Emotion recognition in amyotrophic lateral sclerosis in a dynamic environment.

OBJECTIVE: The aim of our study was to measure the ability of ALS patients to process dynamic facial expressions as compared to a control group of healthy subjects and to correlate this ability in ALS patients with neuropsychological, clinical and neurological measures of the disease. METHODS: Sixty-three ALS patients and 47 healthy controls were recruited. All the ALS patients also underwent i) the Geneva Emotion Recognition Test (GERT) in which ten actors express 14 types of dynamic emotions in brief video clips with audio, ii) the Edimburgh Cognitive and Behavioral ALS Screen (ECAS) test; iii) the ALS Functional Rating Scale Revised (ALSFRS-R) and iv) the Medical Research Council (MRC) for the evaluation of muscle strength. All the healthy subjects enrolled in the study underwent the GERT. RESULTS: The recognition of irritation and pleasure was significantly different between ALS patients and the control group. The amusement, despair, irritation, joy, sadness and surprise had been falsely recognized differently between the two groups. Specific ALS cognitive impairment was associated with bulbar-onset phenotype (OR = 14,3889; 95%CI = 3,96-52,16). No association was observed between false emotion recognition and cognitive impairment (F(1,60)=,56,971, p=,45,333). The number of categorical errors was significantly higher in the ALS patients than in the control group (27,66 ± 7,28 vs 17,72 ± 5,29; t = 8723; p = 0.001). CONCLUSIONS: ALS patients show deficits in the dynamic processing of a wide range of emotions. These deficits are not necessarily associated with a decline in higher cognitive functions: this could therefore lead to an underestimation of the phenomenon.

MiR206 and 423-3p Are Differently Modulated in Fast and Slow-Progressing Amyotrophic Lateral Sclerosis Patients.

Amyotrophic lateral sclerosis (ALS) is a rare neuromuscular disease with a wide disease progression. Despite several efforts to develop efficient biomarkers, many concerns about the available ones still need to be addressed. MicroRNA (miR) are non-coding RNAs that can modulate molecular circuits and are involved in ALS pathogenic mechanisms. 22 fast and 23 slow-progressing-defined ALS patients were recruited. ALSFRS-R, strength, respiratory function, nerve conduction studies, and creatine kinase were evaluated at the baseline and after 6 months of follow-up. The mean monthly reduction of the previous variables (progression index - PI) was calculated. MiR206, 133a-3p, 151a-5p, 199a-5p, and 423-3p were dosed. The univariate analysis showed an independent reduction of miR206 and an increase of miR423-3p in patients with a slow slope of ALSFRS-R and weakness, respectively. MiR206 and 423-3p are differently modulated in fast and slow-progressing ALS patients, suggesting a role for microRNAs in prognosis and therapeutic target.

Chronic inflammatory demyelinating polyneuropathy and HEV antibody status: A case-control study from Lazio, Italy.

INTRODUCTION: Few studies have pointed to the possible role of infectious diseases in triggering Chronic Inflammatory Demyelinating Polyradiculoneuropathy (CIDP). Given the association of Hepatitis E Virus (HEV) with Guillain Barrè syndrome, we conducted a case-control study to determine the possible association of HEV infection with CIDP, analyzing possible risk factors for acquiring HEV infection in both CIDP patients and controls. MATERIALS AND METHODS: 82 CIDP and 260 from the general population have provided some personal information (demographics, anamnestic data and recognized risk factors for HEV infection) and underwent venipuncture blood sampling for virological assays testing for anti-HEV IgG and IgM with ELISA and RNA-HEV performing RT-PCR. RESULTS: Anti-HEV IgG seropositivity resulted in 32 CIDP patients (39.0%) and in 45 controls (17.3%), indicating a significant association between anti-HEV IgG positivity and CIDP (OR 3.04; 95% CI 1.70-5.43, p-value <0.001), but in multivariate logistic regression the only significant associations with anti-HEV positivity were eating pork liver sausages (OR 10.443, 95% CI 2.268-60.12, p-value 0.004) and IVIg/SCIg administration (OR 31.32, 95% CI 7.914-171.7, p-value <0.001). DISCUSSION: The higher prevalence of anti-HEV IgG in CIDP patients than in controls could be justified by chronically administering IVIg/SCIg with a passive acquisition of anti-HEV antibodies. Furthermore, all the 20 CIDP patients who underwent IVIg/SCIg administration reported HEV risk factors, so that they could have acquired the infection. CONCLUSIONS: Further studies in a larger CIDP patient sample in treatment with therapy other than IVIg/SCIg are necessary to rule out the possible confounding effect of IVIg/SCIg.

Genetics screening in an Italian cohort of patients with Amyotrophic Lateral Sclerosis: the importance of early testing and its implication.

INTRODUCTION: Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease with an elusive etiology. While environmental factors have been considered, familial ALS cases have raised the possibility of genetic involvement. This genetic connection is increasingly evident, even in patients with sporadic ALS. We allowed access to the genetic test to all patients attending our clinic to identify the prevalence and the role of genetic variants in the development of the disease and to identify patients with potentially treatable forms of the disease. MATERIALS AND METHODS: 194 patients with probable or definite ALS, were enrolled. A comprehensive genetic testing was performed, including sequencing all exons of the SOD1 gene and testing for hexanucleotide intronic repeat expansions (G4C2) in the C9orf72 gene using fluorescent repeat-primed PCR (RP-PCR). Whole Exome NGS Sequencing (WES) was performed, followed by an in silico multigene panel targeting neuromuscular diseases, spastic paraplegia, and motor distal neuropathies. We conducted statistical analyses to compare different patient groups. RESULTS: Clinically significant pathogenetic variants were detected in 14.43% of cases. The highest prevalence of pathogenetic variants was observed in fALS patients, but a substantial proportion of sALS patients also displayed at least one variant, either pathogenetic or of uncertain significance (VUS). The most observed pathogenetic variant was the expansion of the C9orf72 gene, which was associated with a shorter survival. SOD1 variants were found in 1.6% of fALS and 2.5% of sALS patients. DISCUSSION: The study reveals a significant number of ALS patients carrying pathogenic or likely pathogenic variants, with a higher prevalence in familial ALS cases. The expansion of the C9orf72 gene emerges as the most common genetic cause of ALS, affecting familial and sporadic cases. Additionally, SOD1 variants are detected at an unexpectedly higher rate, even in patients without a familial history of ALS, underscoring the crucial role of genetic testing in treatment decisions and potential participation in clinical trials. We also investigated variants in genes such as TARDBP, FUS, NEK1, TBK1, and DNAJC7, shedding light on their potential involvement in ALS. These findings underscore the complexity of interpreting variants of uncertain significance (VUS) and their ethical implications in patient communication and genetic counseling for patients' relatives. CONCLUSION: This study emphasizes the diverse genetic basis of ALS and advocates for integrating comprehensive genetic testing into diagnostic protocols. The evolving landscape of genetic therapies requires identifying all eligible patients transcending traditional familial boundaries. The presence of VUS highlights the multifaceted nature of ALS genetics, prompting further exploration of complex interactions among genetic variants, environmental factors, and disease development.

Retrospective observational study on the use of acetyl-L-carnitine in ALS.

ALCAR (Acetyl-L-carnitine) is a donor of acetyl groups and increases the intracellular levels of carnitine, the primary transporter of fatty acids across the mitochondrial membranes. In vivo studies showed that ALCAR decrease oxidative stress markers and pro-inflammatory cytokines. In a previous double-blind placebo-controlled phase II trial showed positive effects on self-sufficiency (defined as a score of 3+ on the ALSFRS-R items for swallowing, cutting food and handling utensils, and walking) ALSFRS-R total score and FVC. We conducted an observational, retrospective, multicentre, case-control study to provide additional data on the effects of ALCAR in subjects with ALS in Italy. Subjects treated with ALCAR 1.5 g/day or 3 g/day were included and matched with not treated subjects by sex, age at diagnosis, site of onset, and time from diagnosis to baseline, (45 subjects per group). ALCAR 3 g/day vs not treated: 22 not treated subjects (48.9%) were still alive at 24 months after baseline, compared to 23 (51.1%) treated subjects (adj. OR 1.18, 95% CI 0.46-3.02). No statistically significant differences were detected in ALSFRS nor FVC nor self-sufficiency. ALCAR 1.5 g/day vs not treated: 22 not treated subjects (48.9%) were still alive at 24 months after baseline, compared to 32 (71.1%) treated subjects (adj. OR 0.27, 95% CI 0.10-0.71). For ALSFRS-R, a mean slope of - 1.0 was observed in treated subjects compared to - 1.4 in those not treated (p = 0.0575). No statistically significant difference was detected in the FVC nor self-sufficiency. Additional evidence should be provided to confirm the efficacy of the drug and provide a rationale for the dosage.

Does Patisiran Reduce Ocular Transthyretin Synthesis? A Pilot Study of Two Cases.

BACKGROUND: Variant transthyretin-mediated amyloidosis (ATTR-v) is a well-characterized disease affecting the neurologic and cardiovascular systems. Patisiran has been approved for neurologic involvement as it reduces hepatic synthesis of transthyretin (TTR). Eye involvement is a lateonset feature increasing the risk of glaucoma and cataracts in patients. AIMS: The aim of this case series was to assess whether patisiran can effectively reduce TTR synthesis in such a barrier-protected organ as the eye. METHODS: Two patisiran-treated ATTR-v patients underwent serum and aqueous humor sampling to measure TTR levels detected by SDS-PAGE and immunoblotting. Serum samples were compared to healthy control (HC), whereas aqueous humor samples were compared to non-amyloidotic subjects affected by cataracts and glaucoma. RESULTS: Serum TTR levels representative of hepatic synthesis were sharply lower in treated patients if compared to the HC (-87.5% and -93.75%, respectively). Aqueous humor TTR levels showed mild-tono reduction in treated patients compared to non-amyloidotic subjects with cataracts (-34.9% and +8.1%, respectively) and glaucoma (-41.1% and -2.1%). CONCLUSION: Patisiran does not seem to be as effective in inhibiting ocular TTR synthesis as it is in inhibiting hepatic synthesis. Re-engineering the envelope could allow the drug to target RPE cells thus avoiding any ocular involvement.

Effects of 3,4-diaminopyridine on myasthenia gravis: Preliminary results of an open-label study.

Background: 3,4-diaminopyridine (3,4-DAP) can lead to clinical and electrophysiological improvement in myasthenic syndrome; it may thus represent a valuable therapeutic option for patients intolerant to pyridostigmine. Objective: to assess 3,4-diaminopyridine (3,4-DAP) effects and tolerability in patients with anti-AChR myasthenia gravis. Method: Effects were monitored electrophysiologically by repetitive nerve stimulation (RNS) and by standardized clinical testing (QMG score) before and after a single dose administration of 3,4-DAP 10 mg per os in 15 patients. Patients were divided according to their Myasthenia Gravis Foundation of America (MGFA) class into mild and severe. Results: No significant side effects were found, apart from transient paresthesia. 3,4-DAP had a significant effect on the QMG score (p = 0.0251), on repetitive nerve stimulation (p = 0.0251), and on the forced vital capacity (p = 0.03), thus indicating that it may reduce the level of disability and the decremental muscle response. When the patients were divided according to the MGFA classification, 3,4-DAP showed a positive effect in the severe group, either for the QMG score (p = 0.031) or for the RNS decrement (p = 0.031). No significant difference was observed in any of the outcome measures within the mild group (p > 0.05). A direct effect of 3,4-DAP on nicotinic ACh receptors (nAChRs) was excluded since human nAChRs reconstituted in an expression system, which were not affected by 3,4-DAP application. Conclusion: Our results suggest that 3,4-DAP may be a useful add-on therapy, especially in most severe patients or when immunosuppressive treatment has not yet reached its full effect or when significant side-effects are associated with anticholinesterase.

The Silent Period for Small Fiber Sensory Neuropathy Assessment in a Mixed Cohort of Transthyretin-Mediated Amyloidosis.

BACKGROUND: Transthyretin-mediated amyloidosis (ATTR) is a rare multisystemic disease involving the peripheral nervous system and heart. Autonomic and small fiber involvement is one of the hallmarks of ATTR, and many tools have been proposed to assess this aspect. AIM: The aim of this study was to investigate cutaneous and mixed nerve silent periods (CSP and MnSP) as instruments for small fiber assessment. METHODS: A total of 21 ATTR patients, 20 healthy controls, and 18 asymptomatic carriers underwent a sensory conduction study from the right sural and non-dominant ulnar nerves. A motor conduction study from the right deep peroneal and non-dominant ulnar nerves, with their F waves, CSPs, and MnSPs, was performed. RESULTS: The amplitudes of the sural and ulnar sensory nerves and of the peroneal and ulnar motor nerves were reduced in ATTR patients compared to the other groups. F waves from the ulnar and peroneal nerves showed no differences between the three groups. The CSP and MnSP latency, but not amplitude, were increased in both the ulnar and peroneal nerves of ATTR patients. CONCLUSIONS: ATTR patients showed axonal involvement of large sensory and motor nerve fibers and demyelinating features of small sensory fibers.

Effects of Skin Stimulation on Sensory-Motor Networks Excitability: Possible Implications for Physical Training in Amyotrophic Lateral Sclerosis.

Background: Many different trials were assessed for rehabilitation of patients with amyotrophic lateral sclerosis (ALS), with non-unique results. Beside the effects on muscle trophism, some of the encouraging results of physical training could be ascribed to the modulation of cortical excitability, which was found hyperexcited in ALS. Objective: The effects of tactile skin stimulation in the modulation of the sensory-motor integrative networks in healthy subjects were assayed through the paired associative stimulation (PAS) protocol. Methods: In total, 15 healthy subjects were enrolled. In the standard PAS session, the average amplitude of the motor evoked potential (MEP) after 10 stimuli of transcranial magnetic stimulation (TMS) was measured at the baseline and after the PAS protocol (0, 10, 20, 30, and 60 min). In the skin stimulation session, the average amplitude of the MEP was measured before and after 10 min of skin stimulation over the hand. Subsequently, each subject underwent the PAS stimulation and the measure of the average amplitude of the MEP (0, 10, 20, 30, and 60 min). Results: The tactile skin stimulation on healthy subjects increases the PAS-induced sensory-motor network hyperexcitability in healthy subjects. Conclusion: Skin stimulation should be avoided in the physiotherapeutic approaches for patients with ALS, given the possible hyperexciting effects on the already upmodulated sensory-motor networks. They can be taken into account for diseases characterized by downregulation of cortical and transcortical networks.

Classical and Unexpected Effects of Ultra-Micronized PEA in Neuromuscular Function.

Recently, the endocannabinoid system has attracted growing attention from the scientific community for its involvement in homeostatic and pathological processes as they pertains to human physiology. Among the constituents of the endocannabinoid system, the molecule palmitoyl ethanolamide has particularly been studied for its ability to reduce several inflammatory processes involving the central nervous system. Here, we reviewed published literature and summarized the main targets of the palmitoyl ethanolamide, along with its unique possible mechanisms for restoring correct functioning of the central nervous system. Moreover, we have highlighted a less-known characteristic of palmitoyl ethanolamide, namely its ability to modulate the function of the neuromuscular junction by binding to acetylcholine receptors in different experimental conditions. Indeed, there are several studies that have highlighted how ultra-micronized palmitoyl ethanolamide is an interesting nutraceutical support for the treatment of pathological neuromuscular conditions, specifically when the normal activity of the acetylcholine receptor is altered. Although further multicentric clinical trials are needed to confirm the efficacy of ultra-micronized palmitoyl ethanolamide in improving symptoms of neuromuscular diseases, all the literature reviewed here strongly supports the ability of this endocannabinoid-like molecule to modulate the acetylcholine receptors thus resulting as a valid support for the treatment of human neuromuscular diseases.

Creatine Kinase and Progression Rate in Amyotrophic Lateral Sclerosis.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with no recognized clinical prognostic factor. Creatinine kinase (CK) increase in these patients is already described with conflicting results on prognosis and survival. In 126 ALS patients who were fast or slow disease progressors, CK levels were assayed for 16 months every 4 months in an observational case-control cohort study with prospective data collection conducted in Italy. CK was also measured at baseline in 88 CIDP patients with secondary axonal damage and in two mouse strains (129SvHSD and C57-BL) carrying the same SOD1G93A transgene expression but showing a fast (129Sv-SOD1G93A) and slow (C57-SOD1G93A) ALS progression rate. Higher CK was found in ALS slow progressors compared to fast progressors in T1, T2, T3, and T4, with a correlation with Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) scores. Higher CK was found in spinal compared to bulbar-onset patients. Transgenic and non-transgenic C57BL mice showed higher CK levels compared to 129SvHSD strain. At baseline mean CK was higher in ALS compared to CIDP. CK can predict the disease progression, with slow progressors associated with higher levels and fast progressors to lower levels, in both ALS patients and mice. CK is higher in ALS patients compared to patients with CIDP with secondary axonal damage; the higher levels of CK in slow progressors patients, but also in C57BL transgenic and non-transgenic mice designs CK as a predisposing factor for disease rate progression.

Heteronymous H reflex in temporal muscle as sign of hyperexcitability in ALS patients.

OBJECTIVE: The stimulation of the masseteric nerve elicits a homonymous and a heteronymous H reflex in the masseter muscle and in the temporalis one. The presence of the H reflex may be considered a sign of upper motor neuron (UMN) involvement in amyotrophic lateral sclerosis (ALS) patients. The aim of this study was to evaluate the presence of the heteronymous H reflex in patients with ALS and compare it with normal subjects. METHODS: We enrolled 36 ALS patients and 52 healthy subjects. We stimulated the masseteric nerve in the infratemporal fossa and recorded the muscle responses ipsilaterally to the stimulation. RESULTS: The heteronymous temporalis H reflex was elicitable in 88.9% of ALS patients and in none of the controls. CONCLUSION: The heteronymous H reflex does not disappear when the stimulation intensity is increased. It can be used as sign of UMN involvement and may prove useful in patients with suspected MND/ALS with purely lower motor neurons (LMN) signs and no signs of UMN involvement. SIGNIFICANCE: The heteronymous H reflex is present far more often in ALS patients than in healthy people. It is a simple test that may be used to detect UMN involvement in patients in whom the only evident signs are LMN impairment, improving diagnosis of ALS.

Short-Term Ultramicronized Palmitoylethanolamide Therapy in Patients with Myasthenia Gravis: a Pilot Study to Possible Future Implications of Treatment.

BACKGROUND: The cannabinoid system may be involved in the humoral mechanisms at the neuromuscular junction. Ultramicronized-palmitoylethanolamide (µm-PEA) has recently been shown to reduce the desensitization of Acetylcholine (ACh)-evoked currents in denervated patients modifying the stability of ACh receptor (AChR) function. OBJECTIVE: To analyze the possible beneficial effects of µm-PEA in patients with myasthenia gravis (MG) on muscular fatigue and neurophysiological changes. METHOD: The duration of this open pilot study, which included an intra-individual control, was three weeks. Each patient was assigned to a 1-week treatment period with µm-PEA 600 mg twice a day. A neurophysiological examination based on repetitive nerve stimulation (RNS) of the masseteric and the axillary nerves was performed, and the quantitative MG (QMG) score was calculated in 22 MG patients every week in a three-week follow-up period. AChR antibody titer was investigated to analyze a possible immunomodulatory effect of PEA in MG patients. RESULTS: PEA had a significant effect on the QMG score (p=0.03418) and on RNS of the masseteric nerve (p=0.01763), thus indicating that PEA reduces the level of disability and decremental muscle response. Antibody titers did not change significantly after treatment. CONCLUSION: According to our observations, µm-PEA as an add-on therapy could improve muscular response to fatigue in MG. The possible modulation of AChR currents as a means of eliciting a direct effect from PEA on the conformation of ACh receptors should be investigated. The co-role of cytokines also warrants an analysis. Given the rapidity and reversibility of the response, we suppose that PEA acts directly on AChR, though further studies are needed to confirm this hypothesis.

Repetitive transcranial magnetic stimulation for chronic neuropathic pain in patients with bladder pain syndrome/interstitial cystitis.

AIMS: To evaluate the efficacy, safety, and tolerability of repetitive Transcranial Magnetic Stimulation (rTMS) associated with standard drug therapies for neuropathic pain that does not respond to pharmacological treatment alone in patients with Bladder Pain Syndrome/Interstitial Cystitis (BPS/IC). Secondary goals were to assess the effects of rTMS on Lower Urinary Tract Symptoms (LUTS) and Quality of Life (QOL). METHODS: Fifteen patients with BPS/IC were enrolled in this randomized, double-blind, sham stimulation-controlled, crossover study. Patients were treated for 2 weeks with either real-rTMS (for five consecutive days in 20-min sessions) or sham-rTMS (for five consecutive days in 20-min sessions). After a 6-week washout period, the patients who had previously undergone real-rTMS underwent sham-rTMS, and vice versa. Patients were rated at each visit by means of questionnaires on pain, urinary disturbances, depression, and QOL. RESULTS: The statistical analysis revealed significant effects of real-rTMS, when compared with sham-rTMS, on pain (in the VAS, Functional Neuropathic Pelvic Pain, Neuropathic Pain Symptom Inventory, McGill questionnaire, and Central Sensitization Inventory), urinary LUTS (in the Overactive Bladder Questionnaire score, bladder emptying, and daily urinary frequency), and QOL (in the subscores of the SF-36 related to physical pain and to emotional status). No serious adverse events were reported during the study. CONCLUSIONS: The results of this study show that rTMS applied with an H-coil over the M1 in the area corresponding to the pelvic region in patients with BPS/IC appears to improve chronic pelvic pain (CPP) and associated urinary disorders.

Chronic inflammatory demyelinating polyneuropathy: evaluation of the vestibular system with cervical and ocular vestibular evoked myogenic potentials.

PURPOSE: To investigate the possibility of vestibular damage in a group of patients suffering from chronic inflammatory demyelinating polyneuropathy (CIDP) using a diagnostic protocol including the caloric test, C-VEMPs and O-VEMPs. METHODS: Twenty patients suffering from CIDP (mean age 58.5 years, range 33-80 years; 4 women and 16 men) were investigated. To assess any eventual audio-vestibular involvement, all patients of the study underwent pure tone audiometry, Fitzgerald-Hallpike caloric vestibular test, C-VEMPs and O-VEMPs. RESULTS: In 11 patients with CIDP values of both O-VEMPs and C-VEMPs were either absent or abnormal. An absent trace at O-VEMPs testing occurred in 36% of these pathological patients, whereas an increase of n10 latency and amplitude was present in the other 64% . CONCLUSIONS: A specific diagnostic protocol including the caloric test, C-VEMPS, O-VEMPS, could be useful when employed for identifying vestibular damage in CIDP patients.