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Isfahan Neurosciences Research Center, Isfahan University of Medical Sciences, Isfahan, IranDepartment of Neurology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
None of the medications suggested for the treatment of MS tremor has been shown to have significant or consistent benefit in satisfactorily designed studies.
•
Non-randomized studies reported a positive effect for some of these medications.
•
Botulinum toxin A had significant effects on MS-related tremor, but adverse effects and injection procedures limited its application.
Abstract
Background
Tremor is a relatively common symptom in Multiple Sclerosis (MS). It can negatively affect several aspects of the patients' life and is one of the most disabling symptoms in MS. Pharmacological treatment of MS-related tremor was studied for several years, though treatment is still challenging. This study will review all studies on the pharmacological treatment of tremor in MS and update the treatment recommendations.
Methods
Any relevant English-language clinical trial that investigated the pharmacological treatment of MS-related tremor in adults was eligible in this study. We searched Medline (PubMed), Scopus, EMBASE, and Web of Science. Bias assessment was performed by the CASP (Critical Appraisal Skills Programme) checklist. All methods followed PRISMA guidelines.
Results
The initial search resulted in 3024 articles; 26 articles were included as eligible studies, 13 articles had a low risk of bias, and remained for full manuscript review. The results of studies on 5-HT3 receptor antagonists as a single dose treatment were inconsistent. Botulinum toxin A had significant effects on MS-related tremor, but adverse effects and injection procedures limited its application. The application of cannabis-based medicine to treat MS-related tremor could not be recommended due to inconclusive therapeutic effects and several side effects. Levetiracetam had inconsistent results, and other anti-epileptic drugs were not studied precisely. Isoniazid has minor therapeutic effects and possible adverse effects in the treatment of MS-related tremor.
Conclusion
Further well-designed comparative clinical trials with a large sample size can improve clinical management of tremor in patients with MS.
). It can negatively affect several aspects of the patients' quality of life and is one of the most disabling symptoms in MS. Some studies showed that tremor severity is correlated with disability and unemployment rate among patients with MS (
). Despite the disabling effect of tremor of the upper limbs, which impairs activities of daily living, Expanded Disability Status Scale (EDSS) depends to a great degree on mobility.
Tremor can be evaluated by clinical examination, visual tracking, accelerometry, EMG coupling techniques, Stewart–Holmes maneuver, and digitized spirography (for review, see (
)). Several quantitative scales have been studied and validated in MS patients; Bain Score for Tremor Severity (BSTS), Tremor and Coordination Scale (TACS), Fahn Tremor Rating Scale (FTRS), multidimensional assessment of tremor (MAT) are some examples. However, there are important limitations in evidence-based assessment and development of treatment recommendations for tremor in MS. Globally accepted methods for objective assessment of tremor in MS patients are lacking. On the other hand, different studies vary in outcome measures commonly used to evaluate tremor.
MS-related tremor is primarily a large-amplitude tremor, postural or intentional type (
This systematic review searched and recorded relevant English literature through electronic biomedical resources, including Medline (PubMed), Scopus, EMBASE, and Web of Science, available up to March 20, 2021, without time limitation. Search strategy consisted of search terms as follows.
("Tremor*" OR "Limb Tremor*" OR "Muscle Tremor*" OR "Action Tremor*" OR "Coarse Tremor*" OR "Continuous Tremor*" OR "Rest Tremor*" OR "Ataxia" OR "Intention Tremors" OR "Coarse Tremors" OR " Darkness Tremor*" OR "Fine Tremor*" OR "Intermittent Tremor*" OR "Involuntary Quiver" OR "Massive Tremor*" OR "Passive Tremor*" OR "Persistent Tremor*" OR "Pill Rolling Tremor*" OR "Resting Tremor*" OR "Rest Tremors*" OR "Tremor*, Perioral" OR "Saturnine Tremor*" OR "Senile Tremor*") AND ("Sclerosis Multiple" OR "MS" OR "Disseminated Sclerosis" OR "Myelitis, Transverse" OR "Demyelinating Diseases" OR "Encephalomyelitis, Acute Disseminated" OR "Optic neuritis" OR "Device" OR "ADEM" OR "neuromyelitis optica") AND ("Treatment" OR "Medical Treatment" OR "Therapeutic" OR "Surgery" OR "drug therapy").
We also checked reference lists from relevant articles/reviews. We did not consider "child" or "adolescent" in the search lines.
2.2 Study design
We included all randomized and non-randomized clinical trials in which they reported pharmacological treatment of MS-related tremor in adults. We also included cross-over clinical trials.
2.3 Participants
The inclusion criteria consisted of adult patients with MS, 18 years old and above, with either gender. Studies including patients with different neurological diseases were included if they reported results for the MS patients' group.
2.4 Intervention
Pharmacological treatment was considered the intervention group and compared with the placebo/control group.
2.5 Outcome
Any improvement in the severity of tremor caused by pharmacologic treatments measured by any validated method was considered the primary outcome. In addition, the incidence and impact of adverse effects were considered.
2.6 Eligibility criteria and study selection
At the initial step, two reviewers (AP and RR) independently screened the title/abstract of articles after removing the duplicate records in a reference manager software (Endnote version 18). Letters, conference papers, book chapters, reviews, and animal studies were excluded in this screening step. Moreover, articles were excluded if they did not contain MS patients and were not clinical trial studies. At the second step, full texts of the remaining articles (- records) were reviewed entirely, and those articles with topics or participants irrelevant to our review were excluded (Fig 1). To reach a consensus, we discussed resolving any disagreement on including a paper.
2.7 Methodological quality and risk of bias assessment
The methodological quality of eligible articles was evaluated by the CASP (Critical Appraisal Skills Programme) randomized controlled trial standard checklist. It consists of 11 items to evaluate the methodological quality in clinical trials. Quality assessments of all eligible studies were completed by two reviewers independently. Disagreements were resolved by discussion, and if required, a third (corresponding author) reviewer was arbitrated. Overall quality status was categorized as low (i.e., participants not recruited properly and with weak results), moderate (i.e., participants recruited properly and with weak to intermediate results), or high (i.e., participants recruited properly and with strong results). Moreover, the Jadad scale was used to evaluate the risk of bias of eligible clinical trials. This scale consists of 3 items to assess randomization, blinding, and reporting of withdrawals. The Jadad scale ranges from 0 to 5 (score ≤ 2: high risk of bias, and ≥ 3: low risk of bias). Finally, studies with a high risk of bias according to the Jadad scale were excluded from this review (Table 1).
Table 1Assessing the risk of bias with the Jadad scale and methodological quality with CASP randomized controlled trial standard checklist. Included studies are marked with (*).
Cannabinoids for treatment of spasticity and other symptoms related to multiple sclerosis (CAMS study): multicentre randomised placebo-controlled trial.
Do cannabis-based medicinal extracts have general or specific effects on symptoms in multiple sclerosis? A double-blind, randomized, placebo-controlled study on 160 patients.
Efficacy of levetiracetam on upper limb movement in multiple sclerosis patients with cerebellar signs: a multicenter double-blind, placebo-controlled, crossover study.
The protocol of this systematic review was registered in PROSPERO (registration number: CRD42021253252).
3. Results
Our systematic literature search resulted in a total of 3652 publications (from PubMed, Web of Science, EMBASE, and Scopus database), of which 628 articles were duplicated and removed from the screening process. 26 articles were eligible for inclusion in our systematic review. Then we evaluated the methodological quality and risk of bias assessment, and 13 studies had moderate to high overall quality with low risk of bias (Table 1). The screening process is summarized in Fig. 1. 9 studies had a placebo-controlled, double-blind, crossover design (
Do cannabis-based medicinal extracts have general or specific effects on symptoms in multiple sclerosis? A double-blind, randomized, placebo-controlled study on 160 patients.
Efficacy of levetiracetam on upper limb movement in multiple sclerosis patients with cerebellar signs: a multicenter double-blind, placebo-controlled, crossover study.
Cannabinoids for treatment of spasticity and other symptoms related to multiple sclerosis (CAMS study): multicentre randomised placebo-controlled trial.
Cannabinoids for treatment of spasticity and other symptoms related to multiple sclerosis (CAMS study): multicentre randomised placebo-controlled trial.
Do cannabis-based medicinal extracts have general or specific effects on symptoms in multiple sclerosis? A double-blind, randomized, placebo-controlled study on 160 patients.
Efficacy of levetiracetam on upper limb movement in multiple sclerosis patients with cerebellar signs: a multicenter double-blind, placebo-controlled, crossover study.
The main characteristics of included studies are shown in Table 2. The study size ranged from 5 to 630 patients. The primary outcome in the majority of included studies was tremor assessment. Tremor was evaluated by clinical examination, handwriting, visual analog scale (VAS), videotaped assessment of tremor, and activities of daily living (ADL) questionnaire, ataxia scale, spirography, 9-hole peg test (9HPT), tremor severity scale, FTRS, BTRS, tremogram, and accelerometry. Assessment of cerebellar symptoms and ataxia was the primary outcome in two studies (
Cannabinoids for treatment of spasticity and other symptoms related to multiple sclerosis (CAMS study): multicentre randomised placebo-controlled trial.
) used self-report, videotaped tremor assessment, and accelerometry to evaluate tremor. They started with 300 mg/d and increased the dose up to 1200 mg/d. The treatment phase was continued for four weeks with a one-week washout period. They showed subjective improvement but no significant changes in accelerometry (sample size = 6).
) evaluated tremor with clinical assessment and tremogram. Drug dosage was selected based on the acetylation phenotype of the patients; slow acetylators received 12 mg/kg/d and rapid acetylators 20 mg/kg/d for four weeks. Similarly, they found minimal clinical improvement but no significant changes in objective measures such as tremogram (sample size = 8).
) used a clinical rating scale, spirography, 9HPT, accelerometry, and videotaped tremor assessment to evaluate tremor. For two weeks, patients received cannador, an ethanolic extract of cannabis Sativa standardized to 2.5 mg of Tetrahydrocannabinol (THC) per capsule. They reported no significant improvement in any objective measures of upper limb tremor (sample size = 14).
Do cannabis-based medicinal extracts have general or specific effects on symptoms in multiple sclerosis? A double-blind, randomized, placebo-controlled study on 160 patients.
) used oromucosal spray containing equal amounts of THC and Cannabidiol (CBD) at a dose of 2.5/120 mg for six weeks. They also found similar results, no significant differences between drug and placebo groups (sample size = 54).
Cannabinoids for treatment of spasticity and other symptoms related to multiple sclerosis (CAMS study): multicentre randomised placebo-controlled trial.
) in cannabinoids in multiple sclerosis (CAMS) study as their secondary outcome showed cannabis extract or THC did not significantly affect tremor (sample size = 391). The dosage was adjusted based on the patient's weight, with a maximum dose of 25 mg/d. The treatment phase was continued for 12 weeks.
) reported that 10 patients had mild adverse effects, such as drowsiness and lightheadedness, memory disturbance, dysphoria, euphoria, increased appetite, and dry mouth.
Do cannabis-based medicinal extracts have general or specific effects on symptoms in multiple sclerosis? A double-blind, randomized, placebo-controlled study on 160 patients.
) also reported mild adverse effects, such as dizziness (26 patients), fatigue (12 patients), application site discomfort (21 patients), cognitive and behavioral changes.
Cannabinoids for treatment of spasticity and other symptoms related to multiple sclerosis (CAMS study): multicentre randomised placebo-controlled trial.
) reported several minor adverse effects such as dizziness, dry mouth, constipation, and diarrhea in 361 patients (from 502 patients). However, major adverse events were similar in active and control groups, so they concluded no major safety concerns.
3.2.3 Antiepileptic drugs
Three crossover studies investigated the efficacy of Levetiracetam (LEV).
) used the tremor severity scale, ataxia scale, ADL questionnaire, and VAS to evaluate cerebellar symptoms and ataxia in 8 patients with MS. They showed LEV at a maximum dose of 1500 mg/d modified kinematic parameters such as trajectory jerk index and centripetal acceleration but did not improve clinical scales.
) used FTRS, 9HPT, VAS, ADL questionnaire, and spirography to evaluate tremor in 18 MS patients with disabling intention tremor. They started with 250 mg/d and increased the dose up to the maximum dose (2000 mg/d). They reported that LEV did not affect tremor severity or patients' functionality.
Efficacy of levetiracetam on upper limb movement in multiple sclerosis patients with cerebellar signs: a multicenter double-blind, placebo-controlled, crossover study.
) studied 48 MS patients with cerebellar signs. They started with 500 mg/d and increased the dose up to the maximum dose (3000 mg/d). They found that LEV improved clinical outcomes and upper limb dexterity in patients with MS.
Efficacy of levetiracetam on upper limb movement in multiple sclerosis patients with cerebellar signs: a multicenter double-blind, placebo-controlled, crossover study.
) studied (crossover trial) the efficacy of a single dose intravenous ondansetron on 16 MS patients with cerebellar tremor. They showed significant subjective and objective improvement. In comparison,
) (crossover trial) used a single dose of intravenous dolasetron mesylate on 34 MS patients with cerebellar tremor. They did not find any positive effect.
(parallel trial) studied botulinum toxin A (maximum dose 100–150 units). They reported improvement in tremor severity, disability, and brain activity changes in sensorimotor integration regions.
Both studies reported weakness as an adverse effect.
) reported a significant decrease in muscle strength, which recovered close to baseline by 12 weeks (sample size = 43).
4. Discussion
We reviewed all studies conducted on the pharmacological treatment of tremor in patients with MS. Only 13 of the 26 included studies were designed precisely. Several studies had small sample sizes, the outcome measures were different, and no comparative study with a large sample was conducted.
4.1 Pharmacological agents
4.1.1 Isoniazid
Isoniazid is one of the oldest drugs that has been used to treat tremor in patients with MS. Anti-tremor effect of isoniazid is not fully understood. Isoniazid may inhibit the activity of monoamine oxidase enzyme and GABA-ergic modulatory processes (
). We concluded that isoniazid had limited therapeutic effects in the treatment of MS-related tremor. Its adverse effects such as hepatotoxicity, gastrointestinal, dermatologic, and neuromuscular problems should also be taken into account. Considering the small sample size of the studies and limited randomized trials, the application of Isoniazid in MS-related tremor could not be recommended.
4.1.2 Cannabis-based medicine
Cannabis may be used to treat different symptoms of MS, as spasticity and fatigue (
Do cannabis-based medicinal extracts have general or specific effects on symptoms in multiple sclerosis? A double-blind, randomized, placebo-controlled study on 160 patients.
Cannabinoids for treatment of spasticity and other symptoms related to multiple sclerosis (CAMS study): multicentre randomised placebo-controlled trial.
) showed cannabis had some positive effects on MS-related tremor after 52 weeks of treatment. They concluded that cannabis had more symptomatic benefits with time. Since tremor assessment was not the primary outcome of the CAMS study, their conclusions about tremor are under debate. Inconclusive therapeutic effects and several side effects limited the application of cannabis-based medicine to treat MS-related tremor.
4.1.3 Antiepileptic drugs
LEV is an antiepileptic drug that has been studied in MS-related tremor. The anti-tremor effect of LEV is not studied well. However, the suggested mechanism is restricting hyper synchronization and high-frequency repetitive firing of neuronal cells in the thalamic ventralis intermedius nucleus and cortico cerebello-thalamo-cortical loops (
Efficacy of levetiracetam on upper limb movement in multiple sclerosis patients with cerebellar signs: a multicenter double-blind, placebo-controlled, crossover study.
). Further studies are needed to reveal the therapeutic effects of LEV on MS-related tremor.
Topiramate is another antiepileptic drug that has been studied in MS-related tremor. Case reports and non-randomized trials reported that topiramate had positive effects on MS-related tremor (
); however, no randomized trial was conducted. So, the therapeutic effects of topiramate are not clear.
4.1.4 5-HT3 receptor antagonist
Ondansetron and dolasetron mesylate for the intravenous route have been studied in MS-related tremor. A suggested anti-tremor mechanism is the modulation of the cerebellar serotonergic system (
); Further studies with more extended treatment periods are needed to reveal the therapeutic effects of 5-HT3 receptor antagonists on MS-related tremor.
4.1.5 Botulinum toxin A
Botulinum toxin A is a bacterial toxin locally injected and blocks the nerve signals to the muscle. One open-label pilot study reported no therapeutic effect (
). Botulinum toxin A injection has several limitations. A trained physician should perform the injection. It is invasive, and sometimes targeting the muscle is challenging. Muscle weakness is expected as an adverse effect.
) have been used in the treatment of MS-related tremor. Case reports and non-randomized trials reported positive effects on MS-related tremor; however, no randomized trial was conducted. So, the therapeutic effects of these drugs are not clear. Further studies are needed to show the therapeutic effects of them on MS-related tremor.
4.2 Future studies
Due to the scarcity of evidence from controlled studies with large sample sizes, concluding a conclusive clinical recommendation was with certain limitations. However, some suggestions can be provided to help overcome the unmet needs in clinical practice. Not all addressed topics can improve therapeutic and diagnostic approaches, but they may guide future therapeutic and diagnostic studies in tremor of MS-related tremor.
4.2.1 Adequate assessment tools
MS-related tremor is a heterogeneous phenomenon. There is no well-validated, sensitive, and internationally agreed assessment tool to evaluate tremor and differentiate subtypes of MS-related tremor. Clinically, different forms of tremor and pseudo-tremor can manifest in patients with MS. In accelerometric studies coupled with electromyographic (EMG) monitoring to evaluate tremor in patients with MS, most patients had a pseudo-rhythmic activity rather than true tremor (
). Hence, assessing tremor properly, according to predefined diagnostic criteria, should be considered in all clinical trials addressing MS-related tremor.
4.2.2 Precision medicine
The pathophysiology of MS-related tremor remains incompletely understood yet. The thalamus, cerebellum, and basal ganglia play important roles. Previous studies showed a correlation between lesions in the cerebello-thalamo-cortical network and tremor in MS patients (
). In addition, the volumetric and lesion analysis showed significant correlations between tremor severity and thalamic atrophy, thalamic lesion load, superior cerebellar peduncle atrophy, cortical peri-central sulcus lesions, and pons lesion load (
). Interestingly, a recent white matter microstructural integrity study on patients with essential tremor and Parkinson's disease showed a myelin-related process disrupts the cerebello-thalamo-cortical network, ultimately leading to the manifestation of action tremor (
). MS-related tremor is best explained by a multilevel lesion that results in different connectivity and functional disturbances within the cortico-cerebellar-subcortical networks. A better understanding of underlying pathophysiological mechanisms of tremor in MS can improve future therapeutic and diagnostic approaches. In a recent systematic review and meta-analysis,
) reviewed the therapeutic effects of DBS on tremor in patients with MS. In the present study, we reviewed the therapeutic effects of pharmacological treatments of tremor in these patients.
4.2.3 Disease-modifying therapies
Some studies suggested that tremor is a part of disease progression in MS. They showed that tremor severity is correlated with disease severity measured by EDSS, nine-hole peg test, and Barthel index of activities of daily living (
) showed that patients taking natalizumab were more likely to experience tremor improvement. Further studies are needed to reveal and compare the therapeutic effects of DMTs on tremor in MS.
5. Conclusion
Tremor is a disabling and relatively common symptom in MS. Pharmacological treatment of MS-related tremor was studied for several years, though treatment is challenging yet. Several drugs were studied and systematically reviewed here. None of the medications suggested for the treatment of MS tremor has been shown to have significant or consistent benefit in satisfactorily designed studies, despite uncontrolled case reports suggesting a positive effect. Most improvement in tremor has been reported with injections of botulinum toxin A, but with the effect of increased weakness which limits its use. Concluding a certain clinical recommendation was limited due to the scarcity of evidence from controlled studies with large sample sizes. Further well-designed comparative clinical trials with a large sample size can improve clinical management of tremor in patients with MS.
Declaration of Competing Interest
None.
Acknowledgments
None.
References
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Interference of upper limb tremor on daily life activities in people with multiple sclerosis.
Do cannabis-based medicinal extracts have general or specific effects on symptoms in multiple sclerosis? A double-blind, randomized, placebo-controlled study on 160 patients.
Efficacy of levetiracetam on upper limb movement in multiple sclerosis patients with cerebellar signs: a multicenter double-blind, placebo-controlled, crossover study.
Cannabinoids for treatment of spasticity and other symptoms related to multiple sclerosis (CAMS study): multicentre randomised placebo-controlled trial.
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