Parkinson’s disease is the second most common neurodegenerative disorder (after Alzheimer’s disease), primarily affecting older adults (Levin et al., 2022). The lifetime risk of the disease is 8.5% for men and 7.7% for women, and the overall prevalence of PD in the population is 120–150 per 100,000 people ( Driver et al., 2009). In most cases, Parkinson’s disease is sporadic; however, in about 10% of patients, the disease may be hereditary (Illarioshkin, 2015)
Current understanding of the mechanisms of Parkinson’s Disease includes protein misfolding and accumulation a-synuclein spreading trans-synaptically along neuronal pathways via a prion-like mechanism, as well as the interaction of a number of exogenous (toxic, infectious-inflammatory) and genetic factors acting against the background of age-related depletion of the cell’s protective mechanisms (Illarioshkin, 2015; Heras-Garvin, Ste fanova, 2020; Coleman, Martin, 2022; Yacoubian et al., 2023). Pathognomonic morphological markers of Parkinson’s disease (PD) are the degeneration of dopaminergic neurons in the substantia nigra pars compacta of the midbrain and the appearance of eosinophilic cytoplasmic inclusions—Lewy bodies—in dying neurons (Illarioshkin et al., 2019). It is believed that the manifestation of the first symptoms of PD requires the death of more than half of the dopaminergic neurons of the substantia nigra Chahine et al., 2023). The hidden (latent) stage of neurodegeneration in the development of Parkinson’s disease lasts, according to approximate estimates, on average from 10 to 25 years (Illarioshkin, 2013b)
Loss of neurons in the substantia nigra of the midbrain is accompanied by chronic dysfunction of the nigrostriatal, mesolimbic, and mesocortical dopaminergic pathways, which, combined with the involvement of other neurotransmitter systems (noradrenergic, serotonergic, cholinergic, GABAergic), leads to the disintegration of multilevel neural networks not only in the basal nuclei but also throughout the brain ( Jenner et al., 2013). Moreover, during the latent stage of PD, the earliest changes with the appearance of pathological aggregates a-synuclein is noted not in the substantia nigra, but in the olfactory bulbs, neurons of the dorsal nucleus of the vagus nerve, raphe nuclei and reticular formation, as well as in the cells of the intestinal plexuses and other parts of the peripheral autonomic nervous system (Illarioshkin et al., 2019 Braak et al., 2003). All this underscores the complexity of the molecular pathogenesis of Parkinson’s disease and explains the numerous challenges associated with treating this condition.
The clinical picture of Parkinson’s disease (PD) is well studied. The most characteristic motor symptoms of PD include hypokinesia, muscle rigidity, resting tremor, and postural disturbances (falls, freezing, posture changes, etc.) (Levin et al., 2022). The primary target for MRgFUS and functional stereotactic interventions is pronounced, disabling tremor. In PD, tremor is asymmetric from the onset of the disease, distal, with oscillations of 4–6 Hz (sometimes more frequent), usually starting in the hand, most pronounced at complete rest, and decreases with movement of the affected limb (Illarioshkin, Ivanova-Smolenskaya, 2011). Particularly characteristic of PD is the resting tremor of the fingers, described as “pill-rolling” or “coin counting,” which may be the first manifestation of the disease in 60–70% of patients. Once it begins in the hand, the tremor gradually spreads to the ipsilateral leg, then to the contralateral limbs (hand, leg), and in the later stages of PD, tremor of the lower jaw, muscles of the lower face (lips, chin), and some other body parts is typical. Parkinsonian tremor intensifies with active movements of other body parts, mental strain, stress, and anxiety.
Table 1. Differential Diagnosis of Essential and Parkinsonian Tremor
In some patients with Parkinson’s disease, resting tremor is combined with kinetic tremor of the same frequency. Moreover, sometimes postural tremor may be the first manifestation of the disease or even the leading type of tremor in Parkinson’s disease (Illarioshkin, Ivanova-Smolenskaya, 2011; Levin et al., 2022). In such cases, it is particularly difficult to differentiate between Parkinson’s disease and essential tremor (Table 7.1)
In addition to typical motor manifestations, Parkinson’s disease is characterized by a wide range of non-motor symptoms, many of which may occur even in the latent stage of the neurodegenerative process (Illarioshkin, Levin, 2017; Levin et al., 2022). These include autonomic insufficiency (constipation, urinary disorders, erectile dysfunction, regulation disorders of salivation and sweating, orthostatic hypotension, etc.), affective symptoms (depression, anxiety, apathy), sleep disturbances (difficulty falling asleep, fragmented night sleep, daytime sleepiness, REM sleep behavior disorders, etc.), cognitive decline (up to dementia in the late stage of Parkinson’s disease), sensory symptoms (hyposmia, pain, impaired contrast color perception). Non-motor manifestations of Parkinson’s disease, which play an important role in the diagnosis of the disease, often have an even greater impact on the quality of life of patients with Parkinson’s disease than motor function disorders.
Traditional concepts of the progression of clinically manifest Parkinson’s Disease suggest the identification of several stages that consistently follow one another and are most clearly described by the Hoehn and Yahr functional scale (Appendix 4). Within this scale, stage 3 (bilateral symptoms with postural instability) lasts the longest—≥10 years; it primarily determines the various “scenarios” of clinical syndrome development, patient quality of life, and long-term prognosis (Illarioshkin, 2013b)
Parkinson’s disease is characterized by pronounced phenotypic heterogeneity. Several forms of PD are recognized: mixed (most common), akinetic-rigid (10–15% of cases), and tremor-dominant (about 5% of cases). In patients with predominantly tremor phenotypes, non-motor symptoms and complications of dopaminergic therapy develop more slowly, and the process usually takes a milder course (Illarioshkin, Ivanova-Smolenskaya, 2011). Considering the diagnostic challenges of such a polymorphic neurodegenerative disease MDS clear and detailed criteria for diagnosing PD are proposed Postuma et al., 2015). They are presented in Appendix 3.2.
Although the diagnosis of Parkinson’s disease remains clinical, various modern neuroimaging methods that allow the identification of certain characteristic changes in the brain are increasingly being used in the diagnostic process (Illarioshkin, Levin, 2017; Illarioshkin et al., 2019; Levin et al., 2022)
The most significant markers are:
• the disappearance of nigrosome-1 – the largest cluster of dopaminergic neurons in the dorsolateral part of the substantia nigra ( Chau et al., 2020). The research is conducted on ultra-high-field MRI scanners (at least 3 T) in T2* modes SWI;
• reduced binding of dopamine radiopharmaceuticals in the striatum, indicating damage to nigrostriatal neurons. These changes can be detected using PET with fluorodopa and SPECT with presynaptic dopamine transporter markers ( de Natale et al., 2018);
• hyperechogenicity of the substantia nigra, detected using transcranial sonography on expert-class ultrasound machines (provided the patient has a sufficient temporal ultrasound “window”) (Illarioshkin et al., 2019)
A number of these methods have already been included in the relevant recommendations of the international expert community (Illarioshkin, Levin, 2017; Berardelli et al., 2013; Postuma et al., 2015; Tao et al., 2019), what contributes to the improvement of early diagnosis of Parkinson’s disease
As of today, Parkinson’s disease therapy is symptomatic. Developed therapeutic strategies are aimed at correcting the neurotransmitter imbalance in the CNS that develops with this disease, primarily focusing on compensating for dopamine deficiency in the nigrostriatal system. The universally recognized “gold standard” for treating Parkinson’s disease is levodopa, a biological precursor of dopamine (Illarioshkin, 2009; Illarioshkin, Levin, 2017; Levin et al., 2022). Levodopa therapy has significantly changed the lives of patients with Parkinson’s disease, providing a pronounced clinical effect and maintaining work capacity over many years of continuous therapy. Moreover, the introduction of levodopa-based drugs at the turn of the 1960s-1970s and the initial results of its use in clinical practice led to a noticeable decrease in the number of destructive surgeries on the subcortical nuclei for Parkinson’s disease worldwide.
As practical experience accumulated, it became clear that the stable effect of levodopa medications gradually decreases over the years, and patients develop predictable drug complications from the therapy—daily symptom fluctuations and drug-induced dyskinesias (Illarioshkin, 2009 Jenner et al., 2013). Fluctuations represent changes in the severity of parkinsonism symptoms, which can be either predictable in relation to levodopa intake or unpredictable. The main types of motor fluctuations include the wearing-off effect of levodopa, the “on-off” syndrome, delayed “on,” freezing, missed doses, uneven effect of levodopa throughout the day, worsening after a dose of levodopa, and yo-yoing. In many cases, motor fluctuations are accompanied by fluctuations in non-motor symptoms—autonomic, sensory, mental, etc. Chaudhuri et al., 2006). Motor dyskinesias (peak-dose dyskinesias, biphasic dyskinesias, etc.) can occur at different phases of the functional state of patients and reflect profound disturbances in receptor pharmacodynamics. The development of fluctuations and dyskinesias is primarily explained by the short half-life of levodopa (approximately 60 minutes) and the progressive death of nigrostriatal endings, which disrupts the buffering properties of the remaining nigral neurons and their inherent ability to tonically release dopamine stored in terminals (Levin et al., 2022; Stocchi et al., 2008). In these conditions, pulsating stimulation of postsynaptic dopamine receptors in the striatum is formed. The distortion of sensitivity of the postsynaptic receptors is also significant D2-receptors under conditions of desensitization and periodically repeated suprathreshold stimulation ( Jenner et al., 2013). The development of complications in chronic levodopa therapy for Parkinson’s disease is also facilitated by factors of peripheral pharmacokinetics (reduced absorption and bioavailability of levodopa due to impaired gastrointestinal tract motility, competition of levodopa with dietary amino acids in overcoming the gastrointestinal barrier and the blood-brain barrier, etc.) (Levin et al., 2022)
Risk factors for complications of long-term levodopa therapy include young age (which should always be considered when determining treatment tactics, including timely referral for surgical treatment), as well as low body weight, female gender, genetic predisposition, and the presence of the akinetic-rigid form of the disease (Illarioshkin, 2013b). Symptom fluctuations and dyskinesias significantly hinder the daily activities of patients with PD and reduce quality of life (Illarioshkin, 2009)
Other antiparkinsonian drugs also play a significant role in the treatment of Parkinson’s disease—dopamine receptor agonists, amantadines, enzyme inhibitors of levodopa metabolism—monoamine oxidase B (MAO-B) and catechol- O-methyltransferases (COMT) (including as part of combination drugs), central anticholinergics. Various correctors are also used to combat various manifestations (clonazepam and other benzodiazepines, anticonvulsants, local injections of botulinum toxin, etc.). In advanced stages of PD, complex multicomponent therapy is usually used, which includes (in various combinations and dosages) many of the aforementioned medications (Illarioshkin, Levin, 2017)
If motor disorders are not effectively controlled, more complex methods of delivering dopaminergic medications may be used—for example, continuous administration of levodopa suspension into the duodenum/jejunum via a micro-gastrostomy using a special intestinal pump, or continuous subcutaneous administration of the dopamine receptor agonist apomorphine via an apomorphine pump ( Reese et al., 2012). However, these technologies are quite complex, expensive, and not always accessible, and they are associated with a large number of serious complications, which limits their use. In recent years, a number of new antiparkinsonian agents and/or new forms of their delivery into the body for the treatment of Parkinson’s disease have been proposed (a drug with a complex mechanism of action safinamide, inhalation and sublingual apomorphine, forms of levodopa for inhalation and subcutaneous administration, etc.), but all of them, while filling certain niches in drug therapy for Parkinson’s disease, also cannot radically affect the course of the disease.
Thus, at a certain stage in the progression of Parkinson’s disease, the resources of drug therapy become exhausted and no longer provide a sufficient level of functional activity for the patient. As a result, the discussion of the possibilities of neurosurgical assistance comes to the forefront. Methods of functional and stereotactic surgery have been applied in patients with Parkinson’s disease since the early 1950s (Kandel, 1981) and today include both ablative (destructive) surgeries and surgical neuromodulation – a technology DBS. Most often, for ablative functional interventions in Parkinson’s disease, radiofrequency thermodestruction is currently used, targeting the thalamic nuclei, globus pallidus, subthalamic nucleus, lenticular loop, and other targets; combined effects are also used (pallidothalamotomy, destruction of the dorsolateral part of the subthalamic nucleus + pallidofugal fibers + zona inserta and so on) (Kandel, 1981; Levin et al., 2022; Laitinen et al., 1992; Okun, Vitek, 2004). Such operations for PD in 82–90% of cases are accompanied by the disappearance or noticeable reduction of tremor and muscle rigidity on the side contralateral to the performed lesion (Kandel, 1981 Kandel, 1989; Alti nel et al., 2019). Randomized prospective studies have shown the possibility of maintaining the achieved clinical effect for 10 years or more ( Fine et al., 2000; Hariz, Bergenheim, 2001; Vitek et al., 2003). Recurrence of symptoms after destructive surgeries is usually observed in the first few months, and repeat surgeries in such cases are not very effective. The surgery does not prevent further progression of motor and non-motor manifestations of PD – hypokinesia, axial symptoms, cognitive, emotional-volitional, and autonomic disorders
Bilateral destructive treatment of Parkinson’s disease using the standard method has not become widespread due to the high risk of dysarthria, dysphonia, and cognitive impairments ( De Bie et al., 2002). With the advent of non-invasive ablation techniques (Gamma Knife), the situation has somewhat changed. In one study, 4 patients with Parkinson’s disease after bilateral thalamotomy using the Gamma Knife did not experience any neurological disorders ( Duma et al., 1998); a similar experience is also available from other authors ( Ochiai, 2021). Nevertheless, due to a number of serious limitations of this technology (lack of intraoperative control, delayed effect, risk of radionecrosis of brain tissue), the use of gamma knife for widespread application in patients with PD is currently not recommended.
Leading positions in the surgical treatment of PD are held by the method DBS. Its main advantages are functionality (adaptation of the stimulation mode depending on the patient’s condition), the possibility of bilateral impact, and the absence of irreversible brain tissue damage. The main indications for use DBS in patients with PD serve:
a) advanced stages of the disease with disabling, poorly controlled triad of motor disorders (tremor, hypokinesia, rigidity) – in this case, the subthalamic nucleus is usually stimulated
b) pharmacoresistant tremor (stimulation preferred VIM);
c) pronounced side effects of levodopa therapy (in this case, stimulation is most often performed GPi) (Levin et al., 2022; Limousin et al., 1995, 1998; Hacker et al., 2018; Merola et al., 2021).
In chronic stimulation of the subthalamic nucleus (the main target for DBS) a reduction in tremor by 53–81%, hypokinesia in limbs by 19–60%, and overall severity of movement disorders by 25–66% is achieved (Levin et al., 2022). Clinical effectiveness of bilateral DBS c from the perspective of impact on Parkinson’s disease motor symptoms, it is comparable to bilateral ablation surgeries, but DBS has a significantly lower risk of side effects Blomstedt et al., 2006). Positive effect DBS is also manifested by the possibility of reducing the dose of dopaminergic agents (Gusha et al., 2018). The advisability of earlier invasive deep brain stimulation in patients with PD is being discussed Suarez-Cedeno et al., 2017). One of the advantages DBS is the possibility of its application after previously performed destructive surgeries
As mentioned above, despite its appeal, the method DBS is characterized by significant drawbacks (invasiveness, presence of foreign bodies in the body, influence of magnetic fields on the stimulator’s operation, infectious and hemorrhagic complications, limited battery life, etc.), which in some cases may hinder its use in clinical practice, especially in elderly patients
Neurosurgical aspects of PD are detailed in Chapter 1.
The new term in the functional treatment of Parkinson’s disease, significantly expanding the possibilities of providing radical assistance to patients with advanced stages of the disease, is the use of the innovative MRgFUS technology.
Treatment with MRgFUS was initially approved for Parkinson’s disease with a clinical picture dominated by tremor ( Bond et al., 2017), in 2021, the application of the method for correcting muscle rigidity and drug-induced dyskinesias was described Eisenberg et al., 2020).
Starting from the first studies, the primary target for ultrasound exposure in tremor phenotypes of Parkinson’s disease was VIM (Bond et al., 2017). This structure was recognized as safer compared to GPi or cwith the subthalamic nucleus. Since destructive surgeries in PD patients are traditionally limited to one side to avoid complications, thalamotomy using MRgFUS has become a significant alternative for patients with asymmetrical symptoms who have contraindications for DBS. Unilateral VIM-thalamotomies using the MRgFUS method noted a reduction in the severity of parkinsonian tremor according to CRST by 62% during a 3-month observation period, but the degree of impact on tremor hyperkinesis with such ablation in patients with PD was less than in patients with ET ( Elias et al., 2016; Bond et al., 2017).
Long-term results of unilateral VIM-thalamotomies using the MRgFUS method for PD were evaluated in the study A. Sinai et al. (2022). The study included 26 patients with predominantly tremor phenotypes of the disease, observed over 1–5 years (median follow-up 36 months). Treatment led to the immediate disappearance of tremor on the contralateral side in 23 patients and a 90% reduction in 3 patients. Significant improvement was also noted in 15 patients with leg tremor, 2 patients with chin tremor, and 1 patient with head tremor. Over 5 years, the median scores for CRST и UPDRS (both overall and in relation to the “treated” half of the body) significantly decreased compared to the baseline level ( p < 0,0001). In 2 patients during the observation period, the tremor returned completely, and in 8 patients, a partial recurrence was noted. According to the authors, MRgFUS thalamotomy performed for tremor in patients with Parkinson’s disease also allows delaying the prescription of levodopa Sinai et al., 2022).
The obvious disadvantage of using VIM as a target for MRgFUS is the inability to affect hypokinesia and muscle rigidity – the main symptoms of PD
In 2014, the experience of using another target for Parkinson’s disease was published – the pallidothalamic tract ( pallidothalamic tract, PTT) (Magara et al., 2014). Targeting PTT (Fields of Forel H1 and H2) are performed in the area where the pallidothalamic fibers of the lenticular fasciculus and lenticular loop converge on the way to the ventroanterior and ventrolateral nuclei of the thalamus, therefore such destruction combines the advantages of thalamotomy and pallidotomy ( Aufenberg et al., 2005). Pallidothalamotractotomy (another name for this operation is campotomy) at the level of Forel’s fields H1 and H2 allows for maximum release of thalamocortical pathways from the inhibition of the globus pallidus with a small ablation area, leaving the thalamus intact. This approach appears more physiological. Use of PTT as a target, in addition to suppressing tremor, it positively affects rigidity and hypokinesia – the severity of these symptoms decreases by an average of 70–73% after surgery ( Gallay et al., 2021).
The effectiveness and safety of MRgFUS using pallidothalamotractotomy were demonstrated in the treatment of 47 patients with advanced-stage Parkinson’s disease and the presence of drug-induced dyskinesias and fluctuations against the background of long-term levodopa use Gallay et al., 2020b). Notably, 15 patients in this study underwent bilateral intervention. As a result, there was an 84% reduction in tremor, 70% reduction in muscle rigidity, and 73% reduction in distal hypobradykinesia. Moreover, the procedure led to the complete disappearance of levodopa-induced dyskinesias and a significant reduction in pain syndrome severity ( p < 0,001), dystonia ( p < 0,001) and behavioral disorders in the REM sleep phase ( p < 0,01), a 55% reduction in the average dose of levodopa. Patients also reported overall symptom relief: 82% in the contralateral side of the operation, 69% throughout the body. There was no statistically significant improvement in speech disorders, axial rigidity, and gait. It is important to note that in the subgroup of patients with bilateral pallidothalamotomy, similar results were observed one year after examination, without serious complications. The authors discuss the need for preoperative assessment of the thalamocortical network to improve treatment outcomes ( Gallay et al., 2020б).
In messages from other authors, a very favorable effect of unilateral pallidothalamic tractotomy using MRgFUS at the level of Forel’s fields H1 and H2 in patients with mixed/tremor forms of Parkinson’s disease is also noted. Thus, F. Godinho et al. (2019) at the 2-year postoperative follow-up, a significant reduction in contralateral resting tremor was observed (by 65.7%; p < 0,001), rigidity (by 87.8%; p < 0,001), bradykinesia (by 68%; p < 0,001) and axial symptoms (by 24.2%; p < 0,05) in a state of “shutdown”. Indicators regarding III UPDRS decreased by 43.9% (p < 0,001), gait improved by 31.9% (p < 0,05), walking time for a distance of 7 m decreased by 43.2% (p < 0,05), and the pain decreased by 33.4% (p < 0,01), at the same time, the neuropsychological status did not change. A statistically significant improvement in the quality of life of operated patients was also noted
After the above-mentioned first experience of bilateral pallidothalamotractotomy in predominantly tremor phenotypes of PD, published M.N. Gallay et al. (2020b) the number of such reports is gradually increasing. In one study, after staged (with a 1-year interval between ablations) bilateral pallidothalamotractotomy over a 36-month observation period, a 91% reduction in tremor severity was noted p = 0,006), distal muscle rigidity – by 67% ( p = 0,006) and distal hypokinesia – by 54% ( p = 0,01) compared to the condition before MRgFUS against the background of conservative therapy ( Gallay et al., 2021). After 1 year following the impact on the second side, the overall score on UPDRS decreased in the “off” state by 52% compared to the initial preoperative indicator in the “on” state ( p < 0,007). No effect of bilateral surgery on postural symptoms was noted. Dyskinesias were relieved in all 4 patients, dystonic manifestations in 4 out of 5 patients, and sleep disturbances in 3 out of 4 patients. There was also an 89% reduction in pain and a decrease in the levodopa dose from 690 ± 250 to 110 ± 190 mg. However, an adverse consequence of the bilateral surgeries was a 58% worsening of speech disorders (hypophonia, tachyphemia) (p = 0.06) Gallay et al., 2021).
Currently, patients with the akinetic-rigid form of PD who have undergone treatment using MRgFUS are being monitored Horisawa et al., 2021a). The results of unilateral pallidothalamic tractotomy in 14 such patients were quite convincing: 1 year after the surgery, there was a decrease in the total score in part III MDS-UPDRS from 45 ± 4.6 to 32.9 ± 4.8 ( p = 0,005), muscle rigidity score – from 4.4 ± 0.5 to 1.7 ± 0.4 points and hypobradykinesia – from 10.4 ± 1.5 to 5.2 ± 1.4 points ( p = 0,011). Posture improved by 20% p = 0,038), but no statistically significant changes in gait were noted. A reduction in the severity of dyskinesias was also demonstrated – by 79.2% ( p = 0,0012) and muscle dystonia – by 91.7% ( p = 0,041) (Horisawa et al., 2021a).
MRgFUS destruction of the subthalamic nucleus in patients with PD, with effectiveness similar to pallidothalamotractotomy, was accompanied by a greater number of complications ( Martínez-Fernández et al., 2020). In a cohort of 27 operated patients, a decrease in the average score was noted after 4 months in part III MDS-UPDRS from 19.9 to 9.9 p < 0,001). At the same time, a number of adverse side effects were registered, such as non-drug-induced dyskinesia in the form of ballism and chorea ( n = 12), paresis n = 5), speech disorders n = 15) and walking ( n = 13). In 6 patients, some of these disorders were noted even after 1 year ( Martínez-Fernández et al., 2020).
Currently, registered clinical trials of the MRgFUS method are ongoing worldwide, aimed at assessing movement disorders in PD, using targets PTT and the subthalamic nucleus ( NCT03454425, NCT04728295, NCT04744493, NCT04692116).
In Russia, the treatment of Parkinson’s disease using MRgFUS was initiated by us in May 2020 at the V.S. Buzaev International Medical Centre (Ufa) (Galimova et al., 2020, 2022; Akhmadeeva et al., 2022)
Treatment using the MRgFUS method was conducted in 82 patients with Parkinson’s Disease (62 men, 20 women), where tremor (T-PD) predominated in the clinical picture. In all cases, there was significant disability among patients, as long-term antiparkinsonian drug therapy no longer adequately controlled the severity of movement disorders.
The average age of patients was 64.5 [55,0; 70,5] years (men – 65.0 [52,5; 70,0] years, women – 63.0 [61,0; 72,0] years) (Fig. 7.1). Men and women did not differ significantly by age ( p = 0,95 by the Wilcoxon criterion). Stage 2 on the Hoehn-Yahr functional scale was present in 37 patients, stage 2.5 in 16, stage 3 in 28, stage 4 in 1
Inclusion criteria:
• diagnosis of PD, established according to recommendations MDS (Appendix 3.2);
• age over 30 years
• lack of sufficient control of movement disorders when using basic medications (levodopa, etc.) in adequate doses for more than 3 months
Exclusion criteria were standard for this type of treatment: significant cognitive decline, contraindications for MRI, increased skull bone density, etc. (see Chapter 4)
In all cases, we performed the intervention on only one side due to the increased risk of neurological complications described in bilateral ablation surgeries in patients with PD
Initially, as a target for MRgFUS in patients with T-PD, we used VIM. This was due to the fact that the choice of this target was the standard for the manufacturer’s controlling experts. As mentioned in the previous section, over time, publications appeared about a second promising target – PTT at the level of the Forel fields H1 and H2, which allowed us to use this core for treating patients with PD. Out of 82 treatment cases, the impact on PTT using the MRgFUS method was performed in 12 cases, impact on VIM – in 34 cases, and the combination VIM + PTT used in 36 cases. In further analysis, due to the small group size PPT as an isolated target and with the aim of a detailed assessment of the impact results on this new target, data from the RRT groups and VIM + RRT were combined and compared with data from the group with isolated exposure to VIM.
Coordinates of the impact points are shown in Fig. 7.2. The median KUPKT value was 0.48 [0,41; 0,58].
The intervention in the area of the left thalamus was performed on 51 patients, and on the right thalamus side on 31 patients. The first operation on the chosen side was performed on 73 patients, and reoperation on the chosen side on 9.
Upcoming results All operated patients were examined according to the approved protocol with clinical and neurological assessments conducted at least at 1, 3, 6, and 12 months. The results of unilateral treatment using MRgFUS were evaluated based on the dynamics of motor symptoms in part III UPDRS. According to the normality test p = 0,007 according to the Shapiro-Wilk criterion), the data did not follow a normal distribution, so we used non-parametric methods for analysis, such as the Wilcoxon test (including the paired test for “before” and “after” observations in the same patients)
According to the subjective assessment scale of surgical outcomes proposed by us (see Chapter 5), an “excellent” result was achieved in 56 patients with T-PD, a “good” result in 24, and a “satisfactory” result in 1. In 1 more case, no result was obtained due to the presence of cranial hyperostosis in the patient (the CT density index was borderline at 0.35, but it was not possible to achieve a temperature above 50°C at the focal point using focused ultrasound waves, and after 10 trial sonications, the patient was removed from the table without side effects)
Median of the total score for the section III UPDRS in our cohort of patients with T-PD was 54 before treatment [43; 65], after treatment – 31 [24; 39], differences are statistically significant ( p < 0,00001). The median difference in scores before and after the surgery was 21.5 [13,0; 31,0], what amounted to 40.1 [30,2; 51,7]% improvements compared to the initial state. The treatment results of T-PD using a unilateral operation with the MRgFUS method are presented graphically in Fig. 7.3.
In men and women, treatment outcomes expressed as the ratio of the difference between initial and obtained values in terms of III UPDRS to the initial value (in percentage), were not statistically significantly different – 40.0 [31,8; 52,0] и 43,9 [29,6; 51,5]% accordingly ( p = 0,68).
We conducted an analysis of the effectiveness of MRgFUS in patients with T-PD depending on the chosen target – VIM or PTT. In Fig. 7.4, it can be seen that improvement in the assessment of part III UPDRS was clearer when using PTT as a target. In the group VIM improvement was 32.0 [24,5; 40,2]%, when combining targets VIM + PTT – 50,0 [40,3; 57,5]%, in the group PTT as an isolated target – 40.1 [37,2; 58,7]%, differences are statistically significant ( p < 0,001 by the Kruskal-Wallis criterion)
Median improvement in the assessment of part III UPDRS in the group using PTT how the targets amounted to 47.9 [38,8; 57,6]%, without using PTT – 32,0 [24,2; 40,2]%. In absolute terms, the median improvement in terms of III UPDRS in the group PTT составила 29 [21; 34] points, and in the group without PTT – 13,5 [10,2; 21,0] points, differences are statistically significant ( p < 0,0001 by the Wilcoxon criterion)
Long-term results. The median follow-up duration for patients with tremor operated on using MRgFUS was 376.0 [107,5; 612,0] days. Partial return of tremor with less severity compared to the preoperative state occurred in 18 patients. In the group PTT such a recurrence was observed in 5 patients, in the group without RCT – in 13.
In 9 out of 18 patients, treatment was repeated (7 men, 2 women; median age 63 [41; 69] years). In all 9 patients, the procedure was successful. Of these, 5 patients underwent sonications PTT, in 3 patients – sonications VIM and in 1 patient – ablation of both targets ( PTT + VIM). As a result, an “excellent” outcome after the repeat surgery was noted in 7 cases, and a “good” outcome in 2.
In 8 patients with recurrent tremor, the symptoms were not significant enough to indicate repeat treatment, and they were kept under observation. One patient declined further intervention.
Below is a typical clinical example with repeat intervention due to tremor recurrence.
Patient R ., 1950 Year of birth. Diagnosis: PD, mixed form, with predominant tremor in the left limbs, stage 3 according to Hoehn and Yahr; motor fluctuations (“on-off,” morning akinesia); freezing during “off” periods, camptocormia; autonomic disorders (constipation); hyposmia. Complaints of severe stiffness and tremor in the hands (more on the left), especially at the end of levodopa’s effect, short duration of levodopa’s effect (up to 2 hours), constipation, freezing while walking. The tremor significantly hinders performing household tasks and hobbies: the patient is involved in furniture repair and restoration, and the tremor in the left hand prevents working with small parts.
Has been ill since 2010, starting with tremor in the right leg. Soon, tremor in the right hand appeared, and after 1 year, in the left limbs. The disease gradually progressed, and over the years, increasing stiffness, difficulties in self-care, and posture and gait disturbances were noted. Diagnosed with Parkinson’s disease by a neurologist at the place of residence, levodopa medications were prescribed with a good initial effect, but after a few years, the response to the medication worsened and the aforementioned motor fluctuations appeared.
Family history – the mother had hand tremor, diagnosis was not established.
Comorbidities: hypertension II stages. At the time of visiting the clinic, he was taking the following medications: levodopa/carbidopa 250/25 mg 4–5 tablets per day, amantadine sulfate 100 mg 2 times a day, metoprolol 25 mg once a day, enalapril 5 mg once a day
Neurological status before surgery, “off” period. The patient is left-handed. Marked hypomimia. Pronounced bradylalia, hypophonia. Significant chin tremor (up to 1 cm in amplitude). Full range of active movements, sufficient strength. Generalized marked oligobradykinesia. Noticeable increase in muscle tone in the limbs of extrapyramidal type ( D>S). Tendon reflexes are active, symmetrical, with no pathological foot or hand reflexes. There is a constant pronounced large-amplitude resting tremor in the left hand, and a constant medium-amplitude resting tremor in the right hand; constant resting tremor in the right leg, periodic in the left. Postural-kinetic tremor of medium amplitude in the hands, more pronounced on the left. Coordinative tests in the hands are performed with moderate kinetic tremor on the left, mild tremor on the right, heel-knee test without disturbances. Gait with freezing, at a slow pace, reduced step width and foot lift height. Stable in the Romberg test, with postural instability when pushed (up to 3 steps). Postural disorders (camptocormia). No disturbances in superficial and deep sensitivity. Motor and sensory components of speech, gnosis, praxis are not impaired. Assessment by MDS-UPDRS 149 points (part I – 26 points, part II – 32 points, part III – 91 score, part IV – 0 points)
Period of “activation.” Moderate hypomimia. Moderate bradylalia, hypophonia. Episodic chin tremor. Moderately expressed hypokinesia, more pronounced during dynamic tests in the right hand. Muscle tone in the limbs is moderately increased in an extrapyramidal manner ( D>S). Intermittent moderately pronounced medium-amplitude resting tremor of the left hand, resting tremor of smaller amplitude in the right hand, intermittent resting tremor in the legs. Mild postural-kinetic tremor persists in the hands ( S>D). Walking, trunk stability, and postural changes are almost the same as during the “off” period
Cognitive Functions: Assessment Scale MoCA 24 points (mild cognitive impairment)
Result of MRgFUS. On 21.07.2023, the patient underwent right-sided ablation PTT и VIM. Duration of therapy was 2 hours and 20 minutes. The focus in the projection PTT on the right 2 hours after surgery – 3 × 4 × 6 mm, in projection VIM – 2 × 2 × 3 mm. Perifocal edema up to 4 mm. No complications or side effects of therapy. Significant clinical improvement achieved – reduction in the severity of hypokinesia and muscle rigidity in the left limbs (by 80%), reduction in resting tremor and postural-kinetic tremor in the left arm and leg (by 90%) in the “off” state. Total score in part III MDS-UPDRS decreased from 91 to 59.
One month after the treatment, the patient experienced a partial return of tremor in the left hand, more in the wrist.
Neurological status 6 months after surgery, “off” period. Moderate hypomimia, bradylalia, hypophonia. Chin tremor up to 1 cm in amplitude. Moderate general oligobradykinesia, hypokinesia in the right limbs (minimal in the left). Muscle tone in the limbs is increased in an extrapyramidal pattern, significantly more on the right (minimal on the left). Constant pronounced resting tremor in the right hand and right leg, no resting tremor in the left leg, periodic, large-amplitude tremor in the left hand, which increases during stress tests. Moderate constant postural tremor in the right hand and right leg, no postural tremor in the left leg, intermittent, large-amplitude tremor in the left hand. Moderate kinetic tremor during the finger-nose test on the left, mild on the right. No disturbances in the Romberg test, instability persists when pushed (5 steps). Gait with freezing, at a slow pace. Camptocormia. Evaluation by MDS-UPDRS 129 points (part I – 25 points, part II – 28 points, part III – 76 points, part IV – 0 баллов).
19.12.2023 the patient underwent a repeat right-sided MRgFUS ablation PTT и VIM; lesion in the projection PTT on the right in 2 hours – 5 × 3 × 7 mm, in the projection VIM – 5 × 3 × 6 mm. Perifocal edema up to 5 mm. No complications or side effects of therapy. Clinical improvement achieved – elimination of resting tremor and postural-kinetic tremor in the left hand (100% during the “off” period). Noted reduction in symptom severity in part III MDS-UPDRS from 76 to 58 points
Long-term results. The patient was examined 1 and 5 months after the first surgery and 1.5 months after the repeat surgery. During follow-up visits, the patient underwent brain MRI (Fig. 7.5). Neurological examination revealed that on the contralateral side of the body (left arm, left leg) the total score for MDS-UPDRS did not change compared to the assessment conducted immediately after the repeat surgery. The patient himself noted a significant improvement in quality of life: he was able to fully return to his hobby (furniture repair and restoration) and was once again able to confidently hold a spoon while eating. The antiparkinsonian medication therapy remained the same due to the pronounced motor symptoms in the right limbs.
Kaplan–Meier Outcome Analysis R-studio версия 2021.09.2 B382) after the use of MRgFUS in men and women is presented in Fig. 7.6: no significant differences in long-term results for this indicator between the compared groups were found ( p = 0,64). In Fig. 7.7, Kaplan-Meier curves are presented depending on the specific target, and in Fig. 7.8 and Table 7.2, an analysis of long-term treatment results using the MRgFUS method in patient groups is presented using PTT as a target and without using PTT. As seen in the figures and table, the impact on PTT allowed to achieve significantly better long-term results than treatment without targeting this area ( p = 0,039).
Complications. In 73 patients, treatment with MRgFUS was successful without side effects. During the MRgFUS procedure, the following complications were noted: headache, which led to the early termination of the manipulation ( n = 1); headache, not causing premature termination of the procedure ( n = 3); arterial hypertension ( n = 5); temporary suppression of consciousness to stupor ( n = 1); arterial hypotension in response to lidocaine administration during stereotactic frame placement ( n = 2). After the procedure, the indicated disorders were not detected.
All observed immediate and long-term postoperative complications of treatment are presented in Table 7.3. In the 1st month
after the surgery, apraxia occurred in 6 out of 45 patients in the group PTT and in 2 out of 37 patients in the group without using as a target PTT (differences are statistically insignificant); in 2 patients in the group PTT there was dysarthria, 1 had speech slowness, 1 had numbness of the tongue tip. At least 1 complication was observed in 9 out of 45 patients in the group PTT and in 3 out of 37 patients in the group without using as a target PTT (the differences are statistically insignificant). Most neurological symptoms decreased by the 6-month follow-up. After 1 year, apraxia in the group PTT persisted in 2 patients, in the group without PTT – also in 2 patients. In 1 patient in the group PTT normotensive hydrocephalus developed, which was most likely not related to the treatment provided, as symptoms appeared 6 months later
Four patients underwent treatment using MRgFUS for the akinetic-rigid phenotype of PD (AR-PD). The target was the RPT. We preferred to preserve the subthalamic nucleus in case of necessity DBS with the stimulation of this nucleus in the future
General analysis of the results of unilateral pallidothalamic tractotomy using MRgFUS in a cohort with AR-PD showed that operated patients achieved a reduction in the severity of motor symptoms during the “off” period according to part III UPDRS (for 21–32 points), reduction in the severity of therapy-related movement complications in terms of IV UPDRS (from 2 to 9 points), as well as a reduction in the dose of medications taken (levodopa/carbidopa 250 + 25 mg) – from a maximum of 11 tablets (2750 mg of levodopa) to (in 1 patient) 2 tablets (500 mg of levodopa) per day without clinically significant dyskinesias
Since such observations are rare in the world, we provide 2 brief descriptions of operated patients with AR-BP from our cohort
Patient R. , 64 years, since 2004, has been suffering from AR-BP. The disease began with stiffness in the left arm, which gradually progressed. The diagnosis was established only after 5 years. Treatment began with pramipexole, after which the patient noted a noticeable improvement in condition. Since 2012, levodopa (levodopa/carbidopa 250 + 25 mg) was started. A good effect was achieved, but gradually the duration of levodopa’s action decreased (dose-wearing-off effect), necessitating constant increases in frequency of intake. By the time of consultation at our clinic, the patient was receiving antiparkinsonian medications according to the following regimen: levodopa/carbidopa (250 + 25 mg) 1 tablet 10 times a day, morning levodopa/carbidopa/entacapone (100 mg of levodopa), pramipexole 24-hour action (1.5 mg). The main complaint of the patient and his relatives was the inconsistent and short-term (less than 2 hours) effect of levodopa. The patient also had widespread choreiform hyperkinesis throughout the waking period. He was almost completely immobilized, unable to stand up or move during “off” periods. Additionally, the patient did not adhere to the levodopa regimen (complex therapeutic scheme).
Neurological status was checked 1.5 hours after taking levodopa (“on” state) and 2 hours after taking it (“off” state). In the “off” state, the patient could not move independently. During these times, his wife took care of him, helping him sit, stand, and walk. Numerous freezing episodes were noted during initiation and attempts to move, with marked hypomimia. Speech was moderately slowed, with bradylalia. Muscle tone in the limbs was significantly increased in an extrapyramidal pattern. The patient could not raise his arms independently for hypokinesia tests, performing tests only with arms down. In the right hand, bradykinesia and hypokinesia were maximal. The patient could only perform light pronation-supination at 30°-40°. In the left hand, the range of motion was somewhat greater. In the legs, hypokinesia with a decrement in amplitude and speed of movements was observed; he could not perform distal movements with the right leg, and movements with the left leg were limitedly possible. No tremor was noted. Posture was slightly impaired, with a forward lean. Evaluation by individual subscales UPDRS compiled by: in part I – 10 points, in terms of II – 16 points, in terms of III – 82 points, in terms of IV –15 баллов.
The duration of the “on” period and the patient’s clinical condition during this time were assessed after taking different doses of medication. With a standard single dose (levodopa/carbidopa 250 + 25 mg), the “on” period began after 1 hour and 10 minutes, with the duration of the “on” period lasting 1.5 hours. The patient experienced pronounced widespread choreic hyperkinesia in the trunk and limbs throughout the “on” period, except for the last 10 minutes. At this point, muscle stiffness in the right lower limb emerged and gradually intensified against the background of existing hyperkinesia in the trunk and left limbs. The duration of the “on” period after taking 3/4 of a tablet was 45 minutes. Clinically, moderate choreic hyperkinesia was observed. The duration of this period after taking 1/2 tablet was about 20 minutes. In this case, there was incomplete “on” response, with moderate stiffness in the right leg. Sometimes, the “on” period did not occur after taking 1/2 tablet.
For 3 months, the patient was prepared and consulted using telemedicine technologies. During the preparation period, the medication regimen was gradually adjusted: the single dose of levodopa was reduced, and the daily dose of dopamine receptor agonists was increased. Additionally, MAO-B inhibitors and amantadines were prescribed. However, the adjustment did not improve the patient’s condition. As before, there were pronounced dyskinesias with small doses of levodopa and significant akinesia after a short “on” period. Amantadines caused visual hallucinations. The patient refused to take atypical antipsychotics (prescribed to reduce the severity of dyskinesias). It was proposed to refer the patient for DBS or the installation of a pump with intestinal administration of levodopa gel, but the patient refused these invasive procedures
Due to the lack of effect from medication treatment and the patient’s refusal to undergo DBS 6 In April 2022, the patient underwent pallidothalamotractotomy using the MRgFUS method. The operation was performed on the left side (for the most compromised right limbs), targeting the PTT.
The treatment duration was 176 minutes. The average maximum energy reached 30,750.25 ± 6246.06 J (range 20,096–35,731 J) with an average maximum temperature of 58.8 ± 3.1° C (range 54–62° C). Location PTT: on the mid-commissural line in the anterior direction, 10.0 mm lateral from the intercommissural line, 7.5 mm to the thalamoventricular border, and 2 mm below the intercommunicating line in the dorsoventral direction. Target center PTT on the left was adjusted approximately 3 mm lateral to the mammillothalamic tract, above and medial to the subthalamic nucleus. The second target was 0.5 mm posterior, 1 mm higher, and 2 mm lateral to the first target. The patient’s MRI scans immediately after the surgery are shown in Fig. 7.9. The patient tolerated the treatment satisfactorily, without side effects.
As a result of the treatment, improvement was achieved with a decrease in the total score in part III UPDRS from 82 to 50, in part IV – from 15 to 6. After treatment, the patient was observed for 48 hours, assessing their neurological status. In the “off” state after MRI-guided focused ultrasound treatment, the patient could stand independently and move with slight support from a cane, occasionally freezing at the start of walking and during turns. Moderate hypomimia was noted against the background of facial symmetry. Speech was moderately slowed. Muscle tone was moderately increased according to Fig. 7.9. MRI of patient R., 64 years old, immediately after MRI-guided focused ultrasound treatment. The destruction focus is indicated by an arrow. Extrapyramidal type (in the right hand – 1 point, in the left – 3-4 points). Tone in the right leg showed no pathological changes, in the left – increased to 2-3 points. During tests for hypokinesia, a decrease in amplitude and speed was recorded on the right side to 1 point, on the left – to 3-4 points. Tremor was not observed. During examination in the “off” state, the total score for part III UPDRS made up 50, in part IV – 6.
Within 1 week after treatment with MRgFUS, the neurological status was assessed after taking 1/2 tablet of standard levodopa/carbidopa (250 + 25 mg). After a single dose, the “on” period occurred after 1 hour and lasted 2.5 hours. Dyskinesias of mild severity occurred only in the left arm and leg while walking and sitting.
One month after treatment with MRgFUS, overall motor activity remained at the same level during the “off” period as after the treatment. The patient could move, take care of himself, and go outside. During the “off” period, the patient learned to overcome freezing by using visual and auditory non-pharmacological aids for movement (chanting a march and bright floor markings). The duration of the effect of 1/2 tablet of medication increased to 2.5 hours, and it was possible to reduce the dose of medications taken (levodopa/carbidopa 250 + 25 mg) from 11 tablets (2750 g of levodopa) to 6 tablets (1500 g of levodopa) per day. The severity of dyskinesias associated with medication intake noticeably decreased after treatment with MRgFUS. They are observed only in the left hand and left leg and during psycho-emotional stress. The patient gained 5 kg in weight, his posture changed, he became more stable, and his mood improved throughout the day.
Patient B , 54 years, ill for 7 years. The first signs of the disease were stiffness and limited mobility in the right arm, followed by gait disturbances in the form of dragging the right leg, and the gait became slightly limping. The diagnosis was made after six months, and the patient was prescribed pramipexole at a standard dose of 1.5 mg/day, with a moderate positive effect noted as partial regression of stiffness and hypokinesia. Due to the gradual progression of the disease and the addition of postural instability, levodopa medications were added after 1 year with a pronounced positive effect. The patient was monitored in person for 1.5 years. At the time of the last examination, he was taking levodopa/carbidopa (250 + 25 mg) at 1/2 tablet 4 times a day, extended-release pramipexole 1.5 mg once, amantadine sulfate 100 mg at 3 tablets a day, rasagiline 1 mg. The patient was troubled by motor and non-motor fluctuations in the form of dose wearing off, and he categorically refused to increase the dose of levodopa, citing possible negative effects on the gastrointestinal tract. Increasing the dose of other antiparkinsonian drugs (amantadine, pramipexole) did not lead to the expected effect. Adding a COMT inhibitor (Stalevo) was not possible for the patient due to economic reasons.
During the observation period, the patient was consulted by a leading neurologist specializing in Parkinson’s at the Research Center of Neurology (the diagnosis and options for adjusting the antiparkinsonian regimen were confirmed), and examined by a functional neurosurgeon at the N.N. Burdenko National Medical Research Center of Neurosurgery – at the time of examination, indications for conducting DBS not detected
The patient was examined in two states – 1.5 hours after taking 3/4 of a tablet of levodopa/carbidopa (250 + 25 mg) to assess the condition during the “on” period and 6 hours later to determine the neurological status during the “off” period.
During the “off” period, 6 hours after taking the specified dose of levodopa, moderate hypomimia was observed, speech was slightly dysarthrophonic, muscle tone in the limbs was increased in an extrapyramidal manner: 4 points in the right limbs, 2 points in the left limbs. Moderate bradykinesia, hypokinesia in the right limbs during tests – 4 points, left – 2–3 points. No tremor. Gait is slow, pace and step height are reduced, occasional freezing. Postural instability – 2–3 steps. Posture is slightly altered with a forward lean.
«The “on” state occurred 1.5 hours after taking 3/4 of a tablet of levodopa/carbidopa (250 + 25 mg), with slight hypomimia observed, speech unchanged, muscle tone in the limbs increased in an extrapyramidal manner: 2 points in the right limbs, normal in the left. Bradykinesia, hypokinesia in the right limbs during tests – 1–2 points, in the left – 1 point. No tremor. Walking at a good pace, without freezing. Postural instability persisted for 2–3 steps. Posture slightly altered with a forward tilt.
Evaluation by MDS-UPDRS compiled by: in part III during the “off” period – 48 points, during the “on” period – 32 points, regarding IV – 6 points
Due to the lack of an acceptable effect from medication treatment and refusal to conduct DBS the patient underwent left pallidothalamic tractotomy using MRgFUS on June 21, 2022. The duration of therapy was 1 hour and 50 minutes. The patient tolerated the MRgFUS treatment satisfactorily, without complications, with improvement in part III MDS-UPDRS from 48 to 28 points, in part IV – from 6 to 4 points
During the examination 1 day after the treatment during the “off” period, there was an 80% reduction in akinesia (hypo- and bradykinesia) in the right limbs, a 90% reduction in rigidity in the right lower limb, a 50% reduction in proximal rigidity in the right upper limb, a 95% reduction distally, a 70% reduction in axial rigidity, and an improvement in posture compared to the motor state before therapy.
During the subsequent 1.5-year follow-up, functionality and daily household and social activity were maintained even during the “off” periods. The daily dose of antiparkinsonian drugs was reduced – amantadine was discontinued. The patient gained 6 kg, straightened up, felt subjectively more stable, and experienced improved sleep and mood.
Our initial experience in treating such patients is quite favorable and indicates that symptom relief in AR-PD can be achieved without complications and with good immediate results. However, to date, there is little data on the long-term outcomes of treating patients with non-tremor forms of PD using MRgFUS, so further research in this area is needed