The Growing Role of Telerehabilitation and Teleassessment in the Management of Movement Disorders in Rare Neurological Diseases: A Scoping Review.

Background: People with rare neurological diseases (RNDs) often experience symptoms related to movement disorders, requiring a multidisciplinary approach, including rehabilitation. Telemedicine applied to rehabilitation and symptom monitoring may be suitable to ensure treatment consistency and personalized intervention. The objective of this scoping review aimed to emphasize the potential role of telerehabilitation and teleassessment in managing movement disorders within RNDs. By providing a systematic overview of the available literature, we sought to highlight potential interventions, outcomes, and critical issues. Methods: A literature search was conducted on PubMed, Google Scholar, IEEE, and Scopus up to March 2024. Two inclusion criteria were followed: (1) papers focusing on telerehabilitation and teleassessment and (2) papers dealing with movement disorders in RNDs. Results: Eighteen papers fulfilled the inclusion criteria. The main interventions were home-based software and training programs, exergames, wearable sensors, smartphone applications, virtual reality and digital music players for telerehabilitation; wearable sensors, mobile applications, and patient home video for teleassessment. Key findings revealed positive outcomes in gait, balance, limb disability, and in remote monitoring. Limitations include small sample sizes, short intervention durations, and the lack of standardized protocols. Conclusion: This review highlighted the potential of telerehabilitation and teleassessment in addressing movement disorders within RNDs. Data indicate that these modalities may play a major role in supporting conventional programs. Addressing limitations through multicenter studies, longer-term follow-ups, and standardized protocols is essential. These measures are essential for improving remote rehabilitation and assessment, contributing to an improved quality of life for people with RNDs.

A method for the synchronization of inertial sensor signals and local field potentials from deep brain stimulation systems.

OBJECTIVE: Recent innovative neurostimulators allow recording local field potentials (LFPs) while performing motor tasks monitored by wearable sensors. Inertial sensors can provide quantitative measures of motor impairment in people with subthalamic nucleus deep brain stimulation. To the best of our knowledge, there is no validated method to synchronize inertial sensors and neurostimulators without an additional device. This study aims to define a new synchronization method to analyze disease-related brain activity patterns during specific motor tasks and evaluate how LFPs are affected by stimulation and medication. Approach: Twelve male subjects treated with subthalamic nucleus deep brain stimulation were recruited to perform motor tasks in four different medication and stimulation conditions. In each condition, a synchronization protocol was performed consisting of taps on the implanted device, which produces artifacts in the LFPs that an inertial sensor can simultaneously record. Main results: In 64% of the recruited subjects, induced artifacts were detected at least once. Among those subjects, 83% of the recordings could be correctly synchronized offline. The remaining recordings were synchronized by video analysis. Significance: The proposed synchronization method does not require an external system and can be easily integrated into clinical practice. The procedure is simple and can be carried out in a short time. A proper and simple synchronization will also be useful to analyze subthalamic neural activity in the presence of specific events (e.g., freezing of gait events) to identify predictive biomarkers. .

Case report: Bilateral double beta peak activity is influenced by stimulation, levodopa concentrations, and motor tasks, in a Parkinson's disease patient on chronic deep brain stimulation.

Introduction: Subthalamic (STN) local field potentials (LFPs) in the beta band are considered potential biomarkers for closed-loop deep brain stimulation (DBS) in Parkinson's disease (PD). The beta band is further dissected into low-and high-frequency components with somewhat different functions, although their concomitance and association in the single patient is far to be defined. We present a 56-year-old male PD patient undergoing DBS showing a double-beta peak activity on both sides. The aim of the study was to investigate how low-and high-beta peaks were influenced by plasma levodopa (L-dopa) levels, stimulation, and motor performances. Methods: A systematic evaluation of raw LFPs, plasma L-dopa levels, and motor tasks was performed in the following four conditions: OFF medications/ON stimulation, OFF medications/OFF stimulation, ON medications/OFF stimulation, and ON medications/ON stimulation. Results: The analysis of the LFP spectra suggests the following results: (1) the high-beta peak was suppressed by stimulation, while the low-beta peak showed a partial and not consistent response to stimulation; (2) the high-beta peak is also influenced by plasma L-dopa concentration, showing a progressive amplitude increment concordant with plasma L-dopa levels, while the low-beta peak shows a different behavir; and (3) motor performances seem to impact beta peaks behavior. Conclusion: This single exploratory case study illustrates a complex behavior of low-and high-beta peaks in a PD patient, in response to stimulation, L-dopa plasma levels, and motor performances. Our results suggest the importance to investigate patient-specific individual LFP patterns in view of upcoming closed-loop stimulation.

Screening for impulse control disorders in Parkinson's disease and dopamine agonist use: a study of pharmacokinetic and psychological risk factors.

INTRODUCTION: Dopamine agonist (DA) use is considered the main risk factor for impulse control disorder (ICD) development in Parkinson's disease (PD). Besides DAs, personality traits and cognitive features may represent risk factors for ICDs. The primary aim of this study was to investigate differences in DA plasma concentrations in PD patients with and without a positive screening for ICDs according to validated tools. The secondary aim was to compare the psychological profile between ICD positive and negative screened patients. METHODS: PD patients receiving chronic DA therapy were screened for ICDs according to the Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease (QUIP). Blood samples for measurement of DA (pramipexole, ropinirole, rotigotine) trough plasma concentrations were drawn in the morning, at mean 16-19 h from the last DA dose. Patients' psychological profile was investigated by Millon Clinical Multiaxal Inventory III and Barratt Impulsiveness Scale (BIS-11). RESULTS: One hundred and five PD patients were enrolled. Forty-one patients (39%) were QUIP positive, mainly for binge eating and hobbyism. Median plasma concentrations of pramipexole (n = 71, 66%), ropinirole (n = 21, 19%), and rotigotine (n = 16, 15%) were similar between QUIP positive and negative patients. QUIP positive patients showed higher motor impulsiveness (p = 0.04) and tended to higher total impulsiveness (p = 0.05). CONCLUSION: This is the first prospective study to evaluate the relationship between DA plasma concentrations and ICDs risk in PD patients. DA plasma levels were overlapping between QUIP positive and negative patients. BIS-11, particularly the motor impulsiveness subscale, might be a useful screening tool in PD patients eligible for DA therapy.

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

BACKGROUND: Different studies, mostly with limited cohorts, have suggested the effects of patients' characteristics on levodopa (LD) pharmacokinetics. OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

User-Centered Design Methodologies for the Prototype Development of a Smart Harness and Related System to Provide Haptic Cues to Persons with Parkinson's Disease.

This paper describes the second part of the PASSO (Parkinson smart sensory cues for older users) project, which designs and tests an innovative haptic biofeedback system based on a wireless body sensor network using a smartphone and different smartwatches specifically designed to rehabilitate postural disturbances in persons with Parkinson's disease. According to the scientific literature on the use of smart devices to transmit sensory cues, vibrotactile feedback (particularly on the trunk) seems promising for improving people's gait and posture performance; they have been used in different environments and are well accepted by users. In the PASSO project, we designed and developed a wearable device and a related system to transmit vibrations to a person's body to improve posture and combat impairments like Pisa syndrome and camptocormia. Specifically, this paper describes the methodologies and strategies used to design, develop, and test wearable prototypes and the mHealth system. The results allowed a multidisciplinary comparison among the solutions, which led to prototypes with a high degree of usability, wearability, accessibility, and effectiveness. This mHealth system is now being used in pilot trials with subjects with Parkinson's disease to verify its feasibility among patients.

Cannabis-Based Products in a Neurological Setting: A Clinical and Pharmacokinetic Survey.

Background and Aim: Limited data are available in clinical settings on the pharmacokinetics of delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). We investigated the use of cannabis-based products in neurological practice, monitoring patients' steady-state cannabinoids (CBs) plasma concentrations matched with different preparations. Methods: This was a prospective, single-center, observational study. Patients underwent venous blood withdrawal before the CBs' morning dose and then 2.5 h post-dosing. Spasticity or pain were patient self-assessed by the Numeric Rating Scale (NRS) before the morning CB's administration and 2.5 h post-dosing. Results: Thirty-three patients were enrolled. Main indications for CBs were spasticity and chronic pain. Sixteen patients were treated with oromucosal spray formulation Sativex® and 17 with oil-based solutions. Both CBs trough plasma concentrations were ≤ limit of detection (0.1 ng/ml) in 45% of patients. Intrasubject CB's plasma levels significantly increased over baseline values in patients treated with Bediol® oil (p < 0.05) and Sativex® (p < 0.01). Post-dosing CB's bioavailability did not significantly differ between oral oil and oromucosal spray. NRS scores decreased (p < 0.01), matching the increase (p < 0.01) in CB's plasma concentrations. Conclusion: This is the first study investigating CB's plasma concentrations of oral and oromucosal preparations in real-world neurological practice. Findings of similar bioavailability for both CBD and THC after galenic oil compared with oromucosal spray dosing may be clinically relevant and deserve additional research in larger cohorts.

Quantitative Assessment of Motor Response to a Low Subacute Levodopa Dose in the Differential Diagnosis of Parkinsonisms at Disease Onset: Data from the BoProPark Cohort.

BACKGROUND: Differential diagnosis between Parkinson's disease (PD) and atypical parkinsonisms (APs) may be difficult at disease onset. The response to levodopa (LD) is a key supportive feature but its definition is largely empirical. Studies evaluating this issue by quantitative tests are scanty. OBJECTIVE: We aimed to assess the utility of a subacute low LD dose kinetic-dynamic test in the differential diagnosis between PD and APs. It was applied at the baseline of a prospective follow-up in patients with parkinsonian signs within three years of disease motor onset ("BoProPark" cohort) and eventually diagnosed as PD or APs according to consensus criteria. METHODS: Patients under at least 3-month LD therapy received a first morning fasting dose of LD/benserazide or carbidopa (100/25 mg) and underwent simultaneous serial assessments of plasma LD concentration and alternate finger tapping frequency up to 3 h. The main outcome was the extent of LD motor response, calculated by the area under the 3 h tapping effect-time curve (AUC_ETap). A receiver operating characteristic (ROC) curve analysis was performed to establish the optimal AUC_ETap cut-off to differentiate PD and APs. RESULTS: The first 100 consecutive "BoProPark" patients were analyzed. Forty-seven patients were classified as possible, 37 as probable PD and 16 as APs. AUC_ETap medians were similar in the PD subgroups but reduced to a third in APs (p < 0.001). The optimal AUC_ETap cut-off value was >2186 [(tap/min) x min], with a sensitivity of 92% and a specificity of 75%. Accuracy of the test was 0.85 (95% CI 0.74-0.95), p < 0.0001. CONCLUSION: The estimation of 3 h AUC_ETap after a subacute low LD dose proved a reliable, objective tool to assess LD motor response in our cohort of patients. AUC_ETap value rounded to ≥2200 supports PD diagnosis, while lower values may alert to AP diagnoses.

Mathematical modeling and parameter estimation of levodopa motor response in patients with parkinson disease.

Parkinson disease (PD) is characterized by a clear beneficial motor response to levodopa (LD) treatment. However, with disease progression and longer LD exposure, drug-related motor fluctuations usually occur. Recognition of the individual relationship between LD concentration and its effect may be difficult, due to the complexity and variability of the mechanisms involved. This work proposes an innovative procedure for the automatic estimation of LD pharmacokinetics and pharmacodynamics parameters, by a biologically-inspired mathematical model. An original issue, compared with previous similar studies, is that the model comprises not only a compartmental description of LD pharmacokinetics in plasma and its effect on the striatal neurons, but also a neurocomputational model of basal ganglia action selection. Parameter estimation was achieved on 26 patients (13 with stable and 13 with fluctuating LD response) to mimic plasma LD concentration and alternate finger tapping frequency along four hours after LD administration, automatically minimizing a cost function of the difference between simulated and clinical data points. Results show that individual data can be satisfactorily simulated in all patients and that significant differences exist in the estimated parameters between the two groups. Specifically, the drug removal rate from the effect compartment, and the Hill coefficient of the concentration-effect relationship were significantly higher in the fluctuating than in the stable group. The model, with individualized parameters, may be used to reach a deeper comprehension of the PD mechanisms, mimic the effect of medication, and, based on the predicted neural responses, plan the correct management and design innovative therapeutic procedures.

Clinical pharmacokinetics of pramipexole, ropinirole and rotigotine in patients with Parkinson's disease.

INTRODUCTION: Pramipexole (PRA), ropinirole (ROP) and rotigotine (ROT) are non-ergoline dopaminergic agonists (DAs) used to treat Parkinson's disease (PD). Clinical pharmacokinetics of DAs is poorly characterized in PD. The main purpose of our study was to investigate the effect of dose, age and sex on steady-state plasma concentrations of DAs in real life PD patients on chronic DAs therapy. METHODS: The study was single center, open and prospective. Blood samples for measurement of DAs plasma concentrations were drawn in the morning, at a median 18-h distance from the last DA dose. RESULTS: Ninety-one patients treated with PRA, 50 with ROP and 37 with ROT were enrolled in the study. Plasma concentration of DAs significantly correlated with weight-adjusted daily dose in all subgroups, although at a given dose, matched plasma concentrations highly varied among patients. Median PRA plasma concentration-to-daily dose ratio (C/D) [(ng/mL)/(mg/kg/d)] was 68% higher in patients >65 years than ≤65 years (158 vs 94, p < 0.001), while was not affected by age in ROP and ROT subgroups. No sex-mediated differences in C/D ratios were observed in any group. CONCLUSION: These are the first observations on DAs pharmacokinetics in PD patients' everyday clinical practice. Of relevance, patients over 65yrs may require about one third of PRA dose compared to under 65yrs to achieve the same plasma concentration. Due to the high intersubject variability in plasma concentrations at the same dosage, we speculate that monitoring of plasma DAs might be helpful in the individualization of treatment in selected patients.

Supervised versus unsupervised technology-based levodopa monitoring in Parkinson's disease: an intrasubject comparison.

We aimed to assess the intrasubject reproducibility of a technology-based levodopa (LD) therapeutic monitoring protocol administered in supervised versus unsupervised conditions in patients with Parkinson's disease (PD). The study design was pilot, intrasubject, single center, open and prospective. Twenty patients were recruited. Patients performed a standardized monitoring protocol instrumented by an ad hoc embedded platform after their usual first morning LD dose in two different randomized ambulatory sessions: one under a physician's supervision, the other self-administered. The protocol is made up of serial motor and non-motor tests, including alternate finger tapping, Timed Up and Go test, and measurement of blood pressure. Primary motor outcomes included comparisons of intrasubject LD subacute motor response patterns over the 3-h test in the two experimental conditions. Secondary outcomes were the number of intrasession serial test repetitions due to technical or handling errors and patients' satisfaction with the unsupervised LD monitoring protocol. Intrasubject LD motor response patterns were concordant between the two study sessions in all patients but one. Platform handling problems averaged 4% of total planned serial tests for both sessions. Ninety-five percent of patients were satisfied with the self-administered LD monitoring protocol. To our knowledge, this study is the first to explore the potential of unsupervised technology-based objective motor and non-motor tasks to monitor subacute LD dosing effects in PD patients. The results are promising for future telemedicine applications.

Pharmacodynamics of a low subacute levodopa dose helps distinguish between multiple system atrophy with predominant Parkinsonism and Parkinson's disease.

The differential diagnosis between multiple system atrophy with predominant parkinsonism (MSA-P) and Parkinson's disease (PD) may be challenging at disease onset. Levodopa responsiveness helps distinguish the two groups, but studies evaluating this issue using objective standardized tests are scanty. We retrospectively examined the extent of levodopa response by an objective kinetic-dynamic test in a series of patients prospectively followed up for a parkinsonian syndrome and eventually diagnosed as MSA-P or PD. Sixteen MSA-P and 31 PD patients under chronic levodopa therapy received a first morning fasting dose of levodopa/benserazide (100/25 mg) or levodopa/carbidopa (125/12.5 or 100/25 mg) and underwent simultaneous serial assessments of plasma levodopa concentration and alternate finger tapping frequency up to 3 h post dosing. The main levodopa pharmacodynamic variables were the maximum percentage increase in tapping frequency over baseline values (ΔTapmax %) and the area under the tapping effect-time curve (AUCTap). Levodopa pharmacokinetics did not show significant differences between MSA-P and PD, whereas both the magnitude and overall extent of levodopa tapping effect were markedly reduced in the MSA-P group (p < 0.001). The combined use of specific cut-off values for both the main pharmacodynamic variables, ΔTapmax % <20% and AUCTap <1900 [(tapping/min)·min], correctly discriminated 15 out of 16 MSA-P patients from PD patients. A combined estimation of these pharmacodynamic variables after a subacute low levodopa dose may be a simple and practical clinical tool to aid the differential diagnosis between MSA-P and PD.

Mucuna pruriens in Parkinson Disease: A Kinetic-Dynamic Comparison With Levodopa Standard Formulations.

OBJECTIVES: We compared levodopa (LD) kinetic-dynamic profile of a dose of LD/aromatic amino acid decarboxylase peripheral inhibitors versus a nominally equivalent dose of a commercial Mucuna pruriens (Mucuna) seeds extract in 2 patients with Parkinson disease chronically taking LD standard combined with self-prescribed Mucuna. METHODS: Patients were challenged with a fasting morning dose of 100 mg LD/25 mg carbidopa (patient 1) or benserazide (patient 2) versus 100 mg LD from Mucuna capsules in 2 different sessions, after a 12-hour standard LD formulations' washout. They underwent kinetic-dynamic LD monitoring based on LD dose intake and simultaneous serial assessments of plasma drug concentrations and motor test performances. Quantitative analysis of LD in Mucuna capsules was also performed. RESULTS: Levodopa bioavailability was markedly lower after Mucuna administration compared with LD standard formulations: in patient 1, peak plasma LD concentration (Cmax) decreased from 2.0 to 1.0 mg/L and the area under the plasma concentration time curve from 137 to 33.6 mg/L per minute; in patient 2, Cmax was 0.7 mg/L after LD/benserazide and nearly undetectable after Mucuna. In patient 1, impaired LD bioavailability from Mucuna resulted in reduced duration and overall extent of drug response compared with LD/carbidopa. In patient 2, no significant subacute LD motor response was observed in either condition. Quantitative analysis of Mucuna formulation confirmed the 100 mg LD content for the utilized capsules. CONCLUSIONS: Our results show an impaired LD bioavailability from Mucuna preparation, as expected by the lacking aromatic amino acid decarboxylase inhibitors coadministration, which might explain the suggested lower dyskinetic potential of Mucuna compared with standard LD formulations.

Dyskinesia detection and monitoring by a single sensor in patients with Parkinson's disease.

OBJECTIVE: In current clinical practice, assessment of levodopa-induced dyskinesias (LIDs) in Parkinson's disease (PD) is based on semiquantitative scales or patients' diaries. We aimed to assess the feasibility, clinical validity, and usability of a waist-worn inertial sensor for discriminating between LIDs and physiological sway in both supervised and unsupervised settings. METHODS: Forty-six PD patients on L-dopa therapy, 18 de novo PD patients, and 18 healthy controls were enrolled. Patients underwent clinical assessment of motor signs and dyskinesias and kinetic-dynamic L-dopa monitoring, tracked by serial measurements of plasma drug concentrations and motor and postural tests. RESULTS: A subset of features was selected, which showed excellent reliability. Sensitivity and specificity of the selected features for dyskinesia recognition were assessed in both supervised and unsupervised settings with an accuracy of 95% and 86%, respectively. CONCLUSIONS: Our preliminary findings suggest that it is feasible to design a reliable sensor-based application for dyskinesia monitoring at home.

Multiple system atrophy with prolonged survival: is late onset of dysautonomia the clue?

Multiple system atrophy (MSA) is a neurodegenerative disease characterised by cardiovascular autonomic failure and/or urinary dysfunctions, associated with parkinsonism, cerebellar and/or corticospinal signs, usually leading to death after an average of 7 years. We describe the disease course of five patients diagnosed with probable MSA (4 with predominant parkinsonism and 1 with predominant cerebellar ataxia) who survived for more than 15 years and were followed throughout the disease course at our department. Cardiovascular autonomic dysfunction of any severity occurred late (mean latency from disease onset 9.4 ± 5 years) in this subgroup of MSA patients. The time of involvement of the urogenital system was more variable (from 0 to 14 years after disease onset) and manifested with symptoms of storage disorders (urinary urgency, frequency and incontinence) and erectile dysfunction in men. Conversely complains suggestive of urinary voiding dysfunction (incomplete bladder emptying and urinary retention) were not recorded and patients required catheterization only late in the disease course. In conclusion, our study showed that late onset of both cardiovascular autonomic failure and urinary voiding disorders may be positive prognostic factors in MSA irrespective of the MSA subtype.

The effect of a clinically practical exercise on levodopa bioavailability and motor response in patients with Parkinson disease.

OBJECTIVE: The aim of the study was to investigate the potential effect of short, moderate intensity (≤70% maximum heart rate) cyclette exercise on levodopa (LD)/dopa decarboxylase inhibitor bioavailability and motor response in a subgroup of Parkinson disease (PD) patients presenting a moderate-to-severe delay in fasting morning LD dose absorption and matched motor response. METHODS: Ten patients underwent an oral LD instrumental kinetic-dynamic test based on simultaneous serial measurements of plasma LD concentrations, finger tapping motor effects, dyskinesia ratings plus Unified Parkinson Disease Rating Scale Motor Section (section III) evaluation after ingestion of their usual fasting first morning LD dose, on 2 occasions, 2 weeks apart, according to an intrasubject randomized cross-over design: once receiving their oral LD test dose immediately before a 15-minute cycling and once at seated rest. The main LD pharmacokinetic variables were time to peak, peak plasma concentration, and the area under the 4-hour plasma concentration-time curve. The main LD pharmacodynamic variables were the latency, duration of the motor effect elicited by the LD test dose, and the area under the 4-hour tapping effect-time curve. RESULTS: The LD pharmacokinetics and pharmacodynamics did not differ between the 2 sessions. CONCLUSIONS: We found no significant effect of a moderate, clinically practical exercise on LD rate and extent of absorption and matched motor response in a subgroup of patients with delayed LD kinetic-dynamic effect.