Therapy for advanced stages of Parkinson's disease

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Introduction

Parkinson's disease (PD) is the second most common disease after Alzheimer's disease, a steadily progressive neurodegenerative disease associated with dopamine deficiency [1]; its prevalence is 160 cases per 100 thousand population. With age, the prevalence increases, although recently the disease has become more often diagnosed in people under 50 years old [2; 3].

The diagnosis of Parkinson's disease is made clinically with a combination of oligobradykinesia with resting tremor or rigidity and includes both motor and non-motor manifestations (visual impairment, sleep disorder, neuropsychiatric and autonomic disorders, cognitive deficit). Disease progression is variable, an accurate prognosis is impossible to establish [4]. Five stages are distinguished in the structure of PD. According to the Delphi Consensus (2015), stages with postural disorders, mainly stages 3 and 4, are considered advanced. Experts have determined motor, non-motor and functional symptoms that indicate that the patient has an advanced stage of the disease [5]. Motor symptoms include moderate motor fluctuations that bother the patient, which should include “off” symptoms for 2 hours a day or more and dyskinesia for 1 hour a day or more, dysphagia that bothers the patient, and 5-time intake of levodopa drugs. The group of experts attributed cognitive impairment in the stage of mild dementia, hallucinations and psychotic disorders that bother the patient, the presence of fluctuations in non-motor symptoms and a moderate degree of sleep disturbance to non-motor symptoms of advanced stages. Among the functional symptoms, the following are distinguished: falls of the patient, repeated, despite treatment, difficulties in independently solving complex problems, constant outside help to maintain activity due to the impaired ability to move independently [5].

Currently, levodopa drugs are the "gold standard" in the PD treatment, 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 PD development. 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 its deficiency [6].

The introduction of levodopa into clinical practice more than 50 years ago 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 non-dopaminergic neurons begin to participate in the synthesis of dopamine, which they are not able to deposit, as a result of which there is 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 perversion of the sensitivity of dopamine receptors develops [6].

In the 4th–5th year of taking levodopa, 80 % of patients develop side effects associated with taking levodopa-containing drugs (as a result of narrowing the therapeutic window), in the form of drug-induced dyskinesias and motor fluctuations. In this regard, the risk 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 a disease duration of more than 5 years, taking antiparkinsonian drugs at least 5 times a day, the presence of the “dose exhaustion” phenomenon, “off” symptoms, dyskinesias or dystonia for at least 2 hours during the day. A little later, within the framework of the educational program Navigate PD, specific criteria for treatment with invasive methods were arrived at: patients taking levodopa drugs more than 5 times a day, having "off" periods lasting more than 1-2 hours during the waking period (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. At the same time, a disease duration of less than 4 years is not an obstacle to invasive treatment methods [9].

Functional methods are recommended for patients with depleted drug reserves or the presence of side effects from antiparkinsonian drugs.

Three functional methods are used in the treatment of movement disorders: ablative or destructive surgery (thalamotomy, pallidotomy); deep brain stimulation (DBS); superficial invasive brain stimulation (eg, extradural or subdural stimulation of the motor cortex) and non-invasive (transcranial magnetic stimulation) [10].

For patients with PD who do not achieve positive dynamics in terms of correction of movement disorders with drug therapy, alternative methods to date have been radiofrequency thalamotomy and DBS [11].

Over the past 20 years, electrical stimulation of deep brain structures has been an effective method for correcting complications of levodopa therapy in patients with PD. The subthalamic nucleus is the best target for the effectiveness of this method [12].

The knowledge accumulated in the field of neurodegeneration studies in recent decades has opened up new horizons in the treatment of PD. In 2014, the first experience of treating PD using focused ultrasound under the control of magnetic resonance imaging (MR-FUS) was published. In 2017, the results of the first randomized double-blind study of the effectiveness of MR-FUS in PD were presented [13].

For the first time in the Russian Federation, thalamotomy using the MR-FUS method was performed on May 5, 2020, at the Intellectual Neurosurgery Clinic of the V.S. Buzaev International Medical Center 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 adjust the stimulation parameters or replace the battery, as with DBS [17; 18].
However, one should remember the possible complications of this method: impaired gait, balance, sensitivity.

A limitation of MR-FUS as a destructive procedure is its use in unilateral operations. However, scientists from Switzerland reported the results of observation of patients with PD after bilateral pallidothalamic tractotomy, and now this issue is being reconsidered [19].

It should be noted that an effective invasive method of treating advanced stages of PD is the drug "Duodopa" – levodopa/carbidopa intestinal gel (LCIG). One cassette of LCIG 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 enters the jejunum through the gastrojejunal tube behind the ligament of Treitz, where levodopa is absorbed. This allows levodopa to be delivered directly to the jejunum, avoiding disruption of gastric motility [20].

Levodopa/carbidopa intestinal gel is recommended for patients with PD at advanced stages complicated by long-term levodopa use in the form of motor fluctuations and drug-induced 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 17 years) [22].

In 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 LCIG therapy use, the following conclusions were made: a statistically significant shortening of the "off" periods and an extension of the "on" periods without increasing dyskinesias were noted, stable positive dynamics were revealed according to the UPDRS scale; a stable shortening of the “off” periods by more than 70 % was achieved [23].

Later, the Russian experience was summarized in a prospective, open, 54-week study (48 patients, 3 centers) [24].

Another significant study, COSMOS, aimed to research 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 showed a positive result of using levodopa gel. A meta-analysis comparing the efficacy and safety of LCIG and the tablet form of levodopa showed that LCIG had a better therapeutic effect compared to oral drugs [26].

Long-term results of levodopa gel administration during the day in patients with Parkinson's disease for 54 weeks after pump placement were published by specialists from Florida in 2022. Longitudinal analysis of daily patterns confirms the long-term effectiveness of intestinal levodopa gel administration in terms of increasing the time to ON-woTD after awakening, improving motor symptom control and reducing sharp fluctuations in state during the day. The data obtained confirm that LCIG provides continuous dopaminergic stimulation during 16 hours of wakefulness of patients, and also improves the predictability of motor states, which allows patients to control motor symptoms, which significantly improves quality of life [27].

Improvements in the PD sleep scale by 14 % were noted in a retrospective study in patients receiving LCIG for 24 months, in addition, nocturnal motor symptoms decreased by 30 % [28].

In addition, a study was conducted among patients with side effects from dopaminergic therapy in the form of impulsive-compulsive disorders (e.g., gambling addiction) who received LCIG. It was noted that the severity of these manifestations decreased to 64 % during 6 months of observation. Perhaps this is due to a decrease in the number of dopamine receptor agonists taken [27].

More recently, a prospective open study of 12 patients observed for 6 months showed that LCIG improved the quality of life not only in patients, but also in their family members [29].

In the world, the practice of using LCIG in PD has been around 19 years. The drug was registered in 2004 in Sweden. Levodopa/carbidopa intestinal gel (LCIG; enteral suspension of carbidopa/levodopa) has been widely used and studied for the correction of motor fluctuations in patients with PD who respond to levodopa therapy and where other methods have failed [30].

There are conflicting opinions regarding the initiation of levodopa gel.
Previously, it was believed that LCIG was preferable for initiation at an older age, but now there are suggestions that LCIG is more effective in patients with a short disease duration and early use [31]. These data are partially confirmed. A retrospective analysis of 177 patients confirmed that in individuals with a disease duration of < 10 years, the reduction in "off" time was greater than in individuals with a disease duration of more than 10 years [32].

However, there are safety concerns with the use of levodopa/carbidopa intestinal gel, which are mainly related to the procedure itself or the device. Complications associated with the device include: accidental removal, occlusion, migration or kinking of the tube [33; 34]. Less common complications associated with the procedure itself were stomatitis and inflammation [35]. Also, complications associated with LCIG, such as hallucinations, sleep disturbances and weight loss, have been reported in the literature [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) is highly effective, well tolerated and has a favorable safety profile over a long observation period.

A personalized approach will optimize the dose of levodopa gel for each patient, thereby increasing the effectiveness of this method. However, the possibilities of using DBS or a pump with levodopa / carbidopa intestinal gel remain limited, largely due to the insufficient 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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