Mario Stampanoni Bassi

Laryngeal adductor breathing dystonia (LABD) is a rare form of focal, task-specific respiratory dystonia affecting the laryngeal muscles of unknown aetiology. Unlike classical laryngeal dystonia (spasmodic dysphonia), LABD is not primarily characterised by impaired speech, but rather by dysfunction of respiratory laryngeal control. The hallmark pathophysiological alteration consists of involuntary, action-induced adductor spasms of the laryngeal muscles during respiration, particularly during inspiration. LABD must be distinguished from inducible laryngeal obstruction (ILO), a broader, heterogeneous condition encompassing episodic, stimulus-triggered supraglottic or glottic closure, associated with asthma, reflux, or psychological triggers, that is generally not task-specific and lacks the neurological substrate characteristic of dystonia. In contrast, LABD is a persistent, effort-dependent, neurologically driven dystonia, demonstrable by paradoxical adductor spasms on fibreoptic laryngoscopy during normal inspiration and confirmed electromyographically by paradoxical thyroarytenoid muscle activation instead of the expected inspiratory relaxation. Traditional treatments, including respiratory retraining, speech therapy, biofeedback, psychotherapy, benzodiazepines, dopamine-blocking agents, and anticholinergic drugs, have proved largely ineffective. Tracheostomy may be required in cases of severe respiratory compromise. Botulinum toxin type A (BoNT/A) injections have been reported to successfully reduce inspiratory stridor in selected patients. Here, we present three cases of LABD displaying distinct phenotypes, in which typical features were associated with involvement of extra-laryngeal cranial districts, further expanding the known phenotypic spectrum of this condition.

The efficacy of botulinum neurotoxin (BoNT) is strongly dependent on its accurate delivery to hyperactive muscles and, ideally, to motor endplate regions. Although guidance techniques such as electromyography (EMG) and ultrasound (US) improve injection precision, each technique provides only partial information—either functional or anatomical. Integrating these techniques could enhance targeting accuracy, optimize dose distribution, and reduce off-target effects. A structured PubMed search was performed using terms related to BoNT, spasticity/dystonia, EMG, and US. Filters included clinical trials, randomized controlled trials, meta-analyses and reviews published within the last decade. Fifty-nine studies met the inclusion criteria. The publications were predominantly in neuroscience and rehabilitation journals. Only 17 studies reported combined EMG–US guidance. These focused mainly on stroke and cervical dystonia. While EMG-US integration is a promising strategy, we emphasize the added value of EMG guidance for US approaches, which is particularly important when treating complex neurological conditions involving complex, overlapping muscle activation patterns, or when targeting structures that are inaccessible to conventional imaging techniques. The EMG-US integrated approach is a promising strategy for optimizing BoNT therapy by combining structural visualization with real-time functional assessment. Despite its promising advantages in terms of accuracy and dose optimization, its clinical adoption is limited by a lack of high-quality evidence.

Drooling and dysphagia are frequent and disabling complications in Parkinson’s disease (PD) and often coexist, with drooling mainly resulting from impaired saliva clearance due to reduced oral motor control and potentially worsening swallowing function. This study aimed to evaluate whether botulinum toxin type A (BoNT/A) injections into the major salivary glands, beyond controlling drooling, could also improve swallowing performance using clinical and neurophysiological measures. Twenty PD patients with severe drooling and dysphagia underwent bilateral ultrasound-guided BoNT/A injections into the parotid and submandibular glands. Assessments were performed at baseline and at 1, 8, and 12 weeks post-injection. Dysphagia severity was evaluated using the Penetration–Aspiration Scale and the Dysphagia Severity Rating Scale. Neurophysiological assessment included electromyographic recordings from suprahyoid/submental and cricopharyngeal muscles, together with mechanomyography analysis of laryngeal movement during swallowing. Following BoNT/A treatment, a consistent reduction in drooling was observed, accompanied by significant improvements in clinical dysphagia scores and neurophysiological swallowing parameters across all follow-up time points. These findings suggest that incobotulinumtoxinA injections into salivary glands not only reduce drooling but also enhance swallowing function in PD patients, possibly by facilitating oral floor and oropharyngeal motor coordination secondary to improved saliva management.

Multiple sclerosis is frequently associated with sleep disorders. This study aimed to evaluate subjective and objective sleep parameters in de novo relapsing–remitting multiple sclerosis patients compared to healthy controls and to explore correlations with cerebrospinal fluid cytokines. Twenty‐one patients underwent CSF cytokine analysis, overnight polysomnography and sleep quality assessments; 21 HCs also participated in sleep evaluations. We analysed sleep macrostructure and the cyclic alternating pattern. Compared to controls, patients exhibited increased sleep period time, time in bed, REM sleep latency, N3 sleep percentage and wakefulness after sleep onset, along with reduced sleep efficiency and REM sleep percentage. These alterations were more pronounced in patients who also had obstructive sleep apnoea. Cyclic alternating pattern analysis revealed increased CAP time and rate—particularly higher A3 indices and duration of A phases—suggesting enhanced sleep fragmentation. A significant association was found between IL‐1β and longer Phase B duration, and IL‐15 showed a positive correlation with A3 mean duration in the cyclic alternating pattern, indicating inflammatory modulation of sleep architecture. Fatigue was negatively correlated with A1 mean duration and cycle mean duration. These findings demonstrate that de novo relapsing–remitting multiple sclerosis is associated with significant sleep fragmentation, particularly in patients with obstructive sleep apnoea and suggest that pro‐inflammatory cytokines might influence sleep homeostasis through adaptive mechanisms. This underscores the importance of addressing sleep quality in multiple sclerosis management.

Background: Neuromyelitis Optica Spectrum Disorder (NMOSD) is a central nervous system inflammatory disease that causes severe disability. Differently from relapsing-remitting multiple sclerosis (RRMS) a group of patients present aquaporin-4 (AQP4) antibodies in the serum. Although its pathogenesis is unclear, cytokine profiles may impact disease activity and severity. Objective: To analyze cerebrospinal fluid (CSF) cytokine levels in NMOSD AQP4 + and their relationship with neurological disability, comparing findings with RRMS patients and non-inflammatory controls (NIC). Methods: Sixty-four participants were recruited: 11 NMOSD AQP4+, 29 RRMS, and 24 NIC. CSF cytokine levels were measured using a multiplex assay. Group comparisons were performed with Kruskal-Wallis and Mann-Whitney U tests, while linear regression models evaluated the association between cytokine levels and Expanded Disability Status Scale (EDSS) scores. Results: NMOSD AQP4 + patients displayed significantly higher CSF levels of IL-1β ( p = 0.040), TNF-α ( p < 0.001), G-CSF ( p = 0.003), Eotaxin ( p = 0.008), and MIP-1α ( p = 0.005) compared to RRMS and NIC. Moreover, IL-1β CSF levels were positively associated with disability at the time of lumbar puncture (β = 22.24, SE = 7.73, p = 0.018), a relationship that remained significant after adjusting for age (β = 18.96, SE = 6.33, p = 0.040). Conclusions: Expression of proinflammatory cytokines may differ between NMOSD and RRMS. Elevated IL-1β levels in NMOSD AQP4 + patients are associated with neurological disability, suggesting a potential role as a biomarker of disease severity. Further studies are needed to confirm these findings and evaluate the therapeutic potential of targeting IL-1β in NMOSD.

Dysphagia is a frequent and potentially life-threatening complication in patients with neurological disorders. Swallowing is a complex neurophysiological mechanism regulated by a widespread network of central nervous system regions. The control of swallowing functions requires the integrity of the central pattern generator located in the brainstem, the sensorimotor cortex, the basal ganglia, and the cerebellum, but also peripheral nerves and swallowing muscles. Neurological diseases affecting either central or peripheral components of this system commonly result in dysphagia. Despite its clinical relevance, the management of neurogenic dysphagia remains challenging. While rehabilitative strategies such as swallowing therapy currently represent the main treatment option, emerging evidence suggests that non-invasive central and peripheral neuromodulation techniques may provide adjunctive beneficial effects. Further research is warranted to better define their efficacy, optimal protocols, and long-term outcomes.

1. IntroductionDysphagia, the disruption of normal swallowing, is a frequent and very severe complication of multiple sclerosis (MS) (1, 2). Several clinical observations have shown that swallowing disorders are much more common in patients with MS than previously thought (2–9). Furthermore, the dysphagia-associated aspiration pneumoniae is the leading cause of death in patients with MS (9, 10).Although dysphagia may be present at all stages of MS, the prevalence increases with age, with disease duration, and is greater in patients with progressive phenotypes (7, 8). The real prevalence of dysphagia in MS may be attested around 30–40% (7, 11). It has been reported that symptomatic dysphagia is more frequent in patients with higher Expanded Disability Status Scale (EDSS) scores and is significantly associated with cerebellar and brainstem dysfunction, as well as cognitive deficits (4, 6, 8, 12). However, about 17% of patients with low EDSS had dysphagia (2, 6). Prevalence of dysphagia increases using instrumental evaluation (8, 13). In a recent study using Fiber Endoscopic Evaluation of Swallowing (FEES), dysphagia has been detected in about 60% of MS patients (8).Accurate diagnosis and assessment of swallowing severity and early management of dysphagia complications improve quality of life and critically contribute to delaying life-threatening complications or invasive therapeutic interventions.2. Dysphagia in MS2.1. Anatomy and physiology of swallowingSwallowing is a physiological innate mechanism allowing the ingestion of liquids and foods without aspiration (14). It is commonly divided into three phases: oral, pharyngeal, and esophageal.Swallowing is initiated by the cerebral cortex and regulated by a central pattern generator (CPG) located bilaterally in the medulla oblongata, involving several brainstem motor nuclei (V, VII, IX, X, and XII) and two major groups of interneurons: one located in the dorsal medulla within the nucleus tractus solitarius (NTS) and adjacent reticular formation, and the other one, placed in the ventrolateral medulla, just above the nucleus ambiguous (14).Swallowing activates a large bilateral cortical–subcortical network, involving sensorimotor regions, and areas associated with cognitive, attentional, and emotional aspects (15–20). Projections from sensorimotor areas are directed toward ipsilateral and contralateral CPGs of swallowing (17). In addition, the role of the cerebellum has been consistently evidenced by studies using PET, fMRI, and transcranial magnetic stimulation TMS (21) and is confirmed by the occurrence of dysphagia in patients with cerebellar dysfunction (22, 23).2.2. Pathophysiology of dysphagia in MSThe pathophysiology of dysphagia in MS is likely due to the combination of several factors such as involvement of the corticobulbar tract, the cerebellum and the brainstem, leading to impairment of one or more of the three phases of swallowing (12, 24, 25).In patients with MS, inflammatory lesions located at the level of the cerebral hemispheres or brainstem can alter the normal physiology of swallowing, leaving the airway vulnerable to food fluid aspiration (3). Demyelinating lesions can alter swallowing when the dominant side of brain areas relevant to swallowing is affected, or when both sides of brainstem swallowing centers are affected (3). The likelihood of swallowing-relevant brain areas/connections being involved rises with increasing lesion load and the number of brainstem nuclei affected. In MS patients with mild disability but suffering from dysphagia, lesions are most likely located in regions strategically relevant to swallowing, such as medullary CPGs (2).The cerebellum may represent another key region involved in swallowing dysfunction in MS. Notably, the cerebellum controls the output for motor nuclei of V, VII and XII cranial nerves and is an effective coordinator of muscle activation during swallowing (14, 26–28). Videofluoscopic studies in dysphagic MS subjects with cerebellar involvement have showed that cerebellar lesions are associated to dysfunction in oral phase and pharyngeal phase of swallowing (29). Other factors that might play a role in MS-related dysphagia include weakness and changes in the stiffness and elasticity of craniofacial muscles involved in swallowing, often associated to demyelination of cranial nerves, lesions in the cerebellar peduncle, internal capsule, or the spinal cord (30).3. Assessment of dysphagia3.1. Clinical examinationA general physical examination should be focused on the cranial nerves that are associated with swallowing, particularly the motor components of V, VII, IX, X and XII cranial nerves, and sensory fibres from V, VII, IX, and X cranial nerves (25, 31). The aspiration in patients with dysphagia may be predicted by the bedside swallowing evaluation (BsSE) (2). Water swallowing tests, such as the timed water swallowing test (TWST), are commonly used to identify patients at risk of dysphagia in different neurological conditions (32, 33), and have been evaluated as screening tools in MS (1, 2, 34).The identification of a simple, rapid, and easy-to-implement instrument that can be used in the outpatient setting should be the ideal goal for dysphagia assessment. We recently developed a questionnaire for the evaluation of dysphagia in MS (Dysphagia in Multiple Sclerosis – DYMUS). The DYMUS is a self-administered questionnaire designed to assess signs and symptoms of dysphagia for both solids and liquids. It consists of 10 items requiring a “yes” or “no” response and can be completed in a few minutes. DYMUS scores were significantly higher in progressive phenotypes and significantly correlated with EDSS (6). Thus, the DYMUS can be used for the preliminary selection of patients for further specific instrumental analyses, and for referring patients to aspiration prevention programs (6, 8). Notably, a study evidenced that...

Dysphagia is a frequent and life-threatening complication of multiple sclerosis (MS). Swallowing disturbances may be present at all stages of MS, although their prevalence increases with age, with disease duration, and in progressive phenotypes. The pathophysiology of dysphagia in MS is likely due to a combination of factors, including the involvement of corticobulbar tracts, the cerebellum, and the brainstem. Accurate diagnosis and early management of swallowing disorders improve quality of life and may delay complications or invasive therapeutic interventions. Here we provide an overview of the pathophysiology, the assessment, and the management of MS dysphagia, also examining the possible role of novel therapeutic strategies. Although studies using imaging and neurophysiological techniques have contributed to better characterize swallowing alterations in MS, the treatment of dysphagia is still challenging. Rehabilitation represents the main therapeutic approach for swallowing disorders. Recently, some innovative neurophysiological approaches, such as pharyngeal electrical stimulation (PES), repetitive transcranial magnetic stimulation (rTMS), and transcranial direct current stimulation (tDCS), have been proposed as a supplement to swallowing therapy in different neurological conditions. However, only few studies have explored the role of neuromodulation for MS dysphagia.

(1) Multiple sclerosis (MS) is identified by a complex interaction between central inflammation and neurodegeneration. Genetic individual variability could play a significative role in clinical presentation. The interleukin-5 (IL-5) rs2069812 single-nucleotide polymorphism (SNP) seems to define the clinical course of Th2 autoimmune diseases, while its role in MS has never been investigated. (2) In a group of 230 patients diagnosed with relapsing–remitting MS (RR-MS) or progressive MS (P-MS) and controls (IC), rs2069812 polymorphism, cerebrospinal fluid (CSF) levels of inflammatory mediators, and clinical and demographic characteristics were determined. In RR-MS patients, No Evidence of Disease Activity (NEDA-3) at three years of follow-up was detected. (3) We identified higher levels of proinflammatory cytokines, particularly IL-2 (median [IQR], RR-MS = 0.2 [0–0.7]; P-MS = 0.1 [0–1.6]; IC = 0.1 [0.0–0.1]; p < 0.005), IL-6 (RR-MS = 0.9 [0.3–2.3]; P-MS = 0.8 [0.1–2.7]; IC = 0.1 [0.0–0.5]; p < 0.005), IL-12 (RR-MS = 0.5 [0–1.1]; P-MS = 0.5 [0–1.1]; IC = 0.0 [0.0–0.3]; p < 0.005), and GM-CSF (RR-MS = 15.6 [4.8–26.4]; P-MS = 14 [3.3–29.7]; IC = 8.9 [4.7–11.7]; p < 0.005) in MS patients compared with IC. Conversely, anti-inflammatory cytokines, specifically IL-5 (RR-MS = 0.65 [0–2.4]; P-MS = 0.1 [0–0.8]; IC = 1.7 [0.6–2.8]; p < 0.005) and IL-1ra (RR-MS = 14.7 [4.9–26.4]; P-MS = 13.1 [4.7–22.2]; IC = 27.8 [17.7–37.6]; p < 0.005) were higher in controls. According to rs2069812, in MS patients, the T-allele was associated with higher concentrations of proinflammatory mediators (IL-2, CT/TT = 0.2 [0.0–2.0]; CC = 0.1 [0.0–0.4], p = 0.015; IL-6, CT/TT = 1.2 [0.4–3.2] vs. CC = 0.7 [0.1–1.7], p = 0.007; IL-15, CT/TT = 0.1 [0.0–9.5] vs. CC = 0.0 [0.0–0.1], p = 0.019; and GM-CSF, CT/TT = 0.1 [0.0–0.6] vs. CC = 0.05 [0.0–0.1], p < 0.001), and CC was associated with anti-inflammatory mediators (IL-5, CT/TT = 0.03 [0.0–1.9] vs. CC = 1.28 [0.0–2.7], p = 0.001; IL-1ra, CT/TT = 12.1 [4.1–25.9] vs. CC = 18.1 [12.1–26.9], p = 0.006). We found the same differences in RR-MS patients (IL-2, T-allele median [IQR] = 0.3 [0.0–2.0] vs. C-allele, median [IQR] = 0.04 [0.0–0.3]; p = 0.005; IL-6, T-allele, median [IQR] = 1.3 [0.4–3.3] vs. C-allele, median [IQR] = 0.6 [0.03–1.5]; p = 0.001; IL-15, T-allele, median [IQR] = 0.1 [0.0–9.5] vs. C-allele, median [IQR] = 0.0 [0.0–0.1]; p = 0.008; GM-CSF, T-allele, median [IQR] = 0.1 [0.0–97.9] vs. C-allele, median [IQR] = 0.0 [0.0–0.001]; p < 0.001; IL-5, T-allele, median [IQR] = 0.02 [0.0–2.2] vs. C-allele, median [IQR] = 1.5 [0.0–2.9]; p = 0.016; and IL-1ra, T-allele, median [IQR] = 12.1 [4.3–26.4] vs. C-allele, median [IQR] = 18.5 [12.7–28.3]; p = 0.006) but not in P-MS, except for IL-5 (T-allele, median [IQR] = 0.1 [0–0.23] vs. C-allele, median [IQR] = 0.6 [0.0–2.5]; p = 0.022). Finally, we identified an association between CC in RR-MS patients and NEDA-3 after three years of follow-up (p = 0.007). (4) We describe, for the first time, the role of an SNP of the IL-5 gene in regulating central neuroinflammation and influencing clinical course in MS patients.

MiR-142-3p has recently emerged as key factor in tailoring personalized treatments for multiple sclerosis (MS), a chronic autoimmune demyelinating disease of the central nervous system (CNS) with heterogeneous pathophysiology and an unpredictable course. With its involvement in a detrimental regulatory axis with interleukin-1beta (IL1β), miR-142-3p orchestrates excitotoxic synaptic alterations that significantly impact both MS progression and therapeutic outcomes. In this study, we investigated for the first time the influence of individual genetic variability on the miR-142-3p excitotoxic effect in MS. We specifically focused on the single-nucleotide polymorphism Val66Met (rs6265) of the brain-derived neurotrophic factor (BDNF) gene, known for its crucial role in CNS functioning. We assessed the levels of miR-142-3p and IL1β in cerebrospinal fluid (CSF) obtained from a cohort of 114 patients with MS upon diagnosis. By stratifying patients according to their genetic background, statistical correlations with clinical parameters were performed. Notably, in Met-carrier patients, we observed a decoupling of miR-142-3p levels from IL1β levels in the CSF, as well as from of disease severity (Expanded Disability Status Score, EDSS; Multiple Sclerosis Severity Score, MSSS; Age-Related Multiple Sclerosis Severity Score, ARMSS) and progression (Progression Index, PI). Our discovery of the interference between BDNF Val66Met polymorphism and the synaptotoxic IL1β-miR-142-3p axis, therefore hampering miR-142-3p action on MS course, provides valuable insights for further development of personalized medicine in the field.