Essential Tremor: Treatment with Focused Ultrasound

Essential Tremor: General Information

Essential tremor is a common disease and the most frequent extrapyramidal movement disorder, occurring in an average of 1–3% of individuals in populations worldwide (Illarioshkin, Ivanova-Smolenskaya, 2011). According to some estimates, the prevalence of ET among individuals over 90 years old may exceed 20% Louis et al., 2009). Genetic factors play a significant role in the development of ET: a positive family history of tremor can be identified in 30–70% of cases, and among those who developed the condition before the age of 40, in 80% of cases (Illarioshkin, Ivanova-Smolenskaya, 2011 Dogu et al., 2003).

The age of ET onset is highly variable, ranging from the 1st to the 8th decade of life, with a bimodal distribution, the first peak at 14.5–15 years and the second peak after 35 years ( Bain et al., 1994).

The leading clinical manifestation of ET is postural or postural-kinetic tremor with a frequency of 4–12 Hz, usually involving the hands and forearms ( Bhatia et al., 2018). In typical cases, tremor is symmetrical, but sometimes it has clear lateralization, including at the onset of the disease (Levin et al., 2022). In the hands, the motor pattern of hyperkinesis in ET most often corresponds to pronation-supination, unlike PD, which is more characterized by flexion-extension movements. Besides the hands, other possible localizations of tremor in patients with ET include facial muscles, tongue, head, vocal cords and diaphragm (voice tremor), legs, and trunk (Illarioshkin, Ivanova-Smolenskaya, 2011; Levin et al., 2022; Lou, Jancovic, 1991; Bhatia et al., 2018).

In most patients, hand tremor is most pronounced during static tension, maintaining a certain antigravity posture (postural tremor). It usually disappears or significantly decreases if the hands are relaxed and in a mid-physiological position with support.

Resting tremor in ET is significantly less common than postural tremor, occurring in about 20% of patients. This type of tremor is more often observed in patients over 60 years old and with a long duration of the disease (more than 15–20 years). Kinetic and often intentional components of tremor in ET lead to difficulties in small and precise (primarily continuous) movements, such as writing. Handwriting is characterized by sharp, shaky letters that are often disconnected; attempts to suppress the tremor that intensifies during writing lead to active tension in the hand and forearm muscles, slowing down writing, causing hand fatigue, and making movements clumsy. This is accompanied by pronounced emotional reactions, insecurity, and a sense of fear when writing is necessary. Such patients often complain that they cannot sign their name in the presence of others. Thus, conditions are created in ET patients that promote the development of focal dyskinesias, particularly writer’s cramp.

All types of tremor in patients with ET are exacerbated by anxiety, mental stress, hypothermia, physical exertion, and coffee consumption. In 65–70% of patients with ET, there is a positive “alcohol test”—a reduction in the severity of tremor hyperkinesis for several hours after alcohol consumption (Illarioshkin, Ivanova-Smolenskaya, 2011)

Sometimes in ET, typical postural-kinetic tremor may be combined with other “mild” motor symptoms—focal dystonias, impaired tandem gait, dysmetria, hypomimia, slight increase in plastic muscle tone. To describe such cases, a group of experts from the International Parkinson and Movement Disorder Society International Parkinson and Movement Disorder Society, MDS) the term “essential tremor plus” was proposed Bhatia et al., 2018).

In recent years, data has been accumulating on the non-motor manifestations of ET, particularly regarding the higher incidence of anxiety and depression in patients with ET compared to healthy individuals. For instance, in a large-scale study from 2007, which included 235 patients with ET and 4379 healthy individuals, the frequency of depression in patients with ET was found to be twice as high compared to the control group ( Louis, 2007). In a 2019 study, it was found that 63.3% of patients with ET had at least mild anxiety, and 54.3% had mild depression, with the presence of head tremor, facial muscles, and voice increasing the risk of anxiety and depression ( Huang et al., 2019). There is reason to believe that affective disorders are not merely a reaction to the emerging motor defect but have independent significance in the mechanisms of ET development. For example, anxiety and depression may precede the onset of movement disorders, and the severity of affective disorders does not correlate with the severity of tremor ( Chatterjee et al., 2004; Louis, 2007). In patients with ET, especially the elderly, there may also be impairments in speech fluency, attention, logical and auditory-verbal memory (Illarioshkin, Ivanova-Smolenskaya, 2011). There is evidence of an increased (by 4–16%) frequency of dementia in ET compared to controls.

Currently, it has been established that a large number of different neurological diseases can present under the guise of ET, manifesting as postural-kinetic tremor (Illarioshkin, Ivanova-Smolenskaya, 2011; Levin et al., 2022; Sepúlveda Soto, Fasano, 2020). These include tremor phenotypes of PD (differential diagnosis of ET and PD, especially at the onset of symptoms, is a challenging task), dystonic tremor, FXTAS (fragile X-associated tremor/ataxia syndrome – tremor/ataxia syndrome associated with fragile X chromosome), tremor in spinocerebellar ataxias, drug-induced and toxic tremor, functional tremor, etc. Therefore, when examining patients with suspected ET, it is necessary to conduct a thorough, targeted differential diagnostic search Elble, 2020; Sepúlveda Soto, Fasano, 2020). It should be remembered that the available neuroimaging methods (CT, MRI, transcranial sonography, as well as PET and single-photon emission CT (SPECT) with dopamine ligands) do not reveal any specific changes in the brain substance in ET.

Although ET is traditionally considered a relatively “benign” disease, the steady progression of movement disorders can lead to significant functional impairments and disability in advanced stages ( Sepúlveda Soto, Fasano, 2020). In the first stage of treatment for such patients, medication therapy is always used. The main option for ET is the prescription of non-selective b-blockers (propranolol 60–240 mg/day) or primidone (up to 125–250 mg/day with slow dose increase). These drugs are considered equivalent and initially provide a distinct positive effect in 70–80% of cases, leading to a reduction in the severity of hyperkinesis (Illarioshkin, Ivanova-Smolenskaya, 2011; Rajput, Rajput, 2014; Sepúlveda Soto, Fasano, 2020). Topiramate at a dose of more than 200 mg/day has similar effectiveness ( Ferreira et al., 2019). Some patients may benefit from clonazepam, alprazolam, levetiracetam, gabapentin, clozapine, and others. If necessary, propranolol can be combined with primidone, topiramate, or second-line drugs. Various algorithms and medication therapy schemes for ET have been proposed depending on the clinical picture (predominance of hand or head tremor), age, comorbid pathology, and other factors (Levin et al., 2022; Ferreira et al., 2019). Limited value in ET is held by local injections of botulinum toxin into muscles involved in hyperkinesis, or various physical treatment methods.

Unfortunately, the initial effect of propranolol and often other medications may decrease over time ( Rajput, Rajput, 2014). Prescribed medications have serious side effects, making it difficult or even impossible to take them in necessary doses, especially in old age. Thus, up to 25–55% of patients with ET at a certain point become resistant to drug therapy or cannot continue it properly ( Louis, 2001). Meanwhile, the increasing loss of daily independence, inability to perform basic everyday activities (such as eating, dressing, hygiene), and social isolation can seriously affect the quality of life for patients with ET. Therefore, as the next stage of treatment, functional stereotactic neurosurgical operations should be considered

As with other movement disorders, in ET, surgical treatment is divided into ablative surgeries and DBS. In many cases, such treatment is the only option that can radically reduce disease symptoms and significantly improve quality of life (Levin et al., 2022; Ferreira et al., 2019). In both types of intervention, the target of impact in patients with ET is most often VIM, less often – ZI and others

The most commonly accepted method for ablative surgeries until recently was radiofrequency thermodestruction, which is performed after stereotactic insertion of a special electrode into the target point: when high-frequency currents pass through it, local thermocoagulation of brain tissue occurs at the electrode tip due to the release of thermal energy. Such operations are usually performed on one side, corresponding to the more affected limb, to avoid complications (pseudobulbar syndrome, paresis) associated with bilateral destruction of subcortical nuclei. It should be noted that compared to patients with Parkinson’s disease, the number of patients with essential tremor who underwent thalamotomy is relatively small. With long-term follow-up, a stable positive result of stereotactic thalamotomy was observed in 60–100% of patients with essential tremor ( Akbostanci et al., 1999). In a series of cases involving 65 patients with ET, complete disappearance or significant reduction of tremor on the contralateral side of the operation was noted in 68.7% of patients, and 8.5% of patients experienced ipsilateral reduction in hand tremor severity after thalamotomy ( Mohadjer et al., 1990).

In several centers, there is experience with unilateral radiosurgery for ET using a gamma knife ( Kondziolka et al., 2008; Niranjan et al., 2017), however, in general, such operations for ET have not become widespread. Despite the absence of incisions and direct mechanical impact on the brain, radiosurgery has its own range of serious drawbacks, the most significant of which are the delayed effect and the inability to functionally assess the impact at the time of surgery: the reduction in tremor severity is usually observed only 5–12 months after the radiation exposure ( Young et al., 2010). Various complications after thalamotomy using the gamma knife were identified in the long-term period in 3.9% of patients ( Young et al., 2010).

A more technologically advanced method for treating ET, which allows avoiding the destruction of brain tissue, is considered DBS. Implantation of electrodes and stimulation VIM in patients with ET, improves quality of life and significantly reduces disability: hand tremor severity decreases by 50–91%, and head and voice tremor by 15–100%. This effect usually lasts for 7 years or more ( Hariz et al., 2002; Altinel et al., 2019). An undeniable advantage DBS is the possibility of relatively safe bilateral electrode implantation (both simultaneously and delayed) to radically eliminate tremor on both sides. Bilateral stimulation is preferable for head and voice tremor. The disadvantages DBS include invasiveness and the need for implantation of foreign bodies (electrodes, pulse generator), risk of infection, bleeding, electrode displacement, device malfunction and other complications, depletion of the generator’s resource with the need for periodic replacement, etc.

A more detailed history and current state of ET surgery are presented in Chapter 1.

Thus, despite the significant successes achieved in the treatment of ET using ablative and stimulation surgical methods, a number of complex problems in managing such patients persist in practice, requiring the introduction of new functional approaches. Such an approach has become the non-invasive MRgFUS technology

Treatment of Essential Tremor Using MRgFUS

According to several authors, MRgFUS may be “ideally” suited for patients with ET, who usually prefer less invasive treatments and for whom bilateral interventions may be safer compared to patients with PD. Typical targets are VIM и ZI; there are studies in which the cerebellothalamic tract was used for ultrasonic destruction in patients with ET Gallay et al., 2016) either dentatorubrothalamic tract Miller et al., 2019).

Evaluation of the effectiveness and safety of MRgFUS for ET was initially conducted in separate pilot studies starting from 2011 ( Elias et al., 2013, 2016; Lipsman et al., 2013; Chang et al., 2015). W.J. Elias et al. (2013) presented the first observation of unilateral ablation VIM using MRgFUS in 15 patients with medication-resistant ET. All patients achieved a positive response to treatment with MRgFUS, with improved indicators in CRST from 20.4 ± 5.2 points initially to 4.3 ± 3.5 points after 3 months and to 5.2 ± 4.8 points after 12 months (a 75% reduction in tremor severity; p = 0.001). After the publication of this study, the MRgFUS treatment method for patients with ET became widely adopted in many countries.

In 2018, the results of a randomized clinical trial were published, involving 76 patients with ET who had moderate to severe movement disorders; an additional selection criterion was tremor resistance to at least two medications, including at least one first-line drug (propranolol or primidone) Zaaroor et al., 2018). After unilateral thalamotomy using MRgFUS, a reduction in the severity of hand tremor was achieved according to CRST from 18.1 to 9.6 points in 3 months, whereas after the sham procedure, the change was minimal – from 16.0 to 15.8 points (95% confidence interval 5.9–10.7; p < 0,001). Improvement in the thalamotomy group persisted at 12 months. Secondary criteria for assessing disability and quality of life also improved compared to the sham procedure ( p < 0,001). Among the identified side effects in the thalamotomy group, the authors noted gait disturbances (36%) and paresthesia/numbness (38%), which persisted at 12 months in 9% and 14% of patients, respectively Zaaroor et al., 2018).

In 2019, data from a 3-year prospective study of unilateral MRgFUS thalamotomy for ET were published Halpern et al., 2019). The statistically significant reduction in the total scores of individual sections of motor scales achieved as a result of the operation was maintained for up to 36 months. The range of improvement compared to the baseline was 38–50% for hand tremor, 43–56% for disability, 50–75% for postural tremor, and 27–42% for quality of life.

In October 2021, the side effects after using MRgFUS were described in detail: in a retrospective study involving 42 patients who underwent unilateral thalamotomy using MRgFUS (39 patients with ET, 1 patient with PD with predominant tremor, and 2 patients with mixed tremor syndrome), 19 patients (45%) experienced gait disturbances. Patients with a history of lower limb neuropathy have a higher likelihood of gait disturbances after MRgFUS thalamotomy than those without neuropathy. This indicates that the disruption of the proprioceptive pathway combined with cerebellar dysfunction due to damage to the dentatorubrothalamic tract leads to an increased predisposition to developing gait disorders Jackson et al., 2021).

When studying the technical features of thalamotomy using MRgFUS in patients with ET M.J. Kim et al. (2021) identified the following factors influencing treatment outcomes: younger age and higher temperature at the ablation site correlated with a reduction in tremor according to multivariate analysis (odds ratio 0.948; p = 0.013 and odds ratio 1.188; p = 0.025, respectively). The threshold value of focal temperature for predicting the achievement of the total score <10 по CRST was 55.8° C. The skull density ratio positively correlated with heating efficiency ( b = 0,005; p < 0,001), but no significant correlation was observed between skull density and tremor reduction. In the group with a lower target heating temperature (52–54° C) 1–2 the repetitions of the procedure were sufficient to cause sustained suppression of tremor during the observation period, whereas the high-temperature group experienced more frequent balance disturbances than the low-temperature group (p = 0.04) Kim et al., 2021).

W.K. Miller et al. (2022) conducted a systematic review of the results of unilateral ET treatment using MRgFUS, including 21 studies (395 patients) with available quantitative data on the hand tremor scale ( Hand Tremor Score, HTS), CRST и QUEST. Before the operation, the total score on the HTS was 19.2 ± 5.0, 3 months after treatment – 7.4 ± 5.0 (improvement by 61.5%; p < 0,001). Average score sum for CRST decreased by 46.2% three months after treatment ( p < 0,001), also after 3 months, a statistically significant improvement was observed in QUEST. Only in 4 studies was the follow-up duration ≥24 months, with patients with ET having a total score of HTS significantly decreased compared to the baseline level at 24 months, the treatment effect slightly (by 8.8%) decreased at 36 months and persisted at 48 months ( Miller et al., 2022).

Y.S. Park et al. (2019) published long-term results of unilateral treatment of patients with ET using MRgFUS 4 years after the intervention. Improvement in HTS was 56%, on the disability scale – 63%, on the posture scale – 70%, and on the action scale – 63% compared to the baseline level. Changes in all quantitative assessments were significant and persisted over a 4-year period after thalamotomy. No persistent side effects were identified during the 4 years of observation.

In the systematic review M. Giordano et al. (2020) an evaluation of the results of several studies on the treatment of ET using MRgFUS was conducted, and in all the included works Elias et al., 2013, 2016; Huss et al., 2015; Chang et al., 2018; Halpern et al., 2019; Park et al., 2019; Sinai et al., 2019; Krishna et al., 2020) treatment was unilateral. For comparative analysis, the authors also highlighted 37 publications on the use of the method in patients with ET DBS and 1 study – comparing MRgFUS and DBS. Based on the results of the comparison, the MRgFUS method had a more significant positive impact on the quality of life of patients, despite a lesser reduction in the severity of tremor compared to DBS. The authors noted that with the same overall complication rate for both methods, each is associated with its own characteristic spectrum of adverse events (for example, speech disturbances and electrode displacement are typical for DBS, whereas gait disturbance or numbness are more commonly observed after MRgFUS)

A new solution for performing MRgFUS to treat ET has been proposed A. Jameel et al. (2022). After performing 14 operations, they found that the impact on the target VIM/VOP and additional impact on PSA (posterior subthalamic area) significantly reduced the tremor of the contralateral hand with improved function, enhanced quality of life, and an acceptable profile of adverse events

Thus, the effectiveness of unilateral ultrasound thalamotomy in patients with ET has been confirmed in open and controlled studies, demonstrating a reduction in hand tremor by an average of 56–70% and the persistence of the effect observed for up to 4 years. An important aspect is also the recorded reduction in patient disability with significant improvement in self-care (eating, drinking, etc.) Martínez-Fernández et al., 2021б).

In ET, as a generalized disease, to ensure a better quality of life, it is desirable to eliminate tremor on both sides of the body. Therefore, there is currently great interest in attempts at bilateral treatment. It should be noted that the experience of bilateral ablative operations on the thalamus in patients with ET is quite limited. Previously, without the use of modern neuronavigation technologies and non-invasive destruction methods, disabling complications after such operations occurred in about 50% of patients with ET ( Zirh et al., 1999; Alshaikh, Fishman, 2017). In work R.F. Young et al. (2014) 68 patients with ET underwent staged bilateral thalamotomy using a gamma knife. The interval between surgeries was more than 12 months, and for localization of the area VIM MRI and a stereotactic frame were used Leksell. After both procedures, the reduction in tremor severity was 60%. In 2 patients (2.9%), complications arose in the form of speech and gait problems; the complications were delayed and developed within 1 year after the second operation ( Young et al., 2014).

The implementation of MRgFUS has improved the accuracy of interventions, significantly altering the outcomes of bilateral ablation procedures. In the study M.N. Gallay et al. (2016) during the treatment of 4 patients with ET using the MRgFUS method, the cerebellothalamic tract was chosen as the target. After bilateral destruction, 1 patient experienced persistent gait disturbance, while no complications were observed in the other 3 patients C. Iorio-Morin et al. (2021) conducted research BEST-FUS (phase 2), aimed at determining the effectiveness and safety of bilateral staged treatment of ET using MRgFUS. The study did not reveal significant deterioration in speech function after surgery on the second side (only 1 patient noted some slurred speech at 3-month follow-up) K. Fukutome et al. (2022), describing their experience treating 5 patients, noted that bilateral thalamotomy using MRgFUS can be an effective method under the following conditions: asymmetric lesions are created and a sufficient interval between operations is maintained (according to the authors, an interval of more than 1 year can be considered “sufficient,” but this statement requires further evaluation)

It can be concluded that clarifying the possibilities of bilateral operations using the MRgFUS method in patients with ET is currently one of the most interesting issues in the study of movement disorders, but the search for its solution is only at the very beginning and requires multicenter research.

Personal Experience in Treating Patients with Essential Tremor Using MRgFUS

In our country, the first operations for treating patients with ET using the MRgFUS method were performed in 2020 by doctors from the V.S. Buzaev International Medical Centre (Ufa) with scientific and organizational support and in close collaboration with the Scientific Center of Neurology (Moscow) (Galimova et al., 2020, 2022)

In all cases of treatment for ET, we used as
targets VIM

Unilateral surgeries

Unilateral treatment was performed on 37 patients (22 men, 15 women). All patients had no contraindications for treatment, such as dementia, use of anticoagulant medications, tumors, malformations, etc.; additionally, patients did not have claustrophobia or implants incompatible with MRI. The left thalamus, affecting symptoms on the right side of the body, was operated on in 29 patients, and the right thalamus (for the left side of the body) in 8 patients.

Inclusion criteria:

• diagnoses of ET and ET-plus, established according to recommendations
  MDS (Appendix 3);
• age over 18 years;
• lack of sufficient control of movement disorders in
  use of basic medications (propranolol,
  primidone, topiramate) in sufficient doses for more than
  3 mth.

(range from 21 to 82 years); median age of women – 58.0 [43,5;
63,5] years, men – 54.5 [39,8; 65,0] years. There were no statistically significant differences between men and women in terms of age and disease onset. The average duration of the disease from
the onset of the first symptoms was 28 [17; 35] years,
minimum – 3 years, maximum – 58 years. The average duration of the disease in men was 24.5 [17,8; 33,8] years, for women – 30.0 [16,5; 40,5] лет.

A family history of tremor was noted in 13 individuals (35.1%), and none of them underwent genetic testing.

The main tool for quantitative assessment of results
treatment was CRST (Appendix 4) ( Fahn et al., 1993). Used
how are the total indicators CRST, as well as some fragments for each side of the limbs separately on the right and left. Tremor was assessed before the procedure, during, and after each exposure to ultrasound; indicators CRST evaluated immediately after the surgery and then after 1 year. Data were analyzed using a software package R 4.1.1 (10.08.2021). Due to the small sample size and non-normal distribution, the non-parametric Wilcoxon test was used (including the paired test for data before and after surgery).

Initially, all patients in the clinical picture revealed
predominance of moderate and severe (from 2 points according to CRST) postural-kinetic tremor of the upper limbs. Clinically
significant tremor of another localization by severity was
moderate and severe (from 2 points according to CRST), including:

• postural-kinetic tremor of the lower limbs – in 9 pa-
  patients (24.3%)
• postural tremor and resting tremor of the head – in 14 patients
  (37,8%);
• voice tremor – in 4 patients (10.8%)

Median total score for CRST for all patients was 51 [40; 61], when dividing patients by gender – 54.5 [40,8; 58,8] у мужчин и 48 [41; 63] in women. The duration of tremor did not correlate with the severity of tremor according to CRST (Fig. 6.2). The duration of the disease ranged from 3 to 58 years (median 143.0 [107,5; 155,0] years) and did not correlate with the severity of symptoms according to CRST (R = 0,2; p = 0,3), which indicates a significant variability in the rate of disease progression. Bone mineral density (BMD) was
0,52 [0,41; 0,57], range – from 0.34 to 0.69. There was a slight trend towards a reduction in the duration of the operation with an increase in the CTDIvol (Fig. 6.3)

The operation using the MRgFUS method was conducted according to the standard protocol. Coordinates VIM-thalamic nuclei (Figure 6.4) were defined as ¼ of the length of the intercommissural line ( AC–PC) anterior to the posterior commissure and 12–14 mm lateral from the midline plane ( ML) at the level of the horizontal plane passing through the commissures ( Lipsman et al., 2013;  Iacopino et al., 2018). In case of extended III ventricle – coordinates shifted 11 mm laterally from its wall

To assess the impact of surgical experience on the duration of the operation, we conducted a corresponding correlation analysis, expressing experience in the number of previous operations (including other diagnoses). As a result, a weak correlation was established between the compared indicators ( R = –0,35; p < 0,05) (Fig. 6.5). The duration of the procedure from the first to the last ultrasound exposure was 99.3 [75,0; 132,3] min, with the shortest operation taking 30.7 min and the longest 189.1 min.

Success was achieved in 36 out of 37 patients after surgery: the result was rated as “excellent” in 19 patients, “good” in 15, and “satisfactory” in 2. Only 1 patient (2.7%) did not respond to treatment due to atypical location VIM (discharged without result). In our cohort of patients with ET, there was not a single case of deterioration after the intervention.

По CRST the maximum possible score for one side of the body is 40, while before unilateral treatment with MRgFUS, the median on the contralateral side in patients was 18.0 [12,5; 24,8] points, after exposure – 5 [3; 7] points, the differences are statistically significant (Fig. 6.6). Hand tremor completely disappeared immediately after the procedure in 34 patients (91.9%), in 4 patients the accompanying leg tremor was also eliminated, and in 11 patients the accompanying head tremor was also reduced. In patients with head tremor, additional impact was applied to the medial portion VIM, in patients with leg tremor – to the lateral.

A more detailed characterization of tremor in patients before and after intervention is presented in Table 6.1. The total score for CRST in patients with ET immediately after unilateral thalamotomy decreased by 36.4 [26,4; 45,4]%, whereas the reduction in tremor severity on the contralateral side to the intervention was 68.5 [60,9; 83,3]%. Thus, as a result of unilateral thalamotomy using MRgFUS, a significant reduction in tremor intensity was achieved p < 0,0001).

Table 6.1 Tremor assessment scale CRST in patients with ET before and after surgery

When assessing the intensity of tremor according to CRST on the control side of the body (without MRI-guided focused ultrasound) before and after the operation, no statistically significant differences were found

Below is a brief description of the observation of a patient with ET who successfully underwent a unilateral MRgFUS procedure.

Patient G., 82 years old . Diagnosis: ET, sporadic case. Complaints of severe hand tremor, which makes it difficult to eat, drink, perform hygiene procedures, dress, do housework, and write; mild intermittent head tremor.

Medical History. Hand tremor appeared at around the age of 60 – the patient began to notice a change in handwriting. Over the years, hyperkinesis in the hands gradually increased, and he sought help 10 years after the onset of the disease. A neurologist prescribed propranolol at a dose of 40 mg 3 times a day, but the patient noted a side effect of lowered blood pressure and pulse, and he independently stopped taking the medication. According to the patient, an anticonvulsant was also prescribed (he does not remember the name), but due to side effects described in the instructions, he refused to take it. Since 2019, he has noted head tremor. From the same time, the progression of the disease has significantly increased. The tremor decreases after alcohol consumption.

Comorbidities: chronic obstructive pulmonary disease, bronchial asthma; varicose veins of the lower extremities, history of deep vein thrombosis of the lower extremities; hypertension III stages, corrected arterial hypertension, grade 1, risk 4, without chronic heart failure

Concomitant medication therapy: metered aerosol Berodual (episodically), torasemide 5 mg/day, eplerenone 50 mg/day, clopidogrel 75 mg/day.

Neurological status before surgery. Cranial nerves – no pathology. Head tremor of the “no-no” type, more to the left. Tongue tremor. Postural-kinetic tremor of the hands – pronounced in the left hand and moderate in the right, increasing in the glass of water test (intentional component), while dressing. No tremor in the legs. Range of motion and strength in the limbs are sufficient, tendon reflexes are active, symmetrical, no pathological reflexes; muscle tone is unchanged. Stable in the Romberg test. Tandem and normal gait without disturbances. Higher functions are intact. The patient is right-handed.

Sum of points for CRST scored 58 (maximum 144 points). Assessment of cognitive functions on the scale MoCA – 25 points (normal). According to HADS anxiety score – 8 points, depression score – 9 points (subclinical anxiety and depression). Blood pressure before surgery 130/80 mmHg

Operation: Thalamotomy using MRgFUS. On February 16, 2021, the patient underwent unilateral ablation VIM on the left using the MRgFUS method. Lesion sizes in the projection VIM on the left immediately after the operation – 9.0 × 6.0 × 5.75 mm. The duration of the operation was 3 hours and 30 minutes.

No complications or side effects were recorded during the treatment. As a result of the procedure, clinical improvement was achieved: elimination of kinetic tremor in the right hand by 75%, postural and intentional tremor in the right hand by 90%. Total score according to CRST decreased from 58 to 36.

Long-term results. The patient was observed at the V.S. Buzaev International Medical Centre at 1, 5, 9, and 12 months after treatment. During follow-up visits, the patient underwent an MRI of the brain (Fig. 6.7). As seen in the tomograms, 9 months after the operation, the lesion is not visualized in T2 mode, but the area of MRgFUS impact can be seen in mode SWAN on hemosiderin deposition. On the contralateral side of the body (right arm) assessment by CRST did not change compared to the examination immediately after the operation. Subjectively, the patient noted a significant improvement in quality of life: eating and drinking became easier, social anxiety decreased – the patient began attending various events, family celebrations, etc., without embarrassment or discomfort

Here is presented QR-code to navigate to YouTube-channel with a video recording of a patient examination with ET before, during, and immediately after treatment using the MRgFUS method

Side effects associated with thalamotomy using MRgFUS are conditionally divided into intraoperative (directly during the procedure) and delayed (immediately after and within 1 year after the procedure)

Intraoperative side effects were observed in a total of 51.4% of patients. Headache was noted in 18 patients (48.6%), dizziness in 7 (18.9%), nausea in 6 (16.2%), vomiting in 2 (5.4%), increased blood pressure >140/90 mm Hg – in 6 (16.2%). The intensity of the headache that occurred during the operation was assessed by patients on a scale from 0 to 10 points; when assessed >5 the patient was intravenously administered an analgesic (ketoprofen 50 mg/ml, 4 ml), and all patients noted a reduction in pain intensity, while the MRgFUS procedure continued. In cases of nausea, vomiting, or increased blood pressure during the procedure, appropriate symptomatic intraoperative therapy was also conducted, which usually allowed the operation to successfully continue.

In 2 patients, side effects that developed during the operation were not alleviated after medication therapy; as a result, the operation was not completed, and a satisfactory clinical effect was not achieved. These patients underwent a repeat operation on the same side 12 months after the first stage (see below). In 1 patient, during pretalamotomy (lying on the MRI table), intense headache occurred due to the effect of cold water on the scalp, accompanied by a sharp reaction similar to a panic attack. The operation was stopped and successfully performed 3 months later after premedication (naproxen) and filling the helmet with warmer water (18–20°C).

Delayed side effects were observed in 30% of patients, including ataxia with gait disturbance in 1 patient (2.7%), subjective instability when walking in 4 (10.8%), drooping of the mouth corner in 2 (5.4%), weakness in the limbs on the contralateral thalamotomy side in 2 (5.4%), speech disturbance in 1 (2.7%). All side effects  

effects resolved within 1 month after surgery and likely
were caused by increasing post-thalamotomy cytotoxic
edema around the ablation site. The specified profile of side reactions
corresponded to that in the work E. Cacho-Asenjo et al. (2021).
After the surgery, the clinic’s doctors continued regular-
but monitor all patients: median follow-up period to the present-
щему времени составляет 109,0 [53,0; 231,0] days, maximum –
627 days

Table 6.2 Scale indicators CRST in patients with partial recurrence of tremor after unilateral thalamotomy using MRgFUS

Recurrence of tremor After unilateral thalamotomy using MRgFUS in 6 patients (16.2%), a partial recurrence of tremor occurred within 1 year (Table 6.2). Patient 1 experienced a partial return of leg tremor 1 year after surgery, patient 2 had a recurrence of head tremor after 3 months, patient 3 had a recurrence of hyperkinesis in the arm after 3 months in the form of intention tremor (while postural tremor and action tremor present before surgery were not noted), and patient 4 experienced a partial return of postural tremor in the arm and head tremor 3 months after surgery. All patients noted that the partial recurrence of tremor was incomparable to the pre-surgery tremor and did not affect their daily life (self-care, communication with people, etc.), so they did not consider reoperation.

Repeat surgery. In the literature, a case is described of reoperation on the left thalamus in an 86-year-old patient with a recurrence of ET after the first surgery, with the target being the dentatorubrothalamic tract ( Weidman et al., 2019); a stable positive result was achieved in the form of the elimination of tremor in the right hand, without side effects. A similar experience is described for Parkinson’s Disease. Thus, A. Fasano et al. (2018) presented the result of a repeat operation using MRgFUS in a patient with Parkinson’s disease, conducted due to partial return of tremor after the first operation: repeat VIM-Thalamotomy contributed to the reduction of tremor on the contralateral side, but caused a persistent side effect in the form of gait disturbance. A similar observation with the complete disappearance of tremor after a repeat operation using MRgFUS six months after the first intervention, without side effects, was also described by another group of authors Valentino et al., 2020).

In our cohort, 2 patients with ET underwent repeat operations using MRgFUS because the first surgery was interrupted due to intraoperative complications (see above)

Patient L., 1957 Year of birth, has been ill since school years when tremor in the right hand appeared, interfering with writing dictations; by the age of 17, was forced to start writing with the left hand, which trembled to a lesser extent. Treatment with propranolol and topiramate was ineffective. At the time of treatment, also taking enalapril (5 mg twice a day) for hypertension. On examination: pronounced postural and kinetic tremor in the hands, predominantly on the right. Unable to perform the test of holding a glass of water or pouring water. Similar difficulties with drawing a spiral and writing. Additionally, there was moderate resting tremor in the right hand. No tremor in other locations was recorded. The severity of the tremor according to CRST – 63 points. Cognitive functions are not impaired (26 points on the MoCA scale)

Treatment with the MRgFUS method was conducted on November 12, 2021. During the 4th therapeutic sonication of the left VIM with a maximum temperature of 57°C, a severe headache occurred with a hypertensive crisis (180/110 mmHg). Despite symptomatic therapy (captopril 25 mg orally and intravenous administration of ketoprofen 50 mg/ml, 4 ml bolus), the patient’s condition did not improve, and treatment was discontinued. Immediately after treatment, a noticeable reduction in intention tremor in the right hand was noted, and kinetic and postural tremors were reduced by half. The total score according to CRST after the surgery was 42 (a decrease of 21 points). Since the achieved result was suboptimal, the patient was offered repeat treatment (after the swelling around the target area subsided). On November 14, 2022, it was possible to perform a repeat MRgFUS procedure on the left thalamus without significant intraoperative complications: after 5 ultrasound treatments (up to 57°C), a significant reduction in tremor was achieved. After the second stage of MRgFUS treatment, the kinetic and postural components of the tremor in the right hand decreased by 90% compared to the data before the first surgery. According to CRST tremor decreased by 39 points

Patient V., 1972 Year of birth, since university studies, she complained of trembling in both hands, which gradually worsened, especially on the right. Propranolol at a dose of 40 mg twice a day provided a temporary effect, which gradually diminished. On examination: a moderate-amplitude postural-kinetic tremor is observed in the hands (more on the right), as well as a fine-amplitude resting tremor in the right hand, and postural tremor in both legs. Tests with a spoon and a glass of water on the right are impossible. Without stabilizing the right hand, the patient cannot draw a spiral. Total score according to CRST – 63, cognitive functions are not impaired (28 points on the scale MoCA).

18 November 2022, an MRgFUS procedure was performed on the left area VIM. Five therapeutic interventions (up to 60°C) were performed. During the sonications, severe headache (up to 9 points on the VAS) occurred, not relieved by ketoprofen, so it was decided together with the patient to interrupt the procedure. Immediately after the MRgFUS procedure, the postural-kinetic tremor of the right hand decreased by 90%, but postural tremor in certain hand positions (e.g., when bending at the elbow) persisted. Evaluation by CRST after the surgery – 39 points (a decrease of 24 points). After 5 months, the patient complained that postural tremor was reducing her quality of life and limiting self-care in certain positions of the bent arm (for example, when bringing a glass of water or a spoon to her mouth), which is why the completion of treatment was planned. A repeat surgery using the MRgFUS method on the left VIM conducted on March 24, 2023, resulting in the severity of the tremor according to CRST scored 33 points (a decrease of 30 points)

Thus, our experience indicates that repeat unilateral treatment using MRgFUS may be a feasible, safe, and effective option for certain patients who did not achieve optimal clinical effect after the first stage. However, these data should be considered preliminary: additional well-planned studies on larger samples are needed to assess the potential risks of repeat MRgFUS treatment and the optimal timing for re-intervention, as well as to develop detailed inclusion and exclusion criteria for patients.

Bilateral surgeries

As already mentioned above, there are separate reports of successful staged (6–9 months between surgeries) bilateral treatment of ET using MRgFUS, but such experience remains limited ( Iorio-Morin et al., 2021; Martínez-Fernández et al., 2021а; Fukutome et al., 2022). At the same time, we did not find any publications on simultaneous bilateral treatment of ET in the available literature. Based on the entire array of data, we hypothesized that the technical advantages of MRgFUS, with the ability to create a microlesion (1 mm), which the surgeon makes only after confirming the correct localization during the trial sonication of the target, may allow for safe bilateral ablations. This should help reduce tremor without a significant risk of side effects.

Such a unique experience was gained with 8 patients with severe, medication-refractory essential tremor: we performed bilateral thalamotomy using MRgFUS on these patients. In 5 cases, a staged bilateral thalamotomy was performed, and in 3 cases, a simultaneous one (for the first time in the world). The target for the MRgFUS intervention in all 8 patients was VIM. The skull bone density (HU) ranged from 0.36 to 0.59 (median 0.47)

For simultaneous bilateral treatment, we specifically selected 3 patients with high KUPCT (0.51, 0.56, and 0.59), which initially suggested the possibility of using low energies to achieve the required ablation temperature in minimal time, with a minimal number of sonications and insignificant swelling of surrounding tissues. The duration of treatment (from the first to the last sonication) in cases of bilateral MRgFUS ablation was 95–188 minutes (median 137 minutes). Meanwhile, the duration of simultaneous bilateral operations was 120, 131, and 145 minutes.

To minimize the risk of side effects when operating on the second side, we adhered to the following intraoperative tactics.

1. Ultrasound ablation on the second side was immediately stopped once a significant reduction in tremor was achieved. The criterion for stopping the procedure was a reduction in postural-kinetic tremor on the side contralateral to the treatment by more than 50% from the baseline (according to CRST); the subjective assessment of tremor reduction by the patient themselves and the evaluation by a neurologist during neurological tests were also considered  
2. The ablation focus on the second side was intentionally created asymmetrically to the first for safety reasons: i.e., on the first side, an impact with a diameter of 8 mm was created, and the targeting of the second focus was conducted 1 mm dorsally compared to the first side. On the second side, we aimed to create a smaller effective lesion (MR thermometry isotherm 5–6 mm in diameter) to reduce the risk of side effects.
3. Each stage of treatment was preceded by a trial ultrasound exposure ( verify) for the early detection of speech disorders and, if necessary, to halt treatment at a safe stage.

The resulting ablation foci in the thalamus were evaluated on MRI immediately and
at various times after treatment (fig. 6.8, 6.9). During the step-by-step inte-
Interventions, the average volume of the ablation focus on the first side unco-
average after treatment was 79 mm3 (range 57–158 mm3), in
while damage on the opposite side of the impact, according to the data
MRI, immediately after surgery, was 41 mm3 (range 13–75 mm3)
The right and left targets of damage were somewhat asymmetrical
in relation to each other. After 6 months, the lesion was so small that it was not visualized on standard MRI modes, however, in the mode SWAN it was possible to visualize the projection of the lesion due to hemosiderin deposition

The effectiveness of treatment and reduction of tremor symptoms were assessed using CRST. The assessment was conducted before, during, and immediately after the surgery. Patients were monitored for 12 months following the procedure. For staged operations, parts were used CRST, reflecting symptoms on the treated side of the body. An assessment of postural, kinetic tremor, and resting tremor for the upper and lower limbs was conducted separately, as well as a spiral drawing test (fig. 6.10) and a water pouring test.

After bilateral operations using the MRgFUS method, all 8 patients reported a significant reduction in tremor on both sides, as reflected in Table 6.3. The median score for CRST decreased from the initial value of 56.0 [42,5; 59,5] points up to 18.0 [17,5; 19,0] points immediately after the second ablation. As a result of bilateral staged and simultaneous thalamotomies, a statistically significant reduction in tremor severity was achieved by 67.8 [58,0; 70,4]% (p = 0,016 by the Wilcoxon criterion)

The results of bilateral treatment of patients with ET (including both staged and simultaneous interventions) were compared with the results of unilateral surgeries (Fig. 6.11). The median difference in the total score CRST before and after treatment for the unilateral impact group was 21 [14; 24], for the bilateral impact group – 38.0 [24,5; 40,2] (p = 0,0015). Reduction of the overall score for CRST in patients with ET immediately after unilateral thalamotomy was 36.4 [26,4; 45,4]%, and during bilateral thalamotomy – 67.8 [58,0; 70,4]%. It can be concluded that in patients with ET, performing bilateral intervention using the MRgFUS method is statistically significantly more effective than unilateral intervention in terms of achieving a positive impact on generalized tremor hyperkinesis p < 0,001). Table 6.4 presents the side effects and adverse events both during the procedure and 6 months after 2 operations. At various stages, the side effects were minimal (headache, dizziness, increased blood pressure) and required standard symptomatic therapy measures (nonsteroidal anti-inflammatory drugs, antihypertensive medications, etc.); all were completely resolved by the 6th month of observation.

Below are brief clinical examples of staged and simultaneous bilateral surgeries in patients with ET.

Table 6.3 Tremor Severity Assessment Results CRST before treatment with MRgFUS and immediately after the second surgery.

Т table 6.4 Side effects of bilateral thalamotomy using MRgFUS

We provide brief clinical examples of staged and simultaneous bilateral surgeries in patients with ET

Patient G., 1988 Year of birth. Diagnosis: ET involving upper and lower limbs, head, tongue, vocal cords; sporadic case. Complaints of pronounced hand tremor, which worsens during work activities, making writing and computer work difficult, as well as during anxiety

Sick since childhood, in the early grades of school noted a slight tremor in the right hand when writing. During the draft board examination in 2009, was referred for a consultation at the Republican Clinical Hospital, where a diagnosis of ET was made and propranolol was prescribed. Took the medication for several months without effect. The tremor does not worsen over time. Positive alcohol test.

In the family history – slight hand tremor in the mother when
excitement

Denies serious comorbidities

Neurological status before surgery. Right-handed. Regarding cranial
nerves – no pathology. Range of motion and strength in the limbs are suffi-
exact, tendon reflexes are active, no side difference, pathologi-
there are no reflexes. Muscle tone in the limbs is unchanged. In the test
Romberg stable. Tandem and regular walking without impairments. Higher
functions are preserved. There is a constant tremor of the head and torso-
ща; tongue tremor. Postural and kinetic tremor of the hands is moderate-
of varying severity, symmetrical, increasing in the test with
a glass of water and when dressing, slight tremor in the right hand and fingers
hands while writing. Postural tremor of the legs. Total score by CRST – 34
(maximum 144 points). Assessment on a scale MoCA – 28 points (normal)
По HADS anxiety score – 4 points, depression – 4 points (normal)

Blood pressure before surgery 110/70 mmHg

1-й этап лечения. 21 August 2020, the patient underwent unilateral thalamotomy VIM on the left using the MRgFUS method. Focus in the projection VIM on the left immediately after the operation – 5 × 6 × 5 mm. There are no complications or side effects during the therapy. The duration of the procedure was 3 hours and 45 minutes. After the intervention, clinical improvement was achieved: elimination of kinetic and postural tremor of the right
hands at 85%

Dynamics of Ablation Focus Development in the Area VIM on the left is presented
in fig. 6.12

2-stage of treatment Due to a satisfactory response to the first stage of treatment and the absence of side effects, the patient returned to the clinic 17 months later to address tremor in the left hand. On January 20, 2022, the patient underwent thalamotomy VIM-nuclei on the right using the MRgFUS method. Lesion in the projection VIM-thalamic nuclei on the right immediately after surgery 3.5×5×3.5 mm. No complications or side effects during therapy. The duration of therapy was 2 hours. Clinical improvement achieved after treatment: elimination of kinetic and postural tremor in the left hand by 90%

Dynamics of Ablation Focus Development in the Area VIM-nuclei on the right are shown in Figure 13

On the scale CRST the total score decreased from 40 to 26 points after the first stage of the surgery, from 26 points to 17 points after the second stage of the surgery

Long-term results

The patient was monitored at the V.S. Buzaev International Medical Centre 1, 6, and 10 months after treatment on the first side and 1, 6, and 18 months after treatment on the second side. A persistent effect of both operations was recorded during the neurological status assessment. The patient was satisfied with the clinical effect of MRgFUS, noting a significant improvement in quality of life: improved handwriting, keyboard work, and reduced social anxiety, which allowed for greater professional productivity.

Patient V., 1951 Year of birth. Diagnosis: Essential Tremor with predominant involvement of the upper limbs and head; familial form. Complaints of pronounced hand tremor, slight head tremor, difficulties with writing, eating. Tremor worsens with anxiety.

Tremor began about 30 years ago. The patient participated in the cleanup of the Chernobyl nuclear power plant accident and associated the onset of tremor with this event. A positive family history is noted: the patient’s father and aunt on the paternal side experienced hand tremor.

The neurologist at the place of residence diagnosed ET. Tried taking propranolol and gabapentin but discontinued due to side effects and low effectiveness. A slight positive effect was observed with alprazolam (0.25–0.50 mg/day). In recent years, the patient noted a significant increase in tremor.

Comorbidities: hypertension III stages, ischemic heart disease, post-infarction cardiosclerosis (according to electrocardiography data) since 2015. Currently taking lisinopril (10 mg/day), bisoprolol (2.5 mg/day), indapamide (1.5 mg/day), alprazolam (0.25 mg/day)

Neurological status before surgery. Right-handed. Cranial nerves – no pathology. Range of motion and strength are sufficient, tendon reflexes are active, no side differences, no pathological reflexes. Muscle tone in the limbs is unchanged. Stable in the Romberg test. Tandem and normal walking without disturbances. Higher functions are preserved. No facial or trunk tremor. Intermittent head tremor (including when lying down). Moderate postural tremor of the hands, more on the right. Kinetic tremor of the hands complicates the glass of water test (spilling more than half of the water), spiral drawing test. Coordination tests in the hands are performed with pronounced intention, more on the right, heel-knee test – performed accurately, without tremor. Total score according to CRST scored 59 (maximum 144 points). Grade on the scale MoCA – 26 points (normal). According to HADS anxiety score – 3 points, depression – 2 points (normal)

Blood pressure before surgery 120/76 mmHg

Simultaneous Bilateral Treatment. On March 3, 2022, the patient underwent bilateral non-invasive thalamotomy VIM using the MRgFUS method. Focus in the projection VIM on the left immediately after the operation 8 × 8 × 9 mm, on the right – 5 × 6 × 7 mm. There were no complications or side effects during the therapy. The duration of the procedure was 2 hours and 10 minutes. As a result of the treatment, clinical improvement was achieved: reduction of kinetic tremor in the right hand by 95%, postural tremor in the right hand by 95%, postural tremor in the head by 100%, kinetic tremor in the left hand by 90%, postural tremor in the left hand by 90% CRST the overall score decreased from 59 to 14.

Long-term results. The patient was monitored at the V.S. Buzaev International Medical Centre using telemedicine technologies at 1, 5, 9, and 12 months after treatment. The dynamics of the development of ablation foci are shown in Fig. 6.14.

The patient was satisfied with the clinical effect of the treatment and stopped taking alprazolam. He noted a significant improvement in quality of life: eating, drinking, personal hygiene, and dressing improved. The patient was able to play a musical instrument (accordion). Thus, we achieved the first experience in Russia of treating ET patients using MRgFUS, as well as described the world’s first experience of performing a simultaneous bilateral operation. The priority of describing a simultaneous bilateral operation for ET is confirmed by relevant publications (Galimova et al., 2022; Galimova et al., 2022). In our cohort, MRgFUS was effective in 97.3% of patients with ET (in 36 out of 37 cases), which is at least comparable to the results of traditional functional stereotactic methods ( DBS, radiofrequency thermodestruction). A clear advantage of the method is its non-invasiveness: according to our data and existing literature, the MRgFUS procedure does not cause serious side effects or long-term consequences in this category of patients. For instance, our patients experienced only transient and relatively mild side effects even after bilateral operations, whereas during DBS the complication rate, according to data from a large registry including more than 600 patients with ET, was 7.1% ( Fasano, Deuschl, 2015). The ability to accurately target, with an assessment of symptom correspondence with the Penfield homunculus, allows for the reduction of tremor in different parts of the body, not just the hand. Our demonstrated ability to perform safe reoperations confirms the broad prospects of MRgFUS in the surgical treatment of patients with ET.