Tremor is an involuntary, rhythmic, muscle movement involving oscillations of one or more parts of the body, resulting from repeated contraction and relaxation of opposing muscle groups.1–3 Multiple sclerosis (MS) is a common chronic inflammatory disease of the central nervous system; it most frequently appears in early adulthood.4–6 Action tremor was for a long time considered to be a common feature of MS. In fact, the French neurologist Jean‐Martin Charcot described tremor as one of the defining features of MS, together with nystagmus, and scanning speech.7

Given that tremor is one of the most prevalent and disabling features of MS,8 we will describe the most significant recent milestones that relate to MS tremor, focusing on prevalence, clinical features, anatomical basis, and treatment.

Data for this review were identified by searching MEDLINE (in May 2012) with the search terms “multiple sclerosis” and “tremor”. References were also identified from relevant articles published between January 1966 and May 2012.

Studies have provided estimates of the prevalence of tremor in the MS population that range widely, between 25% and 58% (Table 1).8 In a 3‐year‐follow up study, Weinshenker et al.9 reported that cerebellar deficits of functional importance were present in one‐third of 259 MS patients. Two more recent studies have assessed the prevalence of tremor in MS.10, 11 Alusi et al. 10 described upper limb tremor in 58% of 100 patients randomly selected from a London MS unit. The tremor was minimal in 27%, mild in 16%, and moderate to severe in 15% of patients.10 However, as that study was conducted from a specialty clinic, the relatively high prevalence and severity of tremor might be due to selection bias. In a community‐based study involving 200 MS patients in Olmsted County, Minnesota, Pittock et al.11 noted tremor in 25.5% of patients, and severe tremor in 3% of patients. This community‐based study probably provides a more realistic estimate of the prevalence of MS‐related tremor.

Despite these estimated figures, the prevalence of tremor in MS remains very difficult to establish accurately for three reasons. First, because of the complex natural history of MS, there is a transience of neurological signs, which may occur only during the relapsing and remitting phase of the disease. Second, there is the problem of distinguishing intention tremor from dysmetria.12 Finally, the Kurtzke Expanded Disability Status Scale (EDSS),13 the gold standard in assessing physical disability in MS, does not assess tremor.

Tremor is defined as a rhythmical, involuntary oscillatory movement of a body part14 and can be classified according to the consensus statement of the Movement Disorder Society.14 Tremor at rest is separated from action tremor, which is produced by voluntary muscle contraction. Action tremor includes postural, isometric, and kinetic tremors, and the last form includes intention tremor.14

MS tremor is manifested on action as postural tremor (tremor present while voluntarily maintaining a position against gravity) and/or intention tremor (occurring during target‐directed movement where tremor amplitude increases during visually guided movements towards the target).15 MS tremor typically involves the upper limbs, although tremor can also involve head, neck, vocal cords, and trunk.15

Involvement of the tongue, jaw or palate has not been reported.15 In the two main prevalence studies,10, 11 tremor was most commonly found in the arms. According to the study by Alusi et al.10 the body parts affected by tremor varied among the patients, with the most common pattern being bilateral arm involvement (36 patients) followed by unilateral arm tremor (nine patients) and tremor of the head and arms (five patients). In every case, tremor was of an action type (postural, kinetic, or both).10

Titubation is defined as nodding head tremor with a frequency of 3–4 Hz and may be seen in midline cerebellar disease.16 This type of tremor can occur in isolation or combined with a postural tremor elsewhere, especially in the arms.16 Titubation can be seen in 9% of the MS patients.10

True rest tremor (tremor present in a body part that is not voluntarily activated and is completely supported against gravity) and Holmes (or “rubral”) tremor are extremely uncommon in patients with MS. Rest tremor was observed only in 1% of the MS patients from the Olmsted County survey,11 whereas Holmes tremor has not been encountered in recent prevalence studies.10, 11 Task‐specific tremors (for example, primary writing tremor) have not been documented in MS.10, 11 Similarly, simple kinetic tremor, which occurs during voluntary non‐target‐directed actions—for example, opening and closing a fist—has not been observed in MS patients in these studies.10, 11

Despite the fact that the basal ganglia are relatively frequently involved by MS plaques17 and that almost any neurological symptom or sign can appear with the disease, movement disorders other than tremor are quite uncommon in MS. Moreover, movement disorders can be observed in patients with MS in the absence of basal ganglia involvement.18 Tranchant et al.,18 in the largest review of movement disorders in MS, concluded that paroxysmal dystonias, ballism, chorea, and palatal myoclonus could be caused by demyelinating lesions, whereas parkinsonism, dystonia, and other types of myoclonus often seemed to be coincidental.

The anatomical basis underlying tremor in MS is poorly understood, mostly because MS is a multifocal disease, and therefore tremor occurrence often cannot be directly linked to a specific neuroanatomical lesion.15

The link between the cerebellum and the MS‐related tremor is supported by clinical and experimental studies. In MS patients, tremor severity has correlated with the degree of dysarthria, dysmetria, and dysdiadochokinesia.10 However, no correlation was found between the severity of tremor and cognitive function, the Barthel disability profile, or grip strength, which provides strong evidence to support a specific defective cerebellar function rather than just with diffuse cerebral damage.10 In addition, the high occurrence of bilateral, symmetrical tremor may be explained by the presence of multifocal damage to the cerebellum and its connections.8 Several animal studies have been undertaken to help understand the anatomical structures involved in the production of MS tremor.19 Experimental studies from the 1930s showed that transection of the superior cerebellar peduncle caused intention tremor in monkeys.19 This is consistent with the case described by Nakamura et al.,20 who, using magnetic resonance imaging (MRI) in a single case, showed that a plaque in the superior cerebellar peduncle resulted in severe postural tremor. Additionally, intention tremor can also be induced by reversible cooling of the dentate nucleus (the origin of most cerebellar efferents) in monkeys.19 Interestingly, Carpenter and Hanna 21 reported that tremor induced by transection of the superior cerebellar peduncle can be diminished by a second lesion in the lateroventral or centromedian thalamus. Taken together, these results strongly suggest that damage to cerebellar efferents (through lesions of the dentate nucleus or superior cerebellar peduncle) may cause disinhibition of thalamic nuclei, which are the main producers of intention tremor. The findings of these primate experiments are supported by newer MRI and/or pathological studies that have further studied the involvement of the cerebellum in MS patients.22–26

Cerebellar grey matter atrophy appears to be more prominent and clinically relevant than white matter atrophy.25 This cerebellar grey matter damage has been associated with clinical cerebellar dysfunction, including patients who have presented with clinically isolated syndromes.27 A pathological study of Kutzelnigg et al.26 found widespread demyelination in the cerebellar cortex in patients with MS, which was more pronounced in patients with progressive disease than those with the relapsing–remitting form. Furthermore, the authors suggested that this cerebellar demyelination may be more prominent than that seen in the cerebrum.26

The absence of rest tremor argues against an involvement of the basal ganglia in the production of MS tremor. However, there are some data which suggest that cerebellar tremors seen in MS might actually be generated by the basal ganglia. Foote et al. 28 reported the satisfactory results in one patient with MS tremor who underwent placement of two thalamic deep brain stimulation (DBS) electrodes (one at the ventralis intermedius nucleus (VIM)/ventralis oralis posterior nucleus border and one at the ventralis oralis anterior/ventralis oralis posterior border). Ventralis oralis posterior is known to be the basal ganglia output nucleus.28

In the 1980s, several studies showed the susceptibility of cerebellar tremor amplitude and frequency to peripheral factors, such as mechanical loads, which implied the involvement of stretch‐elicited peripheral feedback mechanisms in the manifestation of cerebellar tremor.29, 30 Hence, cerebellar tremor is thought to be modulated through increased long latency stretch reflexes.31 In support of this view, load‐compensating tasks, evoking sudden stretch, induced an increase in tremor in cerebellar patients.32

On the other hand, MS intention tremor may be modulated by sensory information.33 This supports the notion that the cerebellum is involved in the production of tremor because the proprioceptive information about the direction, velocity, and amplitude of movements is mainly generated by muscle spindles, and additionally by tendon organs, joint, and cutaneous receptors, and enters into the cerebellum via the spinocerebellar pathway.33

Patients with cerebellar deficits show a specific difficulty in using visual information to control arm and hand movements.34, 35 In the study of Feys et al.36 movement accuracy during slow wrist tracking tasks decreased significantly more in MS patients with tremor than in healthy controls when visual feedback was absent, which is consistent with prior studies.37 Feys et al.36 postulated that tremor amplitude could specifically relate to deficits in online proprioceptive processing, leading to an increased visual dependence during sensorimotor tasks.

The excitability of muscle spindles,38–40 which are an essential part of the reflex loop, and the velocity of peripheral nerve conduction are temperature dependent.41 Thus, decreasing the stretch sensitivity of the muscle spindles and therefore also the long latency stretch reflexes, by means of cooling, may have an important effect on tremor.41 In line with this assumption, several studies have manipulated the sensory input to the central nervous system.42–44 A reduction of cerebellar tremor during handwriting has been found after the application of an ischemic block to the arm.42 In two additional experimental studies, cooling of the arms markedly reduced intention tremor severity in patients with MS.43, 44 Moreover, the effect on tremor seemed to be proportional to the intensity of the cooling.44 Feys et al.44 argue that this effect might have been partly due to decreased muscle spindle function and decreased nerve conduction velocity, which in turn resulted in decreased sensory input into tremor producing cerebellar circuits. In contrast, overall tremor amplitude increased during memory‐guided movements when muscle spindles were artificially activated by means of tendon vibration.45 Following previous data suggesting that MS intention tremor is modulated by sensory information, Feys et al.46 have recently studied the contribution of peripheral reflexes to the generation of MS intention tremor by measuring tendon reflexes, demonstrating that MS patients with tremor have a greater latency of brachioradialis, biceps, and triceps tendon reflexes than healthy controls and MS patients without tremor.

In summary, clinical observation as well as animal and experimental studies strongly point to the cerebellum and its connections as the major source of intention tremor production, but further research is needed to better understand the pathophysiologic model underlying the production of tremor in MS.

In MS tremor, a valid, precise, and reliable scale is required if the efficacy of different interventions is to be assessed accurately. Moreover, it would ideally take into account the ataxic elements, which usually complicate the clinical picture. Most tremor rating scales deployed in therapeutic trials involving patients with MS have not been tested for their reliability and sensitivity.47–49

There are only two published studies examining the reliability of a clinical scale for scoring tremor in MS.50, 51 Hooper et al.50 developed a modified version of the Fahn–Tolosa–Marin Tremor Rating Scale52 to accommodate goal‐directed tremor and studied its reliability in patients with MS. However, they failed to assess the validity of the scale.50 Alusi et al.51 examined the validity and comparative reliability of the 0–10 tremor severity scale devised by Bain et al.,53 which had already been validated in other tremulous conditions. The authors concluded that this scale represents a valid and reliable way of assessing tremor in these patients.51 The most reliable test was shown to be scoring tremor on posture, whereas kinetic tremor and associated ataxic deficits were more difficult to score reliably.51 Despite its reliability, the scale has so far only been used in a few clinical studies.10, 54, 55

According to Alusi et al.,10 the median latency from disease onset to the development of tremor is 11 years. Hence, tremor in MS patients could be considered as an advanced consequence of the disease.

Patients who exhibit clinical signs of cerebellar damage early in the disease course tend to develop severe disability more quickly.56 Although in the majority of MS patients the severity of the tremor is mild, tremor can be severe and very disabling for a small group of patients.10 In the two main prevalence studies,10, 11 tremor was associated with greater disability. The study of Alusi et al.10 showed that 27% of the patients had tremor‐related disability and 10% had incapacitating tremor. Moreover, patients with severe tremor were more likely than those without tremor to be wheelchair dependent and have a worse EDSS.10 In the Olmsted County study, patients with tremor of any severity were more likely to be unemployed or to have retired early because of disability, and they had on average a 2‐point higher EDSS.11 Other studies have shown that intention tremor severity seriously affects many activities of daily living, such as drinking, handwriting, or personal computer interaction.57, 58