MRI-Guided Focused Ultrasound in Cervical Dystonia

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Introduction

Cervical dystonia (CD) is the most prevalent (≤ 50%) clinical dystonia type. CD is a focal dystonia, with involuntary tonic contractions or intermittent spasms of neck muscles and resulting abnormal neck and head position and/or head tremor [1–5]. The CD prevalence is 1.2–5.7 per 1,000,000 person-years [2], while the CD incidence is 8–12 per 1,000,000 person-years [3], with the manifestation peak falling at the age of 30–50 years [2–4]. The disorder is twice as common in female patients [2]. CD etiology varies. There are congenital (idiopathic) and acquired dystonias [5–7]. Idio- pathic CD is shown to be related with DYT2, DYT13, DYT23, DYT24, DYT25, and other loci mutations [8]. Acquired dystonias develop in patients with the brainstem and basal ganglia lesions of various origin, as a result of long-term use of dopamine receptor antagonists, etc. [4, 8]. Patients with dystonia manifestations often demonstrate functional (psychogenic) disease, which requires special attention and diagnosis experience [9].

CD symptoms typically progress within the first several years up to plateau [4, 5]. Clinically, CD implies the abnormal position of the head (torticollis, torticaput, laterocollis, laterocaput, anterocollis, anterocaput, retrocollis, retrocaput), the neck, and the shoulders with dystonic head tremor aggravated in voluntary movement, fatigue, and emotional strain. Many patients use sensory tricks, such as touching the chin or cheek, to reduce symptoms.. CD is often complicated with depression, anxiety, and phobias and makes patients highly incapable, and limits their daily living and social life [3–5, 10]. While several scales are used to assess CD symptom severity, the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) is the fittest and most widely used [11].

Recently, CD management has transformed drama- tically, from exercise therapy, pharmaceutical treatment, and local muscle surgeries through stereotactic ablation and deep brain stimulation (DBS) to innovative non-invasive approaches like MRgFUS [6, 7, 12–17]. Oral agents (clonazepam, anticholinergic agents, myorelaxant agents, etc.) are as a rule ineffective and have significant side effects in therapeutically necessary higher doses [4, 16]. Currently, the gold standard of CD therapy is the use of botulinum toxin type A to treat abnormal movements and to relieve pain [6, 7]. Its disadvantages include the need for repetitive injections every 3–4 months, inadequate effectiveness that depends on CD signs and symptoms, effectiveness decrease, and resistance in some patients [16, 18].

CD surgical treatment dates back to 1641 when the German surgeon named Isaac Minnius sectioned the sternocleidomastoid muscle [10]. Such local interventions had been popular before mid-20th century when the rise of functional stereotactic surgery revolutionized CD neurosurgical treatment and laid the foundation of today practice including DBS and MRgFUS. Soviet and Russian neurosurgeons gained abundant experience in destructive surgery for dystonia [10, 19–21].

In the 1970s, based on W. Hess's experimental results, R. Hassler and G. Dieckmann attempted to consider CD clinical signs and symptoms and to select destruction targets in order to involve the pallidothalamic tract (PTT) in H1 Forel's field (in torticollis) and the thalamic ventral oralis (Vo) complex nucleus (in laterocollis) contralaterally to the head turn side [22, 23]. Following up 112 CD patients post ventro-lateral thalamotomy, E.I. Kandel concluded that the bilateral intervention was more efficient, especially in patients with head hyperkynesias [19]. Follow-up results correspond to the current understanding of CD pathogenesis [14, 24, 25].

Prior to DBS large-scale implementation, destructive surgery was the leading approach in CD symptomatic treatment with effectiveness of 50–70%. Such interventions were performed mostly unilaterally because bilateral destruction was typically (20–70%) complicated by dysarthria, dysphagia, ataxia, and symptomatic parkinsonism [12, 14, 24].

In the late 20^th century, DBS became the leading approach in CD neurosurgical treatment [15, 26, 27]. Right and left globus pallidus internus stimulation (GPI-DBS) is the modality commonly used in patients with CD who did not respond to pharmaceutical and botulinum toxin therapies. Improvement after bilateral GPI-DBS may vary from TWSTRS score 27.8% [15] to TWSTRS score 51.4% [27] or 66.6% [28], depending on stimulation parameters, patient cohorts, and observation periods. According to J. Volkman et al., 10% of the patients did not respond to GPI-DBS despite multiply varied stimulation parameters [17].

The clinical implementation of MRgFUS to treat movement disorders revitalized functional brain destruction. Recently, we have accumulated extensive evidence of MRgFUS safety and efficiency in patients with essential tremor and Parkinson’s disease (PD) [29–32]. However, by the moment, we have found only single reports on MRgFUS to treat dystonia [13, 33, 34]. We are presenting our own experience of MRgFUS use to manage patients with CD.

Objective. To improve outcomes in patients with CD using MRgFUS.

Materials and methods

We retrospectively analyzed 13 cases of various CD types managed with MRgFUS in single or multiple sessions. The mean age of the patients was 42 (39; 53) years (Fig. 1). All of them had no family history of dystonia. The disorder manifested as dystonic hand tremor at early age with subsequent cervical involvement in 2 patients. In other cases, hyperkynesia manifested as isolated CD and was not combined with any other movement disorders.

 

Fig. 1. Age distribution of operated CD patients.

 

All the CD patients were refractory to botulinum toxin therapy after several courses. DBS was rejected due to patients' disregard of head mechanical implants (patients' refusal) or lack of access to the medical centers that could adjust stimulation parameters.

TWSTRS was used to assess patients' statuses and severity of CD symptoms during therapy and the last available observation period. The Hospital Anxiety and Depression Scale (HADS) and the Montgomery–Åsberg Depression Rating Scale (MADRS) were used to assess anxiety and depression [11].

MRgFUS CD symptomatic treatment was conducted at V.S. Buzaev Memorial International Medical Center. We used ExAblate Model 4000 (Insightec v.7.0.404, Insightec), with 1024 ultrasound generators, and GE Optima MRI scanner (MR450W, 1.5 Т). The standard procedure of preparation for MRgFUS was performed in all the patients.

Targets included PTT and/or Vo (see Table). As there is no unified standard or rationale, targets are selec- ted based on published experience in specific CD cases. Reverse ultrasound exposures allow to model effects in a particular brain area and to select the most efficient target for the patient. The targets were sonicated at least twice at temperature over 55ºС. The median MRgFUS time was 117 (79; 139) min; the median sonication number was 12 (11; 14.5). The energy range was 20,096–35,731 J in a temperature range 54–62ºC.

 

Characteristics of included CD patients

CD clinical signs and symptoms	МР-ФУЗ MRgFUS age	CD onset age	Sex	TWSTRS score — assessed CD severity		Target
				pretreatment	post treatment	right hemisphere	left hemisphere
Right torticollis, right torticollis, head tremor	42	4	М	16	9		PTT VO
Left torticollis, left laterocollis, head tremor	53	33	М	22	6	PTT VO
Right torticollis, head tremor	53	43	F	22	4		PTT VO
Right torticollis, head tremor	36	31	F	23	6		PTT VO
Right torticollis, head tremor	39	23	F	4	0		PTT VO
Left torticollis, right laterocollis, orofacial dystonia	39	37	М	27	9	VO	PTT
Left torticollis, left laterocollis, head tremor	42	18	F	17	4	PTT VO
Right torticollis, left laterocollis, orofacial dystonia	57	26	M	29	15	VO	PTT
Left torticollis, retrocollis	46	33	F	26	10	PTT	VO
Left torticollis, head tremor	30	15	М	9	4	PTT
Right torticollis, head tremor	57	27	F	13	2		PTT VO
Right laterocollis, head tremor	32	17	F	17	5	VO	PTT
Right laterocollis	47	27	F	25	14		PTT

Note. M, male; F, female.

 

The MRgFUS procedure included control brain MRI scan (T2-weighted; axial, sagittal, and coronal views; 2-mm thick slices). Intraoperative imaging showed no signs of hemorrhage or non-target heat in any patient. Follow-up brain MRI scans in 2 h and 24 h, and 30 days revealed slight marginal edema (1–3 mm) and necrotic foci at the sites of sonication (Fig. 2).

 

Fig. 2. Axial and coronal MR images in 30 days after right PTT MRgFUS destruction.

The arrow indicates the destruction focus.

 

Results

The mean follow-up period was 13.3 ± 3.4 months (July 2021 to April 2023). The mean CD severity assessment (TWSTRS score) was 22 [16; 25] before MRgFUS and 6 [4; 9] in the last available observation. Therefore, we found 70.6% [55.6; 76.5] improvement (paired samples t-test p = 0.0025).

 

Fig. 3. TWSTRS scores pre (I) and immediately post (II) MRgFUS intervention.

 

Six patients demonstrated mild side effects including gait disorders and postural unsteadiness for 3 weeks. Two patients had significant logorrhea totally reversed on quetiapine (25 mg/day) within a month. Two female patients noted memory deterioration in 1 month post MRgFUS followed by gradual recovery by the end of the follow-up year 1. Two patients showed altered handwriting with slight micrography and gradual postoperative recovery.

One patient with significant head tremor showed recurrent hyperkynesia in 6 months post MRgFUS. This patient received re-intervention in 9 months post initial procedure, with no recurrent head tremor during next 4 months.

The patients reported evident positive changes in their daily living and their social and professional lives throughout the follow-up period. Three patients got better-paid job positions; one patient changed night-time IT position for academic lecturing; one female patient was proposed to get married; one patient stopped having the status of disabled person; one patient resumed working as an operating surgeon; two patients resumed their occupations.

Discussion

Management of CD patients remains a challenge for neurologists [4, 5, 16, 18]. DBS is the best option that can significantly relieve CD symptoms [15, 26], but it is not widely used due to its complexity and low accessibility. MRgFUS can become an alternative, innovative, and non-invasive method of functional neurosurgery in this population though the experience of its use for CD (unlike PD and essential tremor) is especially limited and, according to the guidelines, MRgFUS is no method of choice [13, 33, 34].

In 2021, S. Horisawa et al. published an open-label pilot study and showed that Vo MRgFUS significantly relieved focal hand dystonia in 10 patients, with mild dysarthria in 1 patient as the only adverse event in 12 months [13]. R. Jamora et al. demonstrated general improvement in 3 patients with X-linked dystonia-parkinsonism (XDP) post MRgFUS Vo-thalamotomy [34]. The XDP-MDSP scores improved by 36.2% in 6 months and by 30.1% in 12 months. However, central pain syndrome manifested in 2 patients in 2–7 months post treatment.

We have described our own, first experience in Russia of the MRgFUS use for CD (in 13 patients with follow-up period over 1 year and TWSTRS improvement by 70.6%). Due to recurrent tremor, one patient received re-intervention in 9 months after initial procedure. Complications were relatively mild and resolved by the end of follow-up year 1. We selected PTT and/or Vo as targets, basing on published intervention outcomes in relevant patient categories [13, 14, 33, 34]. So, PTT destruction relieves CD symptoms due to disruption of cortico-basal and thalamo-cortical pathways and modulation of thalamic efferent stimuli while Vo interventions may be useful in patients with laterocollis [25, 35].

Available data allow us to consider MRgFUS as an efficient method to treat symptoms of pharmacoresistant CD. A number of vital aspects of MRgFUS have to be specified in larger CD cohorts in long-term follow-up. This method may be considered as advanced in management of patients with other dystonias, which has to be proven in special studies including multicenter trials. We may expect that, introduced into clinical practice more widely, this mini-invasive method will be gradually used in patients with movement disorders more extensively.

Ethics approval. The study was conducted with the informed consent of the patients. The research protocol was approved by the local Ethics Committee of the Research Center of Neurology (protocol No. 1-8/23, January 25, 2023).

Source of funding. This study was not supported by any external sources of funding.

Conflict of interest. The authors declare no apparent or potential conflicts of interest related to the publication of this article.

About the authors

Rezida M. Galimova

Bashkir State Medical University; Intelligent Neurosurgery Clinic, International Medical Center V.S. Buzaev Memorial

Author for correspondence.
Email: rezida@galimova.com
ORCID iD: 0000-0003-2758-0351

Cand. Sci. (Med.), Department of Neurosurgery, Bashkir State Medical University; Chief, Neurosurgeon, Intelligent Neurosurgery Clinic, International Medical Center V.S. Buzaev Memorial

Russian Federation, Ufa; Ufa

Sergey N. Illarioshkin

Research Center of Neurology

Email: annaly-nevrologii@neurology.ru
ORCID iD: 0000-0002-2704-6282

D. Sci. (Med.), Prof., Academician of the RAS, Deputy Director, Director, Brain Institute

Russian Federation, Moscow

Igor V. Buzaev

Bashkir State Medical University; Intelligent Neurosurgery Clinic, International Medical Center V.S. Buzaev Memorial

Email: igor@buzaev.com
ORCID iD: 0000-0003-0511-9345

D. Sci. (Med.), Prof., Surgery Department, Bashkir State Medical University; Cardiovascular Surgeon, Intelligent Neurosurgery Clinic, International Medical Center V.S. Buzaev Memorial

Russian Federation, Ufa; Ufa

Yulia A. Sidorova

Intelligent Neurosurgery Clinic, International Medical Center V.S. Buzaev Memorial

Email: yuliasi.ufa@gmail.com
ORCID iD: 0000-0002-0992-0239

Neurologist

Russian Federation, Ufa

Dmitriy K. Krekotin

Intelligent Neurosurgery Clinic, International Medical Center V.S. Buzaev Memorial

Email: krekotin@yandex.ru
ORCID iD: 0000-0002-2215-7178

Assistant, Department of MRI

Russian Federation, Ufa

Shamil M. Safin

Bashkir State Medical University

Email: safinsh@mail.ru
ORCID iD: 0000-0002-0100-6100

D. Sci. (Med.), Prof., Head, Department of Neurosurgery

Russian Federation, Ufa

Dinara I. Nabiullina

Intelligent Neurosurgery Clinic, International Medical Center V.S. Buzaev Memorial

Email: nabiullina.dinara@yandex.ru
ORCID iD: 0000-0003-2570-3709

Neurologist

Russian Federation, Ufa

Gulnara N. Akhmadeeva

Bashkir State Medical University; Intelligent Neurosurgery Clinic, International Medical Center V.S. Buzaev Memorial

Email: nevrolog.ufa@gmail.com
ORCID iD: 0000-0001-5516-0587

Cand. Sci. (Med.), Department of Neurology, Bashkir State Medical University; Neurologist, Intelligent Neurosurgery Clinic, International Medical Center V.S. Buzaev Memorial

Russian Federation, Ufa; Ufa

Dinara R. Teregulova

Intelligent Neurosurgery Clinic, International Medical Center V.S. Buzaev Memorial

Email: dinamail@mail.ru
ORCID iD: 0000-0001-6283-3735

Cand. Sci. (Med.), Neurologist

Russian Federation, Ufa

References

Supplementary files