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Tremor in multiple sclerosis: The intriguing role of the cerebellum
Journal of the Neurological Sciences, Volume 358, Issues 1–2, 15 November 2015, Pages 351–356
Tremor is frequently encountered in multiple sclerosis (MS) patients. However, its underlying pathophysiological mechanisms remain poorly understood. Our aim was to assess the potential role of the cerebellum and brainstem structures in the generation of MS tremor. We performed accelerometric (ACC) and electromyographic (EMG) assessment of tremor in 32 MS patients with manual clumsiness. In addition to clinical examination, patients underwent a neurophysiological exploration of the brainstem and cerebellar functions, which consisted of blink and masseter inhibitory reflexes, cerebello-thalamo-cortical inhibition (CTCi), and somatosensory evoked potentials. Tremor was clinically visible in 18 patients and absent in 14. Patients with visible tremor had more severe score of ataxia and clinical signs of cerebellar dysfunction, as well as a more reduced CTCi on neurophysiological investigation. However, ACC and EMG recordings confirmed the presence of a real rhythmic activity in only one patient. In most MS patients, the clinically visible tremor corresponded to a pseudorhythmic activity without coupling between ACC and EMG recordings. Cerebellar dysfunction may contribute to the occurrence of this pseudorhythmic activity mimicking tremor during posture and movement execution.
- Tremor is a frequent symptom in MS patients, yet its underlying mechanisms remain poorly characterized
- The clinically visible tremor in most of our MS cohort corresponded to a pseudorhythmic tremulous activity
- Cerebellar dysfunction seems to play a key role in the generation of rhythmic and pseudorhythmic tremulous activity in MS
Keywords: Ataxia, Brainstem reflexes, Cerebellar signs, Cerebello-thalamo-cortical inhibition, Electromyography, Neurophysiology, Transcranial magnetic stimulation.
Tremor is thought to occur in up to 75% of patients with multiple sclerosis (MS), including various subtypes of postural, kinetic, proximal, or distal tremor  and . However, its exact prevalence remains unknown, since the functional scales used to assess MS patients do not evaluate tremor . In the past fifteen years, only two studies have addressed this issue: tremor was found to occur in 25% and 58% of MS patients in an American and English cohorts, respectively  and .
The pathophysiology of MS tremor is difficult to appraise due to the multiplicity of central nervous system lesions encountered in MS. However, various experimental studies and clinical observations have highlighted the potential role of the cerebellum in the production of MS tremor. In this perspective, lesions affecting the inhibitory cerebellar projections to thalamo-cortical connections appear to have an important impact . Lesions within the brainstem, notably those affecting the pons, could also be involved .
In the present study, we aimed to further characterize tremor in MS patients by means of neurophysiological assessment and to investigate the potential relationship between cerebellar or pontine dysfunction and tremor generation in this context.
2. Materials and methods
Among the different subtypes of upper limb MS tremor described by Alusi et al. , one subtype consisted of a fine, distal, postural tremor without kinetic component, barely clinically visible, and almost unnoticed by the majority of patients. This type of hand tremor, although subtle, could result in clumsiness, a common symptom in MS patients. Therefore, in order to include any MS patient who may have tremor, we screened over a three-month period all MS patients who presented with clumsiness in the Neurology Department of Henri Mondor hospital. Clumsiness was defined as the presence of functional difficulty to perform at least one of the daily life tasks listed in the Chedoke Arm and Hand Activity Inventory (CAHAI) . Thirty-two consecutive MS patients were enrolled according to the following criteria: (i) the presence of clumsiness in one or both upper extremities according to CAHAI screening; (ii) a definite MS diagnosis as per the 2010 McDonald criteria ; (iii) age between 18 and 70 years; (iv) the absence of other neurological or psychiatric diseases; and (v) no contra-indication for transcranial magnetic stimulation, namely with no history of epilepsy or intracranial ferromagnetic implant . The study was approved by the local Institution Review Board and all patients voluntarily gave their written informed consent prior to the study.
2.2. Clinical examination
The patients were interviewed and a standard neurological examination was carried out. The presence or absence of cerebellar signs was determined. The scores of the Extended Disability Status Scale (EDSS)  and Ataxia Clinical Scale (ACS)  were calculated. Patients with severe dysmetria or dysdiadochokinesia (ACS score > 2 for each item) were excluded from the study. Upper limb tremor was assessed on visual inspection at rest, posture and movement, according to a previously described procedure  and the classification of the Consensus Statement of the Movement Disorder Society . Postural tremor was assessed by asking the patients to keep their forearms and arms outstretched forward (“oath position”) or flexed with facing index fingers (“swordsman position”). Kinetic tremor was assessed during the finger-nose-finger test. The examiner (SSA) was trained to pay attention to the rhythmicity of the displayed movement. Tremor was classified as proximal, distal or both.
2.3. Neurophysiological examination
2.3.1. Accelerometric and electromyographic (EMG) tremor recording
Two piezoresistive single-plane accelerometers (TREM0000, Neuroservices, Evry-Lisses, France) were attached, one to the dorsal aspect of the distal phalanx of the index finger, the other one to the anterior face of the shoulder. Surface EMG recordings were obtained from the first dorsal interosseous muscle (FDI) of the hand, flexor and extensor carpi radialis muscles of the forearm, and deltoid muscle of the shoulder, using pre-gelled disposable electrodes (Ref 9013S0242, Natus-Dantec, Skovlunde, Danemark) placed 2 cm apart over the muscle belly. Recordings were performed with a Keypoint EMG machine (Natus-Dantec), the signals were filtered (bandpass: 0.5–50 Hz for accelerometric recordings and 20 Hz–5 kHz for EMG recordings), amplified, and stored on a laboratory computer. An off-line Fast Fourier Transformation (FFT) analysis was performed on 10-second recordings using short sliding windows with the MATLAB software (MathWorks, Natick, MA, USA). The dominant peak of frequency was determined in the power spectrum for each recording and the coherence was studied between accelerometric recordings at the index finger and shoulder, and EMG recordings of the FDI and deltoid muscles. The presence of coherence was defined as at least two contiguous bins of 0.1 Hz on the coherence plot that rose above the 99% confidence limit for random coherence, at a frequency where there were corresponding peaks in the power spectra of accelerometric and EMG recordings . The threshold value for significant tremor-related coherence was calculated as 0.5, as previously reported in other studies  and .
2.3.2. Blink reflex (BR) recording and prepulse inhibition (PPI) measurement
Surface EMG was recorded at the orbicularis oculi muscle using pre-gelled disposable electrodes and a Phasis II machine (EsaOte, Florence, Italy). Electric stimulations were delivered to the supraorbital nerve at the supraorbital notch using a bipolar electrode (stimulation intensity: 25 mA, pulse duration: 0.2 ms). The filtered EMG signals (bandpass 20 Hz-5 kHz) were rectified online. Four trials were averaged. We only analyzed the latency of the ipsilateral R2 response, which reflects the activation of the bulbo-pontine trigeminal pathways. Results were compared to the normative data of our laboratory (upper limit of normal: 42 ms).
By using a paired pulse paradigm, we investigated the PPI of the BR following acoustic and somatosensory conditioning stimuli. The acoustic stimulus was a sound generated by discharging the circular coil of a magnetic stimulator (Magstim 200, Carmentshire, Wales, UK), hanging freely in the air at a one-meter distance from the patient's head . The somatosensory stimulus was an electric shock, set at an intensity of 1.5 times the individual perception threshold, and delivered through a pair of ring electrodes placed at the index finger. The interstimuli interval (ISI) between the conditioning stimulus (acoustic or somatosensory) and the test stimulus was set at 100 ms. To calculate the percentage of inhibition (PPI), the area of the ipsilateral rectified R2 obtained in response to the paired stimulation was measured and compared to that obtained in response to test stimulation alone. Then, the calculated percentage of inhibition was compared to the normative data of our laboratory (lower limit of normal: 40%).
This test explores the control exerted by cholinergic neurons of the pedunculopontine nucleus on reticular structures, in response to the activation of medial or lateral lemniscal pathways , , and .
2.3.3. Masseter inhibitory reflex (MIR) recording
This test was performed as previously described . Surface EMG was recorded at the masseter muscle using pre-gelled disposable electrodes and a Phasis II machine. The patient was instructed to clench the teeth in order to produce the maximum EMG activity in the masseter muscles and maintain it for several seconds with the aid of an auditory feedback. Then, electric stimuli were delivered to the mental nerve using a bipolar electrode (stimulation intensity: 25 mA, pulse duration: 0.2 ms). The area under the curve of SP2, which explores trigeminal afferents entering the pons and projecting to bulbar reticular formation , was measured and compared to pre-stimulus raw EMG activity of the same duration; hence we calculated the percentage of inhibition. Results were compared to the normative data of our laboratory (lower limit of normal: 40%).
2.3.4. Cerebello-thalamo-cortical inhibition (CTCi) measurement
By means of a paired pulse paradigm of transcranial magnetic stimulation using a Bistim module (Magstim), we investigated the inhibition produced by a conditioning cerebellar stimulation on the motor evoked potentials (MEPs) obtained in response to the stimulation of the primary motor cortex, as previously described . The MEPs were obtained (bandpass 20 Hz-5 kHz) from the FDI muscle at rest using pre-gelled disposable electrodes and a Phasis II machine. The test stimulation was performed using a figure-of-eight coil connected to a Magstim 200 magnetic stimulator. The handle of the coil was oriented 45° away from the interhemispheric fissure, perpendicular to the central sulcus to optimally deliver the current postero-anteriorly in the primary motor cortex contralaterally to the MEP recording side. Stimulus intensity was set at the stimulator output required to elicit MEPs of around 1 mV peak-to-peak amplitude. The conditioning cerebellar stimulation was performed ipsilaterally to the MEP recording side using a double-cone coil connected to a MagProX100 magnetic stimulator (MagVenture [Mag2Health], Farum, Denmark). The coil was placed over the cerebellar hemisphere, centered on the midpoint of the line joining the inion and the mastoid process . Stimulus intensity was set at 80% of the maximal stimulator output. The ISI between the conditioning stimulus and the test stimulus was successively set at 5, 6, 7, and 8 ms. Four trials were averaged for each condition (test stimulation alone and paired stimulation at each ISI). The percentage of inhibition was calculated as the reduction in MEP size between the responses obtained to the conditioned stimulation to that obtained with the test stimulation alone. This inhibition reflects the activation of inhibitory efferent projections from the cerebellum to thalamo-cortical motor pathways. The maximal and mean percentage of inhibition was calculated, from all the recordings performed at the four different ISIs. Results were compared to the normative data of our laboratory (lower limit of normal: 50% for maximal inhibition and 30% for mean inhibition).
2.3.5. Somatosensory evoked potentials (SEPs)
The cortical SEPs were recorded (bandpass 20 Hz–20 kHz) using a Phasis II machine with the active electrode placed over the parietal cortex contralaterally to the stimulation side and the reference one located midfrontally. Electric stimulations were delivered to the median nerve at the wrist using a bipolar electrode (stimulation intensity: motor threshold, pulse duration: 0.2 ms, frequency: 2 Hz). Two trials of 500 stimuli were averaged. The latency and amplitude of the N20 component were measured, reflecting the arrival of the lemniscal volleys at the primary somatosensory cortex. Results were compared to the normative data of our laboratory (upper limit of normal: 23 ms for latency; lower limit of normal: 2 μV for amplitude).
2.4. Data analysis
All statistical tests were done using InStat software (GraphPad, San Diego, CA). A Fisher's test was used for categorical variables and a Mann–Whitney test was used for numerical variables, because not all data had normal distribution, according to Kolmogorov–Smirnov test. Multiple comparison adjustments were performed according to the Benjamini–Hochberg procedure . The level of statistical significance, set at p < 0.05, was preserved, since the significance of the comparisons between groups was not affected by multiple comparisons adjustments according to the Benjamini–Hochberg procedure with a false discovery rate as low as 0.1.
Thirty-two patients were included, 23 women and 9 men, aged from 31 to 74 years (mean: 49 years). Disease duration ranged from one to 43 years (mean: 13 years). Eighteen patients had a relapsing–remitting form of MS and fourteen patients had a primary or secondary progressive form. Clinical scores ranged from 1.5 to 8.5 (mean: 3.9) on the 0–10 EDSS and from 0 to 15 (mean: 3.7) on the ACS. Twenty-two patients (69%) had clinical cerebellar signs.
Eighteen patients (56%) had visible tremor on clinical examination: all these patients had an action tremor, which was distal and proximal in four of them and only distal in the other fourteen. Hence, according to Alusi et al. classification , these patients had “distal and proximal postural/kinetic tremor subtype” (n = 4) and “distal postural/kinetic (coarse) tremor subtype” (n = 14).
3.1. Comparison between patients with or without visible tremor
Patients with visible tremor on clinical examination (n = 18) were compared to those without visible tremor (n = 14) according to the recorded clinical and neurophysiological parameters. The detailed results are presented in Table 1. Briefly, ACS score, cerebellar signs, maximal and mean CTCi differed significantly between both groups. In other words, the patients with visible tremor had more ataxia and cerebellar dysfunction than those without visible tremor. The other studied parameters, including age, disease duration, EDSS, BR, BR-PPI, MIR, and SEPs did not show any significant difference.
|Visible tremor (n = 18)||No visible tremor (n = 14)||Mann–Whitney or Fisher's test (p value)|
|Age (years)||47.7 ± 10.3||49.6 ± 6.8||0.33|
|MS form (RR/P)||10/8||8/6||1|
|Disease duration (years)||14.4 ± 11.7||11.4 ± 8.7||0.65|
|EDSS score||4.3 ± 2.4||3.5 ± 1.4||0.55|
|ACS score||5.0 ± 4.3||2.1 ± 2.8||0.0165|
|Cerebellar signs (Y/N)||17/1||5/9||0.0006|
|BR-R2 latency (ms)||37.4 ± 8.2||34.7 ± 8.5||0.36|
|Acoustic BR-PPI (%)||25.6 ± 21.0||38.0 ± 29.0||0.14|
|Sensory BR-PPI (%)||30.2 ± 28.3||40.2 ± 28.9||0.47|
|MIR inhibition (%)||41.9 ± 33.0||55.1 ± 33.2||0.33|
|Maximal CTCi (%)||27.9 ± 25.1||58.8 ± 27.5||0.0135|
|Mean CTCi (%)||4.4 ± 8.7||24.1 ± 22.9||0.0208|
|SEP-N20 latency (ms)||18.7 ± 8.1||20.1 ± 6.3||0.18|
|SEP-N20 amplitude (μV)||3.6 ± 3.0||3.1 ± 2.2||0.88|
MS = multiple sclerosis; RR = relapsing remitting multiple sclerosis; P = progressive multiple sclerosis; EDSS = Extended Disability Severity Scale; ACS = Ataxia Clinical Scale; BR = blink reflex; PPI = prepulse inhibition; MIR = masseter inhibitory reflex; CTCi = cerebello-thalamo-cortical inhibition; and SEP = somatosensory evoked potentials.
3.2. Tremor recordings
Among patients with visible tremor on clinical examination (n = 18), FFT analyses of accelerometric and EMG signals showed an identifiable peak of frequency with significant coherence in only one patient. This patient had a distal and predominantly proximal postural/kinetic tremor at a frequency of about 4 Hz (Fig 1 and Fig 2). In all the other patients with clinical aspect of tremor, accelerometric and EMG recordings did not show any identifiable peak of frequency in the power spectrum with significant coherence. These patients had rather “pseudorhythmic” movements than a “real” tremor according to neurophysiological findings.
Among the thirty-two MS patients with manual clumsiness, eighteen (56%) had visible tremor on clinical examination. They had action tremor, distal in 78%; proximal and distal in 22%. No rest tremor was observed.
Tremor is clinically defined as a “rhythmic, involuntary oscillatory movement of a body part” . According to this definition, a single-channel accelerometric recording is sufficient to show these oscillations defining a tremor, as did Alusi et al. in their MS cohort . However, the neurophysiological definition of tremor is more stringent and requires a central drive, the latter being reflected by the presence of within-limb coupling. In other words, the existence of a central generator is highlighted by an entrainment of the EMG activity at the frequency of the limb oscillations measured by accelerometry , , , and .
In our MS patients in whom we detected tremor on visual inspection, accelerometric and EMG coupling was found in only one patient. Conversely, in the other patients, although clinical examination revealed tremor, neurophysiological study showed a pseudorhythmic activity mimicking tremor.
In the literature, the term “pseudotremor” covers various conditions, including psychogenic tremor , specific forms of rhythmic myoclonus , and pseudorhythmic movements due to muscle denervation  or cerebellar dysfunction . In our MS patients, we hypothesized that cerebellar ataxia or dysmetria could explain the discrepancy between a visible tremor on clinical examination and a pseudorhythmic activity on neurophysiological recordings. Sabra and Hallett  previously emphasized that “dissecting intention tremor from serial dysmetria and postural tremor from ataxia is difficult”. Indeed, the cerebellum contributes to various aspects of motor control, such as postural stabilization and coordination, precision and timing of movements . In case of cerebellar dysfunction, which is frequent in MS , moving a limb to an intended target or maintaining it in a given position leads to continuous adjustments and readjustments which can be mistaken for tremor.
It is important to note that cerebellar dysfunction could also be involved in our single case of definite tremor proved by neurophysiological investigation. Indeed, the tremor in question was an action tremor and had a relatively low frequency (4 Hz). These features are consistent with a tremor originating in the cerebellum or its connections  rather than in the midbrain or the rubro-olivo-cerebello-rubral loop (Guillain–Mollaret triangle). Oscillatory networks present in the latter structures would lead to a slower tremor (usually less than 4 Hz) present at rest, such as limb myorhythmia .
The role played by the cerebellum and its efferent pathways in the generation of MS tremor has been recently reviewed . In particular, it has been shown that the treatment of MS tremor by chronic stimulation of the thalamic ventral intermediate nucleus was associated with CTCi restoration  and . This neurophysiological parameter is sensitive to lesions of the cerebellar cortex or its efferent pathways  and was used in the present study to assess the cerebellar inhibitory control of movement.
However, our results showed that the presence of clinical signs of cerebellar dysfunction and abnormal CTCi was not sufficient per se to explain the presence of a visible tremor. In fact, five patients without tremor presented cerebellar alterations. Therefore, additional dysfunction in brain pathways other than the cerebellar ones may play a role in the production of a visible tremor in MS patients, as previously suggested .
Brainstem structures could be good candidates, since the lesion load in the pons was found to correlate with the severity of tremor in MS patients . In the present study, brainstem (especially pontine) control was not assessed by imaging but with a battery of neurophysiological tests (BR, BR-PPI, MIR, SEPs). We failed to show any significant change in these tests regarding the presence or absence of a visible tremor. However, this negative result cannot formally rule out the involvement of pontine lesions in the generation of a pseudorhythmic activity mimicking tremor. This issue should be addressed in future studies combining imaging and neurophysiological tests.
Finally, some limitations might have arisen from the use of a uniaxial accelerometer which could have missed out-of-plane tremor. Although we were careful to place the accelerometer in the axis of the tremor, the use of a triaxial accelerometer could have been more precise. Another issue would be the lack of tremor severity rating scales which may be of interest to study the relationship between qualitative and qualitative data.
Tremor, a disabling and frequent symptom in MS patients, may be difficult to differentiate on visual inspection from pseudorhythmic activity, e.g., related to cerebellar ataxia or dysmetria. Hence, neurophysiological investigation based on multi-channel accelerometric and EMG recordings is particularly relevant in MS patients to affirm the presence of a rhythmic activity characterizing tremor. Dysfunction in inhibitory cerebellar efferent projections likely plays a key role in the generation of rhythmic or pseudorhythmic tremulous activity during posture or movement execution in MS patients, but additional lesions of other cerebral pathways might be involved.
The authors report no conflicts of interest. They disclose no financial or material support for this work.
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a Faculté de Médecine de Créteil, Université Paris Est Créteil, EA 4391, Créteil, France
b Hôpital Henri-Mondor, AP-HP, Service de Physiologie, Explorations Fonctionnelles, Créteil, France
c Université de Versailles Saint-Quentin-en-Yvelines, Laboratoire d'Ingénierie des Systèmes de Versailles, Vélizy, France
d École Supérieure d'Ingénieurs en Électronique et Électrotechnique de Paris, Département Informatique et Télécommunication, Noisy-Le-Grand, France
e Hôpital Henri-Mondor, AP-HP, Service de Neurologie, Créteil, France
⁎ Corresponding author at: Service de Physiologie, Explorations Fonctionnelles, Hôpital Henri Mondor, 51 avenue du Maréchal de Lattre de Tassigny, 94010 Créteil cedex, France.
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