Botulinum toxin in the rehabilitation of painful syndromes: multiperspective literature analysis, lexical analysis and systematic review of randomized controlled trials.

Pain represents a common symptom of several diseases and is often associated with a reduction in rehabilitation outcomes and recovery. The effectiveness of pain alleviation by botulinum toxin has been recently demonstrated. We searched in PubMed the papers about this topic published in the last ten years, and we selected clinical trials, guidelines, meta-analyses, reviews, and systematic reviews. We used different approaches: multiperspective presentation, lexical evaluation, and systematic review. The systematic review was only performed for the randomized controlled trials. We predominantly found reviews and trials about the rehabilitation of stroke/brain injury and epicondylitis. The most common outcome measures were pain, function, and spasticity. Among the common words, pain was the most frequent and the terms were grouped into different families, especially concerning the outcomes. Rehabilitation showed a relatively low frequency. Finally, the systematic review showed moderate-low levels of bias which confirms the effectiveness of botulinum toxin for pain treatment. The current literature about botulinum toxin is wide and globally diffuse but with some limitations in study strategies and clearness in the formal presentation. The evidence justifies the use of botulinum toxin in treating pain in different diseases.

Rehabilitation of Peripheral Neuropathies: From Lexical Analysis of the Literature to Identification of Clinical Protocols.

Peripheral nervous system diseases are a complex and heterogenous group of diseases affecting the different nerves with various severity and impact on quality of life. The current literature does not provide a structured guide for the rehabilitation of these conditions. We performed a lexical literature evaluation based on graph theory to clarify this topic. We performed a search on PubMed and calculated the frequencies of the words indicating rehabilitation approaches, nerves, and diseases. We found the usefulness of exercises and different physical agents, like laser and ultrasound therapy and neuromuscular stimulation vibration therapy. Orthoses are useful for entrapment, trauma, and hereditary diseases. Correct knowledge and assessment of the neuropathies are fundamental for the therapeutic decision and to guide rehabilitation. Despite the usefulness shown by the different approaches to modulating pain, improving muscle strength and endurance, and ameliorating balance and the sensory system, further studies are needed to define the best-personalized protocols.

Increasing the Passive Range of Joint Motion in Stroke Patients Using Botulinum Toxin: The Role of Pain Relief.

By blocking the release of neurotransmitters, botulinum toxin A (BoNT-A) is an effective treatment for muscle over-activity and pain in stroke patients. BoNT-A has also been reported to increase passive range of motion (p-ROM), the decrease of which is mainly due to muscle shortening (i.e., muscle contracture). Although the mechanism of action of BoNT-A on p-ROM is far from understood, pain relief may be hypothesized to play a role. To test this hypothesis, a retrospective investigation of p-ROM and pain was conducted in post-stroke patients treated with BoNT-A for upper limb hypertonia. Among 70 stroke patients enrolled in the study, muscle tone (Modified Ashworth Scale), pathological postures, p-ROM, and pain during p-ROM assessment (Numeric Rating Scale, NRS) were investigated in elbow flexors (48 patients) and in finger flexors (64 patients), just before and 3-6 weeks after BoNT-A treatment. Before BoNT-A treatment, pathological postures of elbow flexion were found in all patients but one. A decreased elbow p-ROM was found in 18 patients (38%). Patients with decreased p-ROM had higher pain-NRS scores (5.08 ± 1.96, with a pain score ≥8 in 11% of cases) than patients with normal p-ROM (0.57 ± 1.36) (p < 0.001). Similarly, pathological postures of finger flexion were found in all patients but two. A decreased finger p-ROM was found in 14 patients (22%). Pain was more intense in the 14 patients with decreased p-ROM (8.43 ± 1.74, with a pain score ≥ 8 in 86% of cases) than in the 50 patients with normal p-ROM (0.98 ± 1.89) (p < 0.001). After BoNT-A treatment, muscle tone, pathological postures, and pain decreased in both elbow and finger flexors. In contrast, p-ROM increased only in finger flexors. The study discusses that pain plays a pivotal role in the increase in p-ROM observed after BoNT-A treatment.

Development and Rasch Validation of an Observational Assessment Tool of Upper Limb Functional Impairment in Stroke Survivors: Functional Assessment Test for Upper Limb.

OBJECTIVE: To develop and validate a quick observational clinical tool, the Functional ASsessment Test for Upper Limb (FAST-UL), for the evaluation of upper limb impairment in goal-directed functional-oriented motor tasks after stroke. DESIGN: Observational, cross-sectional, psychometric study. SETTING: Inpatient and outpatient rehabilitation clinic. PARTICIPANTS: A total of 188 post-stroke survivors (mean age 65.2±17.7 years, 61% men, 48% with ischemic stroke and 66% in the sub-acute phase; N=188). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Principal component analysis and Rasch analysis through a Partial Credit Model were used to assess the structure and psychometric properties of the 5 items of the FAST-UL (Hand to Mouth [HtM], Reach to Target, Prono-Supination, Grasp and Release, and Pinch and Release [PaR]). RESULTS: The Cronbach's α equal to 0.96 was indicative of an acceptable internal consistency; the reliability, as measured through the Person Separation Reliability equal to 0.87, was good. The FAST-UL tool was unidimensional. All the FAST-UL items were found to fit well the Rasch measurement model. The easiest to perform FAST-UL item was the HtM movement while the most difficult was the PaR movement. CONCLUSIONS: The FAST-UL is a quick, easy-to-administer observational assessment tool of upper limb motor impairment in post-stroke survivors with good item-level psychometric properties.

Effectiveness of Botulinum Toxin on Pain in Stroke Patients Suffering from Upper Limb Spastic Dystonia.

This observational study aimed at investigating pain in stroke patients with upper limb spastic dystonia. Forty-one consecutive patients were enrolled. A 0-10 numeric rating scale was used to evaluate pain at rest and during muscle tone assessment. Patients were asked to indicate the most painful joint at passive mobilization (shoulder, elbow, wrist-fingers). The DN4 questionnaire was administered to disclose neuropathic pain. All patients were assessed just before and 1 month after incobotulinumtoxin-A treatment. Pain was present in 22 patients, worsened or triggered by passive muscle stretching. DN4 scored < 4 in 20 patients. The most painful joints were wrist-fingers in 12 patients, elbow in 5 patients and shoulder in the remaining 5 patients. Both elbow and wrist-fingers pain correlated with muscle tone. BoNT-A treatment reduced pain in all the joints, including the shoulder. We discussed that nociceptive pain is present in a vast proportion of patients with upper limb spastic dystonia. BoNT-A treatment reduced both spastic dystonia and pain in all the joints but the shoulder, where the effect on pain could be mediated by the reduction of pathological postures involving the other joints.

A multinational consensus on dysphagia in Parkinson's disease: screening, diagnosis and prognostic value.

BACKGROUND: Parkinson's disease (PD) is a neurodegenerative disorder characterized by a combination of motor and non-motor dysfunction. Dysphagia is a common symptom in PD, though it is still too frequently underdiagnosed. Consensus is lacking on screening, diagnosis, and prognosis of dysphagia in PD. OBJECTIVE: To systematically review the literature and to define consensus statements on the screening and the diagnosis of dysphagia in PD, as well as on the impact of dysphagia on the prognosis and quality of life (QoL) of PD patients. METHODS: A multinational group of experts in the field of neurogenic dysphagia and/or PD conducted a systematic revision of the literature published since January 1990 to February 2021 and reported the results according to PRISMA guidelines. The output of the research was then analyzed and discussed in a consensus conference convened in Pavia, Italy, where the consensus statements were drafted. The final version of statements was subsequently achieved by e-mail consensus. RESULTS: Eighty-five papers were used to inform the Panel's statements even though most of them were of Class IV quality. The statements tackled four main areas: (1) screening of dysphagia: timing and tools; (2) diagnosis of dysphagia: clinical and instrumental detection, severity assessment; (3) dysphagia and QoL: impact and assessment; (4) prognostic value of dysphagia; impact on the outcome and role of associated conditions. CONCLUSIONS: The statements elaborated by the Consensus Panel provide a framework to guide the neurologist in the timely detection and accurate diagnosis of dysphagia in PD.

From DYMUS to DYPARK: Validation of a Screening Questionnaire for Dysphagia in Parkinson's Disease.

Dysphagia is a common debilitating symptom in people with Parkinson's Disease (PD), adequate screening of swallowing disorders is fundamental. The DYMUS questionnaire has shown very good characteristics for the screening of dysphagia in Multiple Sclerosis, and it might also prove useful for screening dysphagia in PD. The primary aim was to test and validate the DYMUS questionnaire in PD patients. This is an observational multicentric study involving 103 patients affected by PD. All subjects filled in the DYMUS and the Eating Assessment Tool (EAT-10) questionnaires. A subgroup of patients (n = 53) underwent a fiber-optic endoscopic evaluation of swallowing (FEES) and their dysphagia was scored by means of the Dysphagia Outcome Severity Scale (DOSS). DYMUS showed a relatively high level of internal consistency (Cronbach's alpha 0.79). A significant positive correlation was found between the DYMUS and the EAT-10 scores (p < 0.001), while a negative correlation was found between the DYMUS and the DOSS scores (p < 0.001). DYMUS showed a good sensitivity and specificity compared to FEES for detecting dysphagia (area under the curve: 0.82, p < 0.001). The ROC curve analysis showed that a DYMUS score ≥ 6 represents a reliable cut-off for the risk of dysphagia. The DYMUS questionnaire proved to be a reliable screening tool to detect dysphagia in patients suffering from PD. It is easy to understand, it can be self-administered and therefore adequate for adoption in the clinical practice with the more convenient name of DYPARK.

Consensus on the treatment of dysphagia in Parkinson's disease.

BACKGROUND: Dysphagia is common in Parkinson's disease (PD). The effects of antiparkinsonian drugs on dysphagia are controversial. Several treatments for dysphagia are available but there is no consensus on their efficacy in PD. OBJECTIVE: To conduct a systematic review of the literature and to define consensus statements on the treatment of dysphagia in PD and related nutritional management. METHODS: A multinational group of experts in the field of neurogenic dysphagia and/or Parkinson's disease conducted a systematic evaluation of the literature and reported the results according to PRISMA guidelines. The evidence from the retrieved studies was analyzed and discussed in a consensus conference organized in Pavia, Italy, and the consensus statements were drafted. The final version of statements was subsequently achieved by e-mail consensus. RESULTS: The literature review retrieved 64 papers on treatment and nutrition of patients with PD and dysphagia, mainly of Class IV quality. Based on the literature and expert opinion in cases where the evidence was limited or lacking, 26 statements were developed. CONCLUSIONS: The statements developed by the Consensus panel provide a guidance for a multi-disciplinary treatment of dysphagia in patients with PD, involving neurologists, otorhinolaryngologists, gastroenterologists, phoniatricians, speech-language pathologists, dieticians, and clinical nutritionists.

Anodal transcranial direct current stimulation and intermittent theta-burst stimulation improve deglutition and swallowing reproducibility in elderly patients with dysphagia.

BACKGROUND: Dysphagia in the elderly, known as presbydysphagia, has become a relevant public health problem in several countries. Swallowing disorders may be a consequence of different neurological disorders (secondary presbydysphagia) or the expression of the aging process itself (primary presbydysphagia). We aimed to test the therapeutic potential of two different non-invasive brain stimulation (NIBS) techniques in subjects with primary or secondary presbydysphagia. METHODS: A blinded randomized controlled trial with crossover design was carried out in 42 patients, randomly assigned to anodal transcranial direct current stimulation (tDCS) or intermittent theta-burst stimulation (TBS) group. Both tDCS and TBS were applied for 5 consecutive days over the right swallowing motor cortex. The swallowing function was assessed before and 1 and 3 months after the stimulation using the Dysphagia Outcome and Severity Scale (DOSS), scored based on clinical assessment and fiberoptic endoscopic evaluation of swallowing. An electrophysiological method was also applied to evaluate changes in the reproducibility of the swallowing behavior. KEY RESULTS: Both real tDCS and TBS had beneficial effects on the swallowing function in patients with primary and secondary presbydysphagia. Anodal tDCS resulted in an improvement of 0.5 points in DOSS at 1-month follow-up (P = .014), whereas intermittent TBS induced an increase of 0.7 and 0.6 points at 1- and 3-month follow-up evaluations, respectively (P = .0001 and P = .005, respectively). Reproducibility of both the oral and pharyngeal phases of swallowing significantly increased at 1-month follow-up. CONCLUSIONS AND INFERENCES: Our results suggest that non-invasive cortical stimulation may be useful for dysphagia recovery in elderly patients.

A pilot study on the efficacy of transcranial direct current stimulation applied to the pharyngeal motor cortex for dysphagia associated with brainstem involvement in multiple sclerosis.

OBJECTIVE: we investigated the effect of anodal transcranial direct current stimulation (tDCS) applied over the pharyngeal motor area in dysphagia associated with multiple sclerosis (MS). METHODS: Eighteen MS patients with dysphagia associated with brainstem involvement were randomized to receive either "real" or "sham" tDCS. PRIMARY OUTCOME: The Penetration/Aspiration Scale (PAS). SECONDARY OUTCOMES: changes in electromyographic (EMG) parameters and pharyngeal cortical motor evoked potentials (MEPs). Patients were evaluated at baseline (T0), at the end of 5-session cycle of tDCS stimulations (T1), after two (T2), and four (T3) weeks. RESULTS: the PAS values were significantly lower in the active group than in "sham" group at T1, and at T3. Over the post-stimulation periods, PAS significantly improved only in the "real" group. As regards the secondary outcomes, we observed a statistically significant difference between the 2 groups only in the MEPs amplitude at T1. The comparison between baseline and each of the post-stimulation times showed significant differences only of the "real" group across all the secondary parameters. CONCLUSIONS: Our findings support a beneficial effect of anodal tDCS applied to the pharyngeal motor cortex in MS-associated dysphagia. SIGNIFICANCE: Considering its safety and efficacy, tDCS may represent an important resource in MS-associated dysphagia.

Spasmodic Dysphonia in Multiple Sclerosis Treatment With Botulin Toxin A: A Pilot Study.

OBJECTIVES: This study aims to evaluate the effect of botulin toxin A in patients with multiple sclerosis (MS) affected by spasmodic dysphonia (SD) and to show the safety and effectiveness of this treatment in long-term observation. MATERIALS AND METHODS: This is a pilot study on three relapsing-remitting MS patients with SD and their response to botulin toxin A. RESULTS: None of the patients reported dysphagia or other adverse events. Significant improvement was observed in terms of both voice quality and laryngostroboscopy results. The treatment effect was durable for 6-8 months. CONCLUSIONS: Botulin toxin A is a safe treatment that can be successfully used to treat SD in patients with MS. Larger studies are necessary to confirm our results.

Efficacy of Botulinum Toxin A for Treating Cramps in Diabetic Neuropathy.

OBJECTIVE: Muscle cramps occur in >50% of diabetic patients and reduce the quality of life. No effective treatment is available. We evaluated the clinical effectiveness of botulinum toxin A (BTX-A) injections for treating cramps in diabetic patients with neuropathy. METHODS: This single-center, double-blind, placebo-controlled perspective study investigated the efficacy and safety of BTX-A intramuscular injection for treating calf or foot cramps refractory to common pharmacological drugs. Fifty diabetic patients with peripheral neuropathy and cramps were randomly assigned to 2 matched groups. BTX-A (100 or 30 units) or saline was injected on each side into the gastrocnemius or the small flexor foot muscles. Changes in pain intensity (primary outcome) and cramp frequency were evaluated over the course of 20 weeks after BTX-A administration. Cramp interference in daily life and the electrophysiological cramp threshold frequency were also measured. The treatment was repeated 5 months after first injection in 19 responders. RESULTS: All outcome measures improved significantly after BTX-A compared with placebo. The changes with respect to baseline were already significant after 1 week and persisted up to week 14. Only 5 of 25 (20%) patients were nonresponders (<50% decrease of the primary outcome). The responses to a second BTX-A injection provided results similar to the first administration. Mild pain at the injection site (4/25 cases) was the only adverse event, and it disappeared within 2 to 3 days. INTERPRETATION: Local BTX-A infiltration is an efficacious and safe procedure for obtaining a sustained amelioration of muscle cramps associated with diabetic neuropathy. Ann Neurol 2018;84:682-690.

Botulinum Toxin A for Sialorrhoea Associated with Neurological Disorders: Evaluation of the Relationship between Effect of Treatment and the Number of Glands Treated.

Background: Sialorrhoea and drooling are disabling manifestations of different neurological disorders. The aim of this study was to evaluate the effects of botulinum neurotoxin type A (BoNT/A) injection on hypersalivation in 90 patients with neurological diseases of different aetiologies, and to define the minimum number of injected salivary glands to reduce sialorrhoea. Determining the minimum number of glands that need to be engaged in order to have a significant reduction in drooling may be very useful for establishing the minimum total dosage of BoNT/A that may be considered effective in the treatment of hypersalivation. Methods: Twenty-five mouse units (MU) of BoNT/A (onabotulinumtoxin A, Botox; Allergan, Irvine, CA, USA; 100 MU/2 mL, 0.9% saline; or incobotulinumtoxin A, Xeomin; Merz Pharma, Germany; 100 MU/2 mL, 0.9% saline) were percutaneously injected into the parotid (p) glands and/or submandibular (s) glands under ultrasound control. On this basis, patients were divided into three groups. In group A (30 patients), BoNT/A injections were performed into four glands; in group B (30 patients), into three glands, and in group C (30 patients), into two glands. Patients treated in three glands (group B) were divided into two subgroups based on the treated glands (2 p + 1 s = 15 patients; 2 s + 1 p = 15 patients). Similarly, patients being injected in two glands (group C) were subdivided into three groups (2 p = 10 patients; 1 p + 1 s = 10 patients; 2 s = 10 patients). In patients who were injected in three and two salivary glands, saline solution was injected into the remaining one and two glands, respectively. Assessments were performed at baseline and at 2 weeks after the injections. Results: BoNT/A significantly reduced sialorrhoea in 82 out of 90 patients. The effect was more evident in patients who had four glands injected than when three or two glands were injected. The injections into three glands were more effective than injections into two glands. Conclusions: Our results have shown that BoNT/A injections induced a significant reduction in sialorrhoea in most patients (91%). In addition, we demonstrated that sialorrhoea associated with different neurological diseases was better controlled when the number of treated glands was higher.

Pharyngeal electrical stimulation device for the treatment of neurogenic dysphagia: technology update.

Neurogenic dysphagia (ND) can occur in patients with nervous system diseases of varying etiologies. Moreover, recovery from ND is not guaranteed. The therapeutic approaches for oropharyngeal ND have drastically changed over the last decade, mainly due to a better knowledge of the neurophysiology of swallowing along with the progress of neuroimaging and neurophysiological studies. For this reason, it is a priority to develop a treatment that is repeatable, safe, and can be carried out at the bedside as well as for outpatients. Pharyngeal electrical stimulation (PES) is a novel rehabilitation treatment for ND. PES is carried out via location-specific intraluminal catheters that are introduced transnasally and enable clinicians to stimulate the pharynx directly. This technique has demonstrated increasingly promising evidence in improving swallowing performance in patients with ND associated with stroke and multiple sclerosis, probably by increasing the corticobulbar excitability and inducing cortical reorganization of swallowing motor cortex. In this article, we update the reader as to both the physiologic background and past and current studies of PES in an effort to highlight the clinical progress of this important technique.

Pharmacological Therapy of Osteoporosis: A Systematic Current Review of Literature.

Osteoporosis is the most common bone disease affecting millions of people worldwide, particularly in elderly or in post-menopausal women. The pathogenesis is useful to understand the possible mechanism of action of anti-osteoporotic drugs. Early diagnosis, possible with several laboratory and instrumental tests, allows a major accuracy in the choice of anti-osteoporosis drugs. Treatment of osteoporosis is strictly related to severity of pathology and consists on prevention of fragility fractures with a correct lifestyle and adequate nutritional supplements, and use of pharmacological therapy, started in patients with osteopenia and history of fragility fracture of the hip or spine. The purpose of this review is to focus on main current pharmacological products to treat osteoporotic patients.

Mechanism of Action for rTMS: A Working Hypothesis Based on Animal Studies.

Experiments in rodents have elucidated some of the molecular mechanisms underlying repetitive transcranial magnetic stimulation (rTMS). These studies may be useful in a translational perspective so that future TMS studies in rodents can closely match human TMS protocols designed for therapeutic purposes. In the present work we will review the effects of rTMS on glutamate neurotransmission which in turn induce persistent changes in synaptic activity. In particular, we will focus on the role of NMDA and non-NMDA transmission and on the permissive role of BDNF-TrKB interaction in the rTMS induced after-effects.