Search strategy and selection criteria References for this review were identified from searches of Pubmed (from 1966 to 2005) and the Cochrane Library (2005, Issue 2) with the search terms “multiple sclerosis”, “tremor”, “ataxia”, “disability”, “prevalence”, “surgery”, “thalamotomy”, “deep brain stimulation” and “treatment”. Articles were also identified through searches of the reference tables of identified papers. Furthermore we searched the ISI Science Citation Index for relevant articles citing identified papers. Only articles in English and German were included in the review; publications in abstract form were not considered. Introduction Tremor is such a common problem in multiple sclerosis (MS) that the famous French neurologist Charcot (1825–1893) described it as a part of his triad of characteristic symptoms in MS, together with nystagmus, and scanning speech. Tremor of the upper limbs can be very disabling and seriously impair many activities of daily living and quality of life. In practice the treatment of tremor in MS is often frustrating. In this review we discuss medical, surgical and other treatment options. Epidemiology 55 94 95 6 74 Tremor subtypes 5 29 6 74 1 Table 1 Details of the two main prevalence studies on tremor in MS  6 74 Total patients with tremor 58 (58%) 51 (25.5%) Patients with severe tremor 15 (15%) 6 (3%) Arm tremor 56 (56%) 47 (23.5%) Bilateral arm tremor 36 (36%) not reported Leg tremor 10 (10%) 12 (6%) Head tremor 9 (9%) 7 (3.5%) trunk tremor 7 (7%) not reported Pathophysiology of tremor The pathophysiology of tremor in MS is a difficult area of investigation, partly because MS is by definition a multifocal disease, so that tremor occurrence cannot easily be linked to a single neuroanatomical site. Systematic postmortem studies on the link between lesion site and the clinical phenomenon of tremor have never been undertaken. The predominance of action tremors (postural and intention) in patients with MS point to the cerebellum and its connections as the most likely source of tremor production, whereas the rarity of rest tremor argues against an involvement of the basal ganglia. The common occurrence of bilateral tremor might indicate that damage to the cerebellum and its connections is often multifocal. 30 64 56 77 35 6 100 101 31 76 75 42 40 22 34 93 19 20 Although this is an interesting pathophysiologic model of intention tremor production, it remains uncertain whether the results of animal studies can be generalized to patients with MS. In summary, clinical observation, animal studies and some experimental evidence in humans favour the cerebellum and the thalamic nuclei connected to it as the major locus of intention tremor production, but more research is needed to evaluate the role of the basal ganglia and other systems in tremor production in MS. Assessment of tremor 33 11 7 6 4 15 Accelerometry and polarized light goniometry are neurophysiologic methods of tremor assessment. While these methods offer an objective measurement of tremor severity, they can only measure one aspect of an often complex movement problem at a time, and e.g. cannot measure the ataxia which often complicates tremor in MS. 62 2 85 62 Medical treatment 2 Table 2 Studies on medical treatment of tremor in MS Study n* study design intervention(s) tremor assessment patients with tremor reduction (%) patients with improved functional status (%) adverse effects (n) 52 3 double-blind placebo-controlled crossover propranolol (not specified) isoniazid (po.) 1200mg/d ethanol (iv.) 50ml of 10% solution writing tasks, patient self assessment, clinical examination, accelerometry no effect hepatitis while on isoniazid treatment (1) 80 4 case reports isoniazid (po.) 400 to 1200mg/d clinical examination 4 (100%) 4 (100%) abnormal liver function tests (1) 32 12 open label isoniazid (po.) 500–1000mg/d patient self assessment, clinical examination, blinded evaluation of video tapes 10 (83%) 0 drowsiness, dysphagia, increased bronchial secretions (6) abnormal liver function tests (2) fatigue (2) 67 5 open label isoniazid (po.) 700–1200 mg/d clinical examination 4 (80%) 4 (80%) increased weakness (2) drowsiness (1) 38 5 open label isoniazid (po.) 1200 mg/d clinical examination, polarised light goniometry 4 (80%) 0 anorexia and nausea (3) 44 6 double-blind placebo-controlled crossover isoniazid (po.) 1200 mg/d self-rating scales, accelerometry, blinded evaluation of video tapes 6 (100%) 0 None 16 8 double-blind placebo-controlled crossover isoniazid (po.) 12 or 20 mg/kg clinical examination, accelerometry, blinded evaluation of video tapes 6 (75%) 4 (50%) somnolence (3) ** 86 7 single-blind placebo controlled carbamazepine (po.) 400 or 600 mg/d clinical tremor rating scale, accelerometry 7 (100%) not reported none reported 78 16 double-blind placebo-controlled crossover ondansetron (iv.) 8 mg (single dose) nine-hole peg-test, writing tasks, patient self assessment 12 (75%) not reported short-lasting foot dystonia (1) 39 14 open label ondansetron (iv.) 8 mg (single dose) nine-hole peg-test, writing tasks, patient self assessment no effect none reported 2 6 open label Gluthetimide 750 to 1250 mg blinded functional assessment by occupational therapist, computer-aided tracking tasks 5 (83%) 5 (83%) sedation (4) 21 8 open label 9 clinical examination 5 (63%) 2 (25%) none 103 365† double-blind randomized placebo controlled 9 patient self assessment no effect cannabis extract: adverse events in 12 Δ9-THC: adverse events in18 placebo: adverse events in 20 92 13‡ double-blind randomized placebo controlled cannabis extract (po.) visual analogue scale symptom reduction no effect cannabis extract:$ 112 adverse events in 80 patients placebo:$ 53 adverse events in 80 patients 37 14 double-blind randomized placebo controlled crossover cannabis extract (po.) tremor rating scale no effect cannabis extract: adverse events in 10 placebo: adverse events in 2 THC = tetrahydrocannabinol * MS patients completing the study ** in this study, one additional patient was withdrawn because of a severe adverse event (dyspnoea, fever, rash, obtundation) † the main topic of the study is the effect of cannabinoids on spasticity in MS, the patients were asked to assess treatment effect on other symptoms ‡ in this study, patients were asked to name their most troublesome symptom; of the 160 included patients, 13 named tremor $ No details are reported on the subgroup of the 13 tremulous patients, the total number of adverse events is reported for the whole groups on active treatment and on placebo (80 patients in each group) 47 2 96 80 32 67 38 52 52 52 44 16 86 78 65 52 4 2 16 44 38 32 67 80 32 32 67 16 86 3 78 39 3 65 96 63 21 23 9 12 103 37 92 9 103 Surgical treatment 3 4 Table 3 Studies on stereotactic surgery for the treatment of tremor in MS Study n* patient characteristics** lesion site follow-up tremor and disability assessment patients with tremor reduction (%)§ patients with improved functional status (%)§ patients with permanent adverse effects (n) 25 2 disabling intention tremor VL 3 to 12 mo clinical examination 2 (100%) not reported none 24 6 disabling intention tremor unilateral (n = 5) or bilateral (n = 1) VL Not specifically reported clinical examination, assessment of filmed tremor 5 (83%) not reported increase of contralateral hemiparesis (1) 54 4 disabling bilateral intention tremor unilateral (n = 3) or bilateral (n = 1) VL 3 weeks to 6 mo clinical examination 4 (100%) 4 (100%) none 18 4 severe intention tremor unilateral VL 1 to 6 mo clinical examination 4 (100%) 2 (50%) generalized seizure (1) mental change (1) 26 32 disabling bilateral intention tremor unilateral or bilateral VL 12 to 96 mo clinical examination 27 (85%) not reported increase of contralateral hemiparesis (2) 81 25 disabling bilateral arm intention tremor unilateral or bilateral VL not specifically reported clinical examination, assessment of filmed tremor 22 (88%) not reported increase of contralateral hemiparesis (1) 79 29 disabling intention (n = 29) and postural (n = 18) tremor unilateral (n = 28) or bilateral (n = 1) VL not specifically reported clinical examination, patient self assessment questionnaires 29 (100%) “two thirds” of patients increase of leg paresis (2) 10 26 disabling bilateral intention tremor unilateral VL and subthalamus 3 to 97 mo clinical examination 21 (80%) not reported subdural haematoma (1) 8 4 disabling postural (n = 2) and intention (n = 4) tremor unilateral VIM 6 to 36 mo clinical examination 4 (100%) not reported hemiplegia (1) 91 4 severe intention tremor unilateral VL 3 to 86 mo† clinical examination 2 (50%) not reported not reported separately for MS subgroup 45 11 severe intention tremor unilateral (n = 10) or bilateral (n = 1) VL 15 to 86 mo clinical examination 7 (63%) 4 (36%) not reported 68 84 severe action tremor ZI, VOP 36 to 120 mo clinical examination filmed tremor patient self assessment questionnaire 70 (83%) not reported not specifically reported 89 11 severe intention tremor unilateral VL 3 weeks to 132 mo clinical tremor and functional rating scales 8 (73%) 0 (0%) hemiparesis (4) micturition disturbance (2) speech disorder (1) 51 20 severe intention tremor unilateral (n = 15) or bilateral (n = 5) VL (ZI, FF) 12 to 120 mo not reported 14 (70%) not reported none 48 30 tremor Thalamus 24 mo clinical examination functional rating scales 50% 25% not reported 97 9 severe intention tremor unilateral VOA and VOP 3 to 89 mo mean: 24 mo† questionnaire sent to treating neurologist 6 (66%) 6 (66%) hemiparesis (5) mental changes (3) dysphasia (3) dysarthria (2) subdural haematoma (1) 43 2 severe intention tremor unresponsive to medication unilateral VL 3 mo 34 mo clinical tremor rating scale 2 (100%) 0 (0%) dysarthria (1) 98 9 severe rest, kinetic, postural or intention tremor unilateral VL 12 mo clinical examination and evauation of video tapes 9 (100%) 2 (22%) depression (2) 87 33 severe tremor unilateral VIM 3 to 120 mo clinical examination ability to drink from a waterfilled cup 22 (67%) 17 (51%) not reported 50 6 severe postural (n = 4) or intention tremor (n = 2) unilateral VL 14 to 73 mo mean: 51 mo Barthel Index 1 (16%) 1 (16%) not reported 27 24 disabling intention tremor unilateral (n = 22) or bilateral (n = 2) VIM mean: 26 mo clinical tremor and functional rating scales 18 (75%) 2 (8%) hemiparesis (1) seizure (2) MS relapse (3) dysarthria (1) 85 5 severe arm tremor unilateral VIM‡ 6 mo clinical tremor and functional rating scales 5 (100%) 0 (0%) severe gait or balance disturbance (2) 72 3 severe action tremor unilateral VIM 2 to 11 mo median 6 mo† clinical tremor rating scale, patient self assessment of functional improvement 3 (100%) 3 (100%) none 4 11 severe postural and intention tremor unilateral VOP (n = 7), ZI (n = 3), STN (n = 1) 12 mo clinical tremor and functional rating scales 11 (100%) 7 (64%) depression (3) seizures (2) hemiparesis (1) dysphasia (1) 62 6 severe tremor unilateral VIM 3 to 12 mo clinical tremor and functional rating scales, novel movement analysis tool 6 (100%) 0 (0%) MS relapse (2) 15 10 disabling postural and intention arm tremor unilateral VOP (distal tremor), unilateral ZI (proximal tremor) or unilateral VOP and ZI (mixed tremor) 12 to 50 mo: mean 16 mo clinical tremor rating scale not individually reported, overall improvement of mean tremor scores: postural: 78% intention: 72% not reported hemiparesis (3) seizures (1) VOP = nucleus ventralis oralis posterior; VOA = nucleus ventralis oralis anterior; VIM = nucleus ventralis intermedius; ZI = zona incerta; VL = nucleus ventralis lateralis; STN = nucleus subthalamicus; FF = Forel’s Field * MS patients with completed surgical intervention and remaining in the study until end of follow up ** an effort is made to distinguish between predominance of intention or postural tremor although many terms to describe tremor subtypes are used in the studies *** In this study, gamma-knife radiosurgery is used § improvement as described in case reports or measured at the end of follow-up on any scale used in the study † in this study, MS patients were grouped together with patients with other movement disorders, no details are given for the MS-subgroup ‡ thalamotomy was followed six months later by contralateral DBS electrode implantation in patients with bilateral tremor Table 4 Studies on DBS for the treatment of tremor in MS Study N* patient characteristics stimulation site follow-up tremor and disability assessment patients with tremor reduction (%)§ patients with improved functional status (%)§ patients with permanent adverse effects (n) 17 2 severe bilateral arm intention tremor bilateral subthalamic 5 mo 6 mo clinical examination 2 (100%) 2 (100%) ** 71 1 severe unilateral distal postural arm tremor unilateral VIM 17 mo clinical tremor and functional rating scales 1 (100%) 1 (100%) not reported 88 9 severe intention tremor unilateral (n = 8) or bilateral (n = 1) VIM not reported not reported 9 (100%) not reported not reported 13 4 severe arm tremor† VIM† ≥ 6 mo clinical tremor rating scale 0 (0%)‡ no detailed report† intracerebral haemorrhage (1) 41 13 severe postural tremor (n = 12), moderate intention tremor (n = 1) unilateral VIM 8 to 26 mo mean: 13 mo clinical tremor and functional rating scales 9 (69%) 12 (92%) MS relapse (3) 99 5 severe arm tremor VL not reported not reported not reported not reported not reported 46 1 head and limb tremor unilateral thalamus 2 mo not reported 1 (100%) not reported not reported 66 14 disabling arm tremor unilateral VIM variable clinical tremor rating scale 15 (100%) not reported MS relapse (1)# 83 5 severe bilateral postural and intention arm tremor unilateral VIM >6 mo clinical tremor rating scale, patient self assessment of functional improvement 5 (100%) 3 (60%) Ms relapse (2) 90 2 bilateral limb, head or voice tremor† bilateral VIM (bilateral DBS or unilateral DBS plus contralateral thalamotomy) mean: 10 mo clinical tremor rating scale 2 (100%) not reported not reported separately for MS subgroup† 85 5 severe arm tremor unilateral or bilateral VIM 6 mo clinical tremor and functional rating scales 3–5 (60–100%)$ 0 (0%) dysarthria (2) severe gait or balance disturbance (1) arm ataxia (1) 53 61 2 severe tremor unilateral or bilateral VIM† 3 to 24 mo, mean: 12 mo† clinical tremor rating scales, assessment of video tapes 2 (100%) not reported not reported separately for MS subgroup† 62 3 severe tremor unilateral VIM 3 to 12 mo clinical tremor and functional rating scales, novel movement analysis tool 3 (100%) 0 (0%) none 49 10 disabling arm tremor unilateral thalamus 12 mo clinical tremor and functional rating scales 10 (100%) 0 (0%) intracerebral haemorrhage (2) generalized seizure (2) 70 1 severe bilateral postural and intention tremor unilateral ZI 12 mo clinical examination 1 (100%) 1 (100%) increased dystonic posturing of left foot impairing ambulation (1) 14 12 disabling arm tremor unilateral VIM 12 mo clinical tremor and functional rating scales, patient self assessment questionnaire significant tremor reduction, not individually reported no significant improvement wound infection (2) 102 4 bilateral arm tremor bilateral VL 15 to 31 mo clinical tremor rating scale 4 (100%) 4 (100%) MS relapse (1) dysarthria (1) 84 9 disabling arm tremor unilateral thalamus 9 to 48 mo, clinical tremor and functional rating scales, patient self assessment 8 (88%) 3 (33%) MS relapse (3) 69 10 disabling arm tremor unilateral (n = 6) or bilateral (n = 4) VOP and ZI 3 to 23 mo computer-aided tracking tasks significant tremor reduction, not individually reported not reported seizure (1) dysarthria (1) wound infection (1) 15 10 disabling postural and intention arm tremor unilateral VOP (distal tremor), unilateral ZI (proximal tremor) or unilateral VOP and ZI (mixed tremor) 3 to 23 mo: clinical tremor rating scale not individually reported, overall improvement of mean tremor scores: postural: 64% intention: 36% not reported monoparesis (1) VIM = nucleus ventralis intermedius; ZI = zona incerta; VL = nucleus ventralis lateralis * MS patients with completed surgical intervention and remaining in the study until the end of follow up § improvement as described in case reports or measured at the end of follow-up on any scale used in the study ** in this study two patients had complete surgery and in three, surgery was aborted. A worsening of dysarthria is reported in one patient, it is unclear whether this patients had completed surgery *** This study mostly discusses difficulties in target localisation and patient selection # in this study, one patient did not complete surgery due to an intraoperative VIM haemorrhage † in this study, MS patients were grouped together with patients with other movement disorders, no details are given for the MS-subgroup ‡ For the whole group, tremor was “inconsistently, less significantly [than tremor of Parkinson’s Disease and essential tremor] or not improved. If improvement was achieved it lasted only a few months” $ The exact number of patients with improved tremor cannot be ascertained the way the data is presented in this study $$ Both studies are on one patient cohort, the relevant data on MS patients are derived from both studies 25 17 Strategies for patient and treatment site selection 4 69 15 60 4 69 15 73 59 57 58 87 13 66 62 84 Outcome after surgical treatment 3 41 84 102 3 4 72 85 3 4 15 Adverse events reported for the neurosurgical interventions comprised increase of hemiparesis, dysarthria, dysphasia, mental changes, depression, seizures, intracerebral haemorrhage, subdural haematoma, wound infection and MS relapse. Thalamotomy was associated with a higher risk of adverse events than DBS. Bilateral thalamotomy carries such a high risk of adverse effects, that it is no longer recommended. If bilateral treatment is necessary, either bilateral DBS or unilateral thalamotomy followed by contralateral DBS are possible treatment options. Other treatment options Electromagnetic fields, limb cooling, physiotherapy, weight bracelets, orthoses and specialized software have been advocated as additional treatment options. 82 3 35 28 1 9 36 Conclusion The treatment of tremor remains a great challenge for everyone caring for patients with MS. Drug treatment with currently available medication is unsuccessful in most cases and much more research on the pathophysiology and biochemistry of tremor production in MS will be necessary before an efficient medical treatment can be developed. Stereotactic surgery can be an effective means to treat severe tremor, but it is currently uncertain whether lesional surgery or DBS is the treatment of choice. Larger clinical trials comparing both interventions are needed. Other treatment options, including physiotherapy, tremor reducing orthoses, and limb cooling can lead to valuable improvements in activities of daily living.