Brain, Vol. 124, No. 8, 1576-1589,
August 2001
© 2001 Oxford University Press
Stereotactic lesional surgery for the treatment of tremor in multiple sclerosis
A prospective case-controlled study
1 Division of Neurosciences and Psychological Medicine, Imperial College School of Medicine, Charing Cross Hospital Campus, 2 The Multiple Sclerosis Unit, North West London NHS Trust, Central Middlesex Hospital, 3 Department of Clinical Neurology Institute of Neurology, London and 4 University Department of Physiology, Oxford University, Oxford, UK
Correspondence to:
Dr Peter Bain, Department of Neurology, Division of Neuroscience and Psychological Medicine, Imperial College School of Medicine, Charing Cross Hospital Campus, Fulham Palace Road, London W6 8RF, UK E-mail: p.bain{at}ic.ac.uk
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Abstract |
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The effect of stereotactic lesional surgery for the treatment of tremor in multiple sclerosis was examined in a prospective case-controlled study. Surgery was not undertaken in 33 patients (72% of 46 cases referred for stereotactic surgery), two of whom died within 4 months of referral. Twenty-four multiple sclerosis patients were included in the study; 13 underwent surgery and were matched against 11 controls on the basis of age, sex, expanded disability system scores (EDSS) and disease duration. Assessments were carried out at baseline/preoperatively, and then 3 and 12 months later; these included accelerometric and clinical ratings of tremor, spirography, handwriting, a finger-tapping test, nine-hole peg test, tremor-related disability, general neurological examination, Barthel Activities of Daily Living (ADL) Index of general disability, EDSS, a 0–4 ataxia scale, Mini-Mental State (MMS) examination, speech and swallowing assessments and grip strength. Postoperative MRI scans demonstrated that tremor could be attenuated by lesions centred on the thalamus in seven cases, on the zona incerta in five cases and in the subthalamic nucleus in one case. Two patients developed hemiparesis and in two cases epilepsy recurred. Two surgical patients and one control patient died between the 3 and 6 months assessments. Both groups had a significant deterioration in EDSS but not Barthel ADL Index scores at 1 year, but the difference between the groups was not significant. Similarly, no differences between the groups' rates of deterioration of speech or swallowing or MMS were found. Significant improvements in contralateral upper limb postural (P2) and kinetic tremors, spiral scores and head tremor were detected at 3 and 12 months after surgery (but not handwriting or nine-hole peg test performance). Tremor-related disability and finger-tapping speed were also significantly better 12 months after surgery, the latter having significantly worsened for the control group. A 3 Hz `filter' for postural (P2) upper limb tremor was detected by accelerometry/spectral analysis above which tremor was always abolished and at or below which some residual tremor invariably remained. Criteria for selecting multiple sclerosis patients for this form of surgery are discussed.
tremor; frequency; multiple sclerosis; thalamotomy
AC = anterior commissure; ADL = Activities of Daily Living; ANOVA = analysis of variance; EDSS = expanded disability system scores; FTT = finger-tapping test; MMS = Mini-Mental State; PC = posterior commissure; Vim = nucleus ventralis intermedius; Vop = nucleus ventralis oralis posterior
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Introduction |
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Although, over the last 40 years, a considerable number of stereotactic thalamotomies have been performed for the treatment of tremor in multiple sclerosis, it is remarkable how little accurate information is available about the effects of these procedures. In particular, there are very few data available for addressing the crucial questions: (i) What degree of benefit can be expected from thalamotomy in terms of tremor suppression, functional gain and overall disability? (ii) What is the optimal intracerebral target site for treating multiple sclerosis tremor? (iii) Does this form of surgery adversely affect the natural history of the condition? (iv) What is the incidence of adverse effects when modern stereotactic techniques are deployed? (v) Are there predictive markers or criteria that can aid patient selection? This study attempts to address these issues.
In most cases, the action tremors present in patients with multiple sclerosis respond poorly to medication (Alusi et al., 1999
). Consequently, stereotactic surgery has been performed for multiple sclerosis patients with incapacitating tremors. However, current knowledge of this form of surgery is based predominantly on retrospective studies and reports, which have shown highly variable results: thalamotomy is reported initially to alleviate contralateral limb tremor in 65–96% of tremulous multiple sclerosis patients, although tremor is noted to return in ~20% of patients within 12 months. Functional improvement of the relevant arm is estimated to occur in only 25–70% of multiple sclerosis patients after thalamotomy (Cooper, 1960; Broager and Fog, 1962; Krayenbuhl and Yasargil, 1962; Speelman and Van Manen 1984; Kandel and Hondcarian, 1985; Barnett et al., 1992; Whittle and Haddow, 1995; Haddow et al., 1997; Critchley and Richardson, 1998; Hooper and Whittle, 1998). Nevertheless, some patients were reported to regain their capacity to eat and drink independently (Shahzadi et al., 1995). Head tremor was noted by Cooper to be improved by thalamotomy in five out of six patients (Cooper, 1960).
The adverse effects caused by thalamotomy have not been measured and quantified accurately, although their reported incidence varies from 0 to 45% of cases in different series. The most common complications are gait deterioration, hemiparesis and dysarthria, but epilepsy, sensory disturbances, dysphagia and transient bladder disturbance, confusion, depression, lethargy and somnolence have also been described (Cooper, 1960; Samra et al., 1970; Van Manen, 1974; Speelman and Van Mannen 1984; Barnett et al., 1992; Siegfried, 1993; Whittle and Haddow, 1995; Shazadi et al., 1996; Haddow et al., 1997; Hariz et al., 1998; Hooper and Whittle, 1998).
There have been no prospective studies evaluating the influence of thalamotomy on the progression of overall disability and handicap of tremulous multiple sclerosis patients, although this issue has been raised (Speelman and Van Manen 1984; Kandel and Hondcarian, 1985; Haddow et al., 1997; Critchley and Richardson, 1998).
The optimal intracerebral target location for the alleviation of multiple sclerosis tremor is not defined adequately. In one study, peroperative stimulation of the coordinate location for nucleus ventralis lateralis of the thalamus, the classic target for tremor suppression, failed to relieve tremor adequately (Whittle and Haddow, 1995). Furthermore, Hirai and colleagues noted that lesions centred on the lower part of nucleus ventralis intermedius (Vim) needed to be large to alleviate kinetic tremor, particularly if the tremor was low frequency and high amplitude or involved proximal or widely distributed muscle groups (Hirai et al., 1983)—all of which are characteristic of some types of multiple sclerosis tremor that are present in patients referred for stereotactic surgery. Thus Nguyen and Degos proposed that a more effective target for alleviating multiple sclerosis tremor might be nucleus ventralis oralis posterior (Vop) (Nguyen and Degos, 1993).
Consequently, in order to examine the efficacy of stereotactic lesional surgery for alleviating arm tremor in multiple sclerosis and to assess its influence on disease progression, a prospective case-controlled study was carried out.
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Patients |
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Ethics
Approval was obtained for this study from the Riverside Ethics Committee and informed consent obtained from all the subjects included in it. Forty-six tremulous multiple sclerosis patients were referred to the tremor clinic at Charing Cross Hospital from February 1996 to May 1999 for consideration of sterotactic surgery and, in every case, after consideration of medical treatments, their suitability for thalamotomy was assessed.
Patients excluded from the study
Surgery was not undertaken in 33 patients (72% of 46 referred cases). The excluded patients consisted of 10 males, 23 females; mean age: 43 years (range 26–72); mean disease duration: 12 years (range 2–29); mean duration of tremor: 4 years (range 0.25–18). Two patients (4% of referred cases) died within 4 months of referral, before they were assessed for surgery, and four others did not attend their assessments. The rest were not offered surgery for the following reasons: (i) seven patients declined surgery after the risks were explained to them; (ii) disability was related mainly to head tremor rather than upper limb tremor (five patients); (iii) the upper limb movement disorder was caused predominantly by other components of ataxia rather than tremor (two patients) or was associated with profound sensory impairment (two patients); (iv) good upper limb functional capacity could be obtained by using the less tremulous arm (two patients) or functional improvement had been achieved with medication (propranolol) (two patients); (v) the tremulous arm was too weak (MRC scale <4/5) in two patients or there was significant truncal weakness resulting in the patient being bedridden and profoundly disabled (one patient); (vi) tremor was mild and did not justify the risks associated with surgical intervention at that stage (three patients); and (vii) the multiple sclerosis action tremor had been exacerbated by prochlorperazine, which also caused a rest tremor component that disappeared when the drug was withdrawn (one patient).
Patients included in the study
All the patients included in the study fulfilled Poser's criteria for the diagnosis of definite multiple sclerosis (Poser et al., 1983). Thirteen patients underwent unilateral stereotactic surgery between March 1997 and May 1999 in order to relieve arm tremor. Thirteen control multiple sclerosis patients, who were matched to the surgical patients by age (±5 years), sex, expanded disability system scores (EDSS) and disease duration (±5 years), were entered into the study. Two control subjects withdrew from the study shortly after recruitment, leaving a total of 24 participating patients.
Medical treatment
Ten of the 13 patients who underwent surgery had been treated previously with propranolol (dose range 80–240 mg per day), one of the remaining three patients had asthma (a contraindication to the drug's use) and the others declined medical treatment. Propranolol produced considerable temporary benefit (for 4–6 months) in two patients. In a further five cases, there was partial tremor suppression but tremor still compromised arm function, and in the remaining three cases no benefit was obtained. Four patients had been treated with clonazepam (0.5–1.5 mg per day), which was of little or no help to three of them and caused intolerable side-effects in the fourth. Isoniazid was administered to one patient but without benefit.
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Methods |
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A prospective case-controlled design was used in order to (i) monitor the response of tremor and arm function to thalamotomy over a 1-year period and (ii) compare the rates of multiple sclerosis disease progression in the surgical patients with that of their matched controls who did not have any intervention.
Definitions
The following definitions, published in a Consensus Statement of the Movement Disorder Society (Deuschl et al., 1998), were used to describe the various tremor components detected in the patients.
Rest tremor.
This is a tremor present in a body part that is not activated voluntarily and is completely supported against gravity (ideally resting on a couch).
Action tremor.
This tremor is any tremor that is produced by voluntary contraction of a muscle. It includes postural, isometric, kinetic and intention tremor: (i) postural tremor is present whilst voluntarily maintaining a position against gravity; (ii) kinetic tremor is tremor occurring during any voluntary movement; and (iii) intention tremor or tremor during target-directed movement is present when tremor amplitude increases during visually guided movements towards a target at the termination of movement and the possibility of position-specific tremor or postural tremor produced at the beginning and end of a movement is excluded.
Holmes' tremor.
The following criteria apply to this tremor: (i) rest and intention tremor with irregular presentation. In many patients, postural tremor is also present. The tremor is often not as rhythmic as other tremors; (ii) slow frequency, usually <4.5 Hz; (iii) if the time when a lesion occurred can be identified (e.g. a stroke), a variable delay (typically 4 weeks to 2 years) between that lesion and the first appearance of tremor is typical of this tremor type. It has been labelled in the past under different names including rubral tremor, midbrain tremor, thalamic tremor, myorythmia and Benedikt's syndrome (Deuschl et al., 1998).
Assessments
A clinical and in particular a tremor history was obtained from each of the 24 patients included in the study. They were all assessed at baseline/preoperatively and at 3 and 12 months later. The tremor was assessed in three states of muscle activity: rest, posture and movement. In the arms, tremor was assessed at rest and in two postures: (P1) with the arms held outstretched and (P2) with arms in the `bat-wing position' (flexed at the elbows and the forearms pronated with the fingers held near the nose). Upper limb kinetic tremor (K) was assessed during a finger–nose–finger test. Arm tremor severity was rated in each of these situations on a 0–10 scale (Bain and Findley, 1993; Bain et al., 1993a; Alusi et al., 2000). The upper limb postural tremors' frequencies were recorded using EGAX-5-/L2M/MiM miniature accelerometers, using a technique previously described (Bain et al., 1993a, b).
The following tests, which previously have been shown to be reliable and valid ways of measuring tremor in patients with multiple sclerosis, were also performed: (i) a finger-tapping test (FTT), in which the patient is asked to press a key on a calculator as many times as possible in 10 s (Worthington et al., 1989; Alusi et al., 2000); (ii) a nine-hole peg test—results expressed as number of pegs inserted per second (Mathiowetz et al., 1985; Alusi et al., 2000); (iii) rating tremor from samples of the patients' handwriting and drawings of an Archimedes' spiral were obtained and scored on a 0–10 clinical rating scale (Bain and Findley, 1993; Bain et al., 1993a, b; Alusi et al., 2000); and (iv) tremor-related disability, using a Tremor-Activities of Daily Living (ADL) Disability questionnaire (Bain and Findley, 1993; Bain et al., 1993a; Alusi et al., 2000).
In addition, the following were also performed: (i) a standard general neurological examination carried out on every patient by one of the authors (S.H.A.) in order to establish their EDSS (Kurtzke, 1983); (ii) the Barthel ADL Index of general disability (Collin et al., 1988); (iii) a (0–4) clinical scale from the dysmetria, dysdiadochokinesia, dysarthria and gait ataxia (Alusi et al., 2000); (iv) the Mini-Mental State (MMS) examination (Folstein et al., 1975), the results of which were expressed as a fraction of the maximum score physically achievable for that patient at the assessment; (v) speech and swallowing: the former assessed by a (0–4) scale and the latter using a 150 ml swallowing test (a swallowing speed of >10 ml/s was taken to indicate abnormal swallowing) (Nathadwarawala et al., 1992); and (vi) grip strength—quantified using the Jaymar (Jackson, Mich., USA) hand-held dynamometer
Outcome measures
The study's main outcome measures were (i) tremor severity in the operated arm (clinical rating of postural tremor P2, kinetic tremor, spiral drawing and handwriting scores), (ii) arm function in the targeted arm (FTT and nine-hole peg test scores, (iii) general disability (EDSS and Barthel ADL Index results) and (iv) tremor-related disability (measured by the Tremor-ADL Disability questionnaire). Other outcome measures were the severity of dysarthria, swallowing time and the MMS score.
Surgical technique
Surgery was covered with a 3-day course of intravenous methyl-prednisolone (1 g/day), commencing the day before surgery. Preoperatively, under general anaesthesia, a T1-weighted MRI scan using a 3D-Turbo-FLASH sequence [TE (echo time) 7 ms, (TR) repetition time 15 ms] and a Siemans 1.5 T Magnetom Vision Scanner was performed and a Cosman–Roberts–Wells (CRW©) head ring fixed to the patient's head. A stereotactic CT scan of the entire skull was acquired using 3 mm contiguous slices and then the MRI and stereotactic CT images were transferred to the StereoPlan© (Radionics Inc.) workstation. The StereoPlan© software was used for anatomic localization of the thalamic target (Papanastassiou et al., 1998; Orth et al., 1999). Further anatomic verification was performed with the AtlasPlan© module of StereoPlan©. This co-registers the Schaltenbrand and Wahren atlas to the patient's scans using the anterior and posterior commissures (AC and PC). The AtlasPlan© module displays the target on the Schaltenbrand and Wahren atlas images.
Targets within the thalamus are chosen relative to the AC–PC line so that for multiple sclerosis tremor our chosen target is located 10–14 mm lateral to the mid-commissural point (Vop) compared with placement 3–5 mm posteriorly in Vim. The initial choice of Vop was based on our intraoperative observation that macrostimulation in the Vop region, rather than more posteriorly in Vim, was more effective at suppressing multiple sclerosis tremor—a finding supported by the literature that has suggested that Vop might be a more effective target than Vim for suppressing multiple sclerosis tremor (Hirai et al., 1983; Nguyen and Degos, 1993; Whittle and Haddow, 1995).
Patients had an arterial line inserted so that systolic blood pressure was maintained 20 mmHg below preoperative values. Anaesthesia was then reversed. An entry point 1.0 cm anterior to the coronal suture and 2.0 cm lateral to the mid-line was used. The patients' hair was cleaned with aqueous and alcoholic chlorhexidine and just a few hairs shaved at the point of entry. A 2.7 mm twist drill hole was made along the planned trajectory and the dura punctured with a biopsy cannula, to minimize CSF leak and thus brain sag. The average collar and arc angles were 62.3° (range 48–75°) and 11.9° (range 2–20°), respectively, with the frame applied approximately parallel to the orbital–meatal line. A 1.8 mm diameter electrode (5 mm exposed tip) was then passed to target, and macrostimulation studies were performed whilst the patient's neurological signs were examined. Observations of the effects of macrostimulation on the (voltage) threshold for adequate tremor suppression led us (in some cases) to move the electrode millimetre by millimetre along its trajectory from the intended target site to a mean of 7 mm (range –0.5 to 13 mm) beyond the calculated target along the trajectory of the electrode's tract. Typically, tremor suppression could be achieved at 100 Hz and 2–5 V (pulse width: 1 ms), and capsular responses could not be elicited with stimulation of <2 V at 2 Hz (pulse width: 1 ms). Temporary lesions were placed by heating the electrode tip to 45°C for 60 s. Then, providing that the patient's clinical status was satisfactory, permanent lesions were induced by heating the electrode tip to 75°C for 90 s.
The coordinates of the intracerebral targets and the distance that the electrode was moved away from the target are shown in Table 1. All the patients had postoperative MRI scans to identify the locations of the lesions.
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Statistics
A series of one-way analyses of variance (ANOVA) were used to assess change in the main outcome measures (postural tremor P2, kinetic tremor, head tremor, spiral drawing, handwriting and tremor-related disability) for the surgical group from the baseline assessment to the short- (3 months) and long (12 months) -term follow-up assessments. Group differences in change in a number of pertinent outcome measures (FTT, nine-hole peg test, speech scale, swallowing time, MMS, EDDS and Barthel ADL Index) were examined with a series of two-way ANOVAs, with group (surgical versus control patients) as the between-groups variable and time of assessment (baseline, and 3 and 12 months follow-up) as the within-subject repeated measures factor. A priori contrasts were used to examine the effects of time and group x time interactions further, where significant.
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Results |
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Patient characteristics
All the surgical and the control patients had progressive multiple sclerosis. The control group consisted of four males and six females; eight were right- and two left-handed. Five of the control group had tremor. The surgical group comprised seven males and six females; 12 were right-handed and one was left-handed. Their average age, disease duration, tremor duration, median EDSS and Barthel ADL Index scores at baseline are summarized in Table 2
. No examples of rest or Holmes' (rubral) tremors were encountered in the surgical or control patients. In the surgical group, the severity of postural (P2) arm tremor ranged from 2.5 to 10 (0–10 scale) and the following tremor subtypes (classified according to Alusi et al., 2001) were encountered in the target upper limb (Table 3).
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Distal postural and kinetic tremor (DpkT)
Six patients. This caused an extension–flexion oscillation at the wrist whilst the arm was held in posture P1, and extension–flexion horizontal sliding movements of the elbow during posture P2. A kinetic component was present during the finger–nose test.
Proximal postural and kinetic tremor (PpkT)
Four patients. This produced side-to-side and abduction–adduction (up–down) oscillations of the arm at the shoulder on postures P1 and P2, respectively. A severe kinetic component was present during the finger–nose test.
Proximal and distal upper limb postural and kinetic tremor (PDpkT)
Three patients. This was similar to PpkT tremor but in addition caused a flexion–extension tremor at the wrist.
Eleven of the 13 surgical patients had head tremor, seven also had truncal tremor. Leg tremor was observed in four patients. In one case (Case 3), thalamotomy was performed ipsilateral to the side of an unsuccessful thalamotomy.
The lesion sites
The sites of the lesions identified by inspection of postoperative cerebral MRI scans are shown in Table 3
. The lesions were centred on the thalamus in seven cases, on the zona incerta in five cases and in the subthalamic nucleus in one case (see Fig. 1A–C for examples).
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Adverse effects and complications
Several patients were noted to develop profound transient global weakness, lasting for a couple of minutes, as the lesioning electrode was heated to 75°C—a vivid form of Uhtoff's phenomenon. Two patients suffered adverse effects at the time of surgery. These were not caused by intracerebral haemorrhage. The first (Case 3), who had an ipsilateral thalamotomy 10 years previously, developed worsening of dysarthria and a contralateral hemiparesis that persisted. The second (Case 11) developed severe drowsiness and a contralateral hemiparesis that initially resolved, until she had seizures, after which a permanent hemiparesis and a mixed receptive and expressive dysphasia became apparent. This was one of two patients (Cases 7 and 11) with a past history of epilepsy, and seizure recurrence developed in both after surgery.
Six of the 13 patients (46%) reported worsening fatigue that lasted for between 3 and 12 weeks postoperatively. Three patients (23%) had transient worsening of bladder function lasting up to 1 month and one required permanent catheterization after surgery. (Five patients had an indwelling catheter prior to surgery and therefore change could not be identified without further investigation.) Bowel function was said to worsen in one patient who had severe dysfunction prior to thalamotomy. Three patients (23%) reported depression postoperatively, which responded to antidepressant treatment in two of them. The remaining patient had a severe recurrence of depression, leading to suicide.
Grip strength
Two surgical patients with hemipareses had marked deterioration in grip strength postoperatively. However, although there were trends towards reduced grip strength for both the surgical and control patient groups over the study period, these were not statistically significant (Table 4).
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Effect on speech and swallowing
Twelve of the surgical patients (92%) and eight of the control patients (73%) had evidence of dysarthria on the 0–4 dysarthria scale at their baseline assessment. Ten of the surgical (77%) and five control patients (45.5%) had abnormal swallowing time at baseline (Table 4
). No significant difference between the two groups' rates of deterioration of either speech [group, F(1,16) = 2.67, P = 0.122; time, F(2,32) = 0.94, P = 0.401; group x time, F(2,32) = 2.18, P = 0.130] or swallowing [group, F(1,12) = 2.76, P = 0.121; time, F(2,26) = 1.16, P = 0.330; group x time, F(2,26) = 0.68, P = 0.514] was detected over the 12-month period of the study.
Speech
Three patients (23%) reported a transient deterioration of speech after surgery and two (15%) complained of permanent worsening of speech at 1 year. The trend towards deterioration in the mean dysarthria scores from baseline to the 3 and 12 months assessments are shown in Table 4 for both the surgical and control patient groups, but this was only statistically significant for the surgical cases at the 3-month assessment (t = 2.18, P = 0.044).
Swallowing
Deterioration in swallowing after surgery was noted by two patients, being transient in one and permanent in the other. Objectively, both groups showed a trend towards deterioration in their swallowing time at 12 months. The mean swallowing time of the surgical group deteriorated by 30% whilst that of the control group deteriorated by 17% from their baseline values at 12 months (not statistically significant) (Table 4).
Effect on cognitive function
The mean baseline, 3 and 12 months postoperative MMS scores are shown in Table 4. Although there was a gradual decline in the mean MMS scores of the surgical but not control group over the 12 months, the differences between the two groups were not significant at the 5% level [group, F(1,13) = 0.21, P = 0.652; time, F(2,26) = 1.67, P = 0.208; group x time, F(2,26) = 2.89, P = 0.073]. Formal neuropsychological assessments were also undertaken (M. Jahanshahi and colleagues, unpublished results).
Effect on disease progression at 1 year
The mean scores for the Barthel ADL Index and the EDSS at baseline, 3 and 12 months are shown in Table 4. There was no significant change in the Barthel ADL Index scores for either group at either time interval [group, F(1,16) = 0.88, P = 0.362; time, F(2,32) = 0.27, P = 0.768; group x time, F(2,32) = 0.07, P = 0.928]. For the EDSS scores, while the main effect of group [F(1,20) = 0.60, P = 0.446] and the group x time interaction [F(2,40) = 0.04, P = 0.965] were not significant, the main effect of time [F(2,40) = 5.59, P = 0.007] was significant. A priori contrasts showed that the latter effect was due to significant deterioration of the EDSS scores across the two groups at 3 (t = 2.17, P = 0.041) and 12 months (t = 2.49, P = 0.021) relative to the baseline assessment. This deterioration in EDSS scores was present across the two groups, and the rate of deterioration was not different in the two groups as shown by the fact that the group x time interaction was not significant. Figure 2 illustrates the changes in the Barthel ADL Index over the 12-month study for each surgical and control patient.
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Mortality
Two surgical and one control patient died between 3 and 6 months after their baseline assessments (
2; not significant). The causes of death were aspiration pneumonia and depression/suicide in the surgical patients, and septicaemia from pyelonephritis in the control patient.
Beneficial effects
Tremor relief
The surgical patients' median postural (P2) tremor scores at baseline, 3 and 12 months are shown in Fig. 3. Eleven of the 12 living surgical patients had a >60% reduction in their postural (P2) arm tremor severity scores at 3 months, although two of them had marked hemiparesis resulting in a weak non-tremulous arm (Table 3). One patient died a week before the 3-month assessment.
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The relationship between preoperative postural (P2) tremor frequency and complete suppression of arm tremor at 3 months is interesting: discounting the three patients who had either died or developed hemiparesis by the 3-month assessment, all five patients who had complete tremor suppression postoperatively [postural (P2) tremor scores of 0] had preoperative tremor frequencies >3 Hz, whilst all five who had residual tremor [postural (P2) tremor scores 0.5–3] after surgery had frequencies of
3 Hz (2; P < 0.01).
In the 11 postoperative patients still alive at their 12-month assessments, postural (P2) tremor was still suppressed by at least 60% in nine patients (although two had persistent hemipareses) but had returned to at least 50% of baseline values in two patients. The reduction by surgery of the postural (P2) tremor [time, F(2,18) = 39.9, P = 0.0001] and the kinetic tremor [time F(2,16) = 20.76, P = 0.0001] severity scores were significant at 3 (postural tremor, t = 5.48, P = 0.00003; kinetic tremor, t = 6.5, P = 0.00018) and 12 months (postural tremor, t = 5.41, P = 0.00042; kinetic tremor, t = 4.9, P = 0.001) postoperatively relative to the baseline assessment (Table 5).
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There was also a significant postoperative improvement in tremor severity scored from spiral drawings [time F(2,18) = 6.8, P = 0.006; baseline versus 3 months, t = 2.57, P = 0.030; baseline versus 12 months: t = 3.14, P = 0.011] but not handwriting [time F(2,18) = 2.22, P = 0.137] (Table 5
). Five of the 11 patients with head tremor had tremor suppression postoperatively, which was maintained at 1 year. Two patients reported worsening of their head tremor postoperatively, but this was not reflected in the objective tremor scores. For the surgical group as a whole, head tremor was significantly improved [time F(2,18) = 5.99, P = 0.01], both 3 months (t = 2.2, P = 0.05) and 12 months (t = 2.98, P = 0.015) after surgery. Surgery had no effect on tremor severity in the ipsilateral arm of any of the patients.
Effect of lesion site on tremor severity
Comparing preoperative scores with those at 3 months after surgery, the mean postural (P2) tremor severity scores were reduced from 5.5 to 0.25 by lesions centred on Vop (n = 5), from 6.3 to 1.1 by those centred on zona incerta (n = 4) and from 8.0 to 0.5 by the subthalamic nucleus-centred lesion (n = 1) (ignoring the two hemiparetic and the deceased patients).
Arm function—FTT
At baseline, seven of the 13 surgical patients were unable to perform the FTT with either arm despite good power, and hence scored 0 taps in 10 s, whilst all the controls completed the FTT. The mean baseline scores for the dominant arm were 8.6 taps in 10 s (including those who scored 0) in the surgical group compared with 23.8 in the control group.
The group x time interaction was significant [F(2,30) = 3.36, P = 0.48], whereas the main effects of group [F(1,15) = 2.20, P = 0.159] and time [F(2,30) = 0.07, P = 0.933] were not significant. The significant interaction was due to the fact that at 3 months there was no significant difference in the FTT scores within either group compared with baseline, whilst at 12 months the scores of the surgical patients had improved significantly relative to baseline whilst those of the controls had deteriorated significantly (Table 4).
The nine-hole peg test
At baseline, eight of the surgical patients and one control were unable to place a single peg in a hole (0 pegs/s). The average scores were 0.06 pegs/s (for either arm) for the surgical patients (including those who scored 0 pegs/s) and 0.14 and 0.13 pegs/s in the dominant and non-dominant hands, respectively, of the controls (Table 4). By the 3- and 12-month assessments, six and five surgical cases, respectively, were still unable to place at least one peg (but one patient had died by 3 months and two by 12 months). The changes in the nine-hole peg test scores were not significantly different for the surgical and control groups [group, F(1,16) = 0.74, P = 0.403; time, F(2,32) = 0.24, P = 0.787; group x time, F(2,32) = 0.58, P = 0.568] compared either with baseline or with each other (Table 4).
Tremor-related disability
The surgical patients' tremor-related disability scores obtained from the Tremor-ADL Disability questionnaire were significantly improved at 12 months after surgery compared with preoperative values [t (8) = 2.78, P = 0.024] (Table 5). Nine of the 11 surgical patients alive after 1 year stated that there was reduction in the relevant/target arm's tremor magnitude, but function was worse in two cases because of weakness (hemipareses). Two others reported that they had derived no benefit from surgery. Thus seven out of 11 (64%) patients noted a decrease in their tremor-related disability 1 year after surgery.
In those who did benefit from surgery, the extent varied: two regained the use of the relevant arm for eating and drinking as well as other fine tasks such as writing short sentences; three were able to eat with a fork and hold a modified cup; and two were only able to regain gross function (which helped their carers to feed and dress them). Four of the patients asked for contralateral surgery to be performed.
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Discussion |
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The study design
The natural history of multiple sclerosis is difficult to predict in individual patients, although male sex, presentation with cerebellar and/or brainstem deficits and older age at disease onset are all associated with a worse prognosis (Weinshenker et al., 1989
). Thus it is difficult to provide adequate matching in a case-controlled trial involving patients with this disease. Nevertheless, Weinshenker and colleagues established guidelines for selecting controls in this context and showed that disease duration and degree of disability are the two most important factors to equilibrate (Weinshenker et al., 1991).
We attempted to match our surgical patients with control multiple sclerosis patients, using age, sex, disease duration and EDSS as controlling factors (see Methods). The presence of tremor was not a prerequisite for entry into the control group. However, the EDSS of the controls was lower than that of the surgical cases by an average of 0.5 points. The probable reason for this is that patients with severe cerebellar deficits (e.g. tremor) reach a higher level of disability at an earlier age than patients without these signs (Weinshenker et al., 1996; Alusi et al., 2001). However, it is possible that closer matching might have been achieved by controlling for cerebellar deficits as well, but this would have posed considerable practical difficulties for patient recruitment.
The choice of outcome measures
Selecting appropriate outcome measures for use in therapeutic trials involving multiple sclerosis patients is difficult (Rudick et al., 1996; Wingerchuk et al., 1997). Nevertheless, we assessed the efficacy of thalamotomy by studying the reduction of tremor severity, the gain in arm function and the change in the patient-reported tremor-related disability using measures that have established validity and reliability in tremulous multiple sclerosis patients (Alusi et al., 2000). Other more extensive functional scoring systems may have provided more detailed information but would need validation in tremulous multiple sclerosis patients prior to deployment (Hariz et al., 1998; Lyons et al., 1998; Schuurman et al., 2000).
Does stereotactic surgery have serious adverse effects on the overall condition of multiple sclerosis patients?
There is considerable concern that trauma may have a negative influence on the progression of multiple sclerosis (Poser, 1987; Sibley et al., 1991; Sibley, 1993; Jellinek, 1994; Kurland, 1994), particularly as short-term exacerbation of the disease after neurosurgical intervention has been reported (Samra et al., 1970).
In this study, no significant difference in the rate of disease progression, as reflected in the EDSS and Barthel ADL Index, of the surgical patients compared with their controls was found at either 3 months or 1 year. This result provides some reassurance to those involved in this form of surgery. However, it is possible that the study failed to demonstrate a real negative effect of stereotactic lesional surgery on disease progression because (i) all the patients in the surgical group received prophylactic high dose methyl-prednisolone at the time of surgery; (ii) the EDSS, although a good indicator of the natural history of multiple sclerosis (Kurtzke, 1983; Weinshenker et al., 1989; The European Study Group on Interferon ß-1b in secondary Progressive Multiple Sclerosis, 1998), probably lacks adequate sensitivity to change over a 12-month period, especially in the later stages of the disease (Weinshenker et al., 1996); (iii) the Barthel ADL Index is designed for assessing the degree of dependence, and thus improvements in hand function caused by thalamotomy will influence scores; (iv) the results do not rule out the possibility of a longer term negative effect; and (v) the study's sample size may prevent detection of small, but significant, effects. Even so, it would appear that any putative negative influence of thalamotomy on disease progression is not as profound as previously suggested (Broager and Fog, 1962; Speelman and Van Manen, 1984).
Adverse events
Mortality
In this study, stereotactic surgery was not associated with any intra- or postoperative death. However, over the 12-month study period, one control and two surgical patients, who had lesions centred on the zona incerta, died. In addition, two out of 33 patients referred for surgery died within 4 months of referral, giving a total mortality rate of five out of 57 patients (8.8%). Consequently, the prognosis for severely tremulous multiple sclerosis patients is poor, irrespective of whether or not stereotactic surgery is performed.
Morbidity
This study demonstrates that there is significant morbidity associated with stereotactic lesional surgery for patients with multiple sclerosis. Immediate adverse effects included hemiparesis in two cases (15%), which occurred even though the thalamic lesions were placed accurately, demonstrating the functional vulnerability of demyelinated brain tissue. However, in one of these cases, a previous ipsilateral partially misplaced thalamotomy had been performed. In addition, two cases (15%) had postoperative seizures; a higher incidence than previously reported (Samra et al., 1970). Transient postoperative fatigue and worsening of bladder function, typically lasting 3–12 weeks, were detected in six (46%) and three (23%) of the patients, respectively. However, it is pertinent to note that five patients had an in-dwelling urinary catheter prior to surgery, so that a more profound effect could not have been determined without further investigation. Depression developed in three patients (23%) after surgery, in two cases responding to treatment, but in another leading to suicide. No significant differences between the surgical and control groups were detected in the rate of deterioration of either speech or swallowing over the 12-month study period although speech did deteriorate 3 months after surgery; it then stabilized to some extent so that at 12 months there were no significant differences compared with baseline or the control group's values (Table 4).
Beneficial effects
Stereotactic lesional surgery was associated with tremor attenuation in every case, irrespective of whether the lesion was sited predominantly in the thalamus (n = 7), zona incerta (n = 5) or subthalamic nucleus (n = 1), indicating that lesions at any one of these sites may alleviate multiple sclerosis tremor (Table 3). However, irrespective of the lesion site, complete postural tremor suppression in the target arm was invariably evident 3 months after surgery if the preoperative postural (P2) tremor frequencies were >3 Hz, but total tremor suppression was never obtained with preoperative frequencies of 3 Hz (Table 3). This significant finding has at least two possible explanations, namely that a low (3 Hz) frequency spectral peak may (i) originate from tremor in more proximal muscles or (ii) indicate a different underlying tremorgenic mechanism; that in either case does not respond as well to stereotactic lesional surgery.
In this study, significant improvements in upper limb postural (P2) and kinetic tremors and spiral drawings as well as head tremor were detected at 3 and 12 months after surgery (Table 5), although tremor reappeared to some degree by 12 months (Fig. 3). No significant postoperative improvement in handwriting was evident for the group as a whole, although two patients regained the ability to write short sentences. The results of upper limb function testing, using the nine-hole peg test and FTT, showed that for finger tapping there was a significant group by time interaction, so that at 3 months there was no significant change in the finger-tapping scores within either group but at 12 months the scores of the surgical patients had improved significantly relative to baseline whilst those of the controls had deteriorated. The nine-hole peg test results showed no significant change over the duration of the study for either the surgical patients or the controls, although there was a slight trend for the latter to deteriorate over the study period. Stereotactic surgery was also associated with significant improvement in tremor-related disability (assessed using a validated Tremor-ADL Disability questionnaire) 1 year after surgery (Table 5), although good tremor suppression was not always mirrored by improvement in specific arm functions (e.g. writing) or disability, a finding that has been reported previously (Speelman and Van Manen, 1984; Barnett et al., 1992; Whittle and Haddow, 1995; Shahzadi et al., 1995). In summary, stereotactic surgery produced variable results, with overall benefit occurring in seven of the 11 multiple sclerosis patients alive 1 year later.
Is there an optimal surgical target for alleviating multiple sclerosis tremor?
Schuurman and colleagues reported that lesions (n = 5) or stimulation (n = 5) of the Vim decreased multiple sclerosis tremor from a median tremor severity value of 4 to 2 (severe to mild tremor, respectively) on a 0–4 tremor scale (Schuurman et al., 2000). However, at the beginning of this study, our preferred target for alleviating multiple sclerosis tremors had been the Vop of the thalamus, particularly as our previous experience with distal, single frequency, upper limb multiple sclerosis tremor showed that lesions placed in the Vop attenuated multiple sclerosis tremor (Liu et al., 2001).
However, intraoperatively, we noted that tremor suppression was achieved in some patients at lower stimulation voltages more ventromedially and up to 13 mm beyond the thalamic target along the trajectory of the electrode. Thus lesions were placed here and the sites confirmed on postoperative MRI scans (Table 3 and Fig. 1).
These findings led us to conclude that multiple sclerosis tremors, particularly those with a proximal component, may be attenuated more easily by lesions in the subthalamic or zona incerta regions than the thalamus. The anatomical reason for this is that both the medial globus pallidus and the cerebellar nuclei project not only to the thalamus, but also caudally to the upper brainstem, particularly to the fields of Forel and the zona incerta above the red nucleus, and to the pedunculo-pontine nuclei and reticular pontine nuclei below it. These areas contain many neurones whose discharge correlates with activity of the proximal spinal and limb girdle muscles during reaching and locomotion, and their axons cross over to the other side to project directly or indirectly to the ventromedial grey matter of the spinal cord that contains the motor neurones that control these muscles. Proximal tremor is mediated not by distal muscles that are controlled predominantly by thalamocortical circuits, but mainly by these paraspinal and limb girdle muscles which, as Lawrence and Kuypers first showed, are controlled mainly from areas in the medial part of the upper brainstem (Lawrence and Kuypers, 1968). This probably explains why lesions in the region of the zona incerta can alleviate proximal multiple sclerosis tremor, as they interrupt aberrant oscillatory activity in the cerebellar and basal ganglia outputs, which cause this form of tremor.
Selection criteria
Haddow and colleagues, having reviewed the literature, found very little useful information about the criteria for selecting tremulous multiple sclerosis patients for thalamotomy (Haddow et al., 1997). However, in spite of variations in the quality of previous studies and paucity of data about individual patients, they concluded that surgery benefits those patients who have stable tremors and relatively non-progressive disease, a view taken by other authors in this field (Broager and Fog, 1962; Barnett et al., 1992).
In addition, it has been stated that thalamotomy has a predominantly palliative role for those with severe axial and proximal arm tremor (Kandel and Hondcarian, 1985; Whittle and Haddow, 1995) or those who suffer from associated truncal ataxia, which may cause persistent instability of the upper limb despite good tremor relief (Shahzadi et al, 1995; Alusi et al., 1999). Furthermore, the presence of severe arm incoordination/ataxia in a tremulous arm is likely to undermine the benefit of tremor suppression, and patients with marked weakness and/or significant sensory deficits are also unlikely to regain functional capacity after thalamotomy. This moderation of benefit can be explained by the effect of the underlying ataxic disorder on arm function (Speelman and Van Manen, 1984; Whittle and Haddow, 1995; Alusi et al., 1999). However, preoperative assessment of the severity of incoordination/ataxia in tremulous multiple sclerosis patients is difficult, particularly in patients with proximal tremors that may interfere with ataxia testing (Alusi et al., 1999, 2000). In this regard, Liu and colleagues have shown, using a computerized tracking task, that multiple sclerosis patients with distal tremor and minimal ataxia (i.e. pure tremor, manifest as a single frequency peak on spectral analysis in the frequency domain) obtained >50% tremor suppression after Vop thalamotomy, but that those patients with multiple spectral peaks (indicating a complex ataxic movement disorder) obtained <50% suppression of their movement disorder (Liu et al., 2001). This led Liu and colleagues to speculate that pallidal surgery may be a more appropriate procedure for this latter group of patients.
Our finding of a 3 Hz frequency `filter' at or below which stereotactic surgery did not abolish upper limb tremor may provide a useful addition to the criteria for selecting tremulous multiple sclerosis patients for this form of surgery. However, further studies are required to confirm this observation.
In this study, we rejected the majority (77%) of the cases referred for surgery. Nevertheless, in view of our data, we would now also exclude those patients with a previous thalamotomy or a history of epilepsy.
Lesional surgery or deep brain stimulation for multiple sclerosis tremor?
Deep brain thalamic stimulation has been advocated as an alternative treatment to lesional surgery for tremors of various aetiologies including multiple sclerosis (Brice and McLellan, 1980; Pollak et al., 1993; Nguyen et al., 1996; Geny et al., 1996; Tasker, 1998; Whittle et al., 1998; Schuurman et al., 2000). However, the results of a randomized controlled trial of Vim thalamotomy versus stimulation that included 10 multiple sclerosis patients demonstrated that thalamic stimulation was no better than thalamotomy at suppressing multiple sclerosis tremor and induced less improvement in disability, although these differences were not statistically significant (Schuurman et al., 2000). Furthermore, adverse effects were detected in two (of five) lesioned and three (of five) stimulated patients, respectively, and included severe gait disturbance, arm ataxia and dysarthria. Nevertheless, we take the view that if a bilateral procedure is being considered for treating multiple sclerosis tremor, bilateral deep brain stimulation or possibly a unilateral lesion and contralateral stimulation would be preferable to bilateral thalamotomies, as the latter are associated with high risks of producing speech and swallowing deficits (Krayanbuhl and Yasargil 1962; Samra et al., 1970; Andrew et al., 1982).
Prolonging the benefit of surgery
The long-term immunological consequences of having an electrode implanted in multiple sclerosis brain tissue are not yet known, although Nguyen and colleagues demonstrated that the results of thalamic stimulation were similar to those obtained historically by thalamotomy (Nguyen et al., 1998). However, developments in disease-modifying agents may allow the benefits obtained by stereotactic surgery to be prolonged by minimizing the effects of disease progression (Haddow et al., 1997).
Conclusion
This study demonstrates that stereotactic lesional surgery can provide benefit to a highly selected group of tremulous multiple sclerosis patients by suppressing limb and, to a lesser extent, head tremor and thus improve tremor-related disability. Lesions centred on the Vop of the thalamus, zona incerta or subthalamic nucleus can decrease upper limb tremor magnitude. The detection of a 3 Hz postural tremor frequency `filter' at or below which upper limb tremor could not be abolished is intriguing and merits further study. This type of surgery is associated with a high rate of morbidity, but this could be improved by more stringent selection criteria, specifically excluding those patients with a previous thalamotomy or a history of epilepsy. Finally, we could not detect evidence demonstrating a negative influence of lesional surgery on the rate of progression of this unpleasant disease, although the mortality rate for severely tremulous multiple sclerosis patients was 8.8% over the 12-month study, irrespective of whether or not surgery was performed.
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We would like to thank SEARCH and the Smith's charities for funding this study, and the MRC for funding T.Z.A.
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Alusi SH, Glickman S, Aziz TZ, Bain PG. Tremor in multiple sclerosis [editorial]. J Neurol Neurosurg Psychiatry 1999; 66: 131–4.
Alusi SH, Worthington J, Glickman S, Findley LJ, Bain PG. Evaluation of three different ways of assessing tremor in multiple sclerosis. J Neurol Neurosurg Psychiatry 2000; 68: 756–60.
Alusi SH, Glickman S, Worthington J, Bain PG. A study of tremor in multiple sclerosis. Brain 2001: 124: 720–30.
Andrew J, Fowler CJ, Harrison MJ. Tremor after head injury and its treatment by stereotactic surgery. J Neurol Neurosurg Psychiatry 1982; 45: 815–9.
Aziz TZ, Bain PG. A multidisciplinary approach to tremor [editorial]. Br J Neurosurg 1996; 10: 435–7.[Web of Science][Medline]
Bain PG, Findley LJ. Assessing tremor severity. London: Smith-Gordon; 1993.
Bain PG, Findley LJ, Atchison P, Behari M, Vidailhet M, Gresty M, et al. Assessing tremor severity. J Neurol Neurosurg Psychiatry 1993a; 56: 868–73.
Bain PG, Mally J, Gresty M, Findley LJ. Assessing the impact of essential tremor on upper limb function. J Neurol 1993b; 241: 54–61.[Web of Science][Medline]
Barnett GH, Kinkel RP, Bashin C, Palmer J, Namey M, Rudick R. Stereotactic thalamotomy for intractable tremor in multiple sclerosis [abstract]. Neurology 1992; 42 Suppl 3: 327.
Brice J, McLellan L. Suppression of intention tremor by contingent deep-brain stimulation. Lancet 1980; 1: 1221–2.[Web of Science][Medline]
Broager B, Fog T. Thalamotomy for the relief of intention tremor in multiple sclerosis. Acta Neurol Scand 1962; 38 Suppl 3: 153–6.[Web of Science]
Collin C, Wade DT, Davies S, Horne V. The Barthel ADL Index: a reliability study. Int Disabil Stud 1988; 10: 61–3.[Medline]
Cooper IS. Neurosurgical alleviation of intention tremor of multiple sclerosis and cerebellar disease. New Engl J Med 1960; 263: 441–4.
Critchley GR, Richardson PL. VIM thalamotomy for the relief of the intention tremor in multiple sclerosis. Br J Neurosurg 1998; 12: 559–62.[Web of Science][Medline]
Deuschl G, Bain P, Brin M. Consensus statement of the Movement Disorder Society on Tremor. Ad Hoc Scientific Committee. [Review]. Mov Disord 1998; 13 Suppl 3: 2–23.
European Study Group on Interferon beta-1b in secondary progressive MS. Placebo-controlled multicentre randomised trial of interferon beta 1-b in treatment of secondary progressive multiple sclerosis. Lancet 1998; 352: 1491–7.[Web of Science][Medline]
Folstein MF, Folstein SE, McHugh PR. `Mini-Mental State': a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975; 12: 189–98.[Web of Science][Medline]
Geny C, Nguyen JP, Pollin B, Feve A, Ricolfi F, Cesaro P, et al. Improvement of severe postural cerebellar tremor in multiple sclerosis by chronic thalamic stimulation. Mov Disord 1996; 11: 489–94.[Web of Science][Medline]
Haddow LJ, Mumford C, Whittle IR. Stereotactic treatment of tremor due to multiple sclerosis. Neurosurg Q 1997; 7: 23–34.
Hariz GM, Bergenheim AT, Hariz MI, Lindberg M. Assessment of ability/disability in patients treated with chronic thalamic stimulation for tremor. Mov Disord 1998; 13: 78–83.[Web of Science][Medline]
Hirai T, Miyazaki M, Nakajima H, Shibazaki T, Ohye C. The correlation between tremor characteristics and the predicted volume of effective lesions in stereotaxic nucleus ventralis intermedius thalamotomy. Brain 1983; 106: 1001–18.
Hooper J, Whittle IR. Long-term outcome after thalamotomy for movement disorders in multiple sclerosis [letter]. Lancet 1998; 352: 1984.[Web of Science][Medline]
Jellinek EH. Trauma and multiple sclerosis. Lancet 1994; 343: 1053–4.
Kandel EI, Hondcarian OA. Surgical treatment of the hyperkinetic form of multiple sclerosis. Acta Neurol (Napoli) 1985; 7: 345–7.[Medline]
Krayanbuhl H, Yasargil MG. Relief of intention tremor due to multiple sclerosis by stereotaxic thalamotomy. Confin Neurol 1962; 22: 368–74.
Kurland LT. Trauma and multiple sclerosis. Ann Neurol 1994; 36 Suppl: S33–7.
Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology 1983; 33: 1444–52.
Lawrence DG, Kuypers HG. The functional organization of the motor system in the monkey. Brain 1968; 91: 15–36.
Liu X, Aziz TZ, Miall RC, Rowe J, Alusi SH, Bain PG, et al. Frequency analysis of involuntary movements during wrist tracking: a way to identify MS patients with tremor who benefit from thalamotomy. Stereotactic Funct Neurosurg. In press 2001.
Lyons KE, Pahwa R, Busenbark KL, Troster AI, Wilkinson S, Koller WC. Improvements in daily functioning after deep brain stimulation of the thalamus for intractable tremor. Mov Disord 1998; 13: 690–2.[Web of Science][Medline]
Mathiowetz V, Weber K, Kashman N, Volland G. Adult norms for the nine-hole peg test of finger dexterity. Occup Ther J Res 1985; 5: 24–37.
Nathadwarawala KM, Nicklin J, Wiles CM. A timed test of swallowing capacity for neurological patients. J Neurol Neurosurg Psychiatry 1992; 55: 822–5.
Nyguyen JP, Degos JD. Thalamic stimulation and proximal tremor. Arch Neurol 1993; 50: 498–500.
Nguyen JP, Feve A, Keravel Y. Is electrostimulation preferable to surgery for upper limb ataxia? [Review]. Curr Opin Neurol 1996; 9: 445–50.[Web of Science][Medline]
Nguyen JP, Feve A, Cesaro P, Keravel Y. Long term follow-up of patients with multiple sclerosis and action tremor treated by thalamic stimulation [abstract]. Mov Disord 1998; 13 Suppl 2: 132.
Orth RC, Sinha P, Madsen EL, Frank G, Korosec FR, Mackie RT, et al. Development of a unique phantom to assess the geometric accuracy of magnetic resonance imaging for stereotactic localization. Neurosurgery 1999; 45: 1423–31.[Web of Science][Medline]
Papanastassiou V, Rowe J, Scott R, Silburn P, Davies L, Aziz T. Use of the Radionics Image Fusion© and Stereoplan© programs for target localization in functional neurosurgery. J Clin Neurosci 1998; 5: 28–32.[Web of Science][Medline]
Poser CM. Trauma and multiple sclerosis. An hypothesis. J Neurol 1987; 234: 155–9.[Web of Science][Medline]
Poser CM, Patty DW, Scheinberg L, McDonald WI, Davis FA, Ebers GC, et al. New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol 1983; 13: 227–31.[Web of Science][Medline]
Pollak P, Benabid A-L, Gervason CL, Hoffmann D, Seigneuret E, Perret J. Long-term effects of chronic stimulation of the ventral intermediate thalamic nucleus in different types of tremor. Adv Neurol 1993; 60: 408–13.[Medline]
Rudick R, Antel J, Confavreux C, Cutter G, Ellison G, Fischer J, et al. Clinical outcomes assessment in multiple sclerosis. [Review]. Ann Neurol 1996; 40: 469–79.[Web of Science][Medline]
Samra K, Waltz JM, Riklan M, Koslow M, Cooper IS. Relief of intention tremor by thalamic surgery. J Neurol Neurosurg Psychiatry 1970; 33: 7–15.
Schuurman PR, Bosch DA, Bossuyt PM, Bonsel GJ, van Someren EJ, de Bie RM, et al. A comparison of continuous thalamic stimulation and thalamotomy for suppression of severe tremor. N Engl J Med 2000; 342: 461–8.
Shahzadi S, Tasker RR, Lozano A. Thalamotomy for essential and cerebellar tremor. Stereotact Funct Neurosurg 1995; 65: 11–7.[Web of Science][Medline]
Sibley WA . Physical trauma and multiple sclerosis [editorial]. [Review]. Neurology 1993; 43: 1871–4.
Sibley WA, Bamford CR, Clark K, Smith MS, Laguna JF. A prospective study of physical trauma and multiple sclerosis. J Neurol Neurosurg Psychiatry 1991; 54: 584–9.
Siegfried J. Therapeutic stereotactic procedures on the thalamus for motor movement disorders. Acta Neurochir (Wien) 1993; 124: 14–8.[Medline]
Speelman JD, Van Manen J. Stereotactic thalamotomy for the relief of intention tremor in multiple sclerosis. J Neurol Neurosurg Psychiatry 1984; 47: 596–9.
Tasker RR. Deep brain stimulation is preferable to thalamotomy for tremor suppression. Surg Neurol 1998; 49: 145–53.[Web of Science][Medline]
Van Manen J. Stereotaxic operations in cases of hereditary and intention tremor. Acta Neurochir Suppl (Wien) 1974; 21: 49–55.
Weinshenker BG, Bass B, Rice GP, Noseworthy J, Carriere W, Baskerville J, et al. The natural history of multiple sclerosis: a geographically based study. 1. Clinical course and disability. Brain 1989; 112: 133–46.
Weinshenker BG, Rice GP, Noseworthy JH, Carriere W, Baskerville J, Ebers GC. The natural history of multiple sclerosis: a geographically based study. 4. Applications to planning and interpretation of clinical therapeutic trials. Brain 1991; 114: 1057–67.
Weinshenker BG, Issa M, Baskerville J. Long-term and short-term outcome of multiple sclerosis. A 3-year follow-up study. Arch Neurol 1996; 53: 353–8.
Whittle IR, Haddow LJ. CT guided thalamotomy for movement disorders in multiple sclerosis: problems and paradoxes. Acta Neurochir Suppl (Wein) 1995; 64: 13–6.[Medline]
Whittle IR, Hooper J, Pentland B. Thalamic deep-brain stimulation for movement disorders due to multiple sclerosis [letter]. Lancet 1998; 351: 109–10.[Web of Science][Medline]
Wingerchuk DM, Noseworthy JH, Weinshenker BG. Clinical outcome measures and rating scales in multiple sclerosis trials. [Review]. Mayo Clin Proc 1997; 72: 1070–9.[Abstract]
Worthington J, De Souza LH. A simple measurement of speed of index finger movement. Clin Rehabil 1989; 3: 117–23.
Received March 29, 2001. Revised March 29, 2001. Accepted April 5, 2001.
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