Published Ahead of Print on April 10, 2015 as 10.1212/WNL.0000000000001553

Clinical/Scientific Notes

Maria Gabriela dos Santos Ghilardi, MD Rubens Gisbert Cury, MD Jairo Silva dos Ângelos, MD Danilo Costa Barbosa Egberto Reis Barbosa, MD, PhD Manoel Jacobsen Teixeira, MD, PhD Erich Talamoni Fonoff, MD, PhD

Supplemental data at Neurology.org

LONG-TERM IMPROVEMENT OF TREMOR AND ATAXIA AFTER BILATERAL DBS OF VOP/ZONA INCERTA IN FXTAS

Fragile X-associated tremor/ataxia syndrome (FXTAS) is an X-linked adult-onset neurodegenerative disorder that affects carriers of the fragile X mental retardation 1 (FMR1) gene premutation, which is a 55–200 CGG repeat expansion in the 5ʹ untranslated region of the gene.1 The core symptoms of FXTAS are progressive intention tremor and cerebellar ataxia. These symptoms can be disabling and, when combined, severely reduce the patient’s quality of life. Symptomatic control with medication has limited effects.1 Very few cases have been treated with deep brain stimulation (DBS), mostly in the ventrointermediate thalamic (VIM) nucleus. This treatment results in tremor improvement with either no benefit or worsening of the ataxia and balance.2–4 We present a patient who experienced long-term tremor control and ataxia improvement after chronic bilateral stimulation of the ventro-oralis posterior thalamic nucleus and zona incerta (VoP/ZI), which resulted in significant improvement in daily life activities. This study provides Class IV evidence. Case report. A 65-year-old man presented with a history of tremor since age 57 years. Clinical examination revealed dysarthria, postural and action tremor, and cerebellar ataxia. There was no parkinsonism or cognitive impairment. The symptoms were progressive and asymmetrical, worse on the right side. All aspects of the patient’s life were compromised, especially writing, feeding, and walking. He had tried several medications. In the first evaluation, he was taking propranolol, primidone, and clonazepam at therapeutic doses with no significant improvement. He had a positive family history of fragile X syndrome, and genetic testing showed an FMR1 gene premutation: a demethylated fragment of 3.1 Kb corresponding to 150–200 CGG repeats in the 5ʹuntranslated region (Southern blot using EcoRI/ EagI digestion, probed with StB12.3). White matter lesions and moderate/severe generalized brain atrophy were present in MRI, thus fulfilling criteria for probable FXTAS (figures e-1 to e-3 on the Neurology® Web site at Neurology.org). Due to

medication-refractory symptoms and severe functional impairment, bilateral DBS was offered. Because the patient presented disabling tremor and significant gait ataxia, we decided to avoid the VIM and to try the VoP/ZI as the primary target. This decision was based on the literature5,6 and supported by our experience using this target for other secondary tremors. The patient underwent MRI-guided stereotactic implantation of quadripolar DBS leads (St. Jude Medical Inc., St. Paul, MN). The target was identified in T2-weighted images in the corridor between the upper third of the red nucleus and the hypointense subthalamic nucleus. Intraoperative microelectrode recording was used to refine the target, which revealed typical thalamic activity and activity of the upper subthalamic nucleus in the lateral channel, while the central channel was roughly silent below the thalamus, suggesting a fiber-predominant region. Intraoperative high-frequency stimulation evoked consistent tremor control. After the optimal stimulation parameters were reached, no remarkable lasting side effects or tolerance were observed. The patient experienced significant and stable control of the tremor over time, and surprisingly, ataxia improvement, providing functional gain in his daily life activities. These effects persisted 30 months later, as demonstrated on the pre- and post-DBS tremor and ataxia scales (see the table, figures e-1 to e-5, and the video). Discussion. Although the pathophysiology of tremor and ataxia in FXTAS is largely unknown, it has been suggested that dysfunction in the cerebellothalamic projections is involved.7 The use of VIM DBS in complex cases may be discouraged because of its limited effectiveness, especially for proximal postural, distal intention, and cerebellar outflow tremor associated with potential worsening of speech and gait, as well as the development of tolerance. Conversely, dual targeting has been suggested when multiple dysfunctions are present, such as in secondary tremor.5,6 In the present case, the VoP/Zi was targeted in order to provide a wider range of programming options with the contacts covering 12 mm of the ZI up to the bottom of the VoP. In addition, VoP/ZI targeting avoided stimulation of the VIM and possibly the ascending cerebellothalamic tract (CTT) in the caudal ZI. In this case, Neurology 84

May 5, 2015

ª 2015 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

1

Table

Scores in the functional outcome scales used to evaluate tremor and ataxia before surgery and on stimulation 30 months after the procedure Preoperative

On stimulation

Improvement, %

80/144

36/144

55

Part A (magnitude of tremor in different body parts)

22/80

6/80

73

Part B (functional activities of the upper limbs)

35/36

18/36

48

Part C (activities of daily living)

23/28

12/28

48

Scale for the Assessment and Rating of Ataxia

16/40

8/40

50

Posture and Gait subcomponent of the International Cooperative Ataxia Rating Scale

13/34

8/34

38

Fahn, Tolosa, Martin Tremor Rating Scale (total)

Stimulation parameters

Hemisphere

Electrodes

Electrical parameters

Left

[4]

Current: 3.25 mA

[1]

Pulse width: 91 ms

[2]

Frequency: 176 Hz

[2] Right

[2]

Current: 3.00 mA

[3]

Pulse width: 91 ms

[1]

Frequency: 176 Hz

[1] Deeper contact AC/PC coordinates (MCP)

Left

Lateral: 10 mm

Zona incerta

Posterior: 4.5 mm Inferior: 3.5 mm Right

Lateral: 10.5 mm

Zona incerta

Posterior: 4.0 mm Inferior: 3.0 mm Active contact AC/PC coordinates (MCP)

Left

Lateral: 10 mm

Zona incerta

Posterior: 4.5 mm Inferior: 3.5 mm Right

Lateral: 12 mm

Thalamus (VoP)

Posterior: 1.0 mm Superior: 7.0 mm

Abbreviations: AC/PC 5 anterior commissure/posterior commissure; MCP 5 midcommissural point; VoP 5 ventro-oralis posterior thalamic nucleus. There was stable improvement of tremor, remarkable gain in ataxia, and improvement in daily life functionality. The active contacts and stimulation settings were maintained over the follow-up period (30 months), after comprehensive test stimulation was performed over 3–4 weeks after the implant. The stereotactic coordinates of the contacts were calculated after the postoperative CT and the preoperative MRI were fused into the same stereotactic space (programing software MNPS [MEVIS, São Paulo, Brazil]).

the suppression of tremor might be related to the modulation of thalamocortical loop activity by preferential stimulation of the pallidothalamic fibers that lie more anteriorly than the CTT. The ataxia improvement might have occurred because the restricted electrical fields of bipolar stimulation might spare the CTT fibers. Although the effects of high-frequency stimulation on fibers are controversial, it could affect the dysfunctional cerebellothalamic circuitry and worsen the ataxia.7 Data from this case suggest that chronic bipolar stimulation can provide long-term improvement of tremor and ataxia in FXTAS with virtually no side effects. More studies should be conducted to provide definite conclusions. 2

Neurology 84

From the Division of Functional Neurosurgery of Institute of Psychiatry of Hospital das Clinicas (M.G.d.S.G., R.G.C., J.S.d.Â., D.C.B., M.J.T., E.T.F.), University of São Paulo School of Medicine; and the University of São Paulo (R.G.C., E.R.B.), Brazil. Author contributions: M.G. dos Santos Ghilardi contributed to design and conceptualization of the study, data collection, data analysis and interpretation, writing and revising the manuscript. R.G. Cury contributed to conception and revision of the manuscript. J.S. dos Ângelos contributed to design and data collection. D.C. Barbosa contributed to design of the study. E.R. Barbosa contributed to conception and revision of the manuscript. M.J. Teixeira contributed to conception and revision of the manuscript. E.T. Fonoff contributed to design and conceptualization of the study, data collection, data analysis and interpretation, writing and revising the manuscript. Study funding: No targeted funding reported. Disclosure: M. dos Santos Ghilardi, R. Cury, J. dos Ângelos, D. Barbosa, E. Barbosa, and M. Teixeira report no disclosures relevant to the

May 5, 2015

ª 2015 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

manuscript. E. Fonoff reports the support of FAPESP (São Paulo State Research Agency) grant 2011/08529-5 and MCT/CNPq grant 482365/ 2010-2. Go to Neurology.org for full disclosures.

4.

Received March 15, 2014. Accepted in final form December 19, 2014. Correspondence to Dr. Fonoff: [email protected]

5.

© 2015 American Academy of Neurology 6. 1.

2.

3.

Apartis E, Blancher A, Meissner WG, et al. FXTAS: new insights and the need for revised diagnostic criteria. Neurology 2012;79:1898–1907. Senova S, Jarraya B, Iwamuro H, et al. Unilateral thalamic stimulation safely improved fragile X-associated tremor ataxia: a case report. Mov Disord 2012;27:797–799. Ferrara JM, Adam OR, Ondo WG. Treatment of fragile-Xassociated tremor/ataxia syndrome with deep brain stimulation. Mov Disord 2009;24:149–151.

7.

Oyama G, Umemura A, Shimo Y, et al. Posterior subthalamic area deep brain stimulation for fragile X-associated tremor/ataxia syndrome: letter to the editor. Neuromodulation 2014;17:721–723. Sitsapesan HA, Holland P, Oliphant Z, et al. Deep brain stimulation for tremor resulting from acquired brain injury. J Neurol Neurosurg Psychiatry 2014;85:811–815. Foote KD, Okun MS. Ventralis intermedius plus ventralis oralis anterior and posterior deep brain stimulation for posttraumatic Holmes tremor: two leads may be better than one: technical note. Neurosurgery 2005;56(2 suppl):E445; discussion E445. Wang JY, Hessl D, Schneider A, Tassone F, Hagerman RJ, Rivera SM. Fragile X-associated tremor/ataxia syndrome: influence of the FMR1 gene on motor fiber tracts in males with normal and premutation alleles. JAMA Neurol 2013; 70:1022–1029.

Neurology 84

May 5, 2015

ª 2015 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

3