Background and objectives: This study examines how sociodemographic, clinical, and psychological factors within the patient–caregiver dyad affect caregiver burden and health-related quality of life (HRQoL) in cognitive impairment. By comparing baseline data with a 1-year follow-up, the research aims to identify key predictors of caregiver burden and well-being. Methods: A longitudinal observational study was conducted in an Italian rehabilitation hospital, recruiting 132 outpatients and their caregivers at baseline, categorized as (a) Mild Cognitive Impairment (MCI, n = 33); (b) dementia (DEM, n = 58); (c) healthy subjects (No-CI, n = 41). One year after baseline assessment (T0), patients were contacted and invited for an in-person follow-up re-evaluation (T1). Most attrition was related to the COVID-19 pandemic. Statistical analyses included non-parametric tests for group comparisons and stepwise multiple linear regression to identify predictors of burden, adjusting for confounders (e.g., age, gender, education, employment, co-residence). Results: A total of 51 subjects (age: 80.0 ± 6.1) and 34 caregivers (age: 58.8 ± 15.9) were evaluated. Patients were balanced by gender (53% males); most were retired (96%), married (62.7%), and cared for by sons (47%) or wife–husband (47%). Caregivers (females: 85%) were married (68.3%) and active workers (46.4%). Over one year, 17 No-CI subjects developed MCI or DEM; 15 MCI patients progressed to DEM. Caregiver HRQoL negatively correlated with distress and burden in MCI and DEM groups. Patient cognitive status, functional abilities, neuropsychiatric symptoms, and gender predicted caregiver burden, emphasizing the interplay between clinical and demographic factors. Conclusions: It is essential to monitor psychosocial factors in both the patient and the caregiver to develop effective prevention and support strategies.

PURPOSEThe implementation of Technology-Assisted Rehabilitation (TAR) introduces both challenges and opportunities to enhance patient-therapist interactions. However, the therapist's perspective on TAR often remains understudied. This study aims to address this gap by investigating therapist perceptions of Robot-Assisted Gait Training (RAGT) by developing a specific questionnaire.METHODSThe study is a real-life observational and multicentric pilot study. First, a multidisciplinary board was created to develop the questionnaire. Second, an observational pilot study was conducted, where the questionnaire was administered to therapists involved in RAGT working with a lower-limb robotic device for gait disorders.RESULTSThirty-two questionnaires were collected. Results indicate favourable perceptions among therapists in terms of device's usefulness, ease of use and safety. However, despite the overall positive response trend, therapist engagement showed more variability.CONCLUSIONSThe findings underscore the need of reconceptualizing therapist contribution in TAR, for optimal integration into clinical practice and to improve patient-therapist-device interaction.

BACKGROUND:The heightened risk of dementia resulting from multiple comorbid conditions calls for innovative strategies. Engaging in physical and cognitive activities emerges as a protective measure against cognitive decline. This protocol aims to discuss a multidomain intervention targeting individuals with dementias secondary to cerebrovascular or other medical diseases, emphasizing an often underrepresented demographic. METHODS:This study primary objectives are: a) to identify patients affected by Neurocognitive disorder due to vascular disease or multiple etiologies (screening and diagnostic phase) and b) to evaluate the effectiveness of distinct rehabilitation protocols (intervention phase): motor training alone, paper-based cognitive rehabilitation combined with motor training, digital-based cognitive rehabilitation coupled with motor training. DISCUSSION:Identifying cognitive impairment beyond rigid neurological contexts can facilitate timely and targeted interventions. This protocol strives to address the complex interplay of cognitive decline and comorbidities through a multidimensional approach, providing insights that can shape future interventions and enhancing overall well-being in this vulnerable population. TRIAL REGISTRATION:The study has been registered on July 13, 2023 with the ClinicalTrials.gov NCT05954741 registration number (https://classic.clinicaltrials.gov/ct2/show/NCT05954741).

The introduction of technology-assisted rehabilitation (TAR) uncovers promising challenges for the treatment of motor disorders, particularly if combined with exergaming. Patients with neurological diseases have proved to benefit from TAR, improving their performance in several activities. However, the subjective perception of the device has never been fully addressed, being a conditioning factor for its use. The aims of the study were: (a) to develop a questionnaire on patients’ personal experience with TAR and exergames in a real-world clinical setting; (b) to administer the questionnaire to a pilot group of neurologic patients to assess its feasibility and statistical properties. A self-administrable and close-ended questionnaire, Technology Assisted Rehabilitation Patient Perception Questionnaire (TARPP-Q), designed by a multidisciplinary team, was developed in Italian through a Delphi procedure. An English translation has been developed with consensus, for understandability purposes. The ultimate version of the questionnaire was constituted of 10 questions (5 with multiple answers), totalling 29 items, exploring the patient’s performance and personal experience with TAR with Augmented Performance Feedback. TARPP-Q was then administered pre-post training in an observational, feasible, multi-centric study. The study involved in-patients aged between 18 and 85 with neurological diseases, admitted for rehabilitation with TAR (upper limb or gait). FIM scale was run to control functional performance. Forty-four patients were included in the study. All patients answered the TARPP-Q autonomously. There were no unaccounted answers. Exploratory factor analyses identified 4 factors: Positive attitude, Usability, Hindrance perception, and Distress. Internal consistency was measured at T0. The values of Cronbach’s alpha ranged from 0.72 (Distress) to 0.92 (Positive attitude). Functional Independence Measure (FIM®) scores and all TARPP-Q factors (Positive attitude, Usability, Hindrance perception, except for Distress (p = 0.11), significantly improved at the end of the treatment. A significant positive correlation between Positive attitude and Usability was also recorded. The TARPP-Q highlights the importance of patients’ personal experience with TAR and exergaming. Large-scale applications of this questionnaire may clarify the role of patients’ perception of training effectiveness, helping to customize devices and interventions.

Post-COVID-19 motor neuropathies frequently result atypical for location and contemporary involvement of different nervous districts. These aspects often complicate the electromyography (EMG) diagnosis. Inducing severe and atypical forms of disability, motor mononeuropathies early recognition is of primary importance for a specific rehabilitation treatment. Several evidence supported magnetic resonance (MRI) as a useful tool in the early diagnosis of muscle denervation. We describe the case of a 57-year-old male patient with a severe post-COVID-19 motor deficit in the proximal region of left upper limb, with a significant limitation in left shoulder abduction. MRI, required in suspected tendinopathy, showed a high hyperintensity signal in the “fluid sensitive” sequences of both supraspinatus and infraspinatus muscles, suggesting denervation of these muscle districts in a selective, severe injury of the left suprascapular nerve. This diagnostic hypothesis was subsequently confirmed by EMG. This clinical case confirms that MRI could represents a valuable supplementary resource in unusual post-COVID-19 motor neuropathies diagnosis, allowing an early and specific rehabilitation.

This study evaluates the cognitive impairment impact on the caregiver’s burden and quality of life. Patient–caregiver dyads admitted to dementia Diagnostic-Therapeutic Care Pathway underwent a psychological and neuropsychological assessment. Overall, 30 caregivers (age 58.97 ± 14.68) of patients with dementia and 28 caregivers (age 58.57 ± 12.22) of patients with MCI were recruited. Caregiver’s burden is positively correlated to the number (r = .37, p = .003) and severity (r = .37, p = .003) of neuropsychiatric patient’s symptoms and with the caregiver’s distress (r = .36, p = .004). It is also negatively related to good quality of life perception (r =  − .52, p =  < .0001), to lower cognitive impairment (r =  − .26, p = .05), to higher patient’s residual functional abilities in daily living (r =  − .32, p = .010) and to positive perception of the physician’s communication (r =  − .28, p = .026). Moreover, the caregiver’s burden is significantly predicted by the patient’s low level of instrumental activity of daily living (β =  − .74; p = .043) and by the number of neuropsychiatric symptoms (β = .74; p = .029). Thus, this study suggests that the autonomy and neuropsychiatric symptoms may determine the caregiver’s burden.

BACKGROUND Several neurological complications occurred in SARS-Cov2-Disease (COVID-19), mainly related to inflammatory and vascular disorders. The involvement of the Peripheral Nervous System (PNS) has been mostly reported as Guillain-Barrè syndrome, while focal peripheral neuropathies have been rarely described. CASE SERIES We report the cases of ten patients hospitalized in Rehabilitation Units after COVID-19, who presented severe focal motor involvement. Electrophysiological investigations revealed focal sensory-motor neuropathies, atypical for many aspects: bilaterality, location and contemporary involvement of different nervous districts. We speculate that their pathogenesis is possibly related to prolonged abnormal postures maintained during hospitalization in Intensive Care Unit, virus neurotropism and thrombotic vascular damage involving vasa nervorum. CLINICAL REHABILITATION IMPACT Motor neuropathies could induce severe disability and their early recognition in post COVID-19 patients is of primary importance for a specific rehabilitation treatment.

The peculiar combined, or binary involvement of epithelium and stroma makes basal cell carcinoma (BCC) a unique tumour. Nerve fibres have been shown to play an active role in different cancers. A prospective observational study was carried out on punch biopsies harvested within BCC surgical excision specimens. A total of 10 samples of histologically diagnosed BCC, derived from 10 different patients (five females, five males), was included in the study. Within the BCCs, seven different histological sub-types were identified: morphea-like, basosquamous, micronodular, mixed nodular-micronodular, adenoid, nodular and superficial multifocal. Nerve fibres were stained for indirect immunofluorescence targeting protein gene product 9.5. Three different morphological patterns of nerve fibre distribution within the BCCs were identified. Pattern 1 displayed a normal skin nerve pattern, in which the fibres were dislodged by the growing tumour masses. Pattern 2 featured a ball of curved, tangled nerve fibres close to the tumour masses, slightly resembling piloneural collar nerve fibres, wrapped around hair follicles in the normal anatomical setting. Pattern 3 showed nerve fibres crowding in the sub-epidermal layer with focal epidermal hyperinnervation. Such a pattern is reminiscent of the typical anatomical neuro-epithelial interaction in mechanosensory organs. Our study may disclose a hidden third player, of nerves. Thus, tissue involvement of BCCs may be better represented by the triad of epithelium, stroma and nerves, each component retaining some features associated with its developmental setting.

This study aimed to determine the effects of neutral hypnosis and hypnotic temperature suggestions in thermal and pain thresholds compared to resting state. Sixteen healthy medium or high hypnotizable volunteers were enrolled. Hypnotizability was assessed with the Hypnotic Induction Profile (HIP); QST was checked in resting state, in neutral hypnosis, after suggestions of heat and cold, and after deinduction. A significant increase in heat threshold was recorded during hypnosis with both cold and heat suggestions compared to neutral hypnosis. HIP induction score showed a linear correlation with changes of temperature thresholds after heat and cold suggestions. Thermal suggestions may result in a significant increase of heat perception thresholds with respect to neutral hypnosis. HIP score is related to thermal threshold changes. QST is a valuable and manageable tool to measure temperature threshold change during hypnosis.

Pain evoked by tangential movement across the skin is usually defined as dynamic mechanical allodynia (DMA). Some patients complain of DMA as troublesome as spontaneous pain and refer a marked interfering with activities of daily living and sleep. Pathophysiology of DMA is complex and can be related to several mechanisms, both nociceptive and neuropathic. Five exemplificative clinical cases of DMA are presented, each associated to a possible specific mechanism: injured skin DMA, peri-injured skin DMA, far injury DMA, nerve-confined DMA and fear DMA (pseudo allodynia). The identification of these subcategories of DMA can stimulate further studies aimed at evaluating the usefulness of a mechanism-based therapy for the different clinical forms of DMA.

Catecholaminergic Polymorphic Ventricular Tachycardia type 2 (CPVT2) is a highly lethal recessive arrhythmogenic disease caused by mutations in the calsequestrin-2 (CASQ2) gene. We have previously demonstrated that viral transfer of the wild-type (WT) CASQ2 gene prevents the development of CPVT2 in a genetically induced mouse model of the disease homozygous carrier of the R33Q mutation. In the present study, we investigated the efficacy of the virally mediated gene therapy in cardiomyocytes (CMs) differentiated from induced pluripotent stem cells (iPSCs) obtained from a patient carrying the homozygous CASQ2-G112+5X mutation. To this end, we infected cells with an Adeno-Associated Viral vector serotype 9 (AAV9) encoding the human CASQ2 gene (AAV9-hCASQ2). Administration of the human WT CASQ2 gene was capable and sufficient to restore the physiological expression of calsequestrin-2 protein and to rescue functional defects of the patient-specific iPSC-derived CMs. Indeed, after viral gene transfer, we observed a remarkable decrease in the percentage of delayed afterdepolarizations (DADs) developed by the diseased CMs upon adrenergic stimulation, the calcium transient amplitude was re-established and the density and duration of calcium sparks were normalized. We therefore demonstrate the efficacy of the AAV9-mediated gene replacement therapy for CPVT2 in a human cardiac-specific model system, supporting the view that the gene-therapy tested is curative in models with different human mutations of CPVT.

This case presentation describes a 47-year-old woman who developed complex regional pain syndrome type II with severe neuropathic pain following iatrogenic transection of the tibial nerve at the ankle. The pain and disability progressively worsened over time, markedly impaired ambulation, and were not relieved despite various analgesic treatments. After injection of botulinum toxin (abobotulinumtoxinA, BoNT-A) in the leg muscles the tendons of which pass through the tarsal tunnel (together with the tibial nerve), her pain decreased and her walking capacity improved. This case suggests a new therapeutic role for botulin toxin in treating peripheral neuropathic pain caused by movement-evoked ectopic potentials.LEVEL OF EVIDENCE:V.

OBJECTIVES:Intrathecal (IT) drug administration is an advanced technique in pain treatment algorithm for patients poorly responsive to systemic pharmacological treatment or less invasive techniques. The aim is to improve analgesia lowering side effects; despite this premise, many side effects of long-term IT therapy have been described, mainly related to opioid administration. We observed, in some of the patients regularly followed for pump refills in our Pain Unit, the appearance of excessive daytime sleepiness (EDS) interfering with daily life and work activity; this study aims to investigate the incidence of EDS in patients on IT analgesia with opioid or non-opioid drugs and its possible relationship with respiratory problems during sleep.MATERIALS AND METHODS:21 patients on IT therapy for chronic pain answered the Epworth Sleepiness Scale (ESS). The incidence of EDS in patients receiving IT opioids was compared to a control group not receiving opioids. In 10 patients, who performed polysomnography (PSG) and maintenance of wakefulness test (MWT) for sleep complaints, we studied the relationship between PSG data and ESS scores and we verified the concordance of ESS and MWT results.RESULTS:38% of the patients reported EDS, according to ESS data; all the patients with EDS were receiving an IT opioid. Even if some patients presented sleep apneas, we failed to correlate this data with daytime sleepiness. Subjective sleepiness is confirmed by the results of MWT.CONCLUSION:Our data demonstrate that EDS is a frequent and important side effect of IT analgesia and it seems related to opioids administration.

aUnit of Clinical Neurophysiology and Neurodiagnostic Skin Biopsy, “Salvatore Maugeri” Foundation, Scientific Institute of Pavia, Pavia, Italy bUnit of Pain Therapy, “Salvatore Maugeri” Foundation, Scientific Institute of Pavia, Pavia, Italy E-mail address: (M. Buonocore)

The term phantom sensations (PS) refers to sensations in a missing body part. They are almost universal in amputees and can be both painful and not painful. Although PS have been frequently described in limb amputees, they can also occur in other clinical conditions and several pathophysiological interpretations have been proposed, with a predominance of theories based on a central origin. Actually, different mechanisms are able to create a phantom sensation. After an amputation, PS are frequently generated by the genesis of ectopic action potentials in the interrupted nerve fibers but the PS generator can also be more proximal. Sometimes PS are not created by the stimulation of somatosensory fibers with a missing territory, but they can be the result of central sensitization or neuroplastic changes that allow for the convergence of impulses coming from different body parts (referred sensations), one of which is missing. In conclusion, PS can be generated by both neuropathic and non-neuropathic mechanisms developed in the amputated body part or in other parts of the nervous system. Since these mechanisms are not pathognomonic of amputation there are no hidden ghosts to look for in phantom sensations. The only interpretative rule is just to follow the pathophysiological principles.

According to the current definition of neuropathic pain ("pain arising as a direct consequence of a lesion or disease affecting the somatosensory system"), the demonstration of a lesion or disease involving the somatosensory system is mandatory for the diagnosis of definite neuropathic pain. Although several methods are currently available for this aim, none is suitable for every type of disease (or lesion). Neurodiagnostic skin biopsy (NSB) is a relatively new technique for the diagnosis of peripheral nerve lesions. It is an objective method, completely independent from the patient's complaining, based on immunohistochemical staining techniques that allow measurement of the density of the epidermal nerve fibers, currently considered the free nerve endings of small diameter (A-delta and C) afferent fibers. NSB has the important property of being used to investigate the skin, allowing obtaining a diagnosis of small fiber axonal neuropathy of peripheral nerves supplying every body part covered by skin. This feature appears to be very important, particularly in cases of unilateral nerve lesions, because it allows going beyond the possibilities of neurophysiological tests which are available only for a limited number of peripheral nerves. All these characteristics make NSB a precious instrument for the diagnosis of peripheral unilateral neuropathic pain.

Objective: To investigate the analgesic effect of high-frequency transcutaneous peripheral nerve stimulation (HF-TPNS) in the ipsilateral and contralateral skin territory of the stimulated nerve.Design: Prospective, cross-over study.Setting: Clinical neurophysiology unit, institutional care, rehabilitation center.Participants: Ten healthy volunteers (5 male, 5 female).Methods: Participants underwent 3 different sessions. In the first, heat pain thresholds (HPTs) were measured on the left dorsal hand skin without stimulation; in the second and third sessions, HPTs were measured, respectively, in the territory of the left and right radial nerve before, during, and after an electrical stimulation (10 minutes, 100 Hz, 0.1 ms) of the left superficial radial nerve.Main Outcome Measurement: Heat pain threshold.Results: An increase of HPTs was observed in the skin territory of both right and left radial nerve during and after the left radial nerve stimulation.Conclusion: The present study demonstrates an analgesic effect of HF-TPNS not only in the ipsilateral but also in the contralateral side of stimulation, suggesting a possible role of contralateral HF-TPNS in the treatment by physical therapy of patients with unilateral pain syndromes.