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Gamma knife thalamotomy for multiple sclerosis tremor
Surgical Neurology 68 (2007) 394 – 399 www.surgicalneurology-online.com
Radiosurgery
Gamma knife thalamotomy for multiple sclerosis tremorB David Mathieu, MD, Douglas Kondziolka, MD4, Ajay Niranjan, MCh, John Flickinger, MD, L. Dade Lunsford, MD Department of Neurological Surgery, University of Pittsburgh, Center for Image-Guided Neurosurgery, Pittsburgh, PA 15213, USA Department Radiation Oncology, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA Received 6 March 2006; accepted 14 November 2006
Abstract
Background: Some patients with MS suffer from disabling tremor. Improvement with medical treatment is modest, at best. Stereotactic surgery targeting the vim nucleus of the thalamus has been successful in alleviating MS tremor. Gamma knife radiosurgery represents a minimally invasive alternative to radiofrequency lesioning and DBS that can provide improvement in patients suffering from essential and parkinsonian tremor. We reviewed our experience with GK thalamotomy in the management of six consecutive patients suffering from disabling MS tremor. Methods: The median age at the time of radiosurgery was 46 years (range, 31 to 57 years). Intention tremor had been present for a median of three years (range 8 months to 12 years). One 4-mm isocenter was used to deliver a median maximum dose of 140 Gy (range, 130-150 Gy) to the vim nucleus of the thalamus opposite the side of the most disabling tremor. Clinical outcome was assessed using the Fahn-Tolosa-Marin scale. Results: The median follow-up was 27.5 months (range, 5-46 months). All patients experienced improvement in tremor after a median latency period of 2.5 months. More improvement was noted in tremor amplitude than in writing and drawing ability. In four patients, the tremor reduction led to functional improvement. One patient suffered from transient contralateral hemiparesis, which resolved after brief corticosteroid administration. No other complication was seen. Conclusion: Gamma knife radiosurgical thalamotomy is effective as a minimally invasive alternative to stereotactic surgery for the palliative treatment of disabling MS tremor. D 2007 Elsevier Inc. All rights reserved.
Keywords:
Gamma knife; Radiosurgery; Thalamotomy; vim nucleus; Multiple sclerosis; Tremor
1. Introduction Multiple sclerosis is a chronic central nervous system– demyelinating disease. Tremor is estimated to occur in
Abbreviations: AC, anterior commissure; DBS, deep brain stimulation; FIR, fast inversion recovery; FU, follow-up; GK, gamma knife; MRI, magnetic resonance imaging; MS, multiple sclerosis; PC, posterior commissure; SPGR, Spoiled-Gradient Recalled Acquisition in Steady State; vim, ventralis intermedius; vop, ventralis oralis posterior; ZI, zona incerta. B Douglas Kondziolka, MD, Ajay Niranjan, MCh, and L Dade Lunsford, MD, are consultants for Elekta Instruments, Atlanta, Ga. 4 Corresponding author. UPMC Presbyterian Department of Neurosurgery, Pittsburgh, PA, 15213, USA. Tel.: +1 412 647 6782; fax: +1 412 647 8447. E-mail address: [email protected] (D. Kondziolka). 0090-3019/$ – see front matter D 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.surneu.2006.11.049
approximately 25% of MS patients and can be severely disabling in 6% [20]. It is most often an intention tremor that affects the upper extremities, although a resting component is sometimes present. Medical treatment of tremor in MS patients is often disappointing. No drug clearly has emerged as superior to another, and those presently in use provide modest benefit at best [2]. Stereotactic radiofrequency thalamotomy and thalamic DBS of the vim nucleus have been shown to improve tremor in MS patients [2]. Drawbacks of those procedures include their invasiveness and the fact that a significant proportion of patients experience recurrence of tremor in the months after surgery. As a less invasive treatment modality, GK radiosurgery has proven effective in the treatment of parkinsonian and essential tremor, especially in patients who
D. Mathieu et al. / Surgical Neurology 68 (2007) 394 – 399
may not be good candidates for radiofrequency thalamotomy or thalamic DBS [15,18]. The goal of the present study is to report our experience with GK radiosurgery in the management of 6 patients suffering from disabling MS-related tremor. 2. Methods Between May 1998 and August 2000, 6 consecutive patients with severe tremor related to MS had radiosurgery at the University of Pittsburgh Medical Center. Every patient was referred by a neurologist with expertise in the management of MS. They consisted of 3 male and three female individuals, all of white origin. The median age at the time of radiosurgery was 46 years (mean, 44.5 years; range, 31-57 years). Two patients suffered from primary progressive MS, 2 from secondary progressive MS, and 2 from relapsing progressive MS. Median time from the diagnosis of MS to radiosurgery was 16 years (mean, 14.8 years; range, 4.9-25 years). All patients were severely disabled by their disease, 5 of them being wheelchair-bound or bed-bound. The tremor had been present for a median interval of 3 years before GK radiosurgery was undertaken (mean, 4.6 years; range, 10 months to 12 years). The tremor was characterized as intention (rubral) tremor in all patients. In addition, one patient had a resting tremor component. Tremor involved the bilateral upper extremities in all but 1 patient, who had only the right side involved. Head bobbing was also observed in 3 of 6 patients. Various trials of antitremor medications, including propranolol, baclofen, clonazepam,
395
ondansetron, isoniazid and primidone, did not provide satisfactory control of the tremor in any of the patients. Preoperatively, the tremor was graded according to elements of the Fahn-Tolosa-Marin scale [9], which has proven to be reliable to evaluate MS-related tremor [13]. Tremor amplitude, writing, and drawing were evaluated on a scale of 0 (best) to 4 (worst). Tremor amplitude was evaluated by having patients perform the finger-to-nose test. For drawing ability assessment, patients were asked to draw an Archimedes spiral. Tremor was severe in every patient, with median values of 4 on every item of the scale. Typically, the tremor was coarse, jerking, and more severe than in essential tremor patients. It caused a significant impairment in the activities of daily living in every patient, interfering particularly with the ability to feed, drink, and dress. Informed consent was obtained with the patients and their family, after reviewing the different management options, including radiofrequency lesioning and DBS. Gamma knife radiosurgery was preferred as a palliative measure in view of its noninvasiness. Patients were admitted the morning of the procedure. After adequate local anesthesia and sedation, the Leksell G frame (Elekta Instruments, Atlanta, Ga) was attached to the patient’s head. Sagittal scout fast spin echo images were obtained first. After identifying the anterior and PC in sagittal images, high-resolution, 1-mm-thick contrast-enhanced SPGR volumetric images covering the entire thalamus in the axial plane were obtained. We next performed FIR images to differentiate basal ganglia from white matter tracts. The image series was transferred via Ethernet to the planning
Fig. 1. GammaPlan software snapshot showing MRI SPGR images in axial poster (left) with coronal (upper right) and sagittal (lower right) reconstruction. Using stereotactic coordinates, the 50% isodose line of a single 4-mm collimator shot is placed to target the right vim nucleus.
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D. Mathieu et al. / Surgical Neurology 68 (2007) 394 – 399
Table 1 Pertinent clinical information related to treated patients Patient
Age (y), sex
MS type
MS duration (y)
1 2 3 4 5 6
49, 44, 48, 57, 38, 31,
Relapsing progressive Secondary progressive Primary progressive Secondary progressive Relapsing progressive Primary progressive
5 20 25 18 7 14
M F M F M F
Tremor duration (y) 0.83 8 3 3 1 12
Initial tremor score 4 4 4 4 4 4
Max dose (Gy)
FU length (mo)
140 130 140 150 150 140
30 5 42 46 5 25
Tremor score post GK 2 3 2 1 0 1
computer. Using the GammaPlan software (Elekta Instruments), a single 4-mm isocenter was placed, targeting the vim nucleus on the side opposite to the more disabling tremor. The initial thalamic coordinates were obtained using the following formula: x = from the midline, half of the 3rd ventricular width, plus 11 mm; y = from the PC, one fourth of the AC-PC length plus 1 or 2 mm; z = 2 or 2.5 mm above the AC-PC line plane. The coordinates were calculated using high-resolution, 1-mm-thick contrast-enhanced SPGR images. The 50% isodose line using these coordinates with a 4-mm collimator were projected on both SPGR and FIR images. The final adjustments in the target coordinates were made according to the position of the internal capsule and thalamus in FIR images. Five patients were treated on the left side, and 1, on the right side (this patient was lefthanded). A median maximum dose of 140 Gy (range, 130150 Gy) was delivered to the target using a GK model U or B (Elekta Instruments). No beam channel plugging pattern was used. Fig. 1 exemplifies a typical dose plan for GK thalamotomy. Patients were kept overnight in the hospital for observation and were discharged the following day. Clinical follow-up was obtained between 3 to 6 months after radiosurgery and annually thereafter. The Fahn-TolosaMarin scale was used to assess tremor evolution. A followup MRI was scheduled after 6 months to assess for any radiosurgery-induced imaging changes. All evaluations were based on the referring neurologist assessment of clinical improvement and were done by an independent observer. Statistical analysis of the improvement in tremor scores was performed using the SPSSR 13.0 software (SPSS Inc, Chicago, Ill).
(range, 2-3 months). The amplitude of the tremor was the element that improved the most, with a median improvement of 2.5 points on the Fahn-Tolosa-Marin scale (from a median of 4, pre GK, to a median of 1.5 after radiosurgery, P b .0005). Absolute values for this score ranged from 0 to 3 after radiosurgery. The improvement was not as good on the writing and drawing scores. The median pre-GK score was 4 for both of these items. The median writing score remained at 4 after radiosurgery (range, 2-4), whereas the drawing score improved to a median of 3.5 (range, 1-4; P = .034, when compared to pre-GK score). Table 2 reports the Fahn-TolosaMarin scores before and after radiosurgery. The clinical improvement was corroborated by the patient’s referring neurologists. Longer follow-up revealed recurrence of
3. Results
3 4
Every patient was assessable for treatment outcome. Median follow-up length was 27.5 months (mean, 25.5 months; range, 5-46 months). No acute adverse events were seen after the procedure. Three patients eventually died from complications of the primary disease, MS (3, 4, and 4 years after the procedure, respectively). These deaths were deemed unrelated to the GK procedure. Table 1 summarizes the main clinical data for all patients.
Table 2 Grading of tremor amplitude, writing, and drawing according to the FahnTolosa scale, before and after radiosurgery (n = 6 patients) Grades Tremor 0 1 2 3 4 Writing 0 1 2
Drawing 0 1 2
3.1. Tremor improvement
3
Radiosurgical thalamotomy was beneficial for every patient. Median time to improvement was 2.5 months
4 a
Clinical assessment
Before GK (n)
After GKa (n)
No tremor Slight: barely perceivable, may be intermittent Moderate: amplitude b 2 cm, may be intermittent Marked: amplitude 2-4 cm Severe: amplitude N 4 cm
0 0
1 2
0
2
0 6
1 0
Normal Mildly abnormal, slightly untidy, tremulous Moderately abnormal, legible, but with considerable tremor Markedly abnormal, illegible Severely abnormal, unable to keep pencil or pen on paper without holding hands down with the other hand
0 0
0 0
0
1
0 6
0 5
Normal Slightly tremulous, may cross lines occasionally Moderately tremulous, cross lines frequently Accomplishes task with great difficulty, many errors Unable to complete the drawing
0 0
0 1
0
0
1
2
5
3
Median follow-up of 27.5 months.
D. Mathieu et al. / Surgical Neurology 68 (2007) 394 – 399
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Fig. 2. Brain MRI performed 2 years after GK thalamotomy. Contrast-enhanced axial T1-weighted image demonstrating a ring-enhancing lesion in the left vim nucleus (left). Axial T2-weighted image showing the lesion in the left vim nucleus with minimal changes in the surrounding brain (right).
tremor in 2 patients after a period of 12 and 18 months, respectively, had elapsed. Recurrent tremor was not as severe and disabling as it was before radiosurgery. In addition, the only patient with unilateral involvement eventually developed tremor on the uninvolved side. Routine follow-up MRI demonstrated an adequate vim lesion in every patient (Fig. 2). 3.2. Functional improvement Reduction in tremor amplitude after radiosurgery led to functional improvement in 4 patients, according to the patients’ main caregivers. Feeding and drinking ability improved in 3 patients, dressing in 1 patient, and ambulation in 1 patient. Three patients thought the procedure had been beneficial, 2 claimed having no benefit from radiosurgery, and 1 was uncertain. 3.3. Complications One patient suffered a progressive hemiparesis contralateral to the GK lesion 4 months after radiosurgery. Increased T2 signal changes were noted in MRI around the lesion, extending into the internal capsule. This event was managed with corticosteroid therapy for several weeks, after which the neurologic deficit and T2 changes completely resolved. 4. Discussion Tremor is a common symptom of MS. Tremor of moderate and severe magnitude has been reported in 25% and 6% of MS patients, respectively [20]. The pathophysiology of MS-related tremor is not completely understood, but it likely involves demyelinating plaques in the cerebellum, midbrain, and connections between these structures and the thalamus [2]. Severe tremor can
lead to significant disability, interfering with activities of daily living, particularly feeding. Medical treatment of MS-related tremor is usually unsuccessful. Medications used for essential tremor, such as propranolol, primidone, and ethyl alcohol generally provide no benefit in this setting [2]. Other agents, such as isoniazid and cannabinoids, have been tried in prospective studies, but their effect has been modest at best [5,8,10,26]. Based on the success of stereotactic surgery in the management of parkinsonian and essential tremor, neurosurgical management of MS-related tremor has been proposed as a palliative way to improve the quality of life of patients affected by this disability. A few studies have reported success in alleviating MS tremor with either radiofrequency thalamotomy or thalamic DBS [1,3,4,6,11,12,14,16,21,22,24]. Critchley and Richardson [6] reported the results of 29 vim thalamotomies, which were performed on 24 patients suffering from severe intention tremor. It immediately improved arm function in 79% of the procedures. Within 10 months, however, 7 patients had tremor recurrence. Montgomery et al [16] implanted a vim deep brain stimulator in 15 patients, and all were improved postoperatively. Tolerance to the stimulation effect eventually developed in all patients, which necessitated reprogramming of the stimulator. Twelve patients were treated by Berk et al [3] with thalamic DBS. Tremor scores dropped to values ranging from 58% to 70% of preoperative values at 2 months of follow-up, and these results were maintained at 12 months. Quality of life, however, was not significantly improved at 12 months. Bittar et al [4] compared the results of thalamotomy and DBS in the setting of MS-related tremor. Ten patients were treated using each modality. However, the groups were not randomly assigned. Both groups were improved in regard to postural and intention tremor, although thalamotomy
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D. Mathieu et al. / Surgical Neurology 68 (2007) 394 – 399
seemed superior to DBS for the relief of intention tremor (72% vs 36% of improvement in the tremor severity). Permanent significant complications were more common in the thalamotomy group (30% vs 10%), which prompted the authors to quote that DBS should probably be the preferred initial option. However, patients with MS are often significantly debilitated, either by tremor or from other manifestations of the disease. Thus, for this population, a less invasive management modality might be preferable. Gamma knife radiosurgery has demonstrated efficacy when targeting the vim nucleus of the thalamus for the relief of parkinsonian or essential tremor [7,18,25]. Management of MS-related tremor with the GK seems to be a logical evolution based on its success in tremor of other etiologies. In our series, tremor contributed significantly to this disability by interfering with important daily activities, especially feeding. After radiosurgery, tremor amplitude improved from a median value of 4 to a median of 1.5 on the Fahn-Tolosa-Marin scale. A median delay of 2.5 months elapsed before the effect appeared. This did not translate in improvement of writing or drawing skills, however, with median values of 4 and 3.5, respectively, after radiosurgery. These results highlight the fact that MS affects the entire central nervous system, and underlying neurologic deficits, particularly hemiparesis and ataxia, which also contribute to disability, are not improved after GK thalamotomy. Nevertheless, global functional improvement in the activities of daily living was noted in 4 patients according to their caregivers. Two patients experienced some recurrence of tremor after a period of 12 and 18 months, respectively, after radiosurgery, although it was not as severe as before the procedure. Underlying disease progression certainly accounts for this fact, which is also documented in radiofrequency lesioning and DBS series [3,22,23]. It has been suggested that MS-related tremor might respond more favorably to lesioning of the vop nucleus and ZI than the vim [4]. Dentate nucleus projections, which are postulated to contribute to tremor, pass through the ZI on their way to the thalamus. However, targeting this pathway might not be safely achievable with the GK, without the information provided by physiologic monitoring used during more invasive surgical procedures. The major advantage of GK over these procedures is its greater safety profile and the possible ability to affect neuronal function more than with a radiofrequency lesion. Accordingly, the only complication seen in our series was transient hemiparesis in 1 patient, which resolved after a brief course of steroids. Complication rates for DBS and radiofrequency lesioning have been higher when performed for the treatment of MS-related tremor, compared to parkinsonian or essential tremor [4,6,14,16]. Lesser cerebral reserve caused by the global disease burden in MS patients has been postulated to explain these high rates of complications. As a note of caution, it has been reported that MS patients might be more susceptible to demyelination induced by radiation than patients without underlying demyelinating disease
[17,19]. This was postulated to be due to blood-brain barrier breakdown following radiation, which might allow the immune system to interact with white matter myelin. However, those cases were seen after wide field fractionated radiation. So far, this has not been reported after GK radiosurgery for patients suffering from trigeminal neuralgia related to MS, and neither have we seen this complication in our series of thalamotomy for MS tremor. The very sharp falloff of radiation associated with the use of the 4-mm collimator, which limits total radiation to the brain, could explain why radiation-induced demyelination has not been reported after radiosurgery. Keeping this in mind, our results suggest that GK thalamotomy is adequate as a minimally invasive alternative to radiofrequency thalamotomy and thalamic DBS for severely debilitated patients afflicted with MS-related tremor.
5. Conclusion Gamma knife thalamotomy is an effective management alternative for MS tremor. However, more experience will be required to evaluate longer-term effects and more specific effects on function. At the present time, this procedure should be regarded as palliative only because disability often is caused by multiple manifestations of the disease. As such, it should probably be offered to patients unable to tolerate or unwilling to undergo DBS.
References [1] Alusi SH, Aziz TZ, Glickman S, et al. Stereotactic lesional surgery for the treatment of tremor in multiple sclerosis: a prospective casecontrolled study. Brain 2001;124:1576 - 89. [2] Alusi SH, Glickman S, Aziz TZ, et al. Tremor in multiple sclerosis. J Neurol Neurosurg Psychiatry 1999;66:131 - 4. [3] Berk C, Carr J, Sinden M, et al. Thalamic deep brain stimulation for the treatment of tremor due to multiple sclerosis: a prospective study of tremor and quality of life. J Neurosurg 2002;97:815 - 20. [4] Bittar RG, Hyam J, Nandi D, et al. Thalamotomy versus thalamic stimulation for multiple sclerosis tremor. J Clin Neurosci 2005; 12:638 - 42. [5] Bozek CB, Kastrukoff LF, Wright JM, et al. A controlled trial of isoniazid therapy for action tremor in multiple sclerosis. J Neurol 1987;234:36 - 9. [6] Critchley GR, Richardson PL. Vim thalamotomy for the relief of the intention tremor of multiple sclerosis. Br J Neurosurg 1998;12: 559 - 62. [7] Duma CM, Jacques DB, Kopyov OV, et al. Gamma knife radiosurgery for thalamotomy in parkinsonian tremor: a five-year experience. J Neurosurg 1998;88:1044 - 9. [8] Duquette P, Pleines J, du Souich P. Isoniazid for tremor in multiple sclerosis: a controlled trial. Neurology 1985;35:1772 - 5. [9] Fahn S, Tolosa E, Marin C. Clinical rating scale for tremor. In: Jankovic J, Tolosa E, editors. Parkinson’s disease and movement disorders. Baltimore7 Williams and Wilkins; 1993. p. 271 - 80. [10] Fox P, Bain PG, Glickman S, et al. The effect of cannabis on tremor in patients with multiple sclerosis. Neurology 2004;62:1105 - 9. [11] Geny C, Nguyen JP, Pollin B, et al. Improvement of severe postural cerebellar tremor in multiple sclerosis by chronic thalamic stimulation. Mov Disord 1996;11:489 - 94.
D. Mathieu et al. / Surgical Neurology 68 (2007) 394 – 399 [12] Haddow LJ, Mumsford C, Whittle IR. Stereotactic treatment of tremor due to multiple sclerosis. Neurosurg Q 1997;7:23 - 34. [13] Hooper J, Taylor R, Pentland B, et al. Rater reliability of Fahn’s tremor rating scale in patients with multiple sclerosis. Arch Phys Med Rehabil 1998;79:1076 - 9. [14] Hooper J, Taylor R, Pentland B, et al. A prospective study of thalamic deep brain stimulation for the treatment of movement disorders in multiple sclerosis. Br J Neurosurg 2002;16:102 - 9. [15] Kondziolka D. Functional radiosurgery. Neurosurgery 1999;44:12 - 20 [discussion -2]. [16] Montgomery Jr EB, Baker KB, Kinkel RP, et al. Chronic thalamic stimulation for the tremor of multiple sclerosis. Neurology 1999; 53:625 - 8. [17] Murphy CB, Hashimoto SA, Graeb D, et al. Clinical exacerbation of multiple sclerosis following radiotherapy. Arch Neurol 2003; 60:273 - 5. [18] Niranjan A, Jawahar A, Kondziolka D, et al. A comparison of surgical approaches for the management of tremor: radiofrequency thalamotomy, gamma knife thalamotomy and thalamic stimulation. Stereotact Funct Neurosurg 1999;72:178 - 84. [19] Peterson K, Rosenblum MK, Powers JM, et al. Effect of brain irradiation on demyelinating lesions. Neurology 1993;43:2105 - 12.
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[20] Pittock SJ, McClelland RL, Mayr WT, et al. Prevalence of tremor in multiple sclerosis and associated disability in the Olmsted County population. Mov Disord 2004;19:1482 - 5. [21] Schulder M, Sernas T, Mahalick D, et al. Thalamic stimulation in patients with multiple sclerosis. Stereotact Funct Neurosurg 1999;72: 196 - 201. [22] Schulder M, Sernas TJ, Karimi R. Thalamic stimulation in patients with multiple sclerosis: long-term follow-up. Stereotact Funct Neurosurg 2003;80:48 - 55. [23] Whittle IR, Haddow LJ. CT guided thalamotomy for movement disorders in multiple sclerosis: problems and paradoxes. Acta Neurochir Suppl 1995;64:13 - 6. [24] Wishart HA, Roberts DW, Roth RM, et al. Chronic deep brain stimulation for the treatment of tremor in multiple sclerosis: review and case reports. J Neurol Neurosurg Psychiatry 2003;74:1392 - 7. [25] Young RF, Jacques S, Mark R, et al. Gamma knife thalamotomy for treatment of tremor: long-term results. J Neurosurg 2000;93 (Suppl 3):128 - 35. [26] Zajicek J, Fox P, Sanders H, et al. Cannabinoids for treatment of spasticity and other symptoms related to multiple sclerosis (CAMS study): multicentre randomised placebo-controlled trial. Lancet 2003;362:1517 - 26.
Radiosurgery
Gamma knife thalamotomy for multiple sclerosis tremorB David Mathieu, MD, Douglas Kondziolka, MD4, Ajay Niranjan, MCh, John Flickinger, MD, L. Dade Lunsford, MD Department of Neurological Surgery, University of Pittsburgh, Center for Image-Guided Neurosurgery, Pittsburgh, PA 15213, USA Department Radiation Oncology, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA Received 6 March 2006; accepted 14 November 2006
Abstract
Background: Some patients with MS suffer from disabling tremor. Improvement with medical treatment is modest, at best. Stereotactic surgery targeting the vim nucleus of the thalamus has been successful in alleviating MS tremor. Gamma knife radiosurgery represents a minimally invasive alternative to radiofrequency lesioning and DBS that can provide improvement in patients suffering from essential and parkinsonian tremor. We reviewed our experience with GK thalamotomy in the management of six consecutive patients suffering from disabling MS tremor. Methods: The median age at the time of radiosurgery was 46 years (range, 31 to 57 years). Intention tremor had been present for a median of three years (range 8 months to 12 years). One 4-mm isocenter was used to deliver a median maximum dose of 140 Gy (range, 130-150 Gy) to the vim nucleus of the thalamus opposite the side of the most disabling tremor. Clinical outcome was assessed using the Fahn-Tolosa-Marin scale. Results: The median follow-up was 27.5 months (range, 5-46 months). All patients experienced improvement in tremor after a median latency period of 2.5 months. More improvement was noted in tremor amplitude than in writing and drawing ability. In four patients, the tremor reduction led to functional improvement. One patient suffered from transient contralateral hemiparesis, which resolved after brief corticosteroid administration. No other complication was seen. Conclusion: Gamma knife radiosurgical thalamotomy is effective as a minimally invasive alternative to stereotactic surgery for the palliative treatment of disabling MS tremor. D 2007 Elsevier Inc. All rights reserved.
Keywords:
Gamma knife; Radiosurgery; Thalamotomy; vim nucleus; Multiple sclerosis; Tremor
1. Introduction Multiple sclerosis is a chronic central nervous system– demyelinating disease. Tremor is estimated to occur in
Abbreviations: AC, anterior commissure; DBS, deep brain stimulation; FIR, fast inversion recovery; FU, follow-up; GK, gamma knife; MRI, magnetic resonance imaging; MS, multiple sclerosis; PC, posterior commissure; SPGR, Spoiled-Gradient Recalled Acquisition in Steady State; vim, ventralis intermedius; vop, ventralis oralis posterior; ZI, zona incerta. B Douglas Kondziolka, MD, Ajay Niranjan, MCh, and L Dade Lunsford, MD, are consultants for Elekta Instruments, Atlanta, Ga. 4 Corresponding author. UPMC Presbyterian Department of Neurosurgery, Pittsburgh, PA, 15213, USA. Tel.: +1 412 647 6782; fax: +1 412 647 8447. E-mail address: [email protected] (D. Kondziolka). 0090-3019/$ – see front matter D 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.surneu.2006.11.049
approximately 25% of MS patients and can be severely disabling in 6% [20]. It is most often an intention tremor that affects the upper extremities, although a resting component is sometimes present. Medical treatment of tremor in MS patients is often disappointing. No drug clearly has emerged as superior to another, and those presently in use provide modest benefit at best [2]. Stereotactic radiofrequency thalamotomy and thalamic DBS of the vim nucleus have been shown to improve tremor in MS patients [2]. Drawbacks of those procedures include their invasiveness and the fact that a significant proportion of patients experience recurrence of tremor in the months after surgery. As a less invasive treatment modality, GK radiosurgery has proven effective in the treatment of parkinsonian and essential tremor, especially in patients who
D. Mathieu et al. / Surgical Neurology 68 (2007) 394 – 399
may not be good candidates for radiofrequency thalamotomy or thalamic DBS [15,18]. The goal of the present study is to report our experience with GK radiosurgery in the management of 6 patients suffering from disabling MS-related tremor. 2. Methods Between May 1998 and August 2000, 6 consecutive patients with severe tremor related to MS had radiosurgery at the University of Pittsburgh Medical Center. Every patient was referred by a neurologist with expertise in the management of MS. They consisted of 3 male and three female individuals, all of white origin. The median age at the time of radiosurgery was 46 years (mean, 44.5 years; range, 31-57 years). Two patients suffered from primary progressive MS, 2 from secondary progressive MS, and 2 from relapsing progressive MS. Median time from the diagnosis of MS to radiosurgery was 16 years (mean, 14.8 years; range, 4.9-25 years). All patients were severely disabled by their disease, 5 of them being wheelchair-bound or bed-bound. The tremor had been present for a median interval of 3 years before GK radiosurgery was undertaken (mean, 4.6 years; range, 10 months to 12 years). The tremor was characterized as intention (rubral) tremor in all patients. In addition, one patient had a resting tremor component. Tremor involved the bilateral upper extremities in all but 1 patient, who had only the right side involved. Head bobbing was also observed in 3 of 6 patients. Various trials of antitremor medications, including propranolol, baclofen, clonazepam,
395
ondansetron, isoniazid and primidone, did not provide satisfactory control of the tremor in any of the patients. Preoperatively, the tremor was graded according to elements of the Fahn-Tolosa-Marin scale [9], which has proven to be reliable to evaluate MS-related tremor [13]. Tremor amplitude, writing, and drawing were evaluated on a scale of 0 (best) to 4 (worst). Tremor amplitude was evaluated by having patients perform the finger-to-nose test. For drawing ability assessment, patients were asked to draw an Archimedes spiral. Tremor was severe in every patient, with median values of 4 on every item of the scale. Typically, the tremor was coarse, jerking, and more severe than in essential tremor patients. It caused a significant impairment in the activities of daily living in every patient, interfering particularly with the ability to feed, drink, and dress. Informed consent was obtained with the patients and their family, after reviewing the different management options, including radiofrequency lesioning and DBS. Gamma knife radiosurgery was preferred as a palliative measure in view of its noninvasiness. Patients were admitted the morning of the procedure. After adequate local anesthesia and sedation, the Leksell G frame (Elekta Instruments, Atlanta, Ga) was attached to the patient’s head. Sagittal scout fast spin echo images were obtained first. After identifying the anterior and PC in sagittal images, high-resolution, 1-mm-thick contrast-enhanced SPGR volumetric images covering the entire thalamus in the axial plane were obtained. We next performed FIR images to differentiate basal ganglia from white matter tracts. The image series was transferred via Ethernet to the planning
Fig. 1. GammaPlan software snapshot showing MRI SPGR images in axial poster (left) with coronal (upper right) and sagittal (lower right) reconstruction. Using stereotactic coordinates, the 50% isodose line of a single 4-mm collimator shot is placed to target the right vim nucleus.
396
D. Mathieu et al. / Surgical Neurology 68 (2007) 394 – 399
Table 1 Pertinent clinical information related to treated patients Patient
Age (y), sex
MS type
MS duration (y)
1 2 3 4 5 6
49, 44, 48, 57, 38, 31,
Relapsing progressive Secondary progressive Primary progressive Secondary progressive Relapsing progressive Primary progressive
5 20 25 18 7 14
M F M F M F
Tremor duration (y) 0.83 8 3 3 1 12
Initial tremor score 4 4 4 4 4 4
Max dose (Gy)
FU length (mo)
140 130 140 150 150 140
30 5 42 46 5 25
Tremor score post GK 2 3 2 1 0 1
computer. Using the GammaPlan software (Elekta Instruments), a single 4-mm isocenter was placed, targeting the vim nucleus on the side opposite to the more disabling tremor. The initial thalamic coordinates were obtained using the following formula: x = from the midline, half of the 3rd ventricular width, plus 11 mm; y = from the PC, one fourth of the AC-PC length plus 1 or 2 mm; z = 2 or 2.5 mm above the AC-PC line plane. The coordinates were calculated using high-resolution, 1-mm-thick contrast-enhanced SPGR images. The 50% isodose line using these coordinates with a 4-mm collimator were projected on both SPGR and FIR images. The final adjustments in the target coordinates were made according to the position of the internal capsule and thalamus in FIR images. Five patients were treated on the left side, and 1, on the right side (this patient was lefthanded). A median maximum dose of 140 Gy (range, 130150 Gy) was delivered to the target using a GK model U or B (Elekta Instruments). No beam channel plugging pattern was used. Fig. 1 exemplifies a typical dose plan for GK thalamotomy. Patients were kept overnight in the hospital for observation and were discharged the following day. Clinical follow-up was obtained between 3 to 6 months after radiosurgery and annually thereafter. The Fahn-TolosaMarin scale was used to assess tremor evolution. A followup MRI was scheduled after 6 months to assess for any radiosurgery-induced imaging changes. All evaluations were based on the referring neurologist assessment of clinical improvement and were done by an independent observer. Statistical analysis of the improvement in tremor scores was performed using the SPSSR 13.0 software (SPSS Inc, Chicago, Ill).
(range, 2-3 months). The amplitude of the tremor was the element that improved the most, with a median improvement of 2.5 points on the Fahn-Tolosa-Marin scale (from a median of 4, pre GK, to a median of 1.5 after radiosurgery, P b .0005). Absolute values for this score ranged from 0 to 3 after radiosurgery. The improvement was not as good on the writing and drawing scores. The median pre-GK score was 4 for both of these items. The median writing score remained at 4 after radiosurgery (range, 2-4), whereas the drawing score improved to a median of 3.5 (range, 1-4; P = .034, when compared to pre-GK score). Table 2 reports the Fahn-TolosaMarin scores before and after radiosurgery. The clinical improvement was corroborated by the patient’s referring neurologists. Longer follow-up revealed recurrence of
3. Results
3 4
Every patient was assessable for treatment outcome. Median follow-up length was 27.5 months (mean, 25.5 months; range, 5-46 months). No acute adverse events were seen after the procedure. Three patients eventually died from complications of the primary disease, MS (3, 4, and 4 years after the procedure, respectively). These deaths were deemed unrelated to the GK procedure. Table 1 summarizes the main clinical data for all patients.
Table 2 Grading of tremor amplitude, writing, and drawing according to the FahnTolosa scale, before and after radiosurgery (n = 6 patients) Grades Tremor 0 1 2 3 4 Writing 0 1 2
Drawing 0 1 2
3.1. Tremor improvement
3
Radiosurgical thalamotomy was beneficial for every patient. Median time to improvement was 2.5 months
4 a
Clinical assessment
Before GK (n)
After GKa (n)
No tremor Slight: barely perceivable, may be intermittent Moderate: amplitude b 2 cm, may be intermittent Marked: amplitude 2-4 cm Severe: amplitude N 4 cm
0 0
1 2
0
2
0 6
1 0
Normal Mildly abnormal, slightly untidy, tremulous Moderately abnormal, legible, but with considerable tremor Markedly abnormal, illegible Severely abnormal, unable to keep pencil or pen on paper without holding hands down with the other hand
0 0
0 0
0
1
0 6
0 5
Normal Slightly tremulous, may cross lines occasionally Moderately tremulous, cross lines frequently Accomplishes task with great difficulty, many errors Unable to complete the drawing
0 0
0 1
0
0
1
2
5
3
Median follow-up of 27.5 months.
D. Mathieu et al. / Surgical Neurology 68 (2007) 394 – 399
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Fig. 2. Brain MRI performed 2 years after GK thalamotomy. Contrast-enhanced axial T1-weighted image demonstrating a ring-enhancing lesion in the left vim nucleus (left). Axial T2-weighted image showing the lesion in the left vim nucleus with minimal changes in the surrounding brain (right).
tremor in 2 patients after a period of 12 and 18 months, respectively, had elapsed. Recurrent tremor was not as severe and disabling as it was before radiosurgery. In addition, the only patient with unilateral involvement eventually developed tremor on the uninvolved side. Routine follow-up MRI demonstrated an adequate vim lesion in every patient (Fig. 2). 3.2. Functional improvement Reduction in tremor amplitude after radiosurgery led to functional improvement in 4 patients, according to the patients’ main caregivers. Feeding and drinking ability improved in 3 patients, dressing in 1 patient, and ambulation in 1 patient. Three patients thought the procedure had been beneficial, 2 claimed having no benefit from radiosurgery, and 1 was uncertain. 3.3. Complications One patient suffered a progressive hemiparesis contralateral to the GK lesion 4 months after radiosurgery. Increased T2 signal changes were noted in MRI around the lesion, extending into the internal capsule. This event was managed with corticosteroid therapy for several weeks, after which the neurologic deficit and T2 changes completely resolved. 4. Discussion Tremor is a common symptom of MS. Tremor of moderate and severe magnitude has been reported in 25% and 6% of MS patients, respectively [20]. The pathophysiology of MS-related tremor is not completely understood, but it likely involves demyelinating plaques in the cerebellum, midbrain, and connections between these structures and the thalamus [2]. Severe tremor can
lead to significant disability, interfering with activities of daily living, particularly feeding. Medical treatment of MS-related tremor is usually unsuccessful. Medications used for essential tremor, such as propranolol, primidone, and ethyl alcohol generally provide no benefit in this setting [2]. Other agents, such as isoniazid and cannabinoids, have been tried in prospective studies, but their effect has been modest at best [5,8,10,26]. Based on the success of stereotactic surgery in the management of parkinsonian and essential tremor, neurosurgical management of MS-related tremor has been proposed as a palliative way to improve the quality of life of patients affected by this disability. A few studies have reported success in alleviating MS tremor with either radiofrequency thalamotomy or thalamic DBS [1,3,4,6,11,12,14,16,21,22,24]. Critchley and Richardson [6] reported the results of 29 vim thalamotomies, which were performed on 24 patients suffering from severe intention tremor. It immediately improved arm function in 79% of the procedures. Within 10 months, however, 7 patients had tremor recurrence. Montgomery et al [16] implanted a vim deep brain stimulator in 15 patients, and all were improved postoperatively. Tolerance to the stimulation effect eventually developed in all patients, which necessitated reprogramming of the stimulator. Twelve patients were treated by Berk et al [3] with thalamic DBS. Tremor scores dropped to values ranging from 58% to 70% of preoperative values at 2 months of follow-up, and these results were maintained at 12 months. Quality of life, however, was not significantly improved at 12 months. Bittar et al [4] compared the results of thalamotomy and DBS in the setting of MS-related tremor. Ten patients were treated using each modality. However, the groups were not randomly assigned. Both groups were improved in regard to postural and intention tremor, although thalamotomy
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seemed superior to DBS for the relief of intention tremor (72% vs 36% of improvement in the tremor severity). Permanent significant complications were more common in the thalamotomy group (30% vs 10%), which prompted the authors to quote that DBS should probably be the preferred initial option. However, patients with MS are often significantly debilitated, either by tremor or from other manifestations of the disease. Thus, for this population, a less invasive management modality might be preferable. Gamma knife radiosurgery has demonstrated efficacy when targeting the vim nucleus of the thalamus for the relief of parkinsonian or essential tremor [7,18,25]. Management of MS-related tremor with the GK seems to be a logical evolution based on its success in tremor of other etiologies. In our series, tremor contributed significantly to this disability by interfering with important daily activities, especially feeding. After radiosurgery, tremor amplitude improved from a median value of 4 to a median of 1.5 on the Fahn-Tolosa-Marin scale. A median delay of 2.5 months elapsed before the effect appeared. This did not translate in improvement of writing or drawing skills, however, with median values of 4 and 3.5, respectively, after radiosurgery. These results highlight the fact that MS affects the entire central nervous system, and underlying neurologic deficits, particularly hemiparesis and ataxia, which also contribute to disability, are not improved after GK thalamotomy. Nevertheless, global functional improvement in the activities of daily living was noted in 4 patients according to their caregivers. Two patients experienced some recurrence of tremor after a period of 12 and 18 months, respectively, after radiosurgery, although it was not as severe as before the procedure. Underlying disease progression certainly accounts for this fact, which is also documented in radiofrequency lesioning and DBS series [3,22,23]. It has been suggested that MS-related tremor might respond more favorably to lesioning of the vop nucleus and ZI than the vim [4]. Dentate nucleus projections, which are postulated to contribute to tremor, pass through the ZI on their way to the thalamus. However, targeting this pathway might not be safely achievable with the GK, without the information provided by physiologic monitoring used during more invasive surgical procedures. The major advantage of GK over these procedures is its greater safety profile and the possible ability to affect neuronal function more than with a radiofrequency lesion. Accordingly, the only complication seen in our series was transient hemiparesis in 1 patient, which resolved after a brief course of steroids. Complication rates for DBS and radiofrequency lesioning have been higher when performed for the treatment of MS-related tremor, compared to parkinsonian or essential tremor [4,6,14,16]. Lesser cerebral reserve caused by the global disease burden in MS patients has been postulated to explain these high rates of complications. As a note of caution, it has been reported that MS patients might be more susceptible to demyelination induced by radiation than patients without underlying demyelinating disease
[17,19]. This was postulated to be due to blood-brain barrier breakdown following radiation, which might allow the immune system to interact with white matter myelin. However, those cases were seen after wide field fractionated radiation. So far, this has not been reported after GK radiosurgery for patients suffering from trigeminal neuralgia related to MS, and neither have we seen this complication in our series of thalamotomy for MS tremor. The very sharp falloff of radiation associated with the use of the 4-mm collimator, which limits total radiation to the brain, could explain why radiation-induced demyelination has not been reported after radiosurgery. Keeping this in mind, our results suggest that GK thalamotomy is adequate as a minimally invasive alternative to radiofrequency thalamotomy and thalamic DBS for severely debilitated patients afflicted with MS-related tremor.
5. Conclusion Gamma knife thalamotomy is an effective management alternative for MS tremor. However, more experience will be required to evaluate longer-term effects and more specific effects on function. At the present time, this procedure should be regarded as palliative only because disability often is caused by multiple manifestations of the disease. As such, it should probably be offered to patients unable to tolerate or unwilling to undergo DBS.
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