Case Report Received: January 31, 2014 Accepted after revision: June 29, 2014 Published online: October 28, 2014
Stereotact Funct Neurosurg 2014;92:393–396 DOI: 10.1159/000365577
Deep Brain Stimulation of the Thalamic Ventral Lateral Anterior Nucleus for DYT6 Dystonia Hideo Mure a, b Ryoma Morigaki a, d Hidetaka Koizumi c Shinya Okita a, b Toshitaka Kawarai c Ryosuke Miyamoto c Ryuji Kaji a, c Shinji Nagahiro a, b Satoshi Goto a, d
a
Parkinson’s Disease and Dystonia Research Center, Tokushima University Hospital, University of Tokushima, and Departments of b Neurosurgery, c Clinical Neuroscience, and d Motor Neuroscience and Neurotherapeutics, Institute of Health Biosciences, Graduate School of Medical Sciences, University of Tokushima, Tokushima, Japan
Key Words DYT6 dystonia · Deep brain stimulation · Thalamus · Ventral lateral anterior nucleus
creased from 71 to 11, an improvement of more than 80%. Conclusions: The thalamic VLa nucleus could serve as an alternative target in DBS therapy for DYT6 dystonia. © 2014 S. Karger AG, Basel
© 2014 S. Karger AG, Basel 1011–6125/14/0926–0393$39.50/0 E-Mail [email protected] www.karger.com/sfn
Introduction
DYT6 dystonia is inherited as an autosomal dominant trait with a reduced penetrance of ∼60% [1]. Onset of this condition can occur during childhood and adolescence, but also in adulthood. Initial dystonic symptoms occur usually in brachial, cervical, or cranial muscles, and frequently progress to the rest of the body [1]. Mutations in the THAP1 (thanatos-associated protein domain-containing apoptosis-associated protein 1) gene have been shown to cause DYT6 dystonia [2–4]. While medical therapy for primary dystonia is largely unsatisfactory, deep brain stimulation (DBS) of the globus pallidus internus (GPi) is demonstrated to be a safe and effective intervention for a wide range of dystonia subtypes, including DYT6 dystonia [5, 6]. However, recent reports have also shown that unlike other primary dystonias such as DYT1 Satoshi Goto, MD, PhD Department of Motor Neuroscience and Neurotherapeutics University of Tokushima, 3-18-15 Kuramoto-cho Tokushima, 7708503 (Japan) E-Mail sgoto @ clin.med.tokushima-u.ac.jp
Downloaded by: Selçuk Universitesi 193.255.248.150 - 12/24/2014 7:49:07 PM
Abstract Background: A missense mutation of the THAP1 gene results in DYT6 primary dystonia. While deep brain stimulation (DBS) of the internal globus pallidus (GPi) is effective in treating primary dystonia, recent reports indicate that GPi DBS is only mildly effective for DYT6 dystonia. Objective: To describe a patient with DYT6 dystonia who underwent thalamic ventral lateral anterior (VLa) nucleus DBS. Patient: A 35-year-old Japanese man had been experiencing upper limb dystonia and spasmodic dysphonia since the age of 15. His dystonic symptoms progressed to generalized dystonia. He was diagnosed as having DYT6 dystonia with mutations in the THAP1 gene. Because his dystonic symptoms were refractory to pharmacotherapy and pallidal DBS, he underwent thalamic VLa DBS. Results: Continuous bilateral VLa stimulation with optimal parameter settings ameliorated the patient’s dystonic symptoms. At the 2-year follow-up, his Burke-Fahn-Marsden Dystonia Rating Scale total score de-
b
c
d
e
f
Fig. 1. The DBS electrodes implanted in the bilateral thalamic VLa nucleus. a–c Postoperative T1-weighted (SPGR) magnetic resonance (MR) image in axial (a), sagittal (b), and coronal (c) sections. d, e Magnified MR images registered with Morel’s [12] atlas at the
level 0.5 mm dorsal (d) and 12 mm lateral (e) to the AC-PC line, showing the electrode (arrows) in the VLa nucleus (d axial, e sagittal views). f Frontal views of the radiologic location of the dorsal two electrode contacts (arrows) placed in the thalamic VLa nucleus.
dystonia, DYT6 dystonia is often treated unsatisfactorily with pallidal DBS [7–9]. Here, we report a striking benefit obtained with DBS of the thalamic ventral lateral anterior (VLa) nucleus in a patient with DYT6 dystonia whose symptoms were refractory to both pharmacotherapy and GPi DBS.
(40 mg/day) and etizolam (2 mg/day) was started. This treatment is continued to date. The patient was admitted to our university hospital at age 34, when his BFMDRS total score was 71 (motor score = 58; disability score = 13) (online suppl. video 1; for all online suppl. material, see www.karger.com/doi/10.1159/000365577). Direct mutation analysis confirmed that the patient and his mother had a 2-bp deletion c.389_390del (p.S130fs133X) in the THAP1 gene, and he was diagnosed as DYT6 dystonia [10]. We tested each contact point of GPi DBS with various parameters; however, no GPi DBS setting improved his symptoms. According to our previous report, the thalamic nucleus ventrooralis as described by Hassler, which is called the VLa nucleus in recent publications [11–13], could be an effective target for DBS therapy for generalized and focal dystonia [14– 16]. Thus, we chose to stimulate the thalamic VLa as the primary target in our patient. The genetic study and surgery were approved by the ethics committee, and the subject provided written informed consent. Using quadripolar DBS electrodes (model 3387, Medtronic, Minneapolis, Minn., USA) similar to our previous report [17], we located the dorsal two contacts (contacts 2 and 3) within the VLa nucleus by placing the lower edge of the electrode contact 2 at the coordinate setting 1.5 mm behind the midpoint of the line drawn between the anterior and posterior commissures and 13.5 mm lateral to and 0.5 mm dorsal to the line (fig. 1). Along the trajectory, the ventral two contacts (contacts 0 and 1) were lo-
Case Report A 35-year-old Japanese man showed gradual onset and worsening of upper limb dystonia and spasmodic dysphonia beginning at age 15. He also developed lower limb dystonia and retrocollis at age 25. At age 30, he was admitted to another university hospital where he was diagnosed with idiopathic generalized dystonia and underwent bilateral GPi DBS. His preoperative Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) motor score was 55. His dystonic symptoms initially responded to pallidal stimulation, as his postoperative BFMDRS motor score was reduced to 21 at the 3-month follow-up. However, this beneficial effect of GPi DBS gradually lessened and finally disappeared within a year after surgery. Accordingly, the implantable pulse generators (IPGs) for GPi DBS were switched off, and pharmacotherapy including zolpidem
394
Stereotact Funct Neurosurg 2014;92:393–396 DOI: 10.1159/000365577
Mure/Morigaki/Koizumi/Okita/Kawarai/ Miyamoto/Kaji/Nagahiro/Goto
Downloaded by: Selçuk Universitesi 193.255.248.150 - 12/24/2014 7:49:07 PM
Color version available online
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Among primary dystonias, DYT6 dystonia has a unique clinical phenotype that differs from that of DYT1 in its older average age at symptom onset, milder leg involvement, and more severe craniocervical involvement [2]. As the pathophysiology of primary dystonias is largely unknown [5], the anatomical substrates for generating dystonia in DYT6 remain to be elucidated. The use of continuous GPi DBS for the treatment of primary generalized dystonia, particularly DYT1 dystonia, has become widely accepted [5, 6]. However, recent reports of GPi
DBS in a small number of patients with DYT6 have shown less robust results than in DYT1 patients. Panov et al. [8] reported that DYT6 patients initially responded to pallidal stimulation much like DYT1 patients, but seemed to regress after 1–2 years of stimulation. This was also observed for the patient described here. These findings suggest that an impaired function of the GPi is associated with DYT6, but that GPi activity contributes less to the generation and/or maintenance of dystonic symptoms in DYT6 compared to DYT1. To our knowledge, this is the first report of a significant impact of thalamic VLa DBS on DYT6 dystonia in a patient who responded poorly to GPi DBS. It is currently unknown why targeting the VLa nucleus was superior to the GPi as a therapeutic target for DBS in our patient. However, this novel finding may provide insight into the functional anatomy of DYT6 dystonia. The genesis of dystonia may be associated with altered activity not only of the basal ganglia, but also of the cerebellum [18]. Of particular interest is the finding of critical abnormalities involving the cerebellothalamic tracts in DYT6, as well as DYT1, gene carriers [5]. In the VLa nucleus, the anterior portion is largely associated with the pallidothalamic pathway while the posterior portion is associated with the cerebellothalamic pathway [13, 19]. This indicates that unlike GPi DBS, VLa stimulation has the potential to modulate the activity of not only the pallidal pathway, but of the cerebellar pathway at the thalamic level as well. Taken together, we speculate that DYT6 dystonia might be largely attributed to dysfunction of the thalamic cerebellar relay rather than to dysfunction of the GPi. Furthermore, our patient did not respond to bilateral STN DBS. We posit that the STN might not be a suitable DBS target for treat-
First Case of DYT6 Dystonia Responsive to Thalamic DBS
Stereotact Funct Neurosurg 2014;92:393–396 DOI: 10.1159/000365577
cated in the dorsolateral subthalamic nucleus (STN). This was confirmed by intraoperative microelectrode recordings and postoperative magnetic resonance imaging. We implanted the DBS electrodes connected with the IPGs (Soletra, Medtronic) bilaterally. Extensive trials showed that optimal results for bilateral VLa stimulation were obtained at a frequency of 135 Hz, an amplitude of 3.6 V, and a pulse width of 210 and 120 μs on the right and left sides, respectively. On the right IPG, bipolar stimulation was applied with contact 3 as the cathode and contact 2 as the anode. On the left IPG, monopolar stimulation was applied with contact 3 as the cathode and the IPG case as the anode. Although the STN was also stimulated using contacts 0 and 1, STN DBS had no beneficial effects, but caused a stimulation-dependent dyskinesia. We additionally tried the combined stimulation of the GPi and VLa; however, dysarthria appeared after the combined stimulation and then disappeared after terminating GPi DBS. Ultimately, continuous DBS with the optimal parameters of the VLa alone progressively improved the patient’s dystonic symptoms in both the limb and axial regions, including the spasmodic dysphonia (fig. 2). At 2-year follow-up, his BFMDRS total score decreased to 11 (motor score = 7; disability score = 4), which is an improvement of more than 80% (online suppl. video 1).
Discussion
395
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Fig. 2. Therapeutic effects of thalamic Vo-complex stimulation on DYT6 dystonia. The BFMDRS total score (a), motor score (b), and disability score (c) are presented at baseline and at 3-, 6-, and 24-month (M) follow-up after surgery.
ing DYT6 dystonia, although a limited number of reports have shown therapeutic benefits obtained with STN DBS in other dystonia subtypes [20–22]. In conclusion, we suggest that the thalamic VLa nucleus could serve as an alternative target in DBS therapy for THAP1/DYT6 dystonia.
Acknowledgments The authors received the following grants from the Ministry of Education, Culture, Sports, Science and Technology of Japan: grant-in-aid for Scientific Research 23500428; 21390269; 2365945800; 24390223; 26461272.
References
396
8 Panov F, Tagliati M, Ozelius LJ, Fuchs T, Gologorsky Y, Cheung T, Avshalumov M, Bressman SB, Saunders-Pullman R, Weisz D, Alterman RL: Pallidal deep brain stimulation for DYT6 dystonia. J Neurol Neurosurg Psychiatry 2012;83:182–187. 9 Zittel S, Moll CK, Bruggemann N, Tadic V, Hamel W, Kasten M, Lohmann K, Lohnau T, Winkler S, Gerloff C, Schonweiler R, Hagenah J, Klein C, Munchau A, Schneider SA: Clinical neuroimaging and electrophysiological assessment of three DYT6 dystonia families. Mov Disord 2010;25:2405–2412. 10 Miyamoto R, Ohta E, Kawarai T, Koizumi H, Sako W, Izumi Y, Obata F, Kaji R: Broad spectrum of dystonia associated with a novel thanatosis-associated protein domain-containing apoptosis-associated protein 1 mutation in a Japanese family with dystonia 6, torsion. Mov Disord 2012;27:1324–1325. 11 Jones EG: The Thalamus, ed 2. Cambridge, Cambridge University Press, 2007. 12 Morel A: Stereotactic Atlas of the Human Thalamus and Basal Ganglia. New York, Informa Healthcare, 2007. 13 Gallay MN, Jeanmonod D, Liu J, Morel A: Human pallidothalamic and cerebellothalamic tracts: anatomical basis for functional stereotactic neurosurgery. Brain Struct Funct 2008;212:443–463. 14 Constantoyannis C, Kagadis GC, Ellul J, Kefalopoulou Z, Chroni E: Nucleus ventralis oralis deep brain stimulation in postanoxic dystonia. Mov Disord 2009;24:306–308.
Stereotact Funct Neurosurg 2014;92:393–396 DOI: 10.1159/000365577
15 Ghika J, Villemure JG, Miklossy J, Temperli P, Pralong E, Christen-Zaech S, Pollo C, Maeder P, Bogousslavsky J, Vingerhoets F: Postanoxic generalized dystonia improved by bilateral Voa thalamic deep brain stimulation. Neurology 2002;58:311–313. 16 Goto S, Shimazu H, Matsuzaki K, Tamura T, Murase N, Nagahiro S, Kaji R: Thalamic Vo-complex vs pallidal deep brain stimulation for focal hand dystonia. Neurology 2008; 70:1500–1501. 17 Goto S, Tsuiki H, Soyama N, Okamura A, Yamada K, Yoshikawa M, Hashimoto Y, Ushio Y: Stereotactic selective Vo-complex thalamotomy in a patient with dystonic writer’s cramp. Neurology 1997; 49: 1173– 1174. 18 Neychev VK, Gross RE, Lehericy S, Hess EJ, Jinnah HA: The functional neuroanatomy of dystonia. Neurobiol Dis 2011;42:185–201. 19 Morigaki R, Nagahiro S, Kaji R, Goto S: Current Use of Thalamic Surgeries for Treating Movement Disorders. New York, Nova Science Publishers, 2011. 20 Novak KE, Nenonene EK, Bernstein LP, Vergenz S, Cozzens JW, Rezak M: Successful bilateral subthalamic nucleus stimulation for segmental dystonia after unilateral pallidotomy. Stereotact Funct Neurosurg 2008; 86: 80– 86. 21 Ostrem JL, Racine CA, Glass GA, Grace JK, Volz MM, Heath SL, Starr PA: Subthalamic nucleus deep brain stimulation in primary cervical dystonia. Neurology 2011; 76: 870– 878. 22 Fonoff ET, Campos WK, Mandel M, Alho EJ, Teixeira MJ: Bilateral subthalamic nucleus stimulation for generalized dystonia after bilateral pallidotomy. Mov Disord 2012; 27: 1559–1563.
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1 Saunders-Pullman R, Raymond D, Senthil G, Kramer P, Ohmann E, Deligtisch A, Shanker V, Greene P, Tabamo R, Huang N, Tagliati M, Kavanagh P, Soto-Valencia J, Aguiar PD, Risch N, Ozelius L, Bressman S: Narrowing the DYT6 dystonia region and evidence for locus heterogeneity in the Amish-Mennonites. Am J Med Genet A 2007;143A:2098–2105. 2 Bressman SB, Raymond D, Fuchs T, Heiman GA, Ozelius LJ, Saunders-Pullman R: Mutations in THAP1 (DYT6) in early-onset dystonia: a genetic screening study. Lancet Neurol 2009;8:441–446. 3 Djarmati A, Schneider SA, Lohmann K, Winkler S, Pawlack H, Hagenah J, Bruggemann N, Zittel S, Fuchs T, Rakovic A, Schmidt A, Jabusch HC, Wilcox R, Kostic VS, Siebner H, Altenmuller E, Munchau A, Ozelius LJ, Klein C: Mutations in THAP1 (DYT6) and generalised dystonia with prominent spasmodic dysphonia: a genetic screening study. Lancet Neurol 2009;8:447–452. 4 Fuchs T, Gavarini S, Saunders-Pullman R, Raymond D, Ehrlich ME, Bressman SB, Ozelius LJ: Mutations in the THAP1 gene are responsible for DYT6 primary torsion dystonia. Nat Genet 2009;41:286–288. 5 Ozelius LJ, Lubarr N, Bressman SB: Milestones in dystonia. Mov Disord 2011; 26: 1106–1126. 6 Vidailhet M, Jutras MF, Grabli D, Roze E: Deep brain stimulation for dystonia. J Neurol Neurosurg Psychiatry 2013;84:1029–1042. 7 Groen JL, Ritz K, Contarino MF, van de Warrenburg BP, Aramideh M, Foncke EM, van Hilten JJ, Schuurman PR, Speelman JD, Koelman JH, de Bie RM, Baas F, Tijssen MA: DYT6 dystonia: mutation screening, phenotype, and response to deep brain stimulation. Mov Disord 2010;25:2420–2427.
Stereotact Funct Neurosurg 2014;92:393–396 DOI: 10.1159/000365577
Deep Brain Stimulation of the Thalamic Ventral Lateral Anterior Nucleus for DYT6 Dystonia Hideo Mure a, b Ryoma Morigaki a, d Hidetaka Koizumi c Shinya Okita a, b Toshitaka Kawarai c Ryosuke Miyamoto c Ryuji Kaji a, c Shinji Nagahiro a, b Satoshi Goto a, d
a
Parkinson’s Disease and Dystonia Research Center, Tokushima University Hospital, University of Tokushima, and Departments of b Neurosurgery, c Clinical Neuroscience, and d Motor Neuroscience and Neurotherapeutics, Institute of Health Biosciences, Graduate School of Medical Sciences, University of Tokushima, Tokushima, Japan
Key Words DYT6 dystonia · Deep brain stimulation · Thalamus · Ventral lateral anterior nucleus
creased from 71 to 11, an improvement of more than 80%. Conclusions: The thalamic VLa nucleus could serve as an alternative target in DBS therapy for DYT6 dystonia. © 2014 S. Karger AG, Basel
© 2014 S. Karger AG, Basel 1011–6125/14/0926–0393$39.50/0 E-Mail [email protected] www.karger.com/sfn
Introduction
DYT6 dystonia is inherited as an autosomal dominant trait with a reduced penetrance of ∼60% [1]. Onset of this condition can occur during childhood and adolescence, but also in adulthood. Initial dystonic symptoms occur usually in brachial, cervical, or cranial muscles, and frequently progress to the rest of the body [1]. Mutations in the THAP1 (thanatos-associated protein domain-containing apoptosis-associated protein 1) gene have been shown to cause DYT6 dystonia [2–4]. While medical therapy for primary dystonia is largely unsatisfactory, deep brain stimulation (DBS) of the globus pallidus internus (GPi) is demonstrated to be a safe and effective intervention for a wide range of dystonia subtypes, including DYT6 dystonia [5, 6]. However, recent reports have also shown that unlike other primary dystonias such as DYT1 Satoshi Goto, MD, PhD Department of Motor Neuroscience and Neurotherapeutics University of Tokushima, 3-18-15 Kuramoto-cho Tokushima, 7708503 (Japan) E-Mail sgoto @ clin.med.tokushima-u.ac.jp
Downloaded by: Selçuk Universitesi 193.255.248.150 - 12/24/2014 7:49:07 PM
Abstract Background: A missense mutation of the THAP1 gene results in DYT6 primary dystonia. While deep brain stimulation (DBS) of the internal globus pallidus (GPi) is effective in treating primary dystonia, recent reports indicate that GPi DBS is only mildly effective for DYT6 dystonia. Objective: To describe a patient with DYT6 dystonia who underwent thalamic ventral lateral anterior (VLa) nucleus DBS. Patient: A 35-year-old Japanese man had been experiencing upper limb dystonia and spasmodic dysphonia since the age of 15. His dystonic symptoms progressed to generalized dystonia. He was diagnosed as having DYT6 dystonia with mutations in the THAP1 gene. Because his dystonic symptoms were refractory to pharmacotherapy and pallidal DBS, he underwent thalamic VLa DBS. Results: Continuous bilateral VLa stimulation with optimal parameter settings ameliorated the patient’s dystonic symptoms. At the 2-year follow-up, his Burke-Fahn-Marsden Dystonia Rating Scale total score de-
b
c
d
e
f
Fig. 1. The DBS electrodes implanted in the bilateral thalamic VLa nucleus. a–c Postoperative T1-weighted (SPGR) magnetic resonance (MR) image in axial (a), sagittal (b), and coronal (c) sections. d, e Magnified MR images registered with Morel’s [12] atlas at the
level 0.5 mm dorsal (d) and 12 mm lateral (e) to the AC-PC line, showing the electrode (arrows) in the VLa nucleus (d axial, e sagittal views). f Frontal views of the radiologic location of the dorsal two electrode contacts (arrows) placed in the thalamic VLa nucleus.
dystonia, DYT6 dystonia is often treated unsatisfactorily with pallidal DBS [7–9]. Here, we report a striking benefit obtained with DBS of the thalamic ventral lateral anterior (VLa) nucleus in a patient with DYT6 dystonia whose symptoms were refractory to both pharmacotherapy and GPi DBS.
(40 mg/day) and etizolam (2 mg/day) was started. This treatment is continued to date. The patient was admitted to our university hospital at age 34, when his BFMDRS total score was 71 (motor score = 58; disability score = 13) (online suppl. video 1; for all online suppl. material, see www.karger.com/doi/10.1159/000365577). Direct mutation analysis confirmed that the patient and his mother had a 2-bp deletion c.389_390del (p.S130fs133X) in the THAP1 gene, and he was diagnosed as DYT6 dystonia [10]. We tested each contact point of GPi DBS with various parameters; however, no GPi DBS setting improved his symptoms. According to our previous report, the thalamic nucleus ventrooralis as described by Hassler, which is called the VLa nucleus in recent publications [11–13], could be an effective target for DBS therapy for generalized and focal dystonia [14– 16]. Thus, we chose to stimulate the thalamic VLa as the primary target in our patient. The genetic study and surgery were approved by the ethics committee, and the subject provided written informed consent. Using quadripolar DBS electrodes (model 3387, Medtronic, Minneapolis, Minn., USA) similar to our previous report [17], we located the dorsal two contacts (contacts 2 and 3) within the VLa nucleus by placing the lower edge of the electrode contact 2 at the coordinate setting 1.5 mm behind the midpoint of the line drawn between the anterior and posterior commissures and 13.5 mm lateral to and 0.5 mm dorsal to the line (fig. 1). Along the trajectory, the ventral two contacts (contacts 0 and 1) were lo-
Case Report A 35-year-old Japanese man showed gradual onset and worsening of upper limb dystonia and spasmodic dysphonia beginning at age 15. He also developed lower limb dystonia and retrocollis at age 25. At age 30, he was admitted to another university hospital where he was diagnosed with idiopathic generalized dystonia and underwent bilateral GPi DBS. His preoperative Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) motor score was 55. His dystonic symptoms initially responded to pallidal stimulation, as his postoperative BFMDRS motor score was reduced to 21 at the 3-month follow-up. However, this beneficial effect of GPi DBS gradually lessened and finally disappeared within a year after surgery. Accordingly, the implantable pulse generators (IPGs) for GPi DBS were switched off, and pharmacotherapy including zolpidem
394
Stereotact Funct Neurosurg 2014;92:393–396 DOI: 10.1159/000365577
Mure/Morigaki/Koizumi/Okita/Kawarai/ Miyamoto/Kaji/Nagahiro/Goto
Downloaded by: Selçuk Universitesi 193.255.248.150 - 12/24/2014 7:49:07 PM
Color version available online
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Among primary dystonias, DYT6 dystonia has a unique clinical phenotype that differs from that of DYT1 in its older average age at symptom onset, milder leg involvement, and more severe craniocervical involvement [2]. As the pathophysiology of primary dystonias is largely unknown [5], the anatomical substrates for generating dystonia in DYT6 remain to be elucidated. The use of continuous GPi DBS for the treatment of primary generalized dystonia, particularly DYT1 dystonia, has become widely accepted [5, 6]. However, recent reports of GPi
DBS in a small number of patients with DYT6 have shown less robust results than in DYT1 patients. Panov et al. [8] reported that DYT6 patients initially responded to pallidal stimulation much like DYT1 patients, but seemed to regress after 1–2 years of stimulation. This was also observed for the patient described here. These findings suggest that an impaired function of the GPi is associated with DYT6, but that GPi activity contributes less to the generation and/or maintenance of dystonic symptoms in DYT6 compared to DYT1. To our knowledge, this is the first report of a significant impact of thalamic VLa DBS on DYT6 dystonia in a patient who responded poorly to GPi DBS. It is currently unknown why targeting the VLa nucleus was superior to the GPi as a therapeutic target for DBS in our patient. However, this novel finding may provide insight into the functional anatomy of DYT6 dystonia. The genesis of dystonia may be associated with altered activity not only of the basal ganglia, but also of the cerebellum [18]. Of particular interest is the finding of critical abnormalities involving the cerebellothalamic tracts in DYT6, as well as DYT1, gene carriers [5]. In the VLa nucleus, the anterior portion is largely associated with the pallidothalamic pathway while the posterior portion is associated with the cerebellothalamic pathway [13, 19]. This indicates that unlike GPi DBS, VLa stimulation has the potential to modulate the activity of not only the pallidal pathway, but of the cerebellar pathway at the thalamic level as well. Taken together, we speculate that DYT6 dystonia might be largely attributed to dysfunction of the thalamic cerebellar relay rather than to dysfunction of the GPi. Furthermore, our patient did not respond to bilateral STN DBS. We posit that the STN might not be a suitable DBS target for treat-
First Case of DYT6 Dystonia Responsive to Thalamic DBS
Stereotact Funct Neurosurg 2014;92:393–396 DOI: 10.1159/000365577
cated in the dorsolateral subthalamic nucleus (STN). This was confirmed by intraoperative microelectrode recordings and postoperative magnetic resonance imaging. We implanted the DBS electrodes connected with the IPGs (Soletra, Medtronic) bilaterally. Extensive trials showed that optimal results for bilateral VLa stimulation were obtained at a frequency of 135 Hz, an amplitude of 3.6 V, and a pulse width of 210 and 120 μs on the right and left sides, respectively. On the right IPG, bipolar stimulation was applied with contact 3 as the cathode and contact 2 as the anode. On the left IPG, monopolar stimulation was applied with contact 3 as the cathode and the IPG case as the anode. Although the STN was also stimulated using contacts 0 and 1, STN DBS had no beneficial effects, but caused a stimulation-dependent dyskinesia. We additionally tried the combined stimulation of the GPi and VLa; however, dysarthria appeared after the combined stimulation and then disappeared after terminating GPi DBS. Ultimately, continuous DBS with the optimal parameters of the VLa alone progressively improved the patient’s dystonic symptoms in both the limb and axial regions, including the spasmodic dysphonia (fig. 2). At 2-year follow-up, his BFMDRS total score decreased to 11 (motor score = 7; disability score = 4), which is an improvement of more than 80% (online suppl. video 1).
Discussion
395
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Fig. 2. Therapeutic effects of thalamic Vo-complex stimulation on DYT6 dystonia. The BFMDRS total score (a), motor score (b), and disability score (c) are presented at baseline and at 3-, 6-, and 24-month (M) follow-up after surgery.
ing DYT6 dystonia, although a limited number of reports have shown therapeutic benefits obtained with STN DBS in other dystonia subtypes [20–22]. In conclusion, we suggest that the thalamic VLa nucleus could serve as an alternative target in DBS therapy for THAP1/DYT6 dystonia.
Acknowledgments The authors received the following grants from the Ministry of Education, Culture, Sports, Science and Technology of Japan: grant-in-aid for Scientific Research 23500428; 21390269; 2365945800; 24390223; 26461272.
References
396
8 Panov F, Tagliati M, Ozelius LJ, Fuchs T, Gologorsky Y, Cheung T, Avshalumov M, Bressman SB, Saunders-Pullman R, Weisz D, Alterman RL: Pallidal deep brain stimulation for DYT6 dystonia. J Neurol Neurosurg Psychiatry 2012;83:182–187. 9 Zittel S, Moll CK, Bruggemann N, Tadic V, Hamel W, Kasten M, Lohmann K, Lohnau T, Winkler S, Gerloff C, Schonweiler R, Hagenah J, Klein C, Munchau A, Schneider SA: Clinical neuroimaging and electrophysiological assessment of three DYT6 dystonia families. Mov Disord 2010;25:2405–2412. 10 Miyamoto R, Ohta E, Kawarai T, Koizumi H, Sako W, Izumi Y, Obata F, Kaji R: Broad spectrum of dystonia associated with a novel thanatosis-associated protein domain-containing apoptosis-associated protein 1 mutation in a Japanese family with dystonia 6, torsion. Mov Disord 2012;27:1324–1325. 11 Jones EG: The Thalamus, ed 2. Cambridge, Cambridge University Press, 2007. 12 Morel A: Stereotactic Atlas of the Human Thalamus and Basal Ganglia. New York, Informa Healthcare, 2007. 13 Gallay MN, Jeanmonod D, Liu J, Morel A: Human pallidothalamic and cerebellothalamic tracts: anatomical basis for functional stereotactic neurosurgery. Brain Struct Funct 2008;212:443–463. 14 Constantoyannis C, Kagadis GC, Ellul J, Kefalopoulou Z, Chroni E: Nucleus ventralis oralis deep brain stimulation in postanoxic dystonia. Mov Disord 2009;24:306–308.
Stereotact Funct Neurosurg 2014;92:393–396 DOI: 10.1159/000365577
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