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Pallidal surgery for the treatment of primary generalized dystonia: Long-term follow-up
Clinical Neurology and Neurosurgery 110 (2008) 145–150
Pallidal surgery for the treatment of primary generalized dystonia: Long-term follow-up Maria G. Cersosimo ∗ , Gabriela B. Raina, Fabian Piedimonte, Julio Antico, Pablo Graff, Federico E. Micheli Parkinson’s Disease and Movement Disorder Unit, Hospital de Cl´ınicas, University of Buenos Aires, Argentina Received 1 May 2007; received in revised form 1 October 2007; accepted 3 October 2007
Abstract Objective: To describe the results and long-term follow-up after functional surgery of the internal segment of the globus pallidus (GPi) in 10 patients with primary generalized dystonia. Patients and methods: Nine of the 10 patients were positive for the DYT1 gene mutation. Bilateral deep brain stimulation (DBS) of the GPi was performed in three cases, bilateral pallidotomy in two, and combined surgery (unilateral GPi lesion with contralateral stimulation) in the remaining five. All patients were evaluated with the Burke–Fahn–Marsden dystonia scale (BFMDS) before, immediately after surgery, at 3 weeks, 3 and 6 months and then yearly. Follow up time ranged from 15 to 105 months (mean: 66.1 months) with six patients having more than 6 years follow up. Results: All patients improved after surgery. All patients with unilateral or bilateral DBS experienced an immediate improvement before starting stimulation. The magnitude of this initial micro lesion effect did not predict the magnitude of the long-term benefit of DBS. The mean decrease in the in the BFMDS was 34%, 55%, and 65% in the movement scale; and 32%, 48%, and 49% in the disability scale for patients with bilateral pallidal DBS, combined unilateral DBS and contralateral pallidotomy, and bilateral pallidotomy, respectively. Worsening of dystonia after a plateau of sustained benefit was observed in three patients. Two patients required multiple pallidal surgeries. Adverse events included: permanent anarthria (1), misplacement of the electrode requiring further surgery (2), scalp infection (1), and hardware related problems (3). Conclusions: This long-term follow up study confirms the beneficial effect of pallidal DBS or pallidotomy in primary generalized dystonia. In addition, our results extent previous observations by showing that, in these patients, (1) the microlesion effect of DBS is not predictive of long-term benefit; (2) combined DBS with contralateral pallidotomy appears to be more effective than bilateral pallidal DBS; and (3) dystonia can reappear after an initial good response during long term follow up. © 2007 Elsevier B.V. All rights reserved. Keywords: Primary generalized dystonia; DBS; Pallidotomy
1. Introduction Dystonia is a syndrome characterized by repetitive and sustained muscle contractions that result in twisting movements and abnormal postures [1]. When dystonia is the only clinical feature and the etiology is unknown the disorder is considered primary or idiopathic dystonia. Recently, several gene mutations have been recognized in association with a growing number of primary dystonic syndromes [2]. ∗ Corresponding author at: Pe˜ na 2225- P 5 Dpto C (1126), Buenos Aires, Argentina. Tel.: +54 4812 5732; fax: +54 4811 3076. E-mail address: [email protected] (M.G. Cersosimo).
0303-8467/$ – see front matter © 2007 Elsevier B.V. All rights reserved. doi:10.1016/j.clineuro.2007.10.003
According to the extent and body regions affected, dystonia may be classified as focal, segmental, hemi corporal or generalized [3]. Primary generalized dystonia (PGD) is a disabling condition, and its response to pharmacological therapy is usually disappointing. In the past decade, the observation that lesioning of the internal segment of the globus pallidus (GPi) improved off period dystonia and levodopa induced dyskinesias in patients with Parkinson’s disease suggested that the GPi could be a good target for the treatment of dystonias [4–6]. Since then, surgical treatment of PGD by lesion or deep brain stimulation (DBS) of the posteroventral GPi has received increasing attention and a growing number of patients undergoing pallidal surgery for
146
M.G. Cersosimo et al. / Clinical Neurology and Neurosurgery 110 (2008) 145–150
the treatment of dystonia have been reported in the literature [7–13]. However, with few exceptions [14] most published series included either few cases or relatively short follow up following surgery [15]. The aim of this study was to determine the outcome of 10 PGD patients who underwent bilateral GPi DBS, bilateral pallidotomy, or combined unilateral DBS and contralateral lesion DBS in a single center and have been followed, in most cases, for at least 6 years after surgery.
2. Patients From October 1998 to March 2006, 10 patients (six females and four males) with disabling and medically refractory PGD underwent functional bilateral pallidal surgery at the Parkinson Disease Center, Hospital de Clinicas, University of Buenos Aires, Argentina (Table 1). The diagnosis of PGD was made when at least one limb, the trunk and any other body segment was involved, the rest of the neurological examination and brain magnetic resonance imaging (MRI) were normal, and secondary causes were excluded. Nine of the 10 patients harbored the DYT1 mutation. The mean age of patients at the time of surgery was 15 years old (range: 9–28 years old); mean age at disease onset was 9.8 years (range: 5–24 years); and mean disease duration was 5.2 years (range: 2–13 years). Three of the patients were on baclofen, two were on diazepam and one was on trihexyphenidyl at the time of surgery. The remaining patients had failed to respond to drug therapy. Case 10 had a previous unilateral thalamic lesion performed by another medical group 3 years before. All patients gave informed consent for the surgical procedure according to the institutional review board requirements.
3. Methods 3.1. Neurological evaluations All patients were evaluated before and at different times after surgery with the Burke-Fahn-Marsden Dystonia Scale (BFMDS) movement and disability subscores [16]. Post operative evaluations were performed within the first 24 h after surgery with the stimulator off; at 3 weeks at the time of onset of stimulation, at 3, 6 and 12 months during the first year, and at least once a year thereafter. All evaluations were performed by the same neurologist. Mean follow up duration was 66.1 months (range: 15–105 months). Six patients had been followed for more than 6 years (6–8.7 years). 3.2. Surgical intervention Two patients underwent bilateral pallidotomy, three bilateral pallidal DBS, and five unilateral pallidal DBS with a contralateral lesion (combined surgery). Among patients with combined surgery, the lesion was in the GPi in all cases except for case 10 who had a previous unilateral thalamotomy. The surgical procedures in the first six cases had been performed by two different neurosurgical groups while the last four patients were operated by the same group. The decision to perform either bilateral GPi stimulation or lesion was made in each case primarily driven by the cost of the procedure. In cases 1 and 2, cost restraints prevented the patients from undergoing DBS and bilateral pallidotomy was performed to alleviate the disabling dystonia. In five cases, unilateral GPi DBS was combined to contralateral GPi lesion to reduce the expense of surgery and follow-up. All bilateral procedures were performed on same session. Case 10 had a previous contralateral thalamotomy. In
Table 1 Demographic data of patients Case
Gender
Age at disease onset
Disease duration (years)
Age at surgery (years)
DYT1 mutation
Family history of dystonia
Pharmacologic treatment
Follow up Months
Years
Sister with GD (case 3) Brother with focal dystonia Sister with GD (case 1)
BCF 100 mg/d
105
8.7
103
8.5
93
7.7
92 82
7.6 6.8
82
6.8
35 33
2.9 2.7
21 15
1.7 1.2
1
F
6
13
19
Yes
2
M
10
4
14
Yes
3
F
6
4
10
Yes
4 5
M F
7 8
8 2
15 10
No Yes
6
F
9
4
13
Yes
7 8
M F
24 5
4 4
28 9
Yes Yes
9 10
M F
16 7
3 6
19 13
Yes Yes
BCF 90 mg/d DZ 40 mg/d THF 80 mg/d
Sister with GD (case 6) Sister with GD (case 5) Mother with blepharospasm
M = male F = female BCF = baclofen DZ = diazepam THF = trihexyphenidyle GD = generalized dystonia.
BCF 30 mg/d
M.G. Cersosimo et al. / Clinical Neurology and Neurosurgery 110 (2008) 145–150
all cases the electrodes and the implantable pulse generator (IPG) were implanted during the same intervention. Microelectrode recordings were obtained in all patients. Patients were operated under local anesthesia except for the implantation of the extension wire and the pulse generator that was performed under general anesthesia. 3.3. DBS programming Stimulation was initiated after 3 weeks of surgery in a monopolar mode using the deepest contacts, usually contact 0 or contact 1 which were set to negative while the case was set as positive. The initial stimulation settings were a pulse width of 210 ms, a frequency of 135 Hz and an amplitude of 2 V. The time between each programming session was not standardized. We changed parameters when a satisfactory response was not achieved or if adverse events were thought to be related to stimulation. When possible, voltage was not increased above 3.6 V. If no benefit was achieved with these parameters, width pulse or frequency were gradually increased up to 400 ms or 185 Hz, respectively. If clinical response was still poor, then the next contact was used, and the same steps were followed. When monopolar stimulation was associated with undesired side effects, the bipolar stimulation mode using two contiguous electrodes was used.
147
Mean stimulation parameters used in our patients were: width pulse of 286 ms (range: 210–400 ms); frequency of 137 Hz (range: 135–185 Hz), and amplitude of 2.9 V (range: 2.4–3.5 V). Among the 11 electrodes implanted (6 in the bilateral GPi DBS patients and 5 in the unilateral DBS patients), 6 were programmed in a monopolar mode using the case as anode and contacts 0 or 1 as cathode and the remaining five electrodes were set in a bipolar mode using two contiguous contacts.
4. Results 4.1. Effect of bilateral GPi stimulation and or lesion All 10 patients improved following surgery, both in the BFMDS movement and disability scores and regardless the type of procedure (Tables 2 and 3). We considered that maximal improvement was obtained when scores of BFMDS remained unchanged after successive evaluations. The time to achieve the maximal benefit was highly variable among patients, ranging from 24 h (case 7) to 24 months (case 8), and was not related with the type of surgical procedure. In all patients undergoing unilateral or bilateral pallidal DBS (n = 8) an immediate and temporary improvement of dystonic symptoms was observed. This effect was more
Table 2 BFMD Movement Scale score (maximal = 120) Cases
1 2 3 4 5 6 7 8 9 10
Pre operative score
108 42 67 96 52 81 16.5 45 33 39
Surgery
Bilateral pallidotomy Bilateral pallidotomy Bilateral DBS Lesion + DBS Lesion + DBS Lesion + DBS Bilateral DBS Bilateral DBS Lesion + DBS Lesion + DBS
Post operative score 3m
6m
12 m
24 m
36 m
48 m
60 m
72 m
84 m
96 m
70 10 45 66 17 1 5 30 25 27
66 10 34 64 18 1 5 28 24 21
42 10 34 60.5 17 1 4 30 12 16
21 10 55 61 17 1 5 21
22 10 42 63 17 1 5
21 10 39 61 18 12
21 11 56 90 28 18
22 32 55 85 28 20
21 48 45 66
21 50
m = months. Table 3 BFMD disability scale scores (maximal = 30) Cases
Pre operative score
Surgery
1 2 3 4 5 6 7 8 9 10
26 12 20 28 19 26 6 12 13 9
Bilateral pallidotomy Bilateral pallidotomy Bilateral DBS Lesion + DBS Lesion + DBS Lesion + DBS Bilateral DBS Bilateral DBS Lesion + DBS Lesion + DBS
m = months.
Post operative score 3m
6m
12 m
24 m
36 m
48 m
60 m
72 m
84 m
96 m
15 8 16 24 6 0 0 9 8 7
13 8 10 24 6 0 0 9 5 5
9 8 10 23 6 0 0 9 5 4
8 8 16 23 6 0 0 8
8 8 17 23 6 0 0
9 8 14 23 8 6
8 8 14 28 12 8
8 12 17 27 12 8
8 15 18 25
8 15
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relevant for, but not limited to, dystonic jerks or mobile dystonia. This initial improvement was variable in duration and magnitude, and tended to disappear around the third week after surgery, approximately by the time when stimulation was initiated. We systematically measured this immediate improvement after DBS implantation in the (“microlesion” effect) to determine whether it had predictive value in terms of the magnitude of the beneficial effect of DBS. However, this was not the case in our patients. For example, case 3 had a very good microlesion effect that lasted for almost 3 weeks but never attained similar beneficial effect with stimulation. In contrast, case 7 had only a mild and brief effect from microlesion but dramatically improved when DBS was started, obtaining the maximal benefit within the first 24 h. Because of the presence of fixed skeletal deformities secondary to dystonia, two patients required surgical orthopedic correction: of the spine in case 1 and both Achilles tendons in case 8. Three patients required more than one pallidal surgery due to electrode misplacement or migration (cases 3 and 4), poor or non response to surgery (case 3), and worsening of dystonia (case 2). 4.2. Results of bilateral pallidal DBS vs. combined surgery (unilateral pallidal DBS plus contralateral lesion) Patients with bilateral pallidal DBS (n = 3) had a mean follow up of 53.6 months (range: 33–93 months); and those who underwent combined surgery (n = 5) had a mean follow up of 58.4 months (range: 15–92 months). Maximal improvement obtained in the BFMD movement scale averaged 48% in the bilateral pallidal DBS patients, 65% in those with combined surgery and 79% in the two cases with bilateral pallidotomy. The maximal improvement in the BFMD disability scale was 50%, 60% and 58%, respectively. Thus, the mean percentage improvement at each observation point appeared to be greater in the patients that had undergone combined surgery or bilateral pallidotomy than in those with bilateral pallidal DBS (Fig. 1a and b). However, the small number of patients on each group that had been assessed at each time points precluded a statistical analysis of the results. 4.3. Worsening of dystonia Reappearance of dystonic symptoms was observed in five patients that have been followed for more than 6 years. Three of them (cases 2, 5, and 6) had experienced sustained benefit before symptom reappearance. In all cases, dystonia reappeared in the neck (case 2) or trunk (cases 5 and 6), which were segments that were not or only minimally involved initially at the time of surgery. In case 2, neck dystonia, which was only mild before surgery, reappeared after 5 years of sustained benefit; in cases 5 and 6, trunk dystonia appeared after 4 and 5 years of surgery, respectively, whereas limb dystonia remained controlled after surgery. Cases 3 and 4 never
Fig. 1. (a) BFM Movement Scale Percentage of improvement over time for bilateral DBS and Combined surgery and (b) BFM disability scale percentage of improvement over time for bilateral DBS and Combined surgery.
obtained a sustained benefit despite multiple pallidal surgeries due to migration or misplacement of electrodes resulting of transient worsening of dystonia. 4.4. Adverse events A total of eight complications occurred in four patients. One patient (case 2) developed permanent anarthria following bilateral pallidotomy. Most (four out of eight) complications occurred in one patient (case 3) and were hardware-related. They included scalp infection at the emergence of the connecting wires, migration of the electrode, battery expiration and repeated unexplained stimulator switch off, resulting in aggravation of dystonia. Other two patients also had hardware-related complications including migration of the electrode and repeated unexplained stimulator switch off (case 4) and single unexplained stimulator switch off (patient 7). All hardware-related complications were associated with worsening of dystonia. These complications occurred only rarely as we gained more experience with the surgical procedures.
5. Discussion Our results indicate that [1] bilateral DBS or lesion of the GPi or combined unilateral GPi stimulation and contralateral lesion are all effective in producing sustained improvement of
M.G. Cersosimo et al. / Clinical Neurology and Neurosurgery 110 (2008) 145–150
motor symptoms and quality of life in PGD patients followed for more than 3 years; [2] some patients may experience dramatic relief of motor symptoms immediately following electrode implantation (micro-lesion effect); [3] there is late reemergence of dystonia in after a plateau of beneficial effect of pallidal surgery; and [4] combined unilateral GPi stimulation and contralateral lesion provides a less expensive and at least as effective alternative to bilateral GPi DBS in PGD patients. The degree of improvement in BFMD scores observed in our patients at 3 months following surgery was similar to those reported in a large, sham controlled multicenter trial [15] and the degree of sustained benefit at 1 and 3 year follow-up were comparable to those reported in a prospective multicenter study [14]. However, one strength of our study is that all patients were evaluated by the same investigator in the same institution and the population of PGD patient was more homogeneous as most (9/10) cases harbored the DYT1 mutation, compared to only 7/22 cases in another long-term follow up study [14]. Our results indicate that, although improvement of dystonia after pallidal surgery is often delayed and progressive and may take several months to reach its maximum benefit [17,18], this may not be necessarily true for all cases. Our study also shows that electrode implantation into the GPi may produce immediate improvement on motor function (micro lesion effect) and that the maximum benefit may be reached shortly after surgery in some cases. In one of our patients, improvement occurred immediately and in another 48 h after electrode implantation. This initial microlesion effect vanished within 3 weeks and did not predict the magnitude of further improvement after starting DBS. In two cases, maximum benefit was observed only after 1 month of DBS. These observations support the concept that, even in a relatively homogeneous group of PGD patients, the pathophysiological mechanisms underlying dystonia and the effects of DBS are complex and heterogeneous. The main strength of our study is that 6 of our 10 patients have been followed for more than 6 years. This allowed us to detect the reemergence of dystonia in body segments (primarily neck and trunk) that had not been initially affected by the disease. This occurred despite preservation of the beneficial effect of pallidal surgery on the initially affected segments (primarily limbs). This is likely a manifestation of disease progression, plasticity in the basal ganglia-thalamocortical circuits involved in dystonia, or both. Finally, our results suggest that combined unilateral GPi lesion and contralateral stimulation may be more effective than bilateral GPi stimulation in improving motor symptoms and disability in PGD patients, without the risks associated with bilateral pallidotomy. Although the small number of patients in each group did not allow to perform a statistical analysis, our observations, if confirmed by studies in larger number of patients, provide a rationale for an effective, yet less expensive alternative to bilateral GPi DBS for treatment of PGD.
149
The most frequent adverse events observed in our DBS patients were hardware related, which is consistent with another series [14,17–19]. Many of these complications occurred in few of the initial patients undergoing DBS, probably reflecting our early lack of experience with the surgical procedure. The only severe complication was permanent anarthria in a patient that underwent bilateral GPi lesion. Given this risk, bilateral pallidotomy should only be considered for patients with disabling dystonia who cannot afford unilateral or bilateral DBS.
6. Conclusions Our single centre long term follow up study on a relatively homogeneous group of PGD patients further supports the long-term beneficial effect of bilateral functional surgery of the GPi. It also provides new information regarding the heterogeneity of clinical response of these patients, ranging from immediate benefit following implantation (microlesion effect) to reemergence of dystonic manifestations in different segments after a long-term stabilization of the disease following surgery. The use of combined unilateral GPi stimulation and contralateral GPi lesion as a more effective and less expensive alternative to bilateral DBS requires further validation but may have an important impact on clinical practice.
References [1] Fahn S. Concept and classification of dystonia. Adv Neurol 1988; 50:1–8. [2] Ozelius L, Kramer PL, Moskowitz CB, Kwiatkowski DJ, Brin MF, Bressman SB, et al. Human gene for torsion dystonia located on chromosome 9q32-q34. Neuron 1989;2:1427–34. [3] Fahn S, Bressman SB, Marsden CD. Classification of dystonia. Adv Neurol 1998;78:1–9. [4] Jankovic J, Lai E, Ben-Arie L, Krauss JK, Grossman R. Levodopa-induced dyskinesias treated by pallidotomy. J Neurol Sci 1999;167:62–7. [5] Jankovic J, Lai EC, Krauss J, Grossman R. Surgical treatment of levodopa-induced dyskinesias. Adv Neurol 1999;80:603–9. [6] Lozano AM, Lang AE, Galvez-Jimenez N, Miyasaki J, Duff J, Hutchinson WD, et al. Effect of GPi pallidotomy on motor function in Parkinson’s disease. Lancet 1995;346:1383–7. [7] Iacono RP, Kuniyoshi SM, Lonser RR, Maeda G, Inae AM, Ashwal S. Simultaneous bilateral pallidoansotomy for idiopathic dystonia musculorum deformans. Pediatr Neurol 1996;14:145–8. [8] Iacono RP, Kuniyoshi SM, Schoonenberg T. Experience with stereotactics for dystonia: case examples. Adv Neurol 1998;78: 221–6. [9] Lin JJ, Lin SZ, Lin GY, Chang DC, Lee CC. Application of bilateral sequential pallidotomy to treat a patient with generalized dystonia. Eur Neurol 1998;40:108–10. [10] Lin JJ, Lin GY, Shih C, Lin SZ, Chang DC, Lee CC. Benefit of bilateral pallidotomy in the treatment of generalized dystonia: case report. J Neurosurg 1999;90:974–6. [11] Lozano AM, Kumar R, Gross RE, Giladi N, Hutchison WD, Dostrovsky JO, et al. Globus pallidus internus pallidotomy for generalized dystonia. Mov Disord 1997;12:865–70.
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[12] Vitek JL. Surgery for dystonia. Neurosurg Clin N Am 1998;9:345–66. [13] Vitek JL, Zhang J, Evatt M, Mewes K, DeLong MR, Hashimoto T, et al. GPi pallidotomy for dystonia: Clinical outcome and neuronal activity. Adv Neurol 1998;78:211–9. [14] Vidailhet M, Vercueil L, Houeto JL, Krystkowiak P, Lagrange C, Yelnik J, Bardinet E, Benabid AL, Navarro S, Dormont D, Grand S, Blond S, Ardouin C, Pillon B, Dujardin K, Hahn-Barma V, Agid Y, Dest´ee A, Pollak P. French SPIDY Study Group. Bilateral, pallidal, deepbrain stimulation in primary generalised dystonia: a prospective 3 year follow-up study. Lancet Neurol 2007;(3):223–9. [15] Kupsch A, Benecke R, M¨uller J, Trottenberg T, Schneider GH, Poewe W, et al. Deep-Brain Stimulation for Dystonia Study Group. Pallidal deep-brain stimulation in primary generalized or segmental dystonia. N Engl J Med 2006;9(355):1978–90, 19.
[16] Burke RE, Fahn S, Marsden CD, Bressman SB, Moskowitz C, Friedman J. Validity and reliability of a rating scale for the primary torsion dystonias. Neurology 1985;35:73–7. [17] Eltahawy HA, Saint-Cyr J, Giladi N, Lang AE, Lozano AD. Primary dystonia is more responsive than secondary dystonia to pallidal interventions: outcome after pallidotomy or pallidal deep brain stimulation. Neurosurgery 2004;54(3):613–21. [18] Krauss JK, Yianni J, Loher TJ, Aziz TZ. Deep brain stimulation for dystonia. J Clin Neurophysiol 2004;21(1):18–30. [19] Vidailhet M, Vercueil L, Houeto JL, Krystkowiak P, Benabid AL, Cornu P, et al. French Stimulation du Pallidum Interne dans la Dystonie (SPIDY) Study Group. Bilateral deep-brain stimulation of the globus pallidus in primary generalized dystonia. N Engl J Med 2005;3(352):459–67, 5.
Pallidal surgery for the treatment of primary generalized dystonia: Long-term follow-up Maria G. Cersosimo ∗ , Gabriela B. Raina, Fabian Piedimonte, Julio Antico, Pablo Graff, Federico E. Micheli Parkinson’s Disease and Movement Disorder Unit, Hospital de Cl´ınicas, University of Buenos Aires, Argentina Received 1 May 2007; received in revised form 1 October 2007; accepted 3 October 2007
Abstract Objective: To describe the results and long-term follow-up after functional surgery of the internal segment of the globus pallidus (GPi) in 10 patients with primary generalized dystonia. Patients and methods: Nine of the 10 patients were positive for the DYT1 gene mutation. Bilateral deep brain stimulation (DBS) of the GPi was performed in three cases, bilateral pallidotomy in two, and combined surgery (unilateral GPi lesion with contralateral stimulation) in the remaining five. All patients were evaluated with the Burke–Fahn–Marsden dystonia scale (BFMDS) before, immediately after surgery, at 3 weeks, 3 and 6 months and then yearly. Follow up time ranged from 15 to 105 months (mean: 66.1 months) with six patients having more than 6 years follow up. Results: All patients improved after surgery. All patients with unilateral or bilateral DBS experienced an immediate improvement before starting stimulation. The magnitude of this initial micro lesion effect did not predict the magnitude of the long-term benefit of DBS. The mean decrease in the in the BFMDS was 34%, 55%, and 65% in the movement scale; and 32%, 48%, and 49% in the disability scale for patients with bilateral pallidal DBS, combined unilateral DBS and contralateral pallidotomy, and bilateral pallidotomy, respectively. Worsening of dystonia after a plateau of sustained benefit was observed in three patients. Two patients required multiple pallidal surgeries. Adverse events included: permanent anarthria (1), misplacement of the electrode requiring further surgery (2), scalp infection (1), and hardware related problems (3). Conclusions: This long-term follow up study confirms the beneficial effect of pallidal DBS or pallidotomy in primary generalized dystonia. In addition, our results extent previous observations by showing that, in these patients, (1) the microlesion effect of DBS is not predictive of long-term benefit; (2) combined DBS with contralateral pallidotomy appears to be more effective than bilateral pallidal DBS; and (3) dystonia can reappear after an initial good response during long term follow up. © 2007 Elsevier B.V. All rights reserved. Keywords: Primary generalized dystonia; DBS; Pallidotomy
1. Introduction Dystonia is a syndrome characterized by repetitive and sustained muscle contractions that result in twisting movements and abnormal postures [1]. When dystonia is the only clinical feature and the etiology is unknown the disorder is considered primary or idiopathic dystonia. Recently, several gene mutations have been recognized in association with a growing number of primary dystonic syndromes [2]. ∗ Corresponding author at: Pe˜ na 2225- P 5 Dpto C (1126), Buenos Aires, Argentina. Tel.: +54 4812 5732; fax: +54 4811 3076. E-mail address: [email protected] (M.G. Cersosimo).
0303-8467/$ – see front matter © 2007 Elsevier B.V. All rights reserved. doi:10.1016/j.clineuro.2007.10.003
According to the extent and body regions affected, dystonia may be classified as focal, segmental, hemi corporal or generalized [3]. Primary generalized dystonia (PGD) is a disabling condition, and its response to pharmacological therapy is usually disappointing. In the past decade, the observation that lesioning of the internal segment of the globus pallidus (GPi) improved off period dystonia and levodopa induced dyskinesias in patients with Parkinson’s disease suggested that the GPi could be a good target for the treatment of dystonias [4–6]. Since then, surgical treatment of PGD by lesion or deep brain stimulation (DBS) of the posteroventral GPi has received increasing attention and a growing number of patients undergoing pallidal surgery for
146
M.G. Cersosimo et al. / Clinical Neurology and Neurosurgery 110 (2008) 145–150
the treatment of dystonia have been reported in the literature [7–13]. However, with few exceptions [14] most published series included either few cases or relatively short follow up following surgery [15]. The aim of this study was to determine the outcome of 10 PGD patients who underwent bilateral GPi DBS, bilateral pallidotomy, or combined unilateral DBS and contralateral lesion DBS in a single center and have been followed, in most cases, for at least 6 years after surgery.
2. Patients From October 1998 to March 2006, 10 patients (six females and four males) with disabling and medically refractory PGD underwent functional bilateral pallidal surgery at the Parkinson Disease Center, Hospital de Clinicas, University of Buenos Aires, Argentina (Table 1). The diagnosis of PGD was made when at least one limb, the trunk and any other body segment was involved, the rest of the neurological examination and brain magnetic resonance imaging (MRI) were normal, and secondary causes were excluded. Nine of the 10 patients harbored the DYT1 mutation. The mean age of patients at the time of surgery was 15 years old (range: 9–28 years old); mean age at disease onset was 9.8 years (range: 5–24 years); and mean disease duration was 5.2 years (range: 2–13 years). Three of the patients were on baclofen, two were on diazepam and one was on trihexyphenidyl at the time of surgery. The remaining patients had failed to respond to drug therapy. Case 10 had a previous unilateral thalamic lesion performed by another medical group 3 years before. All patients gave informed consent for the surgical procedure according to the institutional review board requirements.
3. Methods 3.1. Neurological evaluations All patients were evaluated before and at different times after surgery with the Burke-Fahn-Marsden Dystonia Scale (BFMDS) movement and disability subscores [16]. Post operative evaluations were performed within the first 24 h after surgery with the stimulator off; at 3 weeks at the time of onset of stimulation, at 3, 6 and 12 months during the first year, and at least once a year thereafter. All evaluations were performed by the same neurologist. Mean follow up duration was 66.1 months (range: 15–105 months). Six patients had been followed for more than 6 years (6–8.7 years). 3.2. Surgical intervention Two patients underwent bilateral pallidotomy, three bilateral pallidal DBS, and five unilateral pallidal DBS with a contralateral lesion (combined surgery). Among patients with combined surgery, the lesion was in the GPi in all cases except for case 10 who had a previous unilateral thalamotomy. The surgical procedures in the first six cases had been performed by two different neurosurgical groups while the last four patients were operated by the same group. The decision to perform either bilateral GPi stimulation or lesion was made in each case primarily driven by the cost of the procedure. In cases 1 and 2, cost restraints prevented the patients from undergoing DBS and bilateral pallidotomy was performed to alleviate the disabling dystonia. In five cases, unilateral GPi DBS was combined to contralateral GPi lesion to reduce the expense of surgery and follow-up. All bilateral procedures were performed on same session. Case 10 had a previous contralateral thalamotomy. In
Table 1 Demographic data of patients Case
Gender
Age at disease onset
Disease duration (years)
Age at surgery (years)
DYT1 mutation
Family history of dystonia
Pharmacologic treatment
Follow up Months
Years
Sister with GD (case 3) Brother with focal dystonia Sister with GD (case 1)
BCF 100 mg/d
105
8.7
103
8.5
93
7.7
92 82
7.6 6.8
82
6.8
35 33
2.9 2.7
21 15
1.7 1.2
1
F
6
13
19
Yes
2
M
10
4
14
Yes
3
F
6
4
10
Yes
4 5
M F
7 8
8 2
15 10
No Yes
6
F
9
4
13
Yes
7 8
M F
24 5
4 4
28 9
Yes Yes
9 10
M F
16 7
3 6
19 13
Yes Yes
BCF 90 mg/d DZ 40 mg/d THF 80 mg/d
Sister with GD (case 6) Sister with GD (case 5) Mother with blepharospasm
M = male F = female BCF = baclofen DZ = diazepam THF = trihexyphenidyle GD = generalized dystonia.
BCF 30 mg/d
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all cases the electrodes and the implantable pulse generator (IPG) were implanted during the same intervention. Microelectrode recordings were obtained in all patients. Patients were operated under local anesthesia except for the implantation of the extension wire and the pulse generator that was performed under general anesthesia. 3.3. DBS programming Stimulation was initiated after 3 weeks of surgery in a monopolar mode using the deepest contacts, usually contact 0 or contact 1 which were set to negative while the case was set as positive. The initial stimulation settings were a pulse width of 210 ms, a frequency of 135 Hz and an amplitude of 2 V. The time between each programming session was not standardized. We changed parameters when a satisfactory response was not achieved or if adverse events were thought to be related to stimulation. When possible, voltage was not increased above 3.6 V. If no benefit was achieved with these parameters, width pulse or frequency were gradually increased up to 400 ms or 185 Hz, respectively. If clinical response was still poor, then the next contact was used, and the same steps were followed. When monopolar stimulation was associated with undesired side effects, the bipolar stimulation mode using two contiguous electrodes was used.
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Mean stimulation parameters used in our patients were: width pulse of 286 ms (range: 210–400 ms); frequency of 137 Hz (range: 135–185 Hz), and amplitude of 2.9 V (range: 2.4–3.5 V). Among the 11 electrodes implanted (6 in the bilateral GPi DBS patients and 5 in the unilateral DBS patients), 6 were programmed in a monopolar mode using the case as anode and contacts 0 or 1 as cathode and the remaining five electrodes were set in a bipolar mode using two contiguous contacts.
4. Results 4.1. Effect of bilateral GPi stimulation and or lesion All 10 patients improved following surgery, both in the BFMDS movement and disability scores and regardless the type of procedure (Tables 2 and 3). We considered that maximal improvement was obtained when scores of BFMDS remained unchanged after successive evaluations. The time to achieve the maximal benefit was highly variable among patients, ranging from 24 h (case 7) to 24 months (case 8), and was not related with the type of surgical procedure. In all patients undergoing unilateral or bilateral pallidal DBS (n = 8) an immediate and temporary improvement of dystonic symptoms was observed. This effect was more
Table 2 BFMD Movement Scale score (maximal = 120) Cases
1 2 3 4 5 6 7 8 9 10
Pre operative score
108 42 67 96 52 81 16.5 45 33 39
Surgery
Bilateral pallidotomy Bilateral pallidotomy Bilateral DBS Lesion + DBS Lesion + DBS Lesion + DBS Bilateral DBS Bilateral DBS Lesion + DBS Lesion + DBS
Post operative score 3m
6m
12 m
24 m
36 m
48 m
60 m
72 m
84 m
96 m
70 10 45 66 17 1 5 30 25 27
66 10 34 64 18 1 5 28 24 21
42 10 34 60.5 17 1 4 30 12 16
21 10 55 61 17 1 5 21
22 10 42 63 17 1 5
21 10 39 61 18 12
21 11 56 90 28 18
22 32 55 85 28 20
21 48 45 66
21 50
m = months. Table 3 BFMD disability scale scores (maximal = 30) Cases
Pre operative score
Surgery
1 2 3 4 5 6 7 8 9 10
26 12 20 28 19 26 6 12 13 9
Bilateral pallidotomy Bilateral pallidotomy Bilateral DBS Lesion + DBS Lesion + DBS Lesion + DBS Bilateral DBS Bilateral DBS Lesion + DBS Lesion + DBS
m = months.
Post operative score 3m
6m
12 m
24 m
36 m
48 m
60 m
72 m
84 m
96 m
15 8 16 24 6 0 0 9 8 7
13 8 10 24 6 0 0 9 5 5
9 8 10 23 6 0 0 9 5 4
8 8 16 23 6 0 0 8
8 8 17 23 6 0 0
9 8 14 23 8 6
8 8 14 28 12 8
8 12 17 27 12 8
8 15 18 25
8 15
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relevant for, but not limited to, dystonic jerks or mobile dystonia. This initial improvement was variable in duration and magnitude, and tended to disappear around the third week after surgery, approximately by the time when stimulation was initiated. We systematically measured this immediate improvement after DBS implantation in the (“microlesion” effect) to determine whether it had predictive value in terms of the magnitude of the beneficial effect of DBS. However, this was not the case in our patients. For example, case 3 had a very good microlesion effect that lasted for almost 3 weeks but never attained similar beneficial effect with stimulation. In contrast, case 7 had only a mild and brief effect from microlesion but dramatically improved when DBS was started, obtaining the maximal benefit within the first 24 h. Because of the presence of fixed skeletal deformities secondary to dystonia, two patients required surgical orthopedic correction: of the spine in case 1 and both Achilles tendons in case 8. Three patients required more than one pallidal surgery due to electrode misplacement or migration (cases 3 and 4), poor or non response to surgery (case 3), and worsening of dystonia (case 2). 4.2. Results of bilateral pallidal DBS vs. combined surgery (unilateral pallidal DBS plus contralateral lesion) Patients with bilateral pallidal DBS (n = 3) had a mean follow up of 53.6 months (range: 33–93 months); and those who underwent combined surgery (n = 5) had a mean follow up of 58.4 months (range: 15–92 months). Maximal improvement obtained in the BFMD movement scale averaged 48% in the bilateral pallidal DBS patients, 65% in those with combined surgery and 79% in the two cases with bilateral pallidotomy. The maximal improvement in the BFMD disability scale was 50%, 60% and 58%, respectively. Thus, the mean percentage improvement at each observation point appeared to be greater in the patients that had undergone combined surgery or bilateral pallidotomy than in those with bilateral pallidal DBS (Fig. 1a and b). However, the small number of patients on each group that had been assessed at each time points precluded a statistical analysis of the results. 4.3. Worsening of dystonia Reappearance of dystonic symptoms was observed in five patients that have been followed for more than 6 years. Three of them (cases 2, 5, and 6) had experienced sustained benefit before symptom reappearance. In all cases, dystonia reappeared in the neck (case 2) or trunk (cases 5 and 6), which were segments that were not or only minimally involved initially at the time of surgery. In case 2, neck dystonia, which was only mild before surgery, reappeared after 5 years of sustained benefit; in cases 5 and 6, trunk dystonia appeared after 4 and 5 years of surgery, respectively, whereas limb dystonia remained controlled after surgery. Cases 3 and 4 never
Fig. 1. (a) BFM Movement Scale Percentage of improvement over time for bilateral DBS and Combined surgery and (b) BFM disability scale percentage of improvement over time for bilateral DBS and Combined surgery.
obtained a sustained benefit despite multiple pallidal surgeries due to migration or misplacement of electrodes resulting of transient worsening of dystonia. 4.4. Adverse events A total of eight complications occurred in four patients. One patient (case 2) developed permanent anarthria following bilateral pallidotomy. Most (four out of eight) complications occurred in one patient (case 3) and were hardware-related. They included scalp infection at the emergence of the connecting wires, migration of the electrode, battery expiration and repeated unexplained stimulator switch off, resulting in aggravation of dystonia. Other two patients also had hardware-related complications including migration of the electrode and repeated unexplained stimulator switch off (case 4) and single unexplained stimulator switch off (patient 7). All hardware-related complications were associated with worsening of dystonia. These complications occurred only rarely as we gained more experience with the surgical procedures.
5. Discussion Our results indicate that [1] bilateral DBS or lesion of the GPi or combined unilateral GPi stimulation and contralateral lesion are all effective in producing sustained improvement of
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motor symptoms and quality of life in PGD patients followed for more than 3 years; [2] some patients may experience dramatic relief of motor symptoms immediately following electrode implantation (micro-lesion effect); [3] there is late reemergence of dystonia in after a plateau of beneficial effect of pallidal surgery; and [4] combined unilateral GPi stimulation and contralateral lesion provides a less expensive and at least as effective alternative to bilateral GPi DBS in PGD patients. The degree of improvement in BFMD scores observed in our patients at 3 months following surgery was similar to those reported in a large, sham controlled multicenter trial [15] and the degree of sustained benefit at 1 and 3 year follow-up were comparable to those reported in a prospective multicenter study [14]. However, one strength of our study is that all patients were evaluated by the same investigator in the same institution and the population of PGD patient was more homogeneous as most (9/10) cases harbored the DYT1 mutation, compared to only 7/22 cases in another long-term follow up study [14]. Our results indicate that, although improvement of dystonia after pallidal surgery is often delayed and progressive and may take several months to reach its maximum benefit [17,18], this may not be necessarily true for all cases. Our study also shows that electrode implantation into the GPi may produce immediate improvement on motor function (micro lesion effect) and that the maximum benefit may be reached shortly after surgery in some cases. In one of our patients, improvement occurred immediately and in another 48 h after electrode implantation. This initial microlesion effect vanished within 3 weeks and did not predict the magnitude of further improvement after starting DBS. In two cases, maximum benefit was observed only after 1 month of DBS. These observations support the concept that, even in a relatively homogeneous group of PGD patients, the pathophysiological mechanisms underlying dystonia and the effects of DBS are complex and heterogeneous. The main strength of our study is that 6 of our 10 patients have been followed for more than 6 years. This allowed us to detect the reemergence of dystonia in body segments (primarily neck and trunk) that had not been initially affected by the disease. This occurred despite preservation of the beneficial effect of pallidal surgery on the initially affected segments (primarily limbs). This is likely a manifestation of disease progression, plasticity in the basal ganglia-thalamocortical circuits involved in dystonia, or both. Finally, our results suggest that combined unilateral GPi lesion and contralateral stimulation may be more effective than bilateral GPi stimulation in improving motor symptoms and disability in PGD patients, without the risks associated with bilateral pallidotomy. Although the small number of patients in each group did not allow to perform a statistical analysis, our observations, if confirmed by studies in larger number of patients, provide a rationale for an effective, yet less expensive alternative to bilateral GPi DBS for treatment of PGD.
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The most frequent adverse events observed in our DBS patients were hardware related, which is consistent with another series [14,17–19]. Many of these complications occurred in few of the initial patients undergoing DBS, probably reflecting our early lack of experience with the surgical procedure. The only severe complication was permanent anarthria in a patient that underwent bilateral GPi lesion. Given this risk, bilateral pallidotomy should only be considered for patients with disabling dystonia who cannot afford unilateral or bilateral DBS.
6. Conclusions Our single centre long term follow up study on a relatively homogeneous group of PGD patients further supports the long-term beneficial effect of bilateral functional surgery of the GPi. It also provides new information regarding the heterogeneity of clinical response of these patients, ranging from immediate benefit following implantation (microlesion effect) to reemergence of dystonic manifestations in different segments after a long-term stabilization of the disease following surgery. The use of combined unilateral GPi stimulation and contralateral GPi lesion as a more effective and less expensive alternative to bilateral DBS requires further validation but may have an important impact on clinical practice.
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