Therapy for advanced stages of Parkinson's disease

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Introduction. Parkinson's disease is the second most common after Alzheimer's disease, a steadily progressive neurodegenerative disease associated with dopamine deficiency. [1]. Prevalence: 160 cases per 100 thousand population. The prevalence increases with age. Recently, the disease has become more common in people under 50 years of age [2, 3].
The diagnosis of Parkinson's disease is made clinically when oligobradykinesia is combined with resting tremor or rigidity and includes both motor and non-motor manifestations (visual impairment, sleep disorder, neuropsychiatric and autonomic disorders, cognitive deficit). The progression of the disease is variable, and an accurate prognosis cannot be established [4]. There are 5 stages in the structure of Parkinson's disease. According to the Delphi Consensus (2015), stages with postural disturbances, mainly 3 and 4, are considered advanced. Experts have put forward motor, non-motor and functional symptoms that signal the presence of an advanced stage of the disease in the patient [5]. Of the motor symptoms, these include moderately pronounced motor fluctuations that bother the patient, among which there should be symptoms of “off” for 2 or more hours and dyskinesia for 1 or more hours a day, dysphagia that bothers the patient after taking levodopa medications 5 times. The group of experts included cognitive impairment in the stage of mild dementia, disturbing hallucinations and psychotic disorders, the presence of fluctuations in non-motor symptoms and moderate sleep disturbances as non-motor symptoms of advanced stages. Functional symptoms include patient falls that are repeated despite treatment, difficulties in independently solving complex problems, and constant outside help to maintain activity due to impaired ability to move independently [5].
Currently, levodopa drugs are the “gold standard” in the treatment of Parkinson’s disease, but they are not able to stop the progression of the disease. Levodopa is a precursor of dopamine, the deficiency of which underlies the mechanism of development of PD. Unlike dopamine, levodopa is able to penetrate the brain through the blood-brain barrier, where it undergoes decarboxylation, as a result of which it is converted into dopamine, replenishing the deficiency [6].
The introduction of levodopa into clinical practice over 50 years has revolutionized the treatment of parkinsonism [7].
As the neurodegenerative process progresses, the number of neurons in the substantia nigra decreases. In the surviving neurons, dopamine metabolism accelerates. Neighboring glial cells and nondopaminergic neurons begin to participate in the synthesis of dopamine, which they are not able to store, resulting in an excessive release of dopamine into the synaptic cleft after each dose of a levodopa-containing drug. The physiological tonic work of dopamine receptors changes to pulsating, as a result of which a distortion of the sensitivity of dopamine receptors develops [6].
  After 4-5 years of taking levodopa, 80% of patients experience side effects associated with taking levodopa-containing drugs (as a result of narrowing of the therapeutic window), in the form of drug-induced dyskinesias and motor fluctuations. In this regard, the danger of worsening postural disorders in the form of falls increases, which leads to traumatization of patients and an increase in the degree of disability [8].
The proposal to outline the circle of patients with advanced stages of PD was formulated by Swedish neurologists and included the duration of the disease for more than 5 years, taking antiparkinsonian drugs at least 5 times a day, the presence of the phenomenon of “dose exhaustion”, “off” symptoms, dyskinesias or dystonia for at least 2 h during the day. A little later, as part of the Navigate PD educational program, they came to specific criteria for treatment with invasive methods: patients taking levodopa drugs more than 5 times a day, having “off” periods lasting more than 1–2 hours during the period of wakefulness (despite optimally selected therapy ), as well as disabling dyskinesias that are not relieved by taking amantadine at a dose of more than 400 mg/day. Moreover, the duration of the disease less than 4 years is not an obstacle to invasive treatment methods [9].
Functional methods are recommended for patients with depleted drug reserve or side effects from antiparkinsonian drugs.
In the treatment of movement disorders, 3 functional methods are used: ablative, or destructive, surgery (thalamotomy, pallidotomy); deep brain stimulation (DBS); superficial invasive brain stimulation (for example, extradural or subdural stimulation of the motor cortex) and non-invasive (transcranial magnetic stimulation) [10].

For patients with Parkinson's disease who do not achieve positive dynamics in terms of correction of motor disorders during drug therapy, alternative methods until now have been radiofrequency thalamotomy, radiosurgical thalamotomy and DBS [11].
Over the past 20 years, electrical stimulation of deep brain structures has been an effective method for correcting complications of levodotherapy in patients with Parkinson's disease. The subthalamic nucleus is the best target for the effectiveness of this method [12].
The knowledge accumulated in recent decades in the field of neurodegeneration has opened new horizons in the treatment of Parkinson's disease. In 2014, the first experience in treating Parkinson's disease using magnetic resonance imaging-guided focused ultrasound (MR-FUS) was published. In 2017, the results of the first randomized, double-blind study of the effectiveness of MR-FUS in Parkinson's disease were presented [13].
For the first time in the Russian Federation, thalamotomy was performed using MR-FUS on May 5, 2020, at the Clinic of Intellectual Neurosurgery of the International Medical Center named after. V.S. Buzaev in Ufa [14]. The advantages of the method are non-invasiveness (without craniotomy), single procedure, constant contact between the doctor and the patient due to the absence of general anesthesia, obtaining results during the procedure or immediately after its completion, no need for hospitalization, the possibility of reversible effects at the first stage of therapy [15, 16]. Destruction of the subcortical nuclei using MR-FUS has become a good alternative for patients with contraindications to DBS and with asymmetric symptoms. In addition, the patient does not need to correct stimulation parameters or replace the battery as with DBS [17, 18]. However, one should remember about the possible complications of this method: impaired walking, balance, sensitivity.
A limitation of MR-FUS as a destructive procedure is its use in unilateral surgeries. However, scientists from Switzerland reported the results of monitoring patients with PD after bilateral pallidothalamic tractotomy and this issue is now being reconsidered [19].
It should be noted that an effective invasive method for treating advanced stages of Parkinson's disease is the drug Duodopa - levodopa/carbidopa intestinal gel (LCIG). One LKIG cassette contains 100 ml of gel. 1 ml of gel contains 20 mg of levodopa and 5 mg of carbidopa monohydrate. Using a special pump, the gel passes through the gastrojejunal tube into the jejunum behind the ligament of Treitz, where levodopa is absorbed. This allows levodopa to be delivered directly to the jejunum, avoiding gastric dysmotility [20].
Levodopa/carbidopa intestinal gel is recommended for patients with Parkinson's disease in advanced stages, complicated by long-term use of levodopa in the form of motor fluctuations and drug dyskinesias, with insufficient effectiveness of other groups of antiparkinsonian drugs [21].
Existing clinical data indicate that the positive effect of LCIG persists for a long time (from 4 to 7 years) [22].
At the Center for Extrapyramidal Pathology and Botulinum Therapy of the Republic of Tatarstan (Kazan), 20 patients with advanced stages of PD were observed who received LCIG in the form of Duodopa gel. As a result of the use of LCIG therapy, the following conclusions were made: there was a statistically significant shortening of the “off” periods and an extension of the “on” periods without increasing dyskinesia, stable positive dynamics were noted on the UPDRS scale; A sustainable shortening of “off” periods by more than 70% was achieved [23].
Later, the Russian experience was generalized in a prospective open-label 54-week study (48 patients, 3 centers) [24].
The purpose of another significant study, COSMOS, was to study the effect of LCIG therapy on reducing polypharmacy in the treatment of advanced stages of PD. A total of 409 patients from 14 countries were included. The use of additional drugs decreased over time with all LCIG regimens, as the average duration of the “off” period and the duration of dyskinesias decreased [25].
Another study conducted by a group of researchers led by X.R. Zhan testified to the positive results of using levodopa gel. A meta-analysis comparing the effectiveness and safety of LCIG in comparison with the tablet form of levodopa showed that LCIG had a better therapeutic effect compared to oral drugs [26].

Long-term results of daily levodopa gel administration in patients with Parkinson's disease for 54 weeks after pump placement were published by Florida researchers in 2022. Longitudinal analysis of daily patterns confirms the long-term effectiveness of intestinal levodopa gel in increasing time to onset of ON-woTD after awakening, improve control of motor symptoms and reduce sudden fluctuations throughout the day. The findings confirm that LCIG provides continuous dopaminergic stimulation throughout patients' 16 hours of wakefulness and also improves the predictability of motor states, allowing patients to control motor symptoms, which significantly improves quality of life [27].
Improvements in Parkinson's disease sleep scores of 14% were noted in a retrospective study of patients receiving LCIG for 24 months, in addition to a 30% reduction in nocturnal motor symptoms [28].
In addition, a study was conducted among patients who had side effects from dopaminergic therapy in the form of impulsive-compulsive disorders (for example, gambling addiction) who received LCIG. It was noted that the severity of these manifestations decreased to 64% during 6 months of observation. This may be due to a decrease in the amount of dopamine receptor agonists taken [27].
More recently, a prospective, open-label study of 12 patients followed for 6 months showed that LCIG improved quality of life not only for patients but also for their family members [29].
In the world, the practice of using LCIG for PD is about 19 years old. The drug was registered in 2004 in Sweden. Levodopa/carbidopa intestinal gel (LCIG; carbidopa/levodopa enteral suspension) has been widely used and studied for the correction of motor fluctuations in patients with Parkinson's disease (PD) responding to levodopa therapy when other methods have failed [30].
There are conflicting opinions about starting the use of levodopa gel. Previously, it was believed that older age was preferable for starting LCIG; now, there are suggestions that in patients with a short history of the disease and early use, LCIG is more effective [31]. These results are partially confirmed. As a result of a retrospective analysis of 177 patients, it was confirmed that in those with a disease duration <10 years, the reduction in “off” time was greater than in those whose disease duration exceeded 10 years [32].
However, there are safety concerns with the use of levodopa/carbidopa enteric gel, which are primarily related to the procedure or device itself. Complications associated with the device include accidental removal, occlusion, migration, or kinking of the tube [33, 34]. Complications associated with the procedure itself were less common: stomatitis, inflammation [35]. The literature also indicates complications associated with LCIG, such as hallucinations, sleep disturbances and weight loss [36].

Conclusions. Thus, patients with advanced stages of PD, complicated by long-term use of levodopa, with pronounced motor fluctuations and drug-induced dyskinesias, have the opportunity to choose a non-oral method of treating the disease. It is important to note that LCIG (Duodopa gel) is highly effective, well tolerated and has a favorable safety profile over a long period of observation. A personalized approach will allow you to optimize the dose of levodopa gel for each patient, thereby helping to increase the effectiveness of this method. However, the use of DBS or levodopa/carbidopa intestinal gel pumps remains limited, largely due to the lack of availability and invasiveness of these technologies.

About the authors

Yu. V. Karakulova

E. A. Vagner Perm State Medical University

Author for correspondence.
Email: julia.karakulova@mail.ru
ORCID iD: 0000-0002-7536-2060

DSc (Medicine), Professor, Head of the Department of Neurology and Medical Genetics

Russian Federation, Perm

E. A. Golchenko

V.I. Voinov Orenburg Regional Clinical Hospital

Email: julia.karakulova@mail.ru
ORCID iD: 0000-0003-3954-1405

Neurologist

Russian Federation, Orenburg

References

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