Abstract
Background
Little is known about the prevalence and clinical characteristics of tremors in patients with multiple sclerosis (MS), their associated clinical disability, and their impact on quality of life (QoL).
Objective
This study aimed to investigate the frequency and types of tremors in patients with relapsing remitting MS (RRMS) in remission, and their impact on patients’ QoL.
Methods
A total of 250 patients with RRMS in remission were examined for tremors. All patients were assessed using the Expanded Disability Status Scale (EDSS). Patients with tremors underwent further assessment using the Fahn‐Tolosa‐Marin Tremor Rating Scale (FTMTRS), the Beck Depression Inventory (BDI), the Montreal Cognitive Assessment (MoCA) scale, and the Short Form 36 Health Survey Questionnaire (SF‐36). Brain MRI was obtained for a subgroup of patients.
Results
Tremors were detected in 36 patients (14.4%) and were associated with significantly worse EDSS scores, BDI (P = 0.021), MoCA, most SF‐36 domains, higher total and last year relapses (P < 0.001) and longer disease duration (P = 0.027). Patients with tremors showed higher lesion load (P = 0.007), more infratentorial (P ≤ 0.001), cerebellar and diencephalic lesions (P = 0.024), and cortical atrophy (P = 0.012). Total FTMTRS was significantly correlated to age, EDSS, and physical functioning. Dystonia was associated with tremors in 17 patients (6.8% of total RRMS patients and 47.2% of patients with tremors).
Conclusion
The current study confirms the common occurrence of tremors and their subtypes among patients with RRMS with mild disability and demonstrates their association with increased disability and impaired QoL.
Keywords: tremor, multiple sclerosis, relapsing remitting, dystonia, quality of life
Multiple sclerosis (MS) is a chronic inflammatory disease of the brain and spinal cord and a leading cause of serious physical disability in young adults. Relapsing–remitting MS (RRMS), the most common clinical type, accounts for 85% of MS cases and is characterized by relapses with complete or incomplete remission. 1 For many years, MS has been regarded as a white matter (WM) disease. Owing to advances in both neuroimaging and histopathological research, MS is currently considered a complex inflammatory and degenerative disease, causing both gray matter and WM pathology. 2
Different movement disorders have been reported in patients with MS that might impair their quality of life (QoL). 3 , 4 Tremors were the most frequently reported, and contributed to patients' disability and unemployment. 3 , 5 , 6 Moreover, there have been case reports of MS patients with parkinsonism, dystonia, and hemifacial spasm, but such occurrence remains rare. 7 The occurrence of all these movement disorders implies the development of MS lesions involving the basal ganglia, the cerebellum, and their afferent or efferent connections. 7 However, only a small number of studies have prospectively investigated the frequency of tremors in patients with RRMS, and even more limited data is available regarding their common phenomenology, correlation with neuroimaging, and impact on patients’ QoL. 6 , 8
Therefore, the current study investigated the frequency and phenomenology of tremors among patients with RRMS in remission, their neuroimaging characteristics, and their impact on patients’ QoL.
Methods
In this cross‐sectional study, 250 patients with RRMS in remission were recruited consecutively from the MS clinic of Ain Shams University hospitals from January to September 2020 and assessed for the presence of tremors. The study was approved by the ethical committee of Ain Shams Faculty of Medicine, and written informed consents were obtained from all patients.
Study Participants
Patients with clinically, radiologically, and laboratory‐confirmed RRMS diagnosed by expert neurologists according to the revised McDonald criteria (2017), 9 ranging from 18 to 60 years old and relapse‐free in the last 3 months, were included. Patients with secondary or primary progressive MS, primary movement disorders, or other diagnoses, eg, autoimmune, chronic inflammatory, and infectious diseases, were excluded. Additionally, patients with comorbid diseases or a history of taking medications known to cause or modify movement disorders were excluded.
Assessment Tools
Detailed history taking and clinical examination were performed for all patients, including the Expanded Disability Status Scale (EDSS), the number and time of relapses, the duration of illness, and detailed drug history. All patients were interviewed, assessed using a standardized movement disorder survey, and underwent a focused examination by a trained neurologist (A.E.). Patients with tremors were evaluated using the Fahn‐Tolosa‐Marin Tremor Rating Scale (FTMTRS), and video recorded by the trained neurologist; the videos were then independently reviewed by two movement disorders experts to confirm phenomenology (A.S. and E.H.). RRMS patients with tremors underwent further assessment using the Beck depression inventory (BDI) for depression, 10 the Montreal Cognitive Assessment (MoCA) scale for cognitive functions, 11 and the Short Form 36 Health Survey Questionnaire (SF‐36) for QoL. All three parts of FTMTRS were included; A, quantifies tremor in nine body parts, B, assesses action tremor during writing, drawing and pouring and C, assesses functional disability during domestic tasks. 12 SF‐36 included eight domains: Physical Functioning (PF), Role Physical (RP), Bodily Pain (BP), General Health (GH), Vitality (VT), Social Functioning (SF), Role Emotional (RE), and Mental Health (MH). Higher scores of these domains reflect better health status. Clinical characteristics of RRMS patients with tremors were compared to RRMS patients without movement disorders or other cerebellar signs.
Magnetic Resonance Imaging (MRI) Technique and Interpretation
At the time of clinical evaluation, available MRI of the brain and cervical spinal cord of MS patients with tremors and a cohort of MS patients without tremors, was assessed by an experienced neuroradiologist, using a dedicated MS protocol on a 1.5 Tesla MR scanner (Achieva; Philips Medical Systems, Best, the Netherlands). The MRI sequences included axial 2D T2WI, T1WI, FLAIR, DWI, and sagittal T2 FLAIR for the brain (slice thickness of 5 mm), and sagittal T2WI, STIR, and axial T2WI for the cervical spine (slice thickness of 3 mm).
MRI scans of both groups were assessed for the total number of the T2WI lesion load (less or more than 10); the presence of confluent lesions (defined as lesion diameter exceeding 20 mm or as two or more T2 lesions connected at one or more margins 13 ); the distribution of the lesions (supratentorial, infratentorial, and/or spinal); evaluation for specific locations (diencephalon, midbrain, pons, medulla, cerebellum, and cerebellar peduncles); and the presence of T1WI black hole lesions. Global brain atrophy was assessed qualitatively, and it was deemed positive when there was age mismatched prominence of the cortical sulci, extra‐axial CSF spaces, and ventricular system.
Statistical Analysis
Statistical analysis was done using SPSS (IBM SPSS version 25, NY, USA, 2017). Descriptive data was represented by either mean ± SD, median and range or frequency and percentage. The Mann Whitney U and T‐test were used for continuous variables, and the Chi‐square test was used for categorical ones. This was followed by analyzing the data covariance using Quade's non‐parametric ANCOVA (Quade's ANCOVA) for comparing not normally distributed data for QoL domains with adjustment of non‐matched EDSS, disease duration and BDI. Spearman's correlation was used for correlation between continuous variables. The level of significance was at P < 0.05. The Bonferroni correction was used for multiple comparisons and correlations with an adjusted P value of P ≤ 0.006.
Results
A total of 250 patients (73.6% females, female to male ratio 2.8:1) with RRMS were included, with a mean age of 33.1 ± 8.3 years and a mean age of onset of 28.6 ± 7.9 years. Patients had a mean disease duration of 4.7 ± 4.29 years and a mean EDSS of 2.54 ± 0.9 (range 1–5). Most of the patients (218 patients, 87.2%) had mild to moderate disability with EDSS <4. The mean total and last‐year numbers of relapses were 3.4 ± 2.9 and 0.8 ± 0.8, respectively.
The majority of our patients were on first‐line therapy, with 32.8% on subcutaneous interferon beta 1A, 12.4% on subcutaneous interferon beta 1B, 17.6% on intramuscular interferon beta 1A, 8.8% on teriflunomide, and 0.4% on dimethyl fumarate, while 28% were on second‐line therapy (fingolimod). A total of 16 patients (6.4%) reported different comorbidities such as diabetes mellitus, hypertension, gout, depression, mitral valve prolapse, ischemic heart disease, and rheumatic heart disease. Tremor subtypes were detected in 36 patients (14.4%) and were associated with limb dystonia in 17 patients (6.8% of total MS patients and 47.2% of MS patients with tremors).
Comparing MS Patients with and without Tremors
Compared to MS patients without movement disorders or cerebellar manifestations (183 patients), MS patients with tremors showed significantly worse EDSS, higher total and last year relapses (P < 0.001) and longer disease duration (P = 0.027). Both groups were matched for age, gender, and age of diagnosis. There was no significant difference regarding the disease‐modifying therapy (Table 1).
TABLE 1.
Demographic data and clinical characteristics of RRMS patients with tremor and patients without involuntary movements or cerebellar manifestations
| Clinical Characteristics | MS patients control group N = 183 | MS patients with tremor N = 36 | Mann Whitney U test/T‐test a /Chi test b | |
|---|---|---|---|---|
| Median (IOR)/Number (%) | Median (IOR)/Number (%) | P | ||
| Age (mean ± SD) a | 32.8 (8.1) | 33.4 (8.90) | 0.691 | |
| Gender (Female/male) b | 141 (77%)/42 (23%) | 23 (63.9%)/13 (36.1%) | 0.096 | |
| Age of diagnosis (mean ± SD) a | 29 (7.9) | 27.3 (7.3) | 0.229 | |
| Age of diagnosis | 31 (12.5) | 26 (9) | 0.306 | |
| Total relapses | 2 (2.3) | 5 (50 | <0.001 | |
| Relapse in last year b | 0 | 78 (42.6%) | 8 (22.2%) | <0.001 |
| 1 | 86 (47.0%) | 15 (41.7%) | ||
| 2 | 18 (9.8%) | 9 (25.0%) | ||
| 3 | 1 (0.5%) | 4 (11.1%) | ||
| Disease (MS) duration | 3 (4) | 4 (7) | 0.027 | |
| EDSS | 2 (0.6) | 3 (2) | <0.001 | |
| Onset of tremor (years) (mean ± SD) a | 2.4 ± 2.5 | |||
| DMT b | Interferon beta 1A SC | 62 (33.9%) | 11 (30.6%) | 0.102 |
| Interferon beta 1B SC | 23 (12.6%) | 8 (22.2%) | ||
| Interferon beta 1A IM | 39 (21.3%) | 3 (8.3%) | ||
| Fingolimod | 40 (21.9%) | 13 (36.1%) | ||
| Teriflunomide | 18 (9.8%) | 1 (2.8%) | ||
| Dimethyl fumarate | 1 (0.5%) | 0 (0%) | ||
Note: Significant P value <0.05. After Bonferroni correction; significant P value will be if <0.006.
Abbreviation: EDSS, Expanded Disability Status Scale; DMT, Disease Modifying Therapy; SC, Sub‐cutaneous; IM, intramuscular.
T test is used.
chi test is used.
Tremor was a presenting symptom in four patients (1.6% of the total sample), including one patient who presented with rest tremor. Nine patients (25%) had postural and/or intention tremor only; 10 patients (27.8%) had tremor and limb/gait ataxia; 6 patients (16.7%) had tremor with dystonia; and 11 patients (30.6%) had tremor associated with limb/gait ataxia and dystonia. Of the 36 patients, two patients (5.6%) had mixed postural, intention, and rest tremor (Holmes’ tremor). Tremors were detected in the upper limbs (34 patients) and lower limbs (31 patients), while isolated UL and LL tremors were observed in 7 and 2 patients, respectively. Using FTMTRS, 26 patients (72.2%) had mild tremors, and 10 (27.8%) had moderate tremors, while none of the cases had a severe tremor. Cerebellar signs were detected in 34 MS patients with tremors (94.4%), inclimb ataxia (14 patients), ataxic gait (2 patients), or a combination of both (20 patients) (Supplementary Table A).
Cognition, depression, and QoL were assessed in a cohort of MS patients without movement disorders or cerebellar manifestations (67 patients) and compared to MS patients with tremors. RRMS patients with tremors showed significantly worse cognition (MoCA) (P < 0.001), depression (BDI) (P = 0.021), and all QoL domains (P < 0.001) (Table 2). Both groups were age and sex matched, but patients with tremor had longer disease duration (P = 0.007) and more disease severity (P < 0.001). After Bonferroni correction, significantly worse cognition, QoL domains, more relapses, and disease severity were confirmed. After control of non‐matched variables (EDSS and disease duration) by Quade's ANCOVA, patients with tremors were confirmed to have significantly more impaired QoL in all domains except BP and SF, irrespective of disease severity or duration (Table 2).
TABLE 2.
Cognition, depression, and quality of life in RRMS patients with tremor and without tremor
| Clinical Characteristics | MS patients control group N = 67 | MS patients with tremors N = 36 | Mann Whitney U test/Chi Test a | Quade's ANCOVA | |
|---|---|---|---|---|---|
| Median (IQR)/number (%) | Median (IQR)/number (%) | P | P | ||
| EDSS | 2 (0.5) | 3 (2) | <0.001 | ||
| Duration of diagnosis | 3 (4) | 4 (6.46) | 0.007 | ||
| MOCA | 27 (2) | 24 (3) | <0.001 | ||
| BDI score | 12.5 (15.8) | 15 (19) | 0.021 | ||
| BDI Classification a | No or minimal | 27 (40.9%) | 8 (22.2%) | 0.144 | |
| Mild to moderate | 12 (18.2%) | 12 (33.3%) | |||
| Moderate to severe | 23 (34.8%) | 12 (33.3%) | |||
| Severe | 4 (6.1%) | 4 (11.1%) | |||
| Short form 36 health survey questionnaire a | |||||
|
87.5 (10) | 50 (35) | <0.001 | <0.001 | |
|
75 (31.3) | 25 (50) | <0.001 | <0.001 | |
|
66.7 (33.3) | 33.3 (66.7) | <0.001 | 0.001 | |
|
55 (20) | 45 (25) | <0.001 | 0.005 | |
|
80 (24) | 52 (28) | <0.001 | <0.001 | |
|
75 (28.1) | 62.5 (25) | <0.001 | 0.054 | |
|
72.5 (30) | 57.5 (45) | 0.001 | 0.122 | |
|
65 (26.3) | 40 (35) | <0.001 | <0.001 | |
Note: Significant P value <0.05. Quade's non‐parametric ANCOVA was performed to control clinical characteristics variables. After Bonferroni correction; significant P value will be if <0.004.
Abbreviation: BDI, Beck Depression Inventory; EDSS, Expanded Disability Status Scale; MOCA, Montreal Cognitive Assessment.
Chi test was used.
MRI Lesions in RRMS Patients with and without Tremor
Brain MRI was available and was further assessed in a cohort of MS patients with tremors (25 patients) and compared to a cohort of MS patients without movement disorders or cerebellar manifestations (50 patients). Both groups were disease duration, age, and sex‐matched, but patients with tremors had more relapses (P = 0.011) and disease severity (P < 0.001). Patients with tremors showed higher lesion load, either numerous or confluent lesions (P = 0.007). Furthermore, patients with tremors showed significantly more infratentorial (P ≤ 0.001), cerebellar (P = 0.029), diencephalic lesions (P = 0.024) and cortical atrophy (P = 0.012) (Table 3). However, after Bonferroni correction, only the infratentorial lesions showed a significant difference.
TABLE 3.
MRI characteristics in RRMS patients with tremors and without involuntary movements or cerebellar manifestations
| MRI lesions | MS patients without involuntary movements or cerebellar manifestations (N = 50 patients) | MS patients with tremor (N = 25 patients) | Chi |
|---|---|---|---|
| Number (%) | Number (%) | P | |
| <10 lesions | 33 (66%) | 7 (28%) | 0.007 |
| ≥10 lesions | 15 (30%) | 15 (60%) | |
| Confluent lesions | 2 (4%) | 3 (12%) | |
| Black Holes | 11 (22%) | 2 (8%) | 0.190 |
| Supratentorial | 50 (100%) | 25 (100%) | 1 |
| Diencephalon | 3 (6%) | 6 (24%) | 0.024 |
| Brain stem | 9 (18%) | 9 (36%) | 0.085 |
| Infratentorial | 20 (40%) | 22 (88%) | <0.001 |
| Midbrain | 4 (8%) | 2 (8%) | 1 |
| Pons | 6 (12%) | 7 (28%) | 0.084 |
| Medulla | 1 (2%) | 2 (8%) | 0.211 |
| Cerebellum | 10 (20%) | 11 (44%) | 0.029 |
| Cerebellar Peduncles | 6 (12.0%) | 7 (28.0%) | 0.084 |
| Spinal (40 vs. 20) | 17 (42.5%) | 13 (65.0%) | 0.100 |
| Cortical atrophy | 0 (0%) | 3 (12.0%) | 0.012 |
Note: Significant P value <0.05. After Bonferroni correction; significant P value will be if <0.003.
Abbreviation: MRI, Magnetic Resonance Imaging.
Correlations of Tremor Severity and QoL
Among patients with tremors, total score of FTMTRS was correlated negatively with PF (ρ = −0.496, P = 0.002), RP (ρ = −0.422, P = 0.010), VT (ρ = −0.394, P = 0.018), MH (ρ = −0.336, P = 0.045), SF (ρ = −0.425, P = 0.010), BP (ρ = −0.443, P = 0.007), and GH (ρ = −0.380, P = 0.022) domains of QoL. Part A of FTMTRS was correlated to PA, MH, and SF, part B was correlated to PF, RP, SF, VT, and BP, and part C was correlated to PF, RP, VT, GH, and BP. However, after Bonferroni correction, a significant correlation was detected between total FTMTRS and PF, and part B and QoL domains, FR and BP (P = 0.006).
Moreover, the total FTMTRS score showed a negative correlation with age (ρ = −0.345, P = 0.039) and a positive correlation with EDSS (ρ = 0.355, P = 0.034), but not with duration, MoCA, or BDI scores.
All domains of QoL (except for RE) of patients with tremors were negatively correlated with the total EDSS score (correlation coefficient ranged from −0.541 to −0.426), and depression severity (BDI) (correlation coefficient ranged from −0.649 to −0.434). After Bonferroni correction, all domains of the SF‐36 except RE were correlated to disease disability (Table 4).
TABLE 4.
Correlations of tremor severity and quality of life domains with clinical characteristics among RRMS patients with tremor
| Tremors correlation | Total FTMTRS | Part A FTMTRS | Part B FTMTRS | Part C FTMTRS | Physical functioning | Role physical | Role emotional | Vitality | Mental health | Social functioning | Bodily Pain | General Health | |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age | Spearman | −0.345 | −0.330 | −0.250 | −0.329 | −0.019 | 0.009 | 0.283 | 0.052 | 0.104 | 0.143 | 0.075 | 0.156 |
| Sig. | 0.039 | 0.050 | 0.141 | 0.050 | 0.913 | 0.960 | 0.095 | 0.764 | 0.547 | 0.406 | 0.666 | 0.363 | |
| Disease (MS) duration | Spearman | −0.049 | −0.074 | −0.055 | −0.069 | −0.081 | −0.138 | 0.258 | 0.142 | 0.137 | 0.114 | −0.052 | 0.112 |
| Sig. | 0.775 | 0.668 | 0.750 | 0.690 | 0.638 | 0.422 | 0.128 | 0.410 | 0.425 | 0.509 | 0.765 | 0.515 | |
| Total EDSS | Spearman | 0.355 | 0.332 | 0.279 | 0.201 | −0.515 | −0.473 | −0.214 | −0.505 | −0.533 | −0.426 | −0.448 | −0.541 |
| Sig. | 0.034 | 0.048 | 0.099 | 0.240 | 0.001 | 0.004 | 0.210 | 0.002 | 0.001 | 0.010 | 0.006 | 0.001 | |
| Total FTMTRS | Spearman | 1.000 | 0.773 | 0.754 | 0.817 | −0.496 | −0.422 | −0.167 | −0.394 | −0.336 | −0.425 | −0.443 | −0.380 |
| Sig. | <0.001 | <0.001 | <0.001 | 0.002 | 0.010 | 0.330 | 0.018 | 0.045 | 0.010 | 0.007 | 0.022 | ||
| Part A FTMTRS | Spearman | 0.773 | 1.000 | 0.321 | 0.427 | −0.354 | −0.221 | −0.144 | −0.289 | −0.338 | −0.353 | −0.293 | −0.277 |
| Sig. | <0.001 | 0.056 | 0.009 | 0.034 | 0.195 | 0.403 | 0.088 | 0.044 | 0.035 | 0.083 | 0.102 | ||
| Part B FTMTRS | Spearman | 0.754 | 0.321 | 1.000 | 0.662 | −0.412 | −0.449 | −0.087 | −0.377 | −0.245 | −0.378 | −0.451 | −0.284 |
| Sig. | <0.001 | 0.056 | <0.001 | 0.012 | 0.006 | 0.614 | 0.023 | 0.150 | 0.023 | 0.006 | 0.094 | ||
| Part C FTMTRS | Spearman | 0.817 | 0.427 | 0.662 | 1.000 | −0.389 | −0.377 | −0.237 | −0.427 | −0.256 | −0.322 | −0.371 | −0.385 |
| Sig. | <0.001 | 0.009 | <0.001 | 0.019 | 0.024 | 0.164 | 0.009 | 0.132 | 0.056 | 0.026 | 0.020 | ||
| MoCA | Spearman | 0.086 | 0.043 | −0.034 | 0.139 | 0.001 | 0.172 | −0.109 | 0.212 | 0.144 | 0.143 | 0.220 | 0.058 |
| Sig. | 0.618 | 0.803 | 0.846 | 0.420 | 0.997 | 0.317 | 0.529 | 0.215 | 0.402 | 0.405 | 0.196 | 0.735 | |
| BDI | Spearman | 0.219 | 0.064 | 0.192 | 0.331 | −0.596 | −0.453 | −0.427 | −0.550 | −0.552 | −0.513 | −0.653 | −0.662 |
| Sig. | 0.198 | 0.713 | 0.261 | 0.049 | <0.001 | 0.006 | 0.009 | 0.001 | <0.001 | 0.001 | <0.001 | <0.001 | |
Note: Significant P value <0.05. After Bonferroni correction; significant P value will be if ≤0.006.
Abbreviation: BDI, Becks Depression Inventory; EDSS, Expanded Disability Status Scale; MOCA, Montreal Cognitive Assessment.
Discussion
Few studies have investigated the prevalence, types, related factors, and impact of tremors on QoL among patients with RRMS. The current study demonstrated that tremors were common among patients with RRMS and were associated with longer disease duration, higher number of total and last‐year relapses, higher disability, and higher MRI lesion load, especially infratentorial lesions. Furthermore, it confirmed the negative impact of tremors on QoL and showed their association with cognitive impairment and depression among RRMS patients.
Notably, our cohort of RRMS patients was characterized by short disease duration and low disease severity with mild to moderate disability and included only patients during remission. Movement disorders in RRMS could be changeable, induced by relapses, and improved by treatment. Therefore, movement disorders that persist during remission will have a more enduring impact on patients’ QoL. 14
In the current study, tremors were detected in 14.4% of patients with RRMS, in agreement with a previous study conducted on 447 RRMS patients, demonstrating a tremor prevalence of 15.2% of the total sample. 15 Another study by Pittock et al. reported a slightly higher prevalence (19.3%). 16 Similar to previous studies, tremors were most frequently mixed postural and intention and affecting upper limbs, while Holmes’ and rest tremors were rare and were detected in two and one patient, respectively. 3 , 6 , 17 , 18 Rest tremors were detected in combination with other tremor subtypes. Interestingly, tongue tremor was detected in only one patient in our study in combination with rest and kinetic tremors, which has never been reported in previous studies.
Moreover, tremor severity was mostly mild to moderate 3 , 16 and was associated with worse disease severity (EDSS) as reported in other studies. 16 , 17 Similarly, patients with tremors had worse disease severity in our study, but with a moderate correlation. Additionally, there was a significant correlation to disease relapses and duration. A higher prevalence of tremors (30%) was reported recently in early MS involving different clinical types. 14 Tremor presence was not related to gender or age in contrast to a previous study that showed higher tremor occurrence in younger male patients. 17
Limb dystonia was frequently detected in association with tremors (47.2%; 6.8% of total MS patients). Consistently, Van der Walt et al. reported the common association of upper limb dystonia with MS tremors and attributed this to the dysfunction of the cerebello‐pallido‐thalamo‐cortical network. 19 Another study reported two patients with hemidystonia and writer's cramp among 253 patients with MS. 4 Identifying dystonia in patients with MS tremors is of clinical importance, as it alludes to the potential efficacy of botulinum toxin in treating those patients. 19
Few studies have investigated the impact of tremors on QoL of RRMS patients. Remarkably, the current study demonstrated the association of tremors with worse QoL and the correlation of tremor severity with worse QoL, especially PF and BP, highlighting the importance of tremor management. Similarly, da Silva et al reported a worse QoL in MS patients with movement disorders compared to MS patients without movement disorders. 4 Another study demonstrated markedly impaired QoL due to tremors. 5 In contrast, Pittock et al. reported similar QoL in MS patients with and without tremors using a scale from 0 to 10. 16
In the current study, patients with tremors had worse cognitive functions, but there was no correlation with tremor severity. Similarly, a previous study showed no correlation between MMSE scores and tremor severity, but comparable cognitive functions between patients with and without tremors. 17 Associated cognitive dysfunction could be attributed to underlying subcortical dysfunction, through the dysfunction of the cerebello‐thalamo‐cortical circuit, rather than diffuse cortical dysfunction. 17 , 18 , 20 Boonstra et al detected cerebellar and thalamic atrophy in patients with MS tremors, that was associated with increased lesion load of the ipsilateral cerebellum. This was associated with the functional plasticity of the ipsilateral cortex. 21 Moreover, several studies attributed the cognitive impairment in people with MS to dysfunction of the cerebellum and its connections. 22 , 23 Consistently, cognitive dysfunction was detected in different cerebellar syndromes, that was described as the cerebellar cognitive affective syndrome (CCAS). 22 Consequently, the underlying cerebellar dysfunction of tremors in patients with MS might explain the associated cognitive impairment. Therefore, further studies using specific cognitive tests for cerebellum related cognitive functions, including executive, visuospatial, and affective functions, are required. 20
Depression is a common manifestation in patients with MS and significantly impairs their QoL. 24 , 25 In the current study, RRMS patients with tremors showed worse depressive scores, but there was no correlation to tremor severity. To our knowledge, no previous studies have investigated the association between tremors and depression in patients with MS, indicating the need for more studies to confirm this association.
The MRI findings in our study showed more WM lesions and involvement of infratentorial structures, particularly cerebellar and diencephalic lesions, in patients with tremors. Similarly, a previous study showed a higher probability of T2 lesions and more severe diffusivity abnormalities in the middle and superior cerebellar peduncles in MS patients in relation to clinical impairment involving ambulation, cerebellar, and brainstem symptoms. 26
Moreover, tremors were associated with more cerebellar lesions and other cerebellar signs, in agreement with other studies, implying the role of cerebellar dysfunction. 27 Consistently, Boonstra et al showed a correlation of tremor severity with the thalamic and superior cerebellar peduncles’ volumes, supporting the role of degeneration of these structures within the cerebellothalamic circuits in the pathogenesis of MS tremor. 8 , 21 Moreover, postural tremor and expectedly intention tremor were correlated to lesions of the brainstem (midbrain) or cerebellothalamic circuits’ dysfunction. 28
Precise differentiation of tremors’ subtypes is challenging in patients with MS, particularly with the coexistence of cerebellar manifestations in most of the patients with tremors (94.4%). Moreover, dissecting intention tremor from dysmetria and limb ataxia is difficult. 29 Neurophysiological studies of MS tremor revealed a pseudorhyhmic pattern mimicking tremor, that could be explained by cerebellar dysfunction. 27 , 28 However, tremors could not be attributed completely to, or might be independent from, cerebellar dysfunction, 28 , 30 implying a role of other regions, particularly the brainstem. 27 , 28 Therefore, neurophysiological assessment is important for the evaluation of MS patients with tremors, and more neurophysiological studies are required for a proper description of the tremors' subtypes in MS patients.
Limitations of this study include the use of non‐standardized video recording to confirm the phenomenology, the inability to use neurophysiology for better characterization of tremor, and the use of 1.5‐tesla MRI and the visual determination of the lesions. Therefore, larger studies using neurophysiology and advanced MRI techniques are required.
Conclusion
The current study demonstrated the common occurrence of tremors and their types among RRMS patients with mild disability and during remission, their association with dystonia, their relation to patients’ disability, and their negative impact on patients’ QoL. Furthermore, the associated MRI structural changes imply the role of the cerebellothalamic circuit in the pathogenesis of MS tremors. Therefore, the proper assessment and management of tremors are crucial for a lower disability and better QoL of patients with RRMS.
Author Roles
(1) Research Project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript Preparation: A. Writing of the First Draft, B. Review and Critique.
A.S.: 1A, 1B, 1C, 2A, 2C, 3A, 3B.
A.E.: 1C, 3A.
M.S.: Y.I.: 1B, 1C, 3B.
E.H.: 1B, 1C, 2A, 2B, 3B.
A.N.: 1A, 1B, 2C, 3B.
Disclosures
Ethical Compliance Statement: The study was approved by the ethical committee of Ain Shams Faculty of Medicine, and written informed consents were obtained from all patients. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines.
Funding Sources and Conflicts of Interest: The authors declare that there are no funding sources or conflicts of interest relevant to this work.
Financial Disclosures for the Previous 12 Months: The authors declare that there are no additional disclosures to report.
Supporting information
Supplementary Table A. Clinical types and distribution of tremors in in RRMS patients
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Supplementary Materials
Supplementary Table A. Clinical types and distribution of tremors in in RRMS patients