DYT6 is an early-onset autosomal dominant primary dystonia, with frequent craniocervical involvement, caused by pathogenic mutations in the thanatos-associated domain-containing apoptosis-associated protein 1 (THAP1) gene. The response of this particular dystonia to DBS at the internal globus pallidus (GPi) is not well defined, because the published literature reports on 11 cases only, with variable outcomes. Reported data suggest that slight-to-moderate improvement of symptoms after bilateral GPi-DBS is to be expected, and results seem less robust, as compared to patients with DYT1 dystonia.[2-5]
We describe the case of a 36-year-old woman with normal birth and psychomotor development. At the age of 6 years, right-hand dystonia was noted that soon progressed to the left hand. In her mid-teens, she developed perioral dystonic movements. Slight antecollis and mild bilateral foot dystonia developed before the age of 20. At the age of 28 years, cervical dystonia worsened and became painful, followed by lingual dystonia, with marked difficulty with protrusion and speech, as well as mild spasmodic dysphonia. The Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) total motor score was 37. Thorough investigation was normal, including MRI and screening for TOR1A mutations (DYT1). THAP1 (DYT6) gene testing revealed a heterozygous frameshift mutation c.436_443del (p.Arg146AspfsX9) in exon 3.
Several drugs were tried without any improvement: levodopa (400 mg/day); trihexyphenidyl (6 mg/day); and baclofen (80 mg/day). Higher doses were not tolerated. Disabling symptoms at this point prevented the patient from working as a psychologist, because she was unable to keep an efficient conversation and people found her speech difficult to understand. Botulinum toxin types A and B were tried for cervical dystonia, with poor benefit. GPi-DBS was thoroughly discussed with the patient in light of current scientific knowledge, including described benefits and adverse effects. She decided to have the procedure and gave her written informed consent. Stereotactic surgery was performed under general anesthesia, with a Leksell G frame (Elekta Instruments AB, Stockholm, Sweden). A stereotactic CT scan was fused with previous MR images. Target coordinates were chosen by direct visualization in MR (distance to AC-PC midpoint was x = 17.1, y = 3.0, and z = 1.5 mm bilaterally). Standard burr holes and dura mater incisions were made, and three recording electrodes were introduced (central, anterior, and lateral). Intraoperative microrecording was used to define the neurophysiological borders of the GPi. Macrostimulation demonstrated that the central trajectory was the most favorable bilaterally. The threshold for pyramidal stimulation was 3.5 mA (at 120 μs/130 Hz) on both sides. Definitive electrodes were implanted (model 3389; Medtronic, Fridley, MN). An Activa RC pulse generator (Medtronic) was implanted in the same session and turned on 24 hours later. Postoperative CT was fused with preoperative MR, showing that the electrodes were positioned 2 mm below the target coordinates. Monopolar stimulation was used at the second-lowest contacts bilaterally (see Table 1 for further details).
|Study||Case No.||Age at Symptom Onset (Years)||Age at Surgery (Years)||BFMDRS Before Surgery||BFMDRS After Surgery (Final Observation)||Clinical Notes||Stimulation Parameters|
|Zittel et al.||1||6||30||NR||NR||Moderate global improvement; no improvement of oromandibular or laryngeal dystonia (7 years after surgery)||NR|
|2||9||35||NR||NR||Moderate global improvement; no improvement of oromandibular or laryngeal dystonia (7 years after surgery)||NR|
|Groen et al.||3||9||48||79.5||50||Improvement of axial and limb dystonia; no improvement of speech||Average, 3 V (range, 2–3.7), 135 ms (range, 90–180) and 144 Hz (range, 130–185)|
|4||7||9||24||18||Mild improvement of axial and limb dystonia|
|5||10||39||40||18||Good improvement of limb and axial dystonia; no improvement of dysarthria|
|6||6||23||31||26||Mild improvement of cervical and limb dystonia; no improvement of dysarthria|
|7||54||70||20||16||Good improvement of cervical dystonia|
|Jech et al.||8||NR||12||NR||6||Improvement of cervical dystonia|| |
Left GPi: 1.6 V/450 μs/130 Hz;
right GPi: 1.8 V/450 μs/130 Hz
|Panov et al.||9||3||15||40||27||Control of the left side was restored and gait improved; continues to have difficulties with speech; torticollis|| |
Left GPi: 3 V/150 μs/130 Hz;
Right GPi: 2.8 V/150 μs/130 Hz
|10||25||36||20.5||16.5||Alleviated pain and spasms in the left foot and hand|| |
Left GPi: 3 V/120 μs/80 Hz;
right GPi: 3 V/120 μs/80 Hz
|11||6||23||77||21||Ambulation and voice improved modestly|| |
Left GPi: 3.5 V/150 μs/80 Hz;
Right GPi: 3.5 V/150 μs/80 Hz
|França et al. (this study)||12||6||36||37||6||Orolingual and hand dystonia improved significantly; cervical pain remitted|| |
Left GPi: 2.7 V/60 μs/130 Hz;
Right GPi: 2.7 V/60 μs/130 Hz
Immediate postoperative improvement of all symptoms (including orolingual dystonia) was noticed, and she improved over the 3-year follow-up period (Table 2; Video)). Orolingual and upper-limb dystonia improved significantly, and cervical pain remitted. A few weeks later, she resumed her work successfully as her speech improved significantly and is now again able to perform tasks requiring fine finger movements; her quality of life has been subjectively much improved. She remained free of medication after surgery.
|Before Surgery||After Surgery (Months)|
|Speech and swallowing||6||4||3||2||1|
We present a case with interesting long-term progression of dystonic features, prominent orolingual dystonia, significant disability, and refractory symptoms. This report suggests the possibility of substantial improvement of dystonic features in DYT6 after bilateral GPi-DBS, including orolingual dystonia. This has not been convincingly shown in previously reported cases (Table 1). Recent data concerning three DYT6 patients who underwent GPi-DBS reported modest gains during the first 2 years after surgery, with symptomatic regression between years 2 and 3, despite adjustments to stimulation parameters and repositioning of one stimulating lead. In our case, the patient remains significantly improved 36 months after surgery.
DYT6 dystonic symptoms seem to respond variably to GPi-DBS, and, thus far, it has not been possible to correlate surgical outcome with genotype or phenotype, although few cases have been reported. We speculate that, in this case, the favorable outcome regarding orolingual dystonia could be related to a close spatial relationship of active contacts with the somatotopic area of GPi linked with the craniofacial region. DBS could be a valuable therapy for significantly disabled DYT6 patients with medically refractory symptoms, but variable response should be discussed whenever the procedure is offered to surgical candidates. Disabling orolingual dystonia might improve after bilateral GPi-DBS.