Levodopa Dose Research Articles

Delirious episode secondary to rotigotine: the psychotic patch

IntroductionThere is a fine line separating psychiatry and neurology. Most movement disorders can have psychiatric symptoms, not only those caused by the disease itself, but also those induced by the drugs used to treat them.ObjectivesPresentation of a clinical case about a patient diagnosed with Parkinson’s disease presenting a several-month-long delirious episode due to dopaminergic drugs.MethodsLiterature review on drug-induced psychosis episodes in Parkinson’s disease.ResultsA 57-year-old patient with diagnosis of Parkinson’s disease for six years, who went to the emergency room accompanied by his wife due to delirious ideation. He was being treated with levodopa, carbidopa and rasagiline for years, and rotigotine patches whose dosage was being increased over the last few months.His wife reported celotypical clinical manifestations and multiple interpretations of different circumstances occurring around her. He chased her on the street, had downloaded an app to look for a second cell phone because he believed she was cheating on him, and was obsessed with sex. He had no psychiatric background. It was decided to prescribe quetiapine.The following day, he returned because he refused to take the medication since he thought he was going to be put to sleep or poisoned. It was decided to admit him to Psychiatry.During the stay, rasagiline and rotigotine were suspended. Olanzapine and clozapine were introduced, with behavioral improvement and distancing from the psychotic symptoms which motivated the admission. The patient was also motorically stable. Although levodopa is best known for causing psychotic episodes, the symptons were attributed to rotigotine patches for temporally overlapping the dose increase.ConclusionsPsychiatric symptoms are the third most frequent group of complications in Parkinson’s disease after gastrointestinal complications and abnormal movements. All medication used to control motor disorders can lead to psychosis, not only dopaminergics, but also selegiline, amantadine and anticholinergics.Excessive stimulation of mesocortical and mesolimbic dopaminergic pathways can lead to psychosis, which is the most common psychiatric problem related to dopaminergic treatment.In the face of a psychotic episode, antiparkinsonian drugs which are not strictly necessary for motor control should be withdrawn. If this is not sufficient, levodopa dose should be reduced, considering the side effects that may occur. When the adjustment of antiparkinsonian treatment is not effective, neuroleptics, especially quetiapine or clozapine, should be administered. In a recent study, pimavanserin, a serotonin 5-HT2 antagonist, was associated with approximately 35% lower mortality than atypical antipsychotic use during the first 180 days of treatment in community-dwelling patients.Medication should always be tailor-made to suit each patient and we usually have to resort to lowering or withdrawing the dopaminergic medication.Disclosure of InterestNone Declared

ANXIETY AND DEPRESSION IN TUNISIAN PATIENTS WITH PARKINSON’S DISEASE

IntroductionAnxiodepressive disorders in Parkinson’s disease (PD) are quite frequent and considered as non-motor signs of the disease. Few studies have studied the link between these entities.ObjectivesThe objective of this study is to determinate the prevalence of anxiety and depression in patients with PD, and factors associated with themMethodsA descriptive and analytical cross-sectional study collected from patients followed at the neurology consultation of Habib Bourguiba’s university Hospital in Sfax, Tunisia. We used:-a sociodemographic, clinical and therapeutic data sheet-Hospital Anxiety and Depression Scale(HADS): to study anxiety and depression. A score ≥10 means a certain anxiety or depressionResultsWe have involved 47 patients. The average age was 61.47 years with a sex ratio (M/W)=1,47. Amantadine was received by 12.77% of patients, anticholinergics by 14.9% of patients and 87.24% of patients were treated with Levodopa.HADS: the average scale of Depression was8.62 ± 4.54 and the median scaleanxiety was 7 [1-18]. Depression and anxiety were presentin 38.29% and 27.68% of cases, respectively. Depression was significantly correlated with Amantadine intake (P=0.036) and Levodopa dose (P=0.016). Anxiety was significantly associated with anticholinergic intake(P=0.011).Both depression and anxiety were notstatistically correlated to the presence ofmotor complications of dopa therapy (P= 0.44 and 0.7 respectively)ConclusionsThe therapeutic management of patients with PD influences the occurrence of anxiety and depression, which proves the importance of early detection of these disordersto ensure better supportDisclosure of InterestNone Declared

Clozapine use in drug induced psychosis in Parkinson´s disease: a case report and review of literature.

IntroductionThe occurrence of psychotic symptoms induced by dopaminergic drugs marks a new phase in the course of Parkinson’s disease (PD). The term drug induced psychosis may be used when other significant psychiatric diseases are excluded in patients with no history of psychosis. The prevalence of dopaminomimetic psychosis varies from 5% to 20%. Therefore, knowledge of the psychopharmacological management of this condition is essential.ObjectivesThe purpose of this case report and literature review is to to learn the psychopharmacological management of this not uncommon medical complication.MethodsDescriptive case study and review of literatureResultsWe present the case of a 71-year-old man with a medical history of Parkinson’s disease with partial response to treatment with high doses of levodopa and carbidopa.He was brought to the emergency department by his family due to the presence of behavioural alterations at home.The patient reported seeing men in foam trying to harm his family. In a disjointed way in his speech, he links this idea with the delusional belief that he is being watched by electronic devices placed throughout the house. In a variegated manner he links this with a coelotypical type of discourse, however the delusional ideation remains unstructured throughout.With no previous personal or family history of mental health and ruling out underlying organic conditions, a diagnosis of psychosis secondary to pharmacological treatment for Parkinson’s disease is presumed.Considering the risks and benefits, it was decided to maintain the anti-Parkinson’s dose in order to avoid worsening the patient’s motor function. Therefore, after reviewing the literature, the best option was to introduce clozapine at low doses, up to 50 mg at night, with the respective analytical control. After a week’s admission, the patient began to improve psychopathologically, achieving an ad integrum resolution of the psychotic symptoms.ConclusionsDespite the availability of other antipsychotic treatments such as quetiapine or the more recent pimavanserin, clozapine remains the treatment of choice for drug-induced psychosis in Parkinson’s disease.Disclosure of InterestNone Declared

Levodopa Equivalent Dose of Safinamide: A Multicenter, Longitudinal, Case-Control Study.

Effects of dopaminergic medications used to treat Parkinson's disease (PD) may be compared with each other by using conversion factors, calculated as Levodopa equivalent dose (LED). However, current LED proposals on MAO-B inhibitors (iMAO-B) safinamide and rasagiline are still based on empirical approaches. To estimate LED of safinamide 50 and 100 mg. In this multicenter, longitudinal, case-control study, we retrospectively reviewed clinical charts of 500 consecutive PD patients with motor complications and treated with (i) safinamide 100 mg (N=130), safinamide 50 mg (N=144), or rasagiline 1 mg (N=97) for 9 ± 3 months and a control group of patients never treated with any iMAO-B (N=129). Major baseline features (age, sex, disease duration and stage, severity of motor signs and motor complications) were similar among the groups. Patients on rasagiline had lower UPDRS-II scores and Levodopa dose than control subjects. After a mean follow-up of 8.8-to-10.1 months, patients on Safinamide 50 mg and 100 mg had lower UPDRS-III and OFF-related UPDRS-IV scores than control subjects, who in turn had larger increase in total LED than the three iMAO-B groups. After adjusting for age, disease duration, duration of follow-up, baseline values and taking change in UPDRS-III scores into account (sensitivity analysis), safinamide 100 mg corresponded to 125 mg LED, whereas safinamide 50 mg and rasagiline 1mg equally corresponded to 100 mg LED. We used a rigorous approach to calculate LED of safinamide 50 and 100 mg. Large prospective pragmatic trials are needed to replicate our findings.

Effects of levodopa on gut bacterial antibiotic resistance in Parkinson's disease rat.

The second most prevalent neurodegenerative ailment, Parkinson's disease (PD), is characterized by both motor and non-motor symptoms. Levodopa is the backbone of treatment for PD at the moment. However, levodopa-induced side effects, such as dyskinesia, are commonly seen in PD patients. Recently, several antibiotics were found to present neuroprotective properties against neurodegenerative and neuro-inflammatory processes, which might be developed to effective therapies against PD. In this study, we aimed to identify if levodopa treatment could influence the gut bacterial antibiotic resistance in PD rat. Fecal samples were collected from healthy rats and 6-OHDA induced PD rats treated with different doses of levodopa, metagenomic sequencing data showed that levodopa resulted in gut bacteria composition change, the biomarkers of gut bacteria analyzed by LEfSe changed as well. More interestingly, compared with levodopa (5 mg/kg)-treated or no levodopa-treated PD rats, levodopa (10 mg/kg) caused a significant decrease in the abundance of tetW and vanTG genes in intestinal bacteria, which were related to tetracycline and vancomycin resistance, while the abundance of AAC6-lb-Suzhou gene increased apparently, which was related to aminoglycosides resistance, even though the total quantity of Antibiotic Resistance Gene (ARG) and Antibiotic Resistance Ontology (ARO) among all groups did not significantly differ. Consequently, our results imply that the combination of levodopa and antibiotics, such as tetracycline and vancomycin, in the treatment of PD may decrease the amount of corresponding antibiotic resistance genes in gut bacteria, which would give a theoretical basis for treating PD with levodopa combined with tetracycline and vancomycin in the future.

Switching from Rasagiline to Safinamide as an Add-On Therapy Regimen in Patients with Levodopa: A Literature Review.

Parkinson's disease (PD) is a complex disease, and the treatment is focused on the patient's clinical symptoms. Levodopa continues to be the most effective drug for symptomatic PD treatment. However, chronic levodopa treatment is associated with the development of motor complications in most patients. Add-on therapeutic drugs, such as dopamine agonists and monoamine oxidase B (MAO-B) inhibitors, for example, safinamide and rasagiline, may be a desirable addition to continuously increase the levodopa dose for the optimization of motor control in PD. The scientific literature shows that safinamide significantly alleviated motor fluctuations with no increase in troublesome dyskinesia, thanks to its unique double mechanism, providing further benefits to fluctuating PD patients when compared to a placebo or other drugs. Switching from rasagiline to safinamide has been shown to improve the wearing-off phenomena, which is defined as the recurrent, predictable worsening of symptoms of parkinsonism at the end of the levodopa dose until the next dose reaches a clinical effect. In this situation, safinamide may be helpful for reducing the total daily dose of levodopa, improving the OFF time and ON time without troublesome dyskinesias, and being more effective than other MAO-B inhibitors. In this narrative review, we explore the switch from rasagiline to safinamide in patients with motor complications as a feasible and effective alternative to optimize antiparkinsonian treatment.

Analysis of deep brain stimulation of the subthalamic nucleus (STN-DBS) in patients with monogenic PRKN and LRRK2 forms of Parkinson's disease

IntroductionDeep brain stimulation of the subthalamic nucleus (STN-DBS) is the most common surgical treatment for Parkinson's disease (PD). Patient selection and genetic background can modify the response to this treatment. The objective of this study was to compare both clinical and pharmacologic response of STN-DBS between patients with monogenic forms of PD and non-mutation carriers with idiopathic PD. MethodsA retrospective analysis among 23 carriers of genetic mutations (8 PRKN and 15 LRRK2) and 74 patients with idiopathic PD was performed. The study included comparisons of Unified Parkinson's Disease Rating Scale (UPDRS) II and III scores, Schwab and England (S&E) scale values, Hoehn & Yahr (H&Y) stage scores, and equivalent doses of levodopa before and after the surgery (at 6 and 12 months) between both groups. ResultsThe mean age at the time in which STN-DBS was performed was 59.5 ± 8.6. Linear mixed models showed the absence of statistically significant differences between mutation and non-mutation carriers regarding levodopa doses (p = 0.576), UPDRS II (p = 0.956) and III (p = 0.512) scores, and S&E scale scores (0.758). The only difference between the two groups was observed with respect to H&Y stage in OFF medication/ON stimulation status being lower in genetic PD at 6 months after surgery (p = 0.030). ConclusionClinical and pharmacological benefit of bilateral STN-DBS is similar in PRKN and LRRK2 mutation carriers and patients with idiopathic PD.

Prognostic factors of unilateral prelemniscal radiations radiofrequency lesions: A surgical technique for the treatment of Parkinson’s disease motor symptoms

ObjectiveA group of patients with Parkinson's disease (PD) were managed with unilateral prelemniscal radiation radiofrequency lesions (U-Raprl). The current study aims to evaluate prognostic factors that could influence clinical response. MethodsPatients previously diagnosed with PD managed with U-Raprl were included in the study, classifying them into two groups according to their percentage of clinical response (</≥ 50%) at 5 years of follow-up in relation to the part III of the Unified Parkinson's Disease Rating Scale (UPDRS-III), analyzing the possible factors associated with their response (age, evolution of PD, Hoehn and Yahr scale (HYS), and levodopa dose). To show differences between groups before and after the intervention, a T-test was performed, and a Mann-Whitney U test was carried out to determine differences between the response groups, added to an effect size calculation using a Cohen's d (α = 0.05, and β = 0.20). ResultsThirty-four patients were included, where the most prevalent symptoms were tremor and rigidity, with 52.9% percentage of males, 59.3 ± 6.4 mean age, and 7.4 ± 2.1 of mean evolution of PD. Analysis shows differences between groups (p < 0.05) according to the HYS, UPDRS, and levodopa intake, after the intervention. The analysis of the groups according to their response showed differences between the HYS (p < 0.01, ∆ > 1.5), Age (p < 0.0001, ∆ = 2.38), Evolution (p < 0.0001, ∆ = 2.38), and post-operative UPDRS (p < 0.01, ∆ = 1.38). The qualitative analysis of the distribution regarding the responder group shows that those patients with an age under 58 years, an evolution fewer than 7 years, and a preoperative HYS score smaller than 2, showed a response ≥ 50% according to the UPDRS-III in all cases. ConclusionU-Raprl is a highly effective procedure with a 5-year persistence of improvement. The most relevant prognostic factors to consider for a clinical response according to UPDRS-III greater than 50% are age under 58 years, less than 7 years of PD evolution, and HYS less or equal to 3.

Levodopa responsive gait dynamics in OFF- and ONOFF-state freezing of gait in Parkinson’s disease

BackgroundIn people with Parkinson’s disease (PwPD), Freezing of Gait (FOG) episodes can be levodopa responsive (OFF-FOG) or levodopa unresponsive (ONOFF-FOG). Steady-state gait abnormalities, outside of the freezing episodes themselves also exist and the response to levodopa in these different groups has not been previously documented. ObjectivesTo define the levodopa responsiveness in steady-state gait in OFF-FOG and ONOFF-FOG individuals. MethodsSteady-state gait was collected in both the effective levodopa OFF-state (doses withheld > 8 h) and ON-state (1 h after levodopa dosing) in 32 PwPD; 10 with OFF-FOG and 22 with ONOFF-FOG. Levodopa response was compared between the two groups in the mean and variability (CV) of 8 spatiotemporal gait parameters. ResultsBoth OFF-FOG and ONOFF-FOG participants showed improvement in mean stride-length and stride-velocity with levodopa. Improvement was seen in the OFF-FOG but not the ONOFF-FOG groups in mean stride-width and CV Integrated pressure with levodopa. DiscussionIn this study we show that steady-state gait deficits improve with levodopa in PwPD with OFF-FOG and ONOFF-FOG, even though episodes of FOG did not resolve in the ONOFF-FOG group. Lowering levodopa in people with ONOFF-FOG, or levodopa-unresponsive freezing of gait, should be undertake with caution and objective gait titration at different levodopa doses may be beneficial. Further work is needed to elucidate the pathophysiologic mechanisms of these differences.

Motor and autonomic disorders influence on pain syndrome of patients with Parkinson’s disease of the I—III H&amp;Y stages

To evaluate the influence of motor and autonomic disorders on the pain of patients with PD of the I-III H&Y stages and possibility of correcting the pain with dopamine receptor agonists (ADR). 252 patients (128 women and 124 men, 42-80 years old) with PD of I-III Hoehn and Yahr stages (H&Y) were examined using the following scales: UPDRS, daily activity Sch&En, quality of life PDQ-39, MMSE, BDI, PFS-16, NMSQuest, GSRS, AUA; 53 patients were piribedil treated during 6 months. Our results indicated a wide prevalence of pain syndrome in PD patients (58.6%), starting from the early stages (50% for the Ist stage). The most stable pain associations were found with the PD stage, levodopa doses, severity of motor symptoms (postural disorders and hypokinesia manifestations) and motor complications («off-periods» and dyskinesias), as well as non-motor PD manifestations depression and autonomic dysfunctions (constipation, swallowing disorders, and frequent urination). The regression analysis showed, that the severity of motor complications and depression were the predictors of pain occurrence. The pain syndrome in patients with PD of I-III stages underwent significant regression (by 51% and 62%, after 1.5 and 6 months of therapy, respectively) after ADR (piribedil) addition to their therapy; it's probably due to improving the motor component and decreasing depressive disorders. The piribedil inclusion contributes to the reduction of pain syndrome, regardless is it used in monotherapy or in conjunction with levodopa preparations.

Effectiveness and safety of safinamide in the Toledo Movement Disorders Unit.

The management of motor fluctuations in Parkinson's disease (PD) can be challenging, and current therapeutic options include the use of monoamine oxidase B inhibitors (MAO-B inhibitors), among others. The aim of this study was to evaluate the effectiveness and safety of safinamide in the clinical practice carried out in the Toledo Movement Disorders Unit. This is a retrospective study in which data were collected at baseline and at six months from PD patients who were started on safinamide as an add-on therapy with a stable dose of levodopa in line with standard clinical practice. An analysis was performed by subgroups: patients who were given low-dose safinamide and patients who previously received rasagiline. Ninety patients (47 previously received rasagiline) completed the six-month follow-up. A statistically significant decrease in morning akinesia, nocturnal akinesia, wearing off, unpredictable off phenomenon and Unified Parkinson's Disease Rating Scale-III was observed both in those who previously received rasagiline and in those treated with low doses of safinamide. No variation was found in the dyskinesias. The adverse events described were mild, with generalised weakness, dizziness, nausea, headache and alopecia. Safinamide has been shown to be effective and safe in improving motor fluctuations, motor symptoms and the subjective perception of disease severity in PD patients previously receiving rasagiline and in those receiving low-dose safinamide, all of which is accompanied by a good safety profile.

A “new” role of amantadines in COVID-19 in patients with Parkinson’s disease: results of own comparative study

Amantadine has begun to be used as a possible alternative in COVID-19 therapy to mitigate its effects. There is anecdotal evidence that patients with Parkinson's disease (PD) treated with amantadine and who test positive for COVID-19 often do not develop clinical manifestations of COVID-19. Objective : to compare the clinical course of COVID-19 in patients with PD who took or did not take amantadine sulfate. Patients and methods . A prospective continuous study included 142 patients with PD who were treated in Republican Clinical Diagnostic Center for Extrapyramidal Pathology and Botulinum Therapy in Kazan from October 2021 to January 2022. Patients filled out a proprietary internally developed questionnaire. Results and discussion . Out of 142 individuals with PD COVID-19 occurred in 77 (54.2%), of which 52.0% had a mild course, 39.0% had a moderate course, 2.6% had a severe course, and in 6.5% the severity of the disease has not been established. Deterioration after COVID-19 infection was noted by 36% of patients: the appearance or increase in motor fluctuations (41%), increased tremor, stiffness or slowness (31%), the appearance of "exhaustion" of the effect of a single dose of levodopa (13%), the appearance or increased dyskinesia (21%), hallucinations (3.5%). Patients taking amantadine sulfate had PD much longer (11.5±5.62 years versus 5.12±3.24 years) and had a more pronounced (III–IV) stage of the disease. These patients were more likely to experience mild COVID-19 (in 60.87% of cases), in contrast to patients not receiving amantadine sulfate (only in 48.15% of cases). There was no correlation between the severity of COVID-19 and levodopa intake. Conclusion . The results of the study showed that patients with PD taking amantadine sulfate are more likely to have a mild course of COVID-19.

Sex Is the Main Determinant of Levodopa Clinical Pharmacokinetics: Evidence from a Large Series of Levodopa Therapeutic Monitoring.

Different studies, mostly with limited cohorts, have suggested the effects of patients' characteristics on levodopa (LD) pharmacokinetics. We primarily aimed at investigating in a large population the relationship between patients' features and LD kinetic variables, to assess the main demographic and clinical predictors of LD clinical pharmacokinetics. The study was retrospective, based on data collected from subjects with parkinsonism on chronic LD undergoing LD therapeutic monitoring (TM). LD TM includes serial quantitative motor tests and blood samples to measure plasma drug concentrations after each subject's chronically taken first-morning LD dose intake. Five hundred patients, 308 males (61.6%), mean (SD) age of 65 (10.1) years were included. Parkinsonian symptoms and LD therapy lasted 5.5 (4.5) and 3.4 (3.9) years, respectively. MDS-UPDRS part III "off" score was 28.8 (15.2). LD dose was 348.2 (187.1) mg/day. From multiple linear regression analysis, test dose, sex, type of LD decarboxylase inhibitor, weight and MDS-UPDRS part III score were linear predictors of both LD peak plasma concentration (Cmax) (R2 = 0.52) and area under the 3-h plasma concentration-time curve (AUC) (R2 = 0.71), while age was a further predictor only for AUC. Besides test dose, sex was the strongest independent contributing variable to LD AUC, which resulted 27% higher in females compared to males. This is the largest collection of data on the relationship between demographic and clinical-therapeutic variables and LD kinetics in patients with parkinsonian symptoms. As a main clinically practical finding, women might require a 25% reduced weight-normalized LD dose compared with men to achieve the same LD bioavailability.

Use of 99mTc-Trodat-1 SPECT to evaluate the efficacy of deep brain stimulation in Parkinson's disease.

This study aimed to explore the availability of striatal dopamine transporter (DAT) after deep brain stimulation (DBS) by single photon emission computed tomography (SPECT) using technetium-99m-labeled tropane derivative (99mTc-Trodat-1). In this cohort, 28 patients with PD were enrolled (including 18 males and 10 females). Among these patients, the age range was 55-75 years. All patients referred for optimized DBS programming were recruited for 99mTc-Trodat-1 imaging and symptom assessment. Dopamine transporter SPECT was performed under medication-off state before DBS and at the 6th month after DBS, respectively. The clinical scales including Unified Parkinson Disease Rating Scale (UPDRS), Modified Hoehn & Yahr Scale (MHYS) and Ability of Daily Life Scale (ADLS) were carried out before DBS and at 6 months after DBS under medication-on and medication-off, respectively. Dopamine transporter availability was assessed based on DAT SPECT. In addition, the correlation between DAT availability and clinical scales was investigated. The data were analyzed using SPSS 23.0. The mean UPDRS total, MHYS and ADLS scores were 62.36, 2.23 and 42.07 under medication-on, respectively. The medication improvement rate of UPDRS total, MHYS and ADLS scores were 27.55%, 21.88% and 54.19%, respectively. Interestingly, we found PD patients with MHYS grade I usually presented unilateral symptoms, but DAT imaging showed that DAT uptake of the bilateral striatum was lower than that of the normal and the S-value of the contralateral side was significantly lower than that of the ipsilateral side. Furthermore, we found that DBS can improve the laterality of symptoms. The DBS improvement rate of UPDRS total scores, ADLS scores and DAT S-value were 37.65%, 72.51% and 18.21%, respectively. The symptom laterality was significantly correlated with the DAT S-value at baseline and at 6 months after DBS (r=0.63, 0.69 and 0.66, 0.75). The dosage of levodopa was 696.43±146.52 and was 455.36±107.44 before DBS surgery and at DBS-on, respectively. Deep brain stimulation can significantly improve the symptom of PD. Dopamine transporter S-value was well correlated with the change of symptoms laterality. Therefore, DAT imaging can be used to diagnose PD in the early stage and to evaluate the curative effect of DBS. However, the validation of this result requires further study.

Neurotensin-Binding Immunoglobulin G in Patients with Parkinson’s Disease

Introduction: Neurotensin (NTS) is a 13-amino acid neuropeptide functionally linked with the brain dopaminergic system via expression of the NTS peptide or its receptor in dopamine neurons. Neuropeptide-binding immunoglobulins (Igs) are present in humans and can be involved in both physiological and pathological processes. Considering the functional link between NTS and dopamine neurons, we studied the occurrence of NTS-binding IgG autoantibodies in patients with Parkinson’s disease (PD). Methods: Plasma levels of NTS-binding IgG were analyzed using enzyme-linked immunosorbent assay in both male and female PD patents and in age-matched healthy controls. Possible microbial origin of NTS cross-reactive IgG was analyzed by sequence alignment of the 6-amino acid C-terminal NTS pharmacophore with bacterial and viral proteins from the public NCBI database. Results: NTS-binding IgG were detected in the plasma of all study subjects, while their levels were consistently lower in PD patients versus controls (p = 0.0001), independently from age or sex of the study participants. Moreover, PD patients with a more severe stage (2.5–3.0) of the disease had lower levels of NTS-binding IgG (p = 0.0004) than those with a milder stage (1.0–2.0). Furthermore, PD patients taking amantadine or high doses of levodopa had higher levels of NTS-binding IgG than those without medication. Contiguous sequence homology for the NTS pharmacophore was present in several microbial proteins occurring in human gut microbiota. Discussion: The study revealed that NTS-binding IgG occur naturally in humans and that PD patients display their low plasma levels accentuated by disease severity. The functional significance of this finding and its relevance to the pathophysiology of PD, including putative link to gut microbiota, remain to be studied.

Tailoring Motor Fluctuation Treatment: Beyond Levodopa Dose Adjustment

Susan Fox opened this satellite symposium at the 8th European Academy of Neurology (EAN) Congress with an overview of the concept of motor fluctuations (MF) in Parkinson’s disease (PD). She emphasised that levodopa remains the gold standard therapy for PD. However, MFs are one of the critical complications of levodopa therapy that affect many patients with advancing PD and, when diagnosed, represent a challenge in patient management. Alternative options are, therefore, needed to provide continuous dopaminergic stimulation while maximising the levodopa benefit. Despite different options, Angelo Antonini showed that neurologists often prefer to adjust levodopa dose rather than add an adjunctive agent. Market research confirms that, in patients with PD, the levodopa dose is adjusted in around 80% of patients, while only 20% have adjunct therapy as a first-line option. Adjusting the levodopa dose, either by increasing or fractionating the dose, or both, remains a valid, tried-and-tested option, although it has limitations. Joaquim Ferreira presented emerging evidence from a Phase II clinical trial, suggesting a potential benefit of adding opicapone 50 mg compared with 100 mg levodopa to treat patients with PD and end-of-dose fluctuations. This symposium aimed to present the effect of opicapone with relatively low total daily doses of levodopa; an option that may not have been traditionally considered by neurologists who are used to adjusting levodopa as a first-line response.

Effect of Surface Charge Density of a w/o/w Emulsion on the Brain Targeting of Levodopa in Rats for the Treatment of Parkinson’s Disease

Background: Amidst levodopa being considered as the “Gold standard” in the treatment of Parkinson’s disease (PD), it still has critical therapeutic issues with its dose regimen and dosage forms leading to severe adverse drug effects, decreased drug efficacy during chronic use, and requires an enforced “drug holiday” in PD patients. Hence, in this study, we designed a novel levodopa and carbidopa water-in-oil-in-water (w/o/w) formulation for bioavailability improvement in the central nervous system (CNS). Methods: The new one-in-one embedment of the w/o/w levodopa and carbidopa emulsion formulation was obtained by a double emulsion technique. The plasma and brain levels following intravenous administration of the emulsions in rats were determined. Results: The incorporation of stearylamine (a cationic surfactant) considerably increased the surface charge density of the emulsion droplets. This formulation exhibited a narrow particle size distribution enabling parenteral administration. The formulation also provided a high drug loading capacity. In in vivo study, this novel formulation significantly increased the bioavailability of levodopa in the CNS (P &lt; 0.001). The strong resistance to desorption (due to higher charge density) and the presence of positive charge on the particles upon dilution may be the main reason for enhanced brain levels of levodopa. Conclusion: Our current formulation F5 may decrease the dose of levodopa, leading to decreased adverse effects and dosing problems, thus appreciably benefit PD patients in the future.

The Importance of Early Identification for Parkinson's Disease Patients with Postural Instability and Gait Disturbance.

More and more evidence-based medicine has proved that Parkinson's disease (PD) patients of tremor-dominant (TD) and postural instability and gait difficulty (PIGD) subtype express great individual differences and heterogeneity. Early identification of different subtypes may be an important way to delay disease progression and improve patients' prognosis. The study aimed to compare the spectrum of motor symptoms (MS) and nonmotor symptoms (NMS) between TD and PIGD dominant in the early and middle stages of PD, and determine predictive factors that are associated with different motor subtypes. 292 PD patients in this study were divided into TD-PD and PIGD-PD, and the clinical characteristics between different motor subtypes were compared based on scales related to sleep, mood, and autonomic function. Univariate and multivariate ordered logistic regression analyses were used to analyze the independent influencing factors of disease severity between different motor subtypes. Through the establishment of binary logistic regression model, the potential independent risk factors for distinguishing TD-PD and PIGD-PD were studied. Compared with TD subtype, patients with PIGD subtype have longer course of disease, higher disease severity, and higher daily dosage of levodopa. The severity of nontremor motor symptoms in PIGD-PD is greater than that of TD subtype. Only PIGD score was independently associated with disease severity for the two motor subtypes. Meanwhile, high scores (LED, total UPDRS, PIGD score, gastrointestinal, thermoregulatory, RBDSQ) and low tremor scores were the potential independent risk factors for distinguishing PIGD-PD from TD-PD. Specific nonmotor symptoms (RBD, gastrointestinal function and thermoregulation function) were associated with the PIGD subtype. Prompt detection and early treatment of NMSs related to the PIGD subtype based on the treatment of motor symptoms may improve patient outcomes.

Exploring the effects of dopamine on sensorimotor inhibition and mobility in older adults.

Dopaminergic activity decreases in older adults (OAs) with normal aging and is further reduced in Parkinson's disease (PD), affecting cortical motor and sensorimotor pathways. Levodopa is the prevailing therapy to counter dopamine loss in PD, though not all PD motor signs improve with levodopa. The purpose of this preliminary study was to explore the effects of levodopa on sensorimotor inhibition, gait and quiet standing in OAs and to investigate the relationships between sensorimotor inhibition and both gait and standing balance both OFF- and ON-levodopa. Fifteen OA males completed a gait, balance and sensorimotor assessments before and 1 h after they were given a 100mg dose of levodopa. Short-latency afferent inhibition quantified sensorimotor inhibition. Wearable sensors characterized gait (two-minute walk) and standing balance (1-min stance). No sensorimotor inhibition, gait, or standing balance measures changed from OFF- to ON-levodopa. When OFF-levodopa, worse inhibition significantly related to increased double stance (r = 0.62; p = 0.01), increased jerkiness of sway (r = 0.57; p = 0.03) and sway area (r = 0.58; p = 0.02). While ON-levodopa, worse inhibition related to increased arm swing range of motion (r = 0.63; p = 0.01) and jerkiness of sway (r = 0.53; p = 0.04). The relationship between SAI and arm swing excursion significantly changed from OFF- to ON-levodopa (z = - 3.05; p = 0.002; 95% confidence interval = - 0.95, - 0.21). Sensorimotor inhibition relationships to both gait and balance may be affected by dopamine in OAs. Cortical restructuring due to the loss of dopamine may be responsible for the heterogeneity of levodopa effect in people with PD and OAs.

Deep Brain Stimulation–Withdrawal Syndrome in Parkinson’s Disease: Risk Factors and Pathophysiological Hypotheses of a Life-Threatening Emergency

Background and ObjectivesSubthalamic nucleus deep brain stimulation (DBS) is the most common therapeutic surgical procedure for patients with Parkinson’s disease with motor fluctuations, dyskinesia, or tremor. Routine follow-up of patients allows clinicians to anticipate replacement of the DBS battery reaching the end of its life. Patients who experience a sudden stop of the DBS battery experience a rapid worsening of symptoms unresponsive to high dose of levodopa, in a life-threatening phenomenon called “DBS-withdrawal syndrome.” In the current context of the COVID-19 pandemic, in which many surgeries are being deprogrammed, it is of utmost importance to determine to what extent DBS battery replacement surgeries should be considered an emergency. In this study, we attempt to identify risk factors of DBS-withdrawal syndrome and provide new insights about pathophysiological hypotheses. We then elaborate on the optimal approach to avoid and manage such a situation. Materials and MethodsWe conducted a systematic review of the literature on the subject and reported the cases of 20 patients (including five from our experience) with DBS-withdrawal syndrome, comparing them with 15 undisturbed patients (including three from our experience), all having undergone neurostimulation discontinuation. ResultsA long disease duration at battery removal and many years of DBS therapy are the main potential identified risk factors (p < 0.005). In addition, a trend for older age at the event and higher Unified Parkinson’s Disease Rating Scale motor score before initial DBS implantation (evaluated in OFF-drug condition) was found (p < 0.05). We discuss several hypotheses that might explain this phenomenon, including discontinued functioning of the thalamic-basal ganglia loop due to DBS-stimulation cessation in a context in which cortical-basal ganglia loop had lost its cortical input, and possible onset of a severe bradykinesia through the simultaneous occurrence of an alpha and high-beta synchronized state. ConclusionsThe patients’ clinical condition may deteriorate rapidly, be unresponsive to high dose of levodopa, and become life-threatening. Hospitalization is suggested for clinical monitoring. In the context of the current COVID-19 pandemic, it is important to widely communicate the replacement of DBS batteries reaching the end of their life. More importantly, in cases in which the battery has stopped, there should be no delay in performing replacement as an emergent surgery.