumab were mailed a survey, as well as a random selection of participants using other MS DMTs. In total, 777 surveys were sent to prospective participants. The surveys did not indicate to participants that their past or current DMT was a criterion for their inclusion in the study. The prior-natalizumab control group was included for two reasons: first, since natalizumab treatment may signify more aggressive or treatment-refractory disease, including this subset would ensure we included respondents with similar disease characteristics to the current natalizumab group. Second, respondents in this group would be able to compare symptom experience between their current DMT and natalizumab.
2.2.
Survey design and outcome measures
All invited participants were mailed a paper survey along with pre-paid return mailing materials. Respondents answered descriptive questions about the natural history of their tremor, parts of the body affected, family history of tremor, current DMT and duration of use, and the use of symptomatic treatments for tremor. Respondents also completed questionnaires assessing various aspects of tremor (Table 1). The TRADL questionnaire was selected to assess the primary endpoint, because it asks about a wide range of functional activities affected by tremor, and lends itself to generation of a summary score to reflect overall tremor severity. Also included in the survey were the Tremor Related Handicap (TRH) (Bain and Findley, 1993) scale, which asks “yes/no” questions about tremor-related physical disability and embarrassment in several common scenarios, and a Visual Analog Scale (VAS) on which respondents report their overall tremor severity. Respondents were asked to complete the TRADL, TRH, and VAS scales twice: once to reflect current symptom experience and a second time to recall their symptoms at the time their current DMT was initiated (a recalled “baseline”). Differences in these questionnaires were used to estimate change in symptom severity over time. Change in the TRADL scale and VAS could be positive or negative: negative scores indicate decreasing symptom burden over time, while positive scores indicate worsening symptoms. For all the tremor-focused outcome measures, lower scores represent less severe tremor or impairment. The survey also adapted a Clinical Ataxia Rating Scale (CARS) (Bain and Findley, 1993), which was intended for use as a physician-administered tool for describing severity of ataxia and tremor, but was adapted for survey respondents using language understandable to non-clinicians. Finally, respondents were asked to draw two Archimedes spirals, one with each hand,
Please cite this article as: Rinker JR II, et al. Improvement of multiple sclerosis-associated tremor as a treatment effect of natalizumab. Multiple Sclerosis and Related Disorders (2014), http://dx.doi.org/10.1016/j.msard.2014.04.001
Improvement of multiple sclerosis-associated tremor as a treatment effect of natalizumab
Table 1
3
Description of Tremor-Focused Rating Scales.
Name of scale
No. of items
Score range per item
Summary score range
Used for before/after comparisons
TRADL TRH VAS TACSb CARS Archimedes spirals
25 9 1 1 4 2
1–4 N/Aa 1–10 0–5 0–4 0–10
25–100 – 1–10 0–5 0–16 0–20
Yes Yes Yes No No No
TRADL: Tremor Related Activities of Daily Living; TRH: Tremor Related Handicap; VAS: Visual Analog Scale; TACS: Tremor and Coordination Scale; CARS: Clinical Ataxia Rating Scale. a Responses are categorical. b Scores retrieved from semi-annual NARCOMS questionnaire (not included as part of tremor survey).
and these were scored by three independent raters using a published rating method (Bain and Findley, 1993). Results of these descriptive measures will be reported separately. Durations of MS, tremor, and DMT usage were derived from the respondents' enrollment and most recent update survey data. Beta-interferon treatment included all subjects on SQ beta-interferon-1b, IM beta-interferon-1a, or SQ beta-interferon-1a.
2.3.
Statistical tests
Statistical analysis was conducted using JMP 10.0.0 (SAS Institute Inc., Cary, NC). Categorical variables were compared using the χ2 test, ordinal variables were compared using the Kruskal–Wallis test, and continuous variables were compared using t-tests or ANOVA, as appropriate. Pairwise comparisons using Tukey's test were used to compare change in TRADL and VAS between cases and control groups. An alpha of 0.05 was considered significant. To adjust for group differences in age, baseline tremor severity, and overall disability (as estimated by the Patient Determined Disease Steps (PDDS)), a multivariate analysis using a least squares regression model was performed including current natalizumab users and those who had never been exposed to natalizumab. Covariates included in the model included DMT (natalizumab or other), subject age, current disability as reported on the PDDS, and TRADL scores at the time of current DMT initiation. In order to assess for demographic or disease characteristics that may be predictive of tremor improvement on the various DMTs, a subgroup analysis was also performed on “responders” and “non-responders” as defined by whether subjects' TRADL scores improved or worsened over time. Subjects whose TRADL scores were unchanged were not included in the subgroup analysis. Chi-square and t-tests were used as appropriate.
3.
Results
Surveys were sent to 777 NARCOMS registrants meeting inclusion criteria, and 567 (73.0%) were returned.
3.1.
Descriptive characteristics
Demographic and clinical characteristics of the cohort are summarized in Table 2. Groups were similar except for several time-based variables: subjects currently or formerly treated with natalizumab were younger, with shorter durations of disease, tremor, and DMT usage than those who had never taken natalizumab. The differences in duration of DMT usage were not unexpected given the more recent commercial availability of natalizumab and the exposurerelated risk of progressive multifocal leukoencephalopathy, which limits treatment duration in some patients. The association of natalizumab use with age and shorter duration of disease and tremor may also be related to a greater likelihood of active, relapsing disease among younger patients, or to other factors which were not captured in this survey (e.g., risk tolerance, increased willingness to change therapies in pursuit of greater efficacy). In both control groups, the majority of respondents were taking either glatiramer acetate or a beta-interferon preparation as their DMT. A small number of subjects who had never taken natalizumab were taking fingolimod, while a larger proportion (29.6%) of subjects who had previously taken natalizumab were taking fingolimod. We do not know from our survey whether subjects switched from natalizumab to fingolimod for reasons of safety, tolerability, or lack of efficacy. Although very few respondents attributed their tremor to a condition other than MS, a higher than expected number of respondents reported a family history of tremor. The population prevalence of essential tremor, the most common form of familial tremor, is estimated to be o1% in the general population (and 4–5% among those 465) (Louis and Ferreira, 2010), so the rates reported here are higher than would be expected of the general population. Fewer than half of respondents took symptomatic medication to suppress tremor (n= 238, 42.0%), with the highest usage rate occurring among those formerly on natalizumab (Table 2). The most commonly utilized class of medications were the anticonvulsants (n =142), with gabapentin the most widely used drug (n= 108). Other tremor-suppressing agents included the benzodiazepines (n = 131), antispasmodic drugs (n= 43), cannabinoids including medical marijuana (n = 32), beta-blockers (n =21), alcohol (n= 17),
Please cite this article as: Rinker JR II, et al. Improvement of multiple sclerosis-associated tremor as a treatment effect of natalizumab. Multiple Sclerosis and Related Disorders (2014), http://dx.doi.org/10.1016/j.msard.2014.04.001
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Table 2
Participant characteristics. Currently on natalizumab (n= 202)
Sex, n (%) Female Male Race, n (%) White Non-White Mean age, years (SD) Employment, n (%) Full time Part time Unemployed Mean age of diagnosis, years (SD) Mean disease duration, years (SD) PDDS, median (IQR) Clinical course, n (%) RRMS SPMS PPMS Unknown Current DMT, n (%) Beta-interferon Glatiramer acetate Fingolimod Mean current DMT duration of use, years (SD) Family history of tremor, n (%) Tremor not attributed to MS, n (%) Mean tremor duration, years (SD) Maximum TACS score, median (IQR) Taking medication to suppress tremor, n (%) Surgical treatment of tremor, n (%)
Never on natalizumab (n = 229)
Previously on natalizumab (n= 136)
p-Value
166 (82.6) 35 (17.4)
170 (74.2) 59 (25.8)
105 (77.8) 30 (22.2)
0.113
170 (96.1) 7 (3.9) 53.5 (9.4)
215 (96.9) 7 (3.1) 58.1 (8.8)
113 (94.2) 7 (5.8) 54.0 (8.9)
0.641
17 (10.1) 16 (9.5) 136 (80.5) 37.2 (9.6) 16.2 (8.4) 4 (3–6)
20 11 169 38.6 19.5 5
(10.0) (5.5) (84.5) (10.0) (8.7) (3–6)
12 13 93 39.1 15.0 5
(10.2) (11.0) (81.7) (8.3) (6.3) (4–6)
94 59 25 20
(47.5) (29.8) (12.6) (10.1)
48 44 15 10
(41.0) (37.6) (12.8) (8.5)
0.385
95 94 5 9.2 34 10 12.5 3 32 5
(49.0) (48.5) (2.6) (4.8) (14.9) (4.4) (7.8) (2–4) (35.8) (2.2)
21 41 26 4.9 18 4 9.7 3 70 2
(23.9) (46.6) (29.6) (3.9) (13.2) (2.9) (7.0) (2–4) (51.5) (1.5)
o0.001
94 46 19 10
(55.6) (27.2) (11.2) (5.9)
– – – 3.5 (1.9) 33 (16.3) 1 (0.5) 11.1 (9.3) 3 (2–3) 86 (42.6) 6 (3.0)
o0.001 0.448
0.154 o0.001 0.180
o0.001 0.681 0.308 0.003 0.388 0.065 0.865
PDDS: Patient Determined Disease Steps; IQR: Interquartile Range; RRMS: Relapsing-Remitting Multiple Sclerosis; SPMS: Secondary Progressive Multiple Sclerosis; PPMS: Primary Progressive Multiple Sclerosis; DMT: Disease Modifying Therapy; TACS: Tremor and Coordination Scale.
and primidone (n = 2). A smaller proportion of respondents felt drugs they were taking worsened their tremor (n= 23), with alcohol (n = 9), medical marijuana (n = 4), pregabalin (n = 3), and gabapentin (n= 3) cited as the most common exacerbating agents.
3.2.
Tremor regression over time
Subjects were asked to report whether they associated their current or any prior DMT with improvement in tremor symptoms. Overall 110 (19.4%) respondents associated one or more DMTs with improvement in tremor, 227 (40.0%) appreciated no improvement, and 204 (36.0%) were unsure. When the question of improvement was linked to subjects' current DMT, natalizumab was significantly more likely to be associated with improvement than the other DMTs (Figure 1a and b). In order to assess the primary endpoint, mean change in TRADL was compared between the natalizumab-treated group and the two control groups (Table 3). Unadjusted,
pairwise comparisons found significant differences between the current natalizumab group and those never treated with natalizumab (p =0.002), while comparisons between prior natalizumab and both current and never natalizumab were not significantly different. Pairwise comparisons of VAS yielded similar results, with current natalizumab users reporting better outcomes in comparison to those who never had never taken natalizumab (p= 0.007). In order to adjust for intergroup differences between cases and controls, we conducted a multi-variable analysis to test whether natalizumab usage was still associated with improved tremor-related outcomes after adjusting for current disability (estimated by PDDS), age, and the TRADL scores at the start of the current DMT. To simplify the comparison, the prior natalizumab control group was excluded from the analysis. Even though all of the included covariates were found to contribute to intergroup differences, the current natalizumab group still experienced less worsening (po0.017) on overall TRADL scores compared to the group that had never taken natalizumab (Table 4).
Please cite this article as: Rinker JR II, et al. Improvement of multiple sclerosis-associated tremor as a treatment effect of natalizumab. Multiple Sclerosis and Related Disorders (2014), http://dx.doi.org/10.1016/j.msard.2014.04.001
Improvement of multiple sclerosis-associated tremor as a treatment effect of natalizumab
5
improvement among “responders” was the same between those currently on natalizumab and those who had never taken natalizumab ( 8.9 points), and was slightly lower among those previously on natalizumab ( 6.1). The same was true for the VAS scale: “responders” among the natalizumab cohort improved by 2.1 points, those never on natalizumab improved by 2.0 points, and those previously on natalizumab improved by 2.1 points. In contrast, among those who worsened on their current DMT, the magnitude of worsening was the least among natalizumab-treated subjects (+8.5 TRADL, +1.6 VAS) and greater in the prior natalizumab (+9.4, +2.2) and never natalizumab (+12.1, +2.1) groups.
3.4.
Predictors of tremor improvement
Due to the baseline differences in age and durations of MS and current DMT usage, we explored whether various demographic or disease characteristics including gender, ethnicity, MS subtype, current age and ages of MS diagnosis and tremor onset, and durations of MS, tremor, and DMT usage were associated with improvement or worsening on the TRADL over time. Among interferon-using subjects (n=91), only gender was associated with responder status. Twelve of 26 males (46.2%) were more likely to report TRADL improvement over time compared to 14 of 65 females (21.5%, p=0.019). Subjects using glatiramer acetate (n=105) did not differ on any of the variables with respect to responder status. Among natalizumab users (n=148), responder status was associated with a younger age of diagnosis (34.6 vs. 38.6, p=0.0081), current age (50.9 vs. 55.0, p=0.005), and longer duration of tremor (14.0 vs. 9.8, p=0.007). Only 21 subjects using fingolimod classified as responders or non-responders, and in this group responders had an older age of diagnosis (41.1 vs. 32.5, p=0.011) and present age (53.4 vs. 46.6, p=0.033) than non-responders. Figure 1 Subjective impression of change in overall tremor severity on current DMT by (a) natalizumab exposure status and (b) current Disease Modifying Therapy. Subjects were asked, “Do you think that any of your current or previous DMTs improved your tremors while you were taking them?” and to then identify which one(s). Answers were matched with current DMT in use so that the figure only depicts perceived change on the current DMT. Panel (a) depicts whether respondents (n =541) reported improvement on their current DMT by natalizumab exposure status, while (b) (n= 469) depicts tremor improvement by the current DMT in use. Chi square tests were performed for both (a) χ2 =25.59, po0.001 and (b) χ2 =28.02, po0.001. DMT: Disease Modifying Therapy.
3.3.
Responders vs. non-responders
Based on the wide distribution of scores in the primary analysis (both improving and worsening over time), we performed a secondary analysis (Figure 2a and b) in which respondents were characterized as “responders” (those who experienced improvement on a DMT), “stable” (those whose scores did not change over time), or “non-responders” (those who worsened over time). The figure illustrates that natalizumab-treated subjects were more likely to experience regression of symptoms over time as measured by both the TRADL and VAS compared to the control groups. However, the magnitude of TRADL
4.
Discussion
These results suggest that for MS patients disabled by tremor, treatment with natalizumab may improve the chances of a reduction in tremor severity over time. While there are several limitations to our study, the results are consistent both with previous descriptions of symptom improvement in natalizumab-treated populations, and also with personal observations in our own clinic. Conventional thinking regards the approved MS DMTs as reducing long-term neurological disability via the prevention of relapses (Hirst et al., 2008). Since relapses are characterized by bouts of inflammatory-mediated demyelination and axonal loss (Prat and Antel, 2005), drugs which prevent or minimize relapses should lessen the accumulation of new injury but have little effect on established symptoms. Nevertheless, subjects enrolled in MS clinical trials can experience improvement in Expanded Disability Status Scale (EDSS)-assessed disability over time, even following a relapse, to scores which are lower than “baseline” levels (Lublin et al., 2003). More recently, natalizumab therapy in particular has been associated with regression of neurological disability in overall EDSS (Phillips et al., 2011), cognition (Lang et al., 2012; Iaffaldano et al., 2012), and visual impairment (Balcer et al., 2012). With demonstration that symptom regression is a possible outcome of DMT
Please cite this article as: Rinker JR II, et al. Improvement of multiple sclerosis-associated tremor as a treatment effect of natalizumab. Multiple Sclerosis and Related Disorders (2014), http://dx.doi.org/10.1016/j.msard.2014.04.001
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Table 3
Measures of change in tremor severity by exposure to natalizumab. Never on natalizumab (n= 229)
Previously on natalizumab (n = 136)
p-Value
45.4 (13.4) 43 (35, 54)
48.2 (15.9) 46 (35, 60)
48.5 (14.7) 48 (37, 58)
0.077
43.7 (15.2) 41 (31, 54)
42.5 (16.9) 37 (27, 54)
44.6 (14.8) 44 (30.5, 55)
0.475
1.8 (10.6) 1 ( 2, 8)
5.3 (13.0) 3 (0, 11)
3.3 (10.6) 0 (0, 4.5)
0.009
4.4 (1.8) 4 (3, 5.25)
4.4 (2.0) 4 (3, 6)
4.6 (2.1) 5 (3, 6)
0.504
4.5 (2.2) 5 (3, 6)
4.1 (2.2) 4 (2, 6)
4.6 (2.4) 5 (2.75, 6)
0.049
0.1 (1.6) 0 ( 1, 1)
0.3 (1.8) 0 (0, 1)
0.1 (1.6) 0 (0, 0)
0.027
Current natalizumab (n= 202) TRADLQ, current Mean (SD) Median (IQR) TRADLQ, at start of DMT Mean (SD) Median (IQR) Change in TRADLQ Mean (SD) Median (IQR) VAS, current Current mean (SD) Median (IQR) VAS, at start of DMT Mean (SD) Median (IQR) Change in VAS Mean (SD) Median (IQR)
TRADLQ: Tremor Related Activities of Daily Living questionnaire; IQR: Interquartile Range; DMT: Disease Modifying Therapy; VAS: Visual Analog Scale.
initiation, at least one group has proposed EDSS improvement be considered as a possible outcome measure for future clinical trials (Phillips et al., 2011). Missing from these encouraging studies on symptom regression have been reports of improved tremor and ataxia among MS patients. Indeed, we have found symptomatic approaches to tremor and ataxia to be of little benefit in most cases of moderate to severe symptoms. Thus, when two patients in our clinic with severe MS-related tremor and ataxia (EDSS Z7.0) experienced marked symptom regression in the months following natalizumab initiation, we questioned whether natalizumab might offer the possibility of improvement for these patients. One of the patients improved to the point of walking unassisted and regaining the ability to drive (EDSS 2.5) while the other regained the ability to walk unaided and complete many household chores which she had been unable to perform (EDSS 4.5). The marked improvement observed in these two patients led to the design of the study reported in this manuscript, questioning whether regression of tremor or ataxia could be observed in the wider MS population. Since the infrequent occurrence of these patients in clinical practice would make a prospective study of tremor regression difficult to conduct, the self-report, retrospective nature of this study was an efficient, cost-effective method to address this particular therapeutic question. However, while the results of this suggest that tremor may improve with natalizumab similar to symptom improvements described elsewhere (Lang et al., 2012; Iaffaldano et al., 2012; Balcer et al., 2012), the strength of our conclusions is limited by the study design. One of the major limitations of this study is the uncontrolled assignment of DMT to each subject. There are many
factors taken into consideration when choosing a DMT for MS, including patient preference, clinician comfort and familiarity with treatments, safety, risk tolerance, convenience, and cost. These factors may influence not only which DMT an individual takes, but also be associated with other disease-related factors such as disability, disease type, and symptom duration. Another important concern in our study design is the reliance on subject recall to demonstrate change in symptom severity over time. We made the decision to base the primary outcome on recalled symptom severity in part to maximize the number of eligible participants, and in part because of the difficulty we would have in using a registry to identify subjects just initiating a DMT and then follow them prospectively over time. In order to minimize the effects of recall bias, we chose as our starting time point the most recent initiation of a DMT (a memorable experience for most patients) instead of a particular time interval. We also omitted any reference to natalizumab as a selection criterion or focus-of-interest for the study in the mailed questionnaire. We also judged that since the tendency of MS is to worsen over time, that there would be an inherent bias against symptom improvement in our data, which would favor the null hypothesis that there was no advantage of one DMT over another for the symptom of MS tremor. There are at least three other limitations to the generalizability of this study. First, the characteristics of the NARCOMS respondents were quite different from those of the author’s two clinic patients whose improvement inspired this investigation. For this study, we set the lower threshold for inclusion at “mild tremor”, which means we included subjects with a wide range of tremor-related impairment. Also, the age of the two clinic responders
Please cite this article as: Rinker JR II, et al. Improvement of multiple sclerosis-associated tremor as a treatment effect of natalizumab. Multiple Sclerosis and Related Disorders (2014), http://dx.doi.org/10.1016/j.msard.2014.04.001
Improvement of multiple sclerosis-associated tremor as a treatment effect of natalizumab
Table 4
7
Regression estimates of parameters explaining change in Tremor Related Activities of Daily Living (n =387).
Treatment group Never natalizumab Current natalizumab Current age PDDS Baseline TRADL score
Parameter estimates
95% CI
Reference 1.2 0.2 2.3 0.4
– 2.1 to 0.1–0.3 1.7–2.8 0.5 to
p-Valuea
0.2
0.4
n/a 0.017 0.003 o0.001 o0.001
CI: Confidence Interval; PDDS: Patient Determined Disease Steps; TRADL: Tremor Related Activities of Daily Living. a For the overall model, po0.0001.
Figure 2 Measured change in tremor severity by comparison of pre- and post-Tremor Related Activities of Daily Living (a) and Visual Analog Scale scores (b). For both measures of tremor, a decrease in scores over time from the start of the current DMT to the present was characterized as “improved”, equivalent scores were coded as “stable” and an increase in total scores was coded as “worsened”. For both measures and all treatment categories, respondents were more likely to report worsening over time than improvement; however, subjects taking natalizumab were more likely to document improvement over time than subjects with past or no prior natalizumab exposure. Chi square tests were performed for both panels (a) χ2 =17.19, p=0.002 and (b) χ2 =18.15, p=0.001. DMT: Disease Modifying Therapy.
(mid-1920s and lower 1930s) was much younger than the mean age of participants in this study. Our results suggest that tremor regression might still occur in patients with long-standing symptoms, and not just in younger, more severely affected patients. Second, since this study was based entirely on assessments provided by subjects themselves without objective confirmation, one must acknowledge the potential for bias introduced by relying on subjects to self-categorize their tremor severity. In a subsequent analysis, we hope to partially address the question of validity by correlating subject-drawn Archimedes spirals with the self-report scales of tremor severity. Third, the baseline characteristics of the cohort demonstrate that factors such as current age and duration of DMT usage clearly differ between the groups as they were defined for primary analysis. Certainly the younger average age of natalizumab users could imply a greater resilience to neurological injury compared to older users of other DMTs. From a different vantage point, since natalizumab is often reserved for patients with more aggressive disease, it is also possible these same subjects are disadvantaged by a more debilitating MS course than subjects on other DMTs. The limitations of this study design preclude distinguishing between these two possibilities. However, the multivariable analysis suggests that while age does factor into likelihood of tremor change over time, the use of natalizumab has an independent beneficial effect on reducing tremor severity. Looking to the future, it will be interesting to reproduce these results in a prospective fashion, and also to explore the mechanism by which a drug like natalizumab, which modifies the MS disease process by limiting lymphocyte trafficking into the CNS (Yednock et al., 1992), might influence the generation of tremor.
Conflict of interest Dr. John Rinker is supported by a Department of Veterans Affairs Career Development Award (CDA2) and received no salary support from this work. Dr. Amber Salter received no salary support and reports no conflicts in regards to this work. Dr. Gary Cutter received no salary support and reports no conflicts in regards to this work.
Please cite this article as: Rinker JR II, et al. Improvement of multiple sclerosis-associated tremor as a treatment effect of natalizumab. Multiple Sclerosis and Related Disorders (2014), http://dx.doi.org/10.1016/j.msard.2014.04.001
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Acknowledgments The authors thank the NARCOMS registrants who took the time to complete the surveys and return them in the mail. We also thank Dr. Stacey Cofield for assistance in survey design, and Jeffry Hebert for constructing the database from the returned paper surveys. This study was funded by an Investigator Initiated Grant/ Trial Award from Biogen Idec (US-TYS-11-10238).
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Please cite this article as: Rinker JR II, et al. Improvement of multiple sclerosis-associated tremor as a treatment effect of natalizumab. Multiple Sclerosis and Related Disorders (2014), http://dx.doi.org/10.1016/j.msard.2014.04.001