Telehealth in Neurodegenerative Diseases: Opportunities and Challenges for Patients and Physicians

Telehealth, by definition, is distributing health-related services while using electronic technologies. This narrative Review describes the technological health services (telemedicine and telemonitoring) for delivering care in neurodegenerative diseases, Alzheimer’s disease, Parkinson’s Disease, and amyotrophic lateral Sclerosis, among others. This paper aims to illustrate this approach’s primary experience and application, highlighting the strengths and weaknesses, with the goal of understanding which could be the most useful application for each one, in order to facilitate telehealth improvement and use in standard clinical practice. We also described the potential role of the COVID-19 pandemic to speed up this service’s use, avoiding a sudden interruption of medical care.


Introduction
Neurodegenerative diseases (NDDs) are a heterogeneous group of debilitating and incurable diseases that currently affect >30 million individuals worldwide with devastating consequences for patients and their families. NDDs are characterized by the progressive degeneration of the central nervous system's structure and function, either due to unknown causes with an idiopathic mechanism or, rarely, to a genetic disorder. NDDs include a large group of patients and they comprehend both common and uncommon diseases with Alzheimer's disease (AD), Parkinson's disease (PD), and Amyotrophic Lateral Sclerosis (ALS), among the most challenging [1]. The most evident risk factor for developing this condition is aging and, with the increase of the population average age, the prevalence of NDDs is remarkably increasing [2,3]. This increase leads to an enormous burden on healthcare systems and national economies, both in terms of direct and indirect costs [4][5][6][7].
Over disease progression, NDDs are characterized by a continuous decline of the motor and/or cognitive functions, which makes travel to the medical centers stressful and laborious for patients and caregivers. Besides, the lack of adequate transport, the residence in rural areas, and the limited economic funding can worsen the problem. Consequently, patient and clinician contact becomes highly troublesome in terms of care, monitoring, and intervention. Consequently, it is precisely in this scenario that a telehealth and telemedicine approach may be a useful tool for facing this challenge. By definition, telehealth is the distribution of health-related services using electronic technologies and, in this set, it can Table 1. Facets of telehealth.

Domain Definition
Telehealth General term to refer to technological health information services, health care education, and health care services

Telemedicine
The term telemedicine refers more specifically to education over a distance of health care services through telecommunications. Telemedicine refers to the use of information technologies and electronic communications to provide remote clinical services to patients (e.g., video consultations, evaluation of medical imaging) Telecoaching Telecoaching is coaching delivered over an electronic medium; in the health sector, it means the process of mentoring the use of devices and patient's management Telecare Telecare means a specific method to monitor fragile patients using of alarms, sensors, and other equipment, to help people live independently for a longer time. Telecare comprises assistive technologies and services tailored to individual needs. It monitors activity changes over time and can call for help in emergencies Despite a theoretical possibility for applying a telehealth approach in several domains, this service's use is still limited; however, steps have been taken during the recent COVID-19 pandemic, when the health service for chronic patients was suddenly interrupted. Indeed, except for visits with urgent characteristics, the out-patient follow-up visits have been immediately suspended, inevitably generating a sense of loss and abandonment due to the lack of dedicated medical and psychological support. In this context, the need to switch to alternatives types of care, including telemedicine and telehealth, is becoming mandatory in preventing a more significant functional decline.
This narrative review aims to analyze and discuss the primary experience and applications of this approach in the three most represented NDDs (AD, PD, ALS) in order to facilitate telehealth improvement and use in standard clinical practice, highlighting the strengths and weaknesses, with the goal of understanding which could be the most useful application for each one. The present review particularly emphasizes the management of telehealth resources before the COVID-19 outbreak, underlining how they changed with the ongoing pandemic emergency.

Alzheimer's Disease
Dementia represents one of the most frequent chronic disabling conditions in the elderly population. It has been estimated that, by 2050, approximately 152 million people will have dementia [9]. AD is the most common cause of dementia, followed by frontotemporal dementia (FTD), Lewy body dementia (LBD), and dementia after brain injuries (i.e., trauma, stroke). Besides the different molecular pathways involved, patients present with cognitive decline or behavioral changes that progress until their total dependence, which often does not have adequate formation and help. Furthermore, these patients often live in rural areas and have difficulties in reaching the leading centers to be in touched with their doctors and perform regular follow-up visits.
The validity of telemedicine for managing patients with dementia has already been investigated and applied. Notably, telemedicine confirmed its feasibility in monitoring patients' disease course (thanks to the administration of cognitive tests), allowing strict, though virtual, contact between patients and the clinicians. This aspect recently gained importance, since, due to the recent pandemic caused by the Sars-CoV-2, regular visits were interrupted, and telemedicine was confirmed as a good tool to monitor these pa-tients' clinical progression, as outlined above [10]. Using self-administered questionnaires, telemedicine has been generally evaluated as an accessible and useful tool by both patients and caregivers, who, in some cases, preferred to continue the clinical follow-up through this instrument. Notwithstanding the above, in some cases, telemedicine may represent a challenge, since not all patients own or can use informatics platforms or are not commonly accessible from the long-term care clinics where patients are often admitted when they are no more independent.
The use of telemedicine in dementia was investigated while considering several aspects, ranging from diagnosis to treatment. Firstly, several studies have evaluated the validity of cognitive tests, which are commonly used during face-to-face visits, when administered using video platforms. Mini Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA), which are commonly used in the clinical setting, but also more complete and complex tests analyzing several cognitive domains, also appeared to be valid when performed using a telemedicine interface [11]. Furthermore, Wadsworth and colleagues [12] demonstrated that commonly used cognitive tests, when performed through telemedicine, could distinguish between patients with and without dementia. Hwang K et al. [13] demonstrated that the virtual interpretation of tests score is also cheaper than the face-to-face one. It is mainly observed in their preliminary cost analysis, a saving of approximately 250,000 Australian Dollars per year (when considering a medium spare of seven dollars per session).
Together with cognitive problems, patients often have pathological behaviors and depression, which may represent one of the current symptoms or may complicate clinical management in the advanced phases. In recent work, Lindauer and colleagues [14] demonstrated that telemedicine platforms represent feasible tools for investigating cognitive domains and behavior and mood items in AD patients evaluated while using the revised memory and behavior problems checklist (RMBPC). Remarkably, the scores obtained using virtual platforms were superimposable to the face-to-face ones.
Another important aspect of dementia management is related to pharmacological treatment. Generally, clinicians decide whether to start or discontinue specific drugs according to clinical course and test scores. Cheong et al. [15] showed that patients followed with telemedicine had longer treatment compliance and, consequently, duration than patients followed in clinics (26.6 and 14.6 months). Furthermore, the authors showed that the use of telemedicine and low Clinical Dementia Rating scores in their rural cohort represented independent predictive factors of longer treatment duration. Several factors may be implied, such as the lower fees of virtual visits, the lack of local specialists, and the higher levels of care that is perceived by the patients.
Telemedicine may also be implied in patients' cognitive rehabilitation through virtual or augmented reality and serious games. Few studies are now available with positive results, even though the need for specialized figures and the platforms' high costs may limit the accessibility to these instruments.
Because dementia is an age-related condition, demented subjects often suffer from several comorbidities, requiring more clinical cures and it may lead patients to the emergency department (ED) for acute illness [16]. Telemedicine has been demonstrated as a useful tool in reducing access to the ED. Particularly, Gillespie et al. [17] demonstrated in a group of 201 patients with dementia reducing 24% of the access to ED. Of note, in this work, the authors focused on patients living in the senior living communities (SLC), thus underlying how these particularly fragile patients may benefit from telemedicine to get in touch with their specialists and have faster solutions to their health problems.
Caregivers play an indispensable role in the daily life of patients with dementia. Video platforms have also been used to follow caregivers' activities and address them in patients' long-term management. Williams et al. [18], as part of the FamTechCare project, randomly assigned caregivers to video platforms or phone call intervention. Both of the instruments were revealed to be useful and they were appreciated by caregivers, especially those living with mild-moderate demented patients, and the results were not related to age, gender, and relationship. The same project [17] also showed promising results in the education of caregivers evaluated using the Short Sense of Competence Questionnaire (SSCQ): just after three months of video sessions, they showed a more significant gain of competencies than the control group, along with a significant reduction of depressive symptoms. Besides these positive aspects, some studies revealed how, somehow unexpected, caregivers' compliance decreases as the video follow-up proceeds, thus opening to question whether these protocols may be revised and improved. Table 2 summarizes the most relevant studies on AD and telemedicine.

Parkinson's Disease
PD is a neurodegenerative disorder that is clinically characterized by a large number of motor (mainly bradykinesia, resting tremor, rigidity, and postural instability) and nonmotor features (autonomic dysfunction, cognitive/neurobehavioral abnormalities, sleep disorders, and sensory disturbances, such as anosmia, paresthesias, and pain) [29]. Severe motor and cognitive disability may occur as PD progresses to more advanced stages. Some patients may be unable to travel long distances, such as regular follow-up visits at tertiary medical centers.
Telemedicine involves the remote delivery of health care services. Because PD is largely visually assessed and, therefore, well suited to telemedicine, this approach can be a powerful resource for evaluating and managing patients. In order to improve current models of care, telemedicine should reliably assess motor features, and this achievement can be obtained through different devices: Ferreira et al. [30] used an objective system (SENSE-PARK System), which allowed through wearable sensors the quantitative and continuous monitoring of 22 PD patients. Further applications were examined in motor fluctuations: a study [31] confirmed the clinical validity of an algorithm that is able to detect and quantify leg dyskinesias while using a single ankle-worn sensor. The possibility to efficiently capture PD motor features can be useful for identifying potential candidates for advanced therapies: for example, a study from Heldman et al. [32] found that advanced therapy referral rate was significantly higher for patients with remote monitoring reports available as compared to standard care alone (63.6% versus 11.8%, p-value < 0.01). Nevertheless, immediate concerns regarding the validity of distant clinical examination have also been raised, since neither rigidity nor balance can be remotely assessed. Additionally, other potentially crucial parts of the neurological exam, such as reflexes or eye movements, are harder to evaluate.
The first studies on telemedicine have mainly focused on this issue: Samii and colleagues [33] reported a three-year use of telemedicine to deliver follow-up care in 34 PD patients, and adequate motor Unified Parkinson's Disease Rating Scale (UPDRS) measurements were proved when using enhanced video quality. The reliability of a modified UPDRS removing rigidity and retropulsion items as compared to the standard motor scale was also confirmed in a secondary analysis of the CALM-PD study [34]. Besides, when considering travel and lodging costs, considerable resource savings could be achieved [33]. Cubo et al. confirmed the cost-effectiveness of home-based motor monitoring plus standard in-office visits compared to in-office visits alone in 35 PD patients [35]: the home-based care model was cost-effective in terms of functional status, motor impairment, and motor complications, as evaluated by UPDRS II, III, and IV.
In the view of an integrated model of care, some studies have also evaluated the telemedicine economic impact. For example, Dorsey et al. [36] examined the feasibility, effectiveness, and economic advantages of this approach: the authors performed a randomized controlled trial in 20 patients, 11 with in-person visits and nine with specialist care via telemedicine. Each telemedicine visits saved participants, on average, 100 miles of travel, with a relevant economic value. However, life quality change did not differ between the two groups (p-value = 0.61). Similar results regarding the quality of life were confirmed in a one-year large, randomized, and controlled trial that was published by Beck et al. [37]: usual care and usual care supplemented by four virtual visits via video conferencing were compared in a cohort of 195 patients. Even though there was consistent economic convenience in the telemedicine group, quality of life did not improve in those receiving virtual house calls. Conversely, a study conducted by Durner et al. [38] found, in a group of 50 PD patients provided with a 24/7 live stream telemedicine home treatment service, that, after one year, there was a significant improvement in Parkinson's Disease Questionnaire 39 (PDQ39) scores, but not in UPDRS, MMSE, or Hoehn & Yahr (H&Y) scores.
One of the earliest applications of telemedicine as part of an integrated model of care was related to fragile and advanced PD patients: Biglan et al. [39] used live teleconference technology to provide care to a patient residing in a remote nursing home over eight months, which resulted in an improvement in motor and cognitive symptoms and satis-faction from the patient's perspective. The feasibility of providing care via telemedicine for patients residing in nursing homes was also considered in a randomized controlled trial [40]: the participants were randomized to receive telemedicine care or their usual care, and three telemedicine visits were performed over six months. Patients receiving telemedicine completed almost all of the scheduled visits and showed significant improvement in the quality of life and motor performance. Moreover, when considering the remote evaluation of advanced-stage PD patients, cognitive impairment is also highly likely to occur. It may represent a relevant nonmotor feature: a pilot study from Abdolahi and colleagues [34] tested whether, in 17 individuals with movement disorders, the MoCA examinations could be remotely assessed via web-based video conferencing confirming the feasibility of this approach.
If telemedicine is a valuable resource for patients who cannot perform regular followup visits because of long travel distances or significant motor and nonmotor deterioration, the management of intermediate PD stages should be addressed. Marzinzik and colleagues [41] analyzed data from 78 patients that were involved in an integrated care program (ICP). Patients sent home-made video recordings to the treating team via the Internet and, during the 30-day evaluation, an average of 3.2 videos per day was sent. After the ICP conclusion, the UPDRS score was significantly lower than baseline, and the questionnaire's information showed the overall acceptance and practicability of this method. Another strength of ICP's use is the consistent schedule of recordings, which can better convey the dynamics of motor fluctuations.
Even though many advantages can be observed, telemedicine programs' implementation and use have raised concerns regarding the doctor-patient relationship. Some studies have evaluated patients' perception: Qiang JK and Marras [42] administered to 34 users and 103 non-users of telemedicine services a satisfaction questionnaire. 29/34 users were interested in continuing with telemedicine, and non-users (55/103) were interested in using telehealth, either partially or wholly replacing in-person visits. Among the predictors of telemedicine interest, the authors found that the most relevant ones were lower H&Y stage and longer travel time. Interest in the use of telemedicine was also confirmed in a national randomized controlled trial that was conducted by Dorsey and colleagues in 2016 [43]: during recruitment, 11.734 individuals visited the study's website, and 927 individuals submitted electronic interest forms, which indicated high interest in receiving remote care. Another survey [44] confirmed the high interest of patients in telemedicine: the main advantages included access to specialists (62%), convenience (60%), and time savings (59%). Therefore, these studies suggest that the doctor-patient relationship is not affected by telemedicine.
Other intriguing developments of telemedicine include speech and physical rehabilitation. Howell et al. [45] proved that delivering the Lee Silverman Voice Treatment (LSVT) by web camera allowed for similar beneficial outcomes when compared to faceto-face treatment in three PD patients. Similar non-inferiority results in subjects treated remotely as compared to conventional in-person LSVT were also found in other studies [46,47]. Moreover, speech assessment can be reliably performed online: Constantinescu and colleagues [48] evaluated, in 61 patients, the level of agreement between an online and face-to-face assessment of hypokinetic dysarthria by two speech-language pathologists and found that, for the majority of parameters, there were no significant differences between the two approaches.
Regarding telerehabilitation, a randomized controlled trial [49] compared, in 76 patients, the treatment with virtual reality (VR) rehabilitation and in-clinic sensory integration balance training (SIBT), and found that, in the VR group, there was a significant improvement in the Berg Balance Scale. Another trial [50] compared 20 patients that were randomized to receive either telecoach-assisted exercise (TAE) or self-regulated exercise (SRE). Both of the groups received the same eight-week exercise prescription with combined strength and aerobic exercise, and the authors found that the TAE participants achieved more robust attendance (99.2%) when compared to SRE participants.
Moreover, a wide variety of nonmotor symptoms may benefit from telemedicine, such as depression and anxiety. A randomized controlled trial [51] proved the feasibility of telephone-administered Cognitive Behavioral Therapy (CBT) to tackle these nonmotor features. Another recent trial [52] further confirmed these results: 72 PD patients were randomized to telephone-based cognitive-behavioral treatment (T-CBT) or treatment as usual. The Hamilton Depression Rating Scale score improved significantly in T-CBT, with a persistent benefit over a six-month follow-up (p-value < 0.01). Another study [53] explored both the feasibility and patients' satisfaction with telepsychiatry services of 33 PD patients who completed 119 telepsychiatry and 62 in-person visits: patients were overall satisfied, even though some technical aspects needed further optimization.
Another relevant PD management issue is related to advanced therapies: a study that was performed by Willows and colleagues [54] evaluated levodopa-carbidopa intestinal gel (LCIG) home titration in 14 patients via telemedicine. The median time that was required for dosage adjustment was lower than hospital titration, with both patients and health practitioners' satisfaction. Additionally, when considering Deep Brain Stimulation (DBS), telehealth resources have been proved beneficial: the experience of the Ontario Telemedicine Network [55] confirmed in 141 patients retrospectively analyzed the feasibility of telemedicine, which provided adequate interventions allowing, at the same time, a significant reduction in the burden and costs of traveling. Another study [56] explored, in six patients, the feasibility of a technological system (which included a kinematic sensor able to detect motor symptoms) for remote real-time control of apomorphine pumps: this approach was acceptable for three patients and facilitated the initial and long-term dose adjustment.
Lately, the impact of the COVID-19 pandemic has led the scientific community to redefine and improve telemedicine's role in the healthcare system: for instance, recent guidelines and recommendations [57,58] have highlighted the importance of telemedicine in substituting outpatients' visits. Expanding telehealth could reduce person-to-person contact, thus lowering the risk of exposure for patients. Substantial innovations are currently being implemented, and the Telemedicine Study Group of the International Parkinson and Movement Disorders Society has updated a guide to telemedicine to tackle these recent challenges (https://www.Movementdisorders.Org/MDS/About/Committees--Other-Groups/Telemedicine-in-Your-Movement-Disorders-Practice-A-Step-by-Step-Guide.Htm (accessed on 12 February 2021)). Various recommendations are being provided, particularly in the management of advanced therapies [59][60][61] and rehabilitation [62,63]. Together with new encouraging models of care (https://www.epda.eu.com/latest/news/parkinsonitalia-calls-for-permanent-italian-tele-medicine-service-for-people-with-parkinsons/ (accessed on 12 February 2021) and [58]), concerns about telemedicine becoming a new gold standard of treatment have also been raised [64]: therefore, additional research is warranted to elucidate the benefits and limitations of telemedicine in PD. Table 3 summarizes the most relevant studies on PD and telemedicine.

Amyotrophic Lateral Sclerosis
ALS is a rare progressive neurodegenerative disease that is caused by the degeneration of upper and lower motoneurons, leading to muscle paralysis and respiratory failure. Currently, there is no cure for ALS, but a specialized multidisciplinary approach has been shown to extend survival and improve the quality of life in patients with ALS, providing a coordinated interdisciplinary team that is able to take charge of patients' complex needs and become the standard of care. Subsequently, as a care model that is able to keep pace based on the new understanding of this disease, the multidisciplinary team has expanded accordingly, including new healthcare providers and using new technologies [66]. However, this setting is only available in specialized centers, which may be far from the patient's home, and/or difficult to reach in the disease's late stages due to functional limitation. Recently, telemedicine, which has received little attention for many years, is proving to be a handy tool in overcoming these difficulties, slowly becoming part of the fundamental features that are offered by multidisciplinary centers [67].
The first study that was published on tele-treatment of patients with ALS dates back to almost 20 years ago [68], intending to discuss disease course and rehabilitation treatment options, observing that tele-treatment was especially suitable for discussing the practical issues, but psychosocial and emotional issues still needed to be discussed during traditional face-to-face contact. However, despite encouraging preliminary results, for many years, this method has not been fully exploited, mostly from European centers.
In 2017, Van De Rijn et al. published the results of the TelePALS study [69]. This study was a retrospective chart review of all patient encounters via video televisits at the MGH ALS clinic (2014-2016), where video televisits were used as a supplement of standard clinical follow-up for patients evaluated at least once in the ALS center. In this study, the authors highlighted that video televisits are convenient for ALS patients, saving time and burden, and evaluating the disease progression in all disease stages. In addition, the same group reported a marked adjusted cost-savings for patients and institutions with telemedicine [70].
A retrospective cohort study analyzed the quality of telemedicine care as compared to traditional ones, observing a higher probability of remaining stable, which means a significantly lower risk of disease progression for patients receiving telemedicine (p-value = 0.03) [71]. From a phycological/satisfaction point of view, telemedicine looks like a useful tool, combining good communication and a comfortable interaction and removing travel and stress burdens. In 2019, an Italian study started to use the remote telemedicine evaluation from ALS patients, showing the safety and effectiveness, improving the perceived quality of care and patient satisfaction, as well as reducing in care costs [72].
Recently, novel telehealth approaches were developed to monitor patients and caregivers regarding their condition and capture the variations in physical and emotional areas. The approach that was described by Hobson in 2018 [73] was based on a digital solution where patients, through an app into which patients have to periodically answer several questions about their condition, and the healthcare providers immediately receive the information. As an alternative or added method, the reported potential benefit of this technology included improved communication and care coordination, reassurance, and identification of complications.
A recent Dutch study [74] proposed self-monitoring and messaging, through which patients could self-monitor their well-being (daily report), body weight (weekly), and functional status (monthly). In this population group, the adoption rate was 80%, with a median follow-up of 11 months. The highest adherence was observed in body weight and functional assessment monitoring. An app was also exploited for dietary monitoring in ALS patients, comparing the standard in-person care with counseling supported by an app ("mHealth"). The authors reported that the app-counseling is safe, even being unable to maintain weight significantly better than standard care in ALS patients [75].
Telemonitoring studies have been developed in parallel with telemedicine, in order to supervise clinical parameters at home. The first study with this approach, which was published by an Italian group in 2010 [76,77], described the use of telemedicine-assisted integrated care (TAIC) to monitor the clinical and oxygen variation (supported by a portable pulse oximeter). The study highlights, in addition to a high level of patient and caregiver satisfaction, an important clinical utility, which made it possible to recommend hospitalization to the patient when necessary. In the same year, the use of modem communication for adaptation of Non-Invasive Ventilation (NIV) was tested, showing that telemonitoring reduces health care utilization and in-hospital admissions with favorable implications on costs and functional status [78,79]. In 2019, Ando et al. [80] used a set of self-report questions (the MND OptNIVent question set) to monitor the respiratory functions in patients with NIV weekly, observing the administration of the questionnaire, together with weekly monitoring of ventilator and oximetry, was able to facilitate the maintenance of ventilation and SpO2 levels, despite illness progression.
The management and monitoring of patients with chronic neurodegenerative diseases suddenly changed due to the tragic situation generated by the COVID-19 pandemic [81].
To date, few groups worldwide have reported on the use of various forms of telehealth for monitoring ALS patients during the COVID-19 pandemic. At the beginning of the pandemic, the members of the Northeast ALS (NEALS) Consortium that were surveyed in the U.S. ALS academic medical centers to investigate the possibility to continue to followup ALS patients: roughly 50% of patients were unable to see in-person patients, but most could offer video visits [82]. However, to date, only Italian prospective studies have been published. Indeed, three independent Italian groups described their different reality in monitoring ALS patients during the COVID-19 pandemic. Firstly, the group of Logroscino [83] showed that, even with some limitations (e.g., refusal of video interaction), telemedicine was effective and successful for people with ALS, and most patients would like to continue to be included in remote evaluation programs. Similarly, two ALS centers in Northern Italy [84,85], which were located in one of the areas most affected by the pandemic, used the telemedicine service, both via phone call and online platform, for monitoring patients. De Marchi et al. [85,86] reported that the multidisciplinary approach currently used with ALS patients could be reproduced with the telehealth approach. This systemic and periodic monitoring is equally useful for stabilizing the functional and metabolic status and for improving the psychological one. An online Italian self-administered ALS Functional Rating Scale-Revised was developed and used to get feedback about themselves from patients and implement telemedicine monitoring [87]. Table 4 summarizes the most relevant studies on ALS and telemedicine.

Expert Opinions and Conclusions
This integrated review has shown the achievements of technology from several perspectives, thanks to the ease of application and reproducibility. Nevertheless, to date, the use of technology is still too little developed, even though the COVID-19 pandemic can be considered as an unexpected opportunity to speed up clinical practice approval.
However, telehealth requires a series of considerations and reflections: (1) legal issues: the protection of data in terms of integrity, access, and security tracking and reporting (as face-to-face out-patient visits) are mandatory. Currently, no global regulation exists, but, in many jurisdictions, there are some limitations: first of all, in several countries, telemedicine visits are not considered to be official, and telehealth is still considered an experimental trial; an added problem is related to the use of this data, where, for privacy and the management of sensitive data, informed consent is required for data collection. Telemedicine technologies have to create encryption between the involved devices, while using virtual private network tunnels for internet connection [89]. In 2015, the European Union increased telemedicine in Europe as a standard medical service, but a set of European rules on telemedicine is still lacking and confusing, and the approach to telemedicine varies in countries [90].
In addition to the legal issues, the reimbursement problem is not secondary: in the U.S., the landscape is evolving, and some insurances provide reimbursement for predefinite subgroups of patients (e.g., >65 years). In the UE, each single member states are responsible for regulating this question, but to date, many members do not have any legal provisions on telemedicine [90]; (2) personal barriers: doubts regarding acceptance from patients and healthcare providers can slow down the telemedicine application. However, as shown, several studies showed a high level of acceptance from patients, caregivers, and physicians. Patients' barriers are also related to personal complexity in the use of technology, due to motor limitations, added to the absence of dedicated caregivers and adequate setting. Indeed, sometimes, the mandatory need of a caregiver-both for demented patients due to cognitive limitations and for patients with ALS due to motor limitations-is a critical point, which can inhibit the use of telemedicine. Besides, some patientsas elderly patients and who live in rural areas-do not have available technological devices (e.g., smartphone, tablet, or personal computer) and they have a poor internet connection, which may not allow great televisits, inducing anxiety and discomfort. Improvements in technology, with the creation of a robust information technology infrastructure, can significantly facilitate the practice of telemedicine, particularly in maintaining connectivity and technological resources; (3) differences with in-person evaluation: although tele-neurological consultations are similar to in-person evaluations, there are significant differences. Information from the virtual visit is only obtained by observing the patient; hence, certain aspects of the examination, such as tone and coordination, may be challenging to assess by visual inspection alone. Moreover, the inconsistencies in responses due to difficulty hearing well or to minor cognitive and behavioral impairment may be more difficult to detect by telemedicine. Hence, techniques for optimizing telemedicine interactions and equipment should be part of a training program for neurologists who participate in telehealth [91]; and, (4) research and clinical trials: telemedicine can be used in research for several aspects, such as for patients' screening and recruitment (avoiding stressful travels to the closest recruiting Centre), for informed consent signature, and for patients monitoring [92]. Indeed, telemedicine could reduce the burden of participation, reducing the outpatient visits. However, a new clinical trial design is needed. The virtual patient 's assessment will require creating, validating, and collecting self-reported outcome measures, in order to directly obtain an objective score from the patients (avoiding the provider's video-interpretation), which should be well integrated with the physician measures.
The benefits of telemedicine are several and promising, and it has several possible