Botulinum Toxin Is Effective in the Management of Neurogenic Dysphagia. Clinical-Electrophysiological Findings and Tips on Safety in Different Neurological Disorders.

Background and Aims: Neurogenic dysphagia linked to failed relaxation of the upper esophageal sphincter (UES) can be treated by injecting botulinum toxin (BTX) into the cricopharyngeal (CP) muscle. We compared the effects of this treatment in different neurological disorders with dysphagia, to evaluate its efficacy over time including the response to a second injection. Materials and Methods: Sixty-seven patients with neurogenic dysphagia associated with incomplete or absent opening of the UES (24 with brainstem or hemispheric stroke, 21 with parkinsonian syndromes, 12 with multiple sclerosis, and 10 with spastic-dystonic syndromes secondary to post-traumatic encephalopathy) were treated with the injection of IncobotulinumtoxinA (dose 15-20 U) into the CP muscle under electromyographic guidance. The patients were assessed at baseline and after the first and second treatment through clinical evaluation and fiberoptic endoscopy of swallowing, while their dysphagia was quantified using the Dysphagia Outcome and Severity Scale (DOSS). An electrokinesiographic/electromyographic study of swallowing was performed at baseline. Results: Most patients responded to the first BTX treatment: 35 patients (52.2%) were classified as high responders (DOSS score increase >2 levels), while other 19 patients (28.4%) were low responders (DOSS score increase of ≤2 levels). The effect of the first treatment usually lasted longer than 4 months (67%), and in some cases up to a year. The treatment efficacy remained high also after the second injection: 31 patients (46.3%) qualified as high responders and other 22 patients (32.8%) showed a low response. Only in the parkinsonian syndromes group we observed a reduction in the percentage of high responders as compared with the first treatment. Side effects were mostly mild and reported in non-responders following the first injection. A severe side effect, consisting of ingestion pneumonia, was observed following the second BTX injection in two patients who had both been non-responders to the first. Non-responders were characterized electromyographically by higher values of the oropharyngeal interval. Conclusion: These findings confirm the effectiveness of IncobotulinumtoxinA injection in the treatment of neurogenic dysphagia due to hyperactivity and relaxation failure of the UES. Caution should be used as regards, the re-injection in non-responders to the first treatment.

The prognostic value of sleep patterns in disorders of consciousness in the sub-acute phase.

OBJECTIVE: This study aimed to evaluate, through polysomnographic analysis, the prognostic value of sleep patterns, compared to other prognostic factors, in patients with disorders of consciousness (DOCs) in the sub-acute phase. METHODS: Twenty-seven patients underwent 24-h polysomnography and clinical evaluation 3.5 ± 2 months after brain injury. Their clinical outcome was assessed 18.5 ± 9.9 months later. Polysomnographic recordings were evaluated using visual and quantitative indexes. A general linear model was applied to identify features able to predict clinical outcome. Clinical status at follow-up was analysed as a function of the baseline clinical status, the interval between brain injury and follow-up evaluation, patient age and gender, the aetiology of the injury, the lesion site, and visual and quantitative sleep indexes. RESULTS: A better clinical outcome was predicted by a visual index indicating the presence of sleep integrity (p=0.0006), a better baseline clinical status (p=0.014), and younger age (p=0.031). Addition of the quantitative sleep index strengthened the prediction. CONCLUSIONS: More structured sleep emerged as a valuable predictor of a positive clinical outcome in sub-acute DOC patients, even stronger than established predictors (e.g. age and baseline clinical condition). SIGNIFICANCE: Both visual and quantitative sleep evaluation could be helpful in predicting clinical outcome in sub-acute DOCs.

Electrophysiological Investigations of Shape and Reproducibility of Oropharyngeal Swallowing: Interaction with Bolus Volume and Age.

Electrophysiological assessment provides valuable information on physiological and pathophysiological characteristics of human swallowing. Here, new electrophysiological measures for the evaluation of oropharyngeal swallowing were assessed: (1) the activation pattern of the submental/suprahyoid EMG activity (SHEMG); (2) the reproducibility of the oral and pharyngeal phases of swallowing, by calculating the similarity index (SI) of the SHEMG (SI-SHEMG) and of the laryngeal-pharyngeal mechanogram (SI-LPM) during repeated swallows; and (3) kinesiological measures related to the LPM. An electrophysiological-mechanical method for measuring the activation pattern of the SHEMG, the SI-SHEMG, and the SI-LPM, and maximal LPM velocity and acceleration during swallowing was applied in 65 healthy subjects divided into three age groups (18-39, 40-59, 60 years or over). All the measures were assessed during three trials of eight consecutive swallows of different liquid bolus volumes (3, 12, and 20 ml). A high overall reproducibility of oropharyngeal swallowing in healthy humans was recorded. However, while values of SI-SHEMG were similar in all the age groups, the SI-LPM was found to fall significantly in the older age group. Both the SI-SHEMG and the SI-LPM were found to fall with increasing bolus volumes. The activation pattern of the SHEMG and the LPM kinesiological measures were differently modified by bolus volume and age in the older subjects with respect to the others. We describe a new approach to the electrophysiological study of swallowing based on computed semi-automatic analyses. Our findings provide insight into some previously uninvestigated aspects of oropharyngeal swallowing physiology, considered in relation to bolus volume and age. The new electrophysiological measures here described could prove useful in the clinical setting, as it is likely that they could be differently affected in patients with different kinds of dysphagia.

Interictal spiking in adult newly-diagnosed focal epilepsy of unknown cause: The effect of age.

OBJECTIVE: To assess the yield of interictal EEG spiking in standard and whole-night sleep EEGs in elderly subjects with recent-onset focal seizures compared to younger patients. METHODS: Detection of interictal epileptiform abnormalities (IEAs) and rating of mean spike index (number of interictal discharges/minute) values for different sleep stages (NREM stages 1-2 and 3-4 and REM sleep) in standard EEG (S-EEG) and 24-h ambulatory EEG (A-EEG) at first referral in three groups of thirty consecutive outpatients [aged 20-39 (young), 40-59 (adults) and ⩾60years (elderly)], retrospectively selected according to a subsequent diagnosis of focal epilepsy of unknown cause, no sleep disorders or drugs or comorbidities affecting sleep and EEG. RESULTS: Elderly subjects showed a lower rate of IEAs on S-EEG (p<0.01) but a higher propensity for spiking during deep NREM sleep, 11/30 showing IEAs exclusively during stages 3-4. Mean spike index showed a significant increase in IEAs between sleep stages 1-2 and 3-4 in the elderly subjects (p<0.001). CONCLUSIONS: A significant association emerged between IEAs during deep sleep and age (p<0.001). SIGNIFICANCE: EEG recordings covering deep NREM sleep should be recommended when IEAs detection is needed to support a diagnosis of epilepsy in elderly subjects.

VEGFA SNP rs2010963 is associated with vascular toxicity in recurrent glioblastomas and longer response to bevacizumab.

Although anti-VEGF therapy is widely used in high-grade gliomas, no predictor of response or toxicity has been reported yet. We investigated here the association of the functional single nucleotide polymorphism (SNP) rs2010963, located in the 5' untranslated terminal region of the VEGFA gene, with survival, response to bevacizumab (BVZ) and vascular toxicity. The rs2010963 was genotyped by Taqman assay in blood DNA from 954 glioma patients with available survival data, including 225 glioblastoma (GBM) patients treated with BVZ. VEGFA plasma levels were assessed by ELISA in 87 patients before treatment. Thrombo-hemorragic adverse events were recorded during BVZ treatment or not, and in an independent population of 92 GBM patients treated with temozolomide. The CC genotype was associated with the occurrence of thrombo-hemorragic events (CC 25 versus CG 13.5 and GG 5.2 %; P = 0.0044) during BVZ. A similar but weaker and non significant trend was observed in patients not receiving BVZ. A CC genotype was associated with higher levels of plasma VEGFA at baseline (107.6 versus 57.50 pg/mL in heterozygotes (CG) and 52.75 pg/mL in GG patients, P = 0.035 and P = 0.028 respectively). The CC genotype tended to be associated to longer PFS when treated with BVZ (P = 0.05), but not when treated with the temozolomide treatment. Our data suggest that the rs2010963 genotype is associated with longer PFS, higher risk of vascular events in recurrent GBM especially treated with BVZ, and higher plasma VEGFA concentration. It may help to identify patients at risk of vascular adverse events during BVZ treatment.

Ocular vestibular evoked myogenic potentials in response to air-conducted 500 Hz short tones: Effect of stimulation procedure (monaural or binaural), age and gender.

BACKGROUND: The ocular vestibular myogenic potentials (oVEMP) can be elicited by monaural air-conducted sound stimulation, and are usually recorded from the contralateral eye. In clinical setting a binaural stimulation would save time and require less effort from the subjects. OBJECTIVE: We evaluated the differences between monaural and binaural stimulation, and the possible effect of age and gender on oVEMP parameters. METHODS: Air-conducted oVEMP were recorded by binaural and by monaural stimulation in a group of 54 normal subjects, aged from 12 to 83 years, and in 50 vestibular patients. From each side, we measured the latency of the N1 component, and the peak-to-peak N1-P1 amplitude. For both parameters we also computed the asymmetry ratio. RESULTS: In normal subjects binaural stimulation produced slightly larger responses than monaural stimulation; detectability, latency and amplitude ratio were the same for the two techniques. We found no differences related to gender, and the age-induced amplitude decline was likely to be negligible.oVEMP recorded not in an acute phase of their disorder, proved to be abnormal in about 20% of the patients, and the normal or abnormal findings obtained either with monaural or with binaural stimulation were always concordant. CONCLUSIONS: The oVEMP obtained after binaural and monaural stimulation are very similar, and they are largely independent from age and gender.

Acute effects of high-frequency microfocal vibratory stimulation on the H reflex of the soleus muscle. A double-blind study in healthy subjects.

This study in healthy subjects examined the effects of a system delivering focal microvibrations at high frequency (Equistasi®) on tonic vibration stimulus (TVS)-induced inhibition of the soleus muscle H reflex. Highfrequency microvibrations significantly increased the inhibitory effect of TVS on the H reflex for up to three minutes. Moreover, Equistasi® also significantly reduced alpha-motoneuron excitability, as indicated by the changes in the ratio between the maximumamplitude H reflex (Hmax reflex) and the maximumamplitude muscle response (Mmax response); this effect was due to reduction of the amplitude of the H reflex because the amplitude of muscle response remained unchanged. The present findings indicate that Equistasi® has a modulatory effect on proprioceptive reflex circuits. Therefore, Equistasi® might interfere with some mechanisms involved in both physiological and pathophysiological control of movement and of posture.

Novel CLN3 mutation causing autophagic vacuolar myopathy.

OBJECTIVE: To identify the genetic cause of a complex syndrome characterized by autophagic vacuolar myopathy (AVM), hypertrophic cardiomyopathy, pigmentary retinal degeneration, and epilepsy. METHODS: Clinical, pathologic, and genetic study. RESULTS: Two brothers presented with visual failure, seizures, and prominent cardiac involvement, but only mild cognitive impairment and no motor deterioration after 40 years of disease duration. Muscle biopsy revealed the presence of widespread alterations suggestive of AVM with autophagic vacuoles with sarcolemmal features. Through combined homozygosity mapping and exome sequencing, we identified a novel p.Gly165Glu mutation in CLN3. CONCLUSIONS: This study expands the clinical phenotype of CLN3 disease. Genetic testing for CLN3 should be considered in AVM with autophagic vacuoles with sarcolemmal features.

Reading while moving: the functional assessment of VOR.

The head impulse test (HIT) is nowadays recognized as the gold standard for clinical testing of the angular vestibulo-ocular reflex (VOR). By imposing unpredictable, abrupt head rotations in canal pairs' planes it aims at unveiling the dysfunction of the semicircular canal towards which the head is rotated based on Ewald's II law. Functional testing of the VOR aims at assessing the ability of the reflex to stabilize gaze in space and thus allow clear vision during head movements. The HIT device (HITD) approach exploits impulsive head rotations spawning a range of angular accelerations while requiring subjects to identify optotypes briefly displayed on a screen. Here we also recorded eye movements, so that the evaluation of the individual subject is based both on the VOR gain and on the percentage of correct answers with respect to a population of controls. Here we used the HITD to study 14 patients suffering from vestibular neuritis and 7 of those were re-tested after three months. We found that the HITD was able to unveil the ipsilesional deficit and the contralesional impairment, together with the improvement in the follow-up test.

Galanin and α-MSH autoantibodies in cerebrospinal fluid of patients with Alzheimer's disease.

BACKGROUND: Neuropeptides galanin and α-melanocyte-stimulating hormone (α-MSH) are involved in the regulation of memory and appetite. Increased galanin and decreased α-MSH levels were reported in postmortem brains of patients with Alzheimer's disease (AD) but the underlying mechanisms are uncertain. Here we studied if autoantibodies (autoAbs) reacting with galanin and α-MSH are altered in AD. METHODS: Levels of free and total IgG autoAbs reacting with galanin and α-MSH were measured in sera and cerebrospinal fluid (CSF) of 18 subjects with AD and in 15 age-matched non-demented controls. Values were correlated with Mini-Mental State Examination (MMSE) score, body mass index (BMI) and CSF levels of AD biomarkers. RESULTS: CSF levels of total but not free IgG autoAbs against galanin were increased in AD, resulting in increased percentage of galanin autoAbs present as immune complexes. CSF levels of galanin total autoAbs and α-MSH free autoAbs correlated negatively with the severity of cognitive impairment as measured by MMSE. Both total and free autoAbs against galanin and α-MSH in CSF correlated negatively with age in AD patients but not in controls. CSF levels of galanin autoAbs and free α-MSH AutoAbs negatively correlated with CSF levels of t-Tau, p-Tau and ratios of t-Tau/Aß42 or p-Tau/Aß42 in AD patients but not in controls. CONCLUSIONS: AutoAbs reacting with galanin and α-MSH are present in CSF and are associated with clinical characteristics of AD patients. The functional significance and therapeutic potential of these autoAbs should be further clarified.

θ-burst stimulation of the cerebellum interferes with internal representations of sensory-motor information related to eye movements in humans.

Continuous theta-burst stimulation (cTBS) applied over the cerebellum exerts long-lasting effects by modulating long-term synaptic plasticity, which is thought to be the basis of learning and behavioral adaptation. To investigate the impact of cTBS over the cerebellum on short-term sensory-motor memory, we recorded in two groups of eight healthy subject each the visually guided saccades (VGSs), the memory-guided saccades (MGSs), and the multiple memory-guided saccades (MMGSs), before and after cTBS (cTBS group) or simulated cTBS (control group). In the cTBS group, cTBS determined hypometria of contralateral centrifugal VGSs and worsened the accuracy of MMGS bilaterally. In the control group, no significant differences were found between the two recording sessions. These results indicate that cTBS over the cerebellum causes eye movement effects that last longer than the stimulus duration. The VGS contralateral hypometria suggested that we eventually inhibited the fastigial nucleus on the stimulated side. MMGSs in normal subjects have a better final accuracy with respect to MGSs. Such improvement is due to the availability in MMGSs of the efference copy of the initial reflexive saccade directed toward the same peripheral target, which provides a sensory-motor information that is memorized and then used to improve the accuracy of the subsequent volitional memory-guided saccade. Thus, we hypothesize that cTBS disrupted the capability of the cerebellum to make an internal representation of the memorized sensory-motor information to be used after a short interval for forward control of saccades.

Changes in skeletal muscle qualities during enzyme replacement therapy in late-onset type II glycogenosis: temporal and spatial pattern of mass vs. strength response.

Muscle quality is defined as muscle strength generated per unit muscle mass. If enzyme replacement therapy (ERT) has some effects on type II glycogenosis (GSDII) skeletal muscle pathology, we should be able to measure a change in strength and mass. We conducted a prospective study including 11 patients aged 54.2 ± 11.2 years, referring to a single institution and receiving ERT for ≥2 years. Median Walton score was 3 (2.5-6). Lower limb skeletal muscles were assessed by dynamometry and quantitative muscle MRI. Three segments (anterior thigh, posterior thigh, leg) were analysed separately. Clinical-MRI correlations were searched for at T0, T6/T8, and T18/24. Changes in lean and fat body composition were assessed by bioelectrical impedance analysis. We found that the anterior thigh showed the best therapeutic response, with an improvement in muscle quality (muscle mass: +7.5%, p = 0.035; strength: +45%, p = 0.002). BMI and lean body mass increased (p = 0.007). Patients with low BMI showed a better outcome. Intramuscular fat accumulation significantly progressed in spite of ERT (+3.7%, p = 0.001), especially in the poorly responsive posterior thigh muscles. Both clinical assessment and MRI revealed a definite improvement in the anterior thigh muscles. However, progression of intramuscular fat accumulation during ERT, as well as the limited responsiveness of posterior thigh muscles, suggests the necessity for early treatment intervention. The better outcome of patients with low BMI, if confirmed, may indicate that dietary protocols could be adopted as adjuvant measures to ERT in adult GSDII.

Long-term observational, non-randomized study of enzyme replacement therapy in late-onset glycogenosis type II.

OBJECTIVES: Type II glycogenosis (GSDII) is a lysosomal storage disorder due to acid alpha-glucosidase (GAA) deficiency. Enzyme replacement therapy (ERT) with human recombinant alpha-glucosidase (rhGAA) has been demonstrated to be effective in the treatment of infantile forms of GSDII, but little information is available concerning late-onset phenotypes. Long-term follow-up studies are not available at present. The aim of this study was to evaluate the ERT long-term effects in late-onset GSDII. METHODS: Twenty-four patients, including 7 juveniles and 17 adults, received bi-weekly infusion of rhGAA (20 mg/kg) for at least 36 months. Clinical conditions, muscular function (6-min walking test, 6MWT; Walton scale, WS), respiratory function (vital capacity, VC; forced expiratory volume, FEV1; arterial pCO(2)), and muscle enzymes were assessed every 6 months. RESULTS: The 6MWT improved in both juvenile and adult patients (p = 0.01, p = 0.0002, respectively), as well as in patients with moderate to severe muscle function impairment (WS >3.5; p = 0.002). An overall improvement in WS was also observed (p = 0.0003). VC and FEV1 remained unchanged, while pCO(2) decreased (p = 0.017). Muscle enzymes decreased significantly (p < 0.0001). Two patients (8%) showed transient secondary events during ERT. CONCLUSIONS: Long-term ERT with rhGAA was shown to be safe, well tolerated, and effective in improving motor function and in stabilizing respiratory function in late-onset GSDII. The response pattern showed a progressive clinical improvement during the follow-up period in juvenile patients, while in adults it reached and maintained a plateau after the first year of treatment.

The angiotensin-converting enzyme insertion/deletion polymorphism modifies the clinical outcome in patients with Pompe disease.

PURPOSE: The insertion/deletion polymorphism of angiotensin-converting enzyme may influence muscle properties. We examined whether Pompe disease clinical manifestations, which are known to be highly variable among late-onset patients, may be modulated by angiotensin-converting enzyme polymorphism. METHODS: We included 38 patients with late-onset Pompe disease, aged 44.6 +/- 19.8 years. We compared the distribution of angiotensin-converting enzyme polymorphism according to demographic and disease parameters. RESULTS: The distribution of angiotensin-converting enzyme polymorphism was in line with the general population, with 16% of patients carrying the II genotype, 37% carrying the DD genotype, and the remaining patients with the ID genotype. The three groups did not differ in mean age, disease duration, Walton score, and other scores used to measure disease severity. The DD polymorphism was associated with earlier onset of disease (P = 0.041), higher creatine kinase levels at diagnosis (P = 0.024), presence of muscle pain (P = 0.014), and more severe rate of disease progression (P = 0.037, analysis of variance test for interaction). DISCUSSION: These findings suggest a potential role of angiotensin-converting enzyme polymorphism in modulating Pompe disease phenotype and prognosis.