New insights into RAGE/Diaph1 interaction as a modulator of actin cytoskeleton dynamics in peripheral nervous system in long-term hyperglycaemia.

This review focuses on receptor for advanced glycation endproducts/diaphonous related formin 1 (RAGE/Diaph1) interaction as a modulator of actin cytoskeleton dynamics in peripheral nervous system (PNS) in diabetes. Deciphering the complex molecular interactions between RAGE and Diaph1 is crucial in expanding our understanding of diabetic length dependent neuropathy (DLDN). DLDN is a common neurological disorder in patients with diabetes. It is well known that actin cytoskeletal homeostasis is disturbed during DLDN. Thus, we review the current status of knowledge about RAGE/Diaph1 impact on actin cytoskeletal malfunctions in PNS and DLDN progression in diabetes. We also survey studies about small molecules that may block RAGE/Diaph1 axis and thus inhibit the progression of DLDN. Finally, we explore examples of cytoskeletal long-non coding RNAs (lncRNAs) currently unrelated to DLDN, to discuss their potential role in this disease. Most recent studies indicated that lncRNAs have a great potential in many research areas, including RAGE/Diaph1 axis as well as DLDN. Altogether, this review is aimed at giving us an insight into the involvement of cytoskeletal lncRNAs in DLDN.

Plasma levels of soluble RAGE, AGEs and AOPPs at the early stage of amyotrophic lateral sclerosis: A preliminary study.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder with largely unknown pathogenesis and no effective cure. It is believed that several, not mutually exclusive mechanisms contribute to the pathogenesis and progression of this disease, including, among others, elevated oxidative stress, excitotoxicity, increased neuroinflammation, and protein aggregation. Receptor for advanced glycation end products (RAGE) is a part of immunoglobulin superfamily; it is believed to participate in ALS pathogenesis. OBJECTIVES: Our previous studies on ALS demonstrated that RAGE is likely one of the key players in ALS, acting on its own and in tandem with its oxidative stress and pro-inflammatory ligands, such as advanced glycation end products (AGEs) or advanced oxidation protein products (AOPPs). In this study, based on our previous results, we aimed to establish blood levels of soluble RAGE, AGE and AOPP in ALS patients. MATERIAL AND METHODS: Forty-six coded and anonymized surplus plasma samples from ALS patients and non-neurological control were used in the study. The plasma levels of RAGE, AGE and AOPP were measured using enzyme-linked immunosorbent assay (ELISA) commercially available kits. Statistical evaluation of data was performed using one-way non-parametric analysis of variance (ANOVA) with Kruskal-Wallis post hoc test. RESULTS: Our results revealed a decline in soluble RAGE level, concurrent with an increase in the levels of AGEs and AOPPs in blood samples from ALS patients, signifying a loss of neuroprotective form of RAGE and a simultaneous increase in AGE and AOPP production and uptake at the early stage of the disease. CONCLUSIONS: The results obtained from our study indicate that further longitudinal study of RAGE, AGE and AOPP levels would be beneficial, outlining the dynamics between RAGE and its ligand levels as the disease progresses, and making them valuable diagnostic tools and potential therapeutic targets.

The adaptation of Polish version of Six-Item Carpal Tunnel Syndrome Symptoms Scale.

BACKGROUND: The Carpal Tunnel Syndrome is one of the most common peripheral neuropathy. The diagnosis could be made by taking the medical history from a patient or by physical examination or by performing electroneurography. The aims of the study were (1) to translate and adaptate the Polish version of the Six-Item Carpal Tunnel Syndrome Symptoms Scale (CTS-6 SS) and (2) to analyse the associations between different Patients-Reported Outcome Measures and nerve conduction studies (NCS). METHODS: One-hundred and fifty patients consistent with inclusion criteria filled the CTS-6 SS, Boston Carpal Tunnel Questionnaire (BCTQ), Disabilities of the Arm, Shoulder and the Hand (DASH) and Michigan Hand Outcomes Questionnaire (MHQ) during their first visit to the clinic. Then, they had the NCS done. After two weeks, 99 patients filled the CTS-6 SS for the second time. RESULTS: The Polish version of CTS-6 SS revealed good psychometric properties: high values of internal consistency, test-retest reliability and validity. The construct validity showed strong correlation with BCTQ - R = 0.87 (p < 0.05) for Symptoms Severity Scale (SSS) and R = 0.64 (p < 0.05) Functional Status Scale (FSS). Additionally CTS-6 SS has at least moderate correlation with DASH R = 0.53 (p < 0.05). CONCLUSIONS: The Polish version of translated scale was adapted and used together with NCS complete the overall picture of patients suffering from CTS. STUDY DESIGN: Prospective study.

Polish version of the Patient-Rated Ulnar Nerve Evaluation in preoperative patients: Translation and psychometric testing.

STUDY DESIGN: Cross-sectional design. INTRODUCTION: This study examined the translated English to Polish version of the Patient-Rated Ulnar Nerve Evaluation (PRUNE) for its internal consistency, test-retest reliability, and construct validity. METHODS: During the first assessment validity testing, a total of 39 consecutive patients with cubital tunnel syndrome completed the PRUNE, Michigan Hand Outcome Questionnaire, Disabilities of the Arm, Shoulder, and Hand questionnaire, and Patient Evaluation Measure in conjunction with the grip and key pinch tests and pain score (by Visual Analogue Scale). Cronbach's alpha (CA), intraclass correlation coefficient (ICC), and the Bland-Altman plot were used to evaluate internal consistency, test-retest reliability, and agreement, respectively. Analysis of variance compared the PRUNE score with the McGowan clinical stages. RESULTS: After a 1-day interval, 19 patients completed the PRUNE for the second time. The total PRUNE score was 44.4 ± 20.4, CA = 0.93, and ICC = 0.921. The total PRUNE score limits of agreement varied from -9.87 to 7.55 points. PRUNE subscale CA ranged from 0.79 to 092; the ICC varied from 0.738 to 0.911. The construct validity revealed a strong association with Michigan Hand Outcome Questionnaire (R = -0.83; P < .000), and moderate with Disabilities of the Arm, Shoulder, and Hand (R = 0.75; P < .000), Patient Evaluation Measure (R = 0.75; P < .000), and Visual Analogue Scale (R = 0.69; P < .000). The grip and pinch tests had low and no correlation with the total PRUNE score, respectively. CONCLUSION: The Polish version of PRUNE showed good psychometric properties for use in both clinical and research practice in patients with cubital tunnel syndrome of varying intensity.

Efficacy and safety of abobotulinumtoxinA liquid formulation in cervical dystonia: A randomized-controlled trial.

BACKGROUND: Approved botulinum toxin A products require reconstitution. AbobotulinumtoxinA solution for injection is a ready-to-use liquid formulation of abobotulinumtoxinA. OBJECTIVES: The objective of this study was to demonstrate the superior efficacy of abobotulinumtoxinA solution for injection to placebo and to test the noninferior efficacy of abobotulinumtoxinA solution for injection versus abobotulinumtoxinA (dry formulation) in cervical dystonia. METHODS: This was a phase-3, multicenter, prospective, double-blind, randomized, active, and placebo-controlled study (N = 369). Patients with cervical dystonia were randomized (3:3:1) to abobotulinumtoxinA solution for injection 500 U, abobotulinumtoxinA 500 U, or placebo. Following the double-blind phase, patients received abobotulinumtoxinA solution for injection, open-label, for up to 4 cycles. The primary outcome was change from baseline at week 4 of the Toronto Western Spasmodic Torticollis Rating Scale total score. Secondary measures included change from baseline or cycle baseline in Toronto Western Spasmodic Torticollis Rating Scale scores. RESULTS: At week 4, both products were superior to placebo (Toronto Western Spasmodic Torticollis Rating Scale total score least square mean decrease from baseline, abobotulinumtoxinA solution for injection 500 U -12.5, abobotulinumtoxinA 500 U -14.0, placebo -3.9; P < .0001 vs placebo). The noninferiority limit of 3 points in the Toronto Western Spasmodic Torticollis Rating Scale total score at week 4 was not met for abobotulinumtoxinA solution for injection versus abobotulinumtoxinA. Toronto Western Spasmodic Torticollis Rating Scale total score reductions were maintained for up to 4 cycles of abobotulinumtoxinA solution for injection open-label follow-up treatment. Safety profiles of abobotulinumtoxinA solution for injection and abobotulinumtoxinA were similar, with dysphagia and injection-site pain the most frequent drug-related adverse events. CONCLUSIONS: Although the predefined noninferiority criterion was not met, abobotulinumtoxinA solution for injection was similarly effective to freeze-dried abobotulinumtoxinA in reducing Toronto Western Spasmodic Torticollis Rating Scale total scores with a similar safety profile. AbobotulinumtoxinA solution for injection efficacy was maintained with chronic open-label treatment, and this novel formulation may add convenience as well as dosing accuracy to treatment with abobotulinumtoxinA. © 2016 International Parkinson and Movement Disorder Society.

[Neuralgic amyotrophy--a case report]. / Neuralgia amiotroficzna--opis przypadku.

We describe a case of a 54-year-old woman reporting weakness of the right upper limb, preceded by a period of severe pain in the right shoulder. Despite several orthopedic consultations and two cycles of physical therapy, the symptoms deteriorated over a period of 6 months, and progressive paresis of the extensor muscles of the upper limb and elbow flexion contracture were observed. On the basis of the clinical presentation and results of medical tests including an electrophysiological study that showed axonal damage to the long thoracic nerve, axillary nerve, and posterior interosseous nerve, neuralgic amyotrophy was diagnosed. A treatment with prednisone was introduced, and the patient's condition significantly improved.

[Thalidomide induced peripheral neuropathy in multiple myeloma patients]. / Polekowa neuropatia obwodowa u pacjentów ze szpiczakiem plaZmocytowym leczonych talidomidem.

INTRODUCTION: Thalidomide, a sedative popular in the 1950s and withdrawn from the market in the 1960s because of its teratogenic effects, has emerged again on the market in the last decade as an effective agent in the treatment of multiple myeloma. Unfortunately, apart from positive treatment effects, numerous side effects have been shown in multiple myeloma patients, including drug-induced damage to peripheral nerves, leading to clinical neuropathy. OBJECTIVES: A clinical and electrophysiological assessment of the prevalence of peripheral neuropathy in patients with multiple myeloma treated with thalidomide. PATIENTS AND METHODS: The study included 43 patients (19 women and 24 men) with a clinical diagnosis of multiple myeloma and treated with thalidomide (average dose, 100 mg/d). Patients with a history of disorders or the presence of factors leading to nervous system damage were excluded from the study. An electrophysiological assessment of motor and sensory fibers of the median, ulnar, peroneal, and tibial nerves was performed. RESULTS: Polyneuropathy was present in 27 patients. In addition, carpal tunnel syndrome coexisting with polyneuropathy was observed in 6 patients. Carpal tunnel syndrome was reported in 4 patients. Moreover, supracondylar damage to the ulnar nerve was reported in 1 patient and Guyon syndrome--in 1 patient. The results of the electrophysiological study were normal in 10 patients. CONCLUSIONS: Our study showed that over 60% of patients treated with thalidomide have peripheral nerve changes typical for peripheral neuropathy. Owing to the high risk of peripheral neuropathy in patients treated with thalidomide, we recommend a routine electrophysiological study in all patients with multiple myeloma in order to diagnose neuropathy at an early stage. Dose reduction or the use of an equally effective but less neurotoxic drug allows to prevent polyneuropathy, while maintaining the basic parameters of cancer treatment.

[Correlations between the lumbrical-interosseous latency comparison test and standard tests used in the diagnosis of carpal tunnel syndrome]. / Korelacje testu porównujacego róznice latencji miedzy miesniem glistowatym a miedzykostnym z testami standardowymi stosowanymi w diagnostyce zespolu ciesni nadgarstka.

The diagnosis of patients with severe carpal tunnel syndrome (CTS) who do not respond to median nerve stimulation and of those with early CTS who report symptoms but show no abnormalities in standard tests is the most challenging. The aim of the study was to assess correlations between the 2LI-DML test and standard tests used for the diagnosis of CTS (SL-D2, DML-APB, D4M-D4U). The study involved 172 patients (253 nerves) with clinical symptoms of CTS. The sensitivity of the 2LI-DML test and standard tests was analyzed in 6 groups of patients classified according to the severity of CTS, assessed by an electrophysiological study. We showed a significant relationship between the results of the 2LI-DML test and those of standard tests (SL-D2, DML-APB, D4M-D4U), as revealed by a topographic analysis of sensory and motor fibers of the median nerve at the site most vulnerable to compression.

[Cardiac abnormalities in patients with myotonic dystrophy--preliminary results]. / Zaburzenia kardiologiczne u pacjentów z dystrofia miotoniczna--doniesienie wstepne.

INTRODUCTION: Myotonic dystrophy (DM) is an inherited multisystem disorder associated with myotonia, progressive skeletal muscle weakness and atrophy, involvement of peripheral and central nervous system and sudden death likely due to atrioventricular block and/or ventricular arrhythmia. AIM OF THE STUDY: to assess the type and degree of cardiac and neurological involvement in patients (pts) with DM. MATERIALS AND METHODS: 10 pts (6 male), in mean age of 35 +/- 13 years, treated for DM type I (DM1)--7 pts and type II (DM2)--3 pts. All pts underwent a neurological examination including muscle strength assessment as well as cardiac diagnostics including: standard and 48-hour ambulatory electrocardiogram, echocardiographic examination, magnetic resonance imaging (MRI) of the heart and late potentials assessment. RESULTS: Muscle strength was moderately diminished (46-48 points in MRC sub score) in 3 pts with DM1 and mildly diminished (56-58 points in MRC sub score) in 2 pts with DM2. These patients showed clinical symptoms of myopathy. Cardiovascular examinations revealed: QRS duration above 110 ms in 5 pts, clinically significant supraventricular arrhythmia or atrioventricular block in 3 pts, focal myocardial fibrosis in 3 pts, asymmetric hypertrophy of inter-ventricular septum in 1 patient, presence of late potentials in 5 pts. We have not observed correlation between impaired muscle strength and cardiac abnormalities. However, most pronounced cardiac abnormalities were observed in 2 male DM1 patients with clinical symptoms of myopathy and lowest MRC score. At a mean follow up of 3.2 +/- 1.4 years none of the pts died. CONCLUSIONS: Cardiac involvement in pts with myotonic dystrophy is frequent and is characterized by phenotypic heterogeneity. Detection of cardiac abnormalities may require extensive diagnostics. The most important is the assessment of ECG. Cardiac and neurological abnormalities vary in intensity between patients without close relationship to each other.

Neurophysiological and Ultrasound Correlations in Guillain Barré Syndrome and CIDP-Case Series.

INTRODUCTION: Guillain-Barré syndrome (GBS) and chronic inflammatory demyelinating polyneuropathy (CIDP) are inflammatory polyneuropathies with an autoimmune etiology. These diseases differ mainly in the timing of their course but also in certain clinical differences. Electroneurography and electromyography are crucial for fulfilling the primary (for CIDP) and secondary (for GBS) diagnostic criteria. High-resolution ultrasound (HRUS) is recognized as a complementary method in the diagnosis of CIDP and GBS. AIM: The aim of this study was to present the neurophysiological and ultrasound findings of patients with clinically diagnosed inflammatory neuropathies (GBS and CIDP). MATERIAL AND METHODS: We collected data from clinically confirmed patients with GBS (3 persons) and CIDP (6 persons). The neurography and high-resolution ultrasound examinations according to the UPSS scale were performed. RESULTS: The neurography tests of GBS and CIDP patients showed mainly demyelinating lesions of the examined nerves, often with abnormal F-wave recordings. Examination using HRUS in GBS patients showed mild and regional nerve swelling with hypoechoic bundles with a predilection for proximal segments and cervical spinal nerve roots. In contrast, CIDP patients had diffused nerve swelling with hypoechoic bundles of greater severity and extent than those with GBS. CONCLUSION: Neurophysiological tests and HRUS of peripheral nerves, plexi, and roots performed together can be very valuable, complementary diagnostic methods for the early diagnosis and effective treatment of inflammatory polyneuropathies.

Validation of the Polish version of the Hand Function Scoring system.

BACKGROUND: The Hand Function Scoring (HFS) system was created to assess the results of rehabilitation treatment after hand injuries. A perceived hand function improvement in patients who underwent carpal tunnel syndrome surgery prompted us to use the Watts HFS questionnaire in our study. OBJECTIVES: The study aimed to: 1) translate and validate the new questionnaire into Polish; 2) analyze the usefulness of the scale in the preand post-operative assessment of patients with carpal tunnel syndrome; and 3) compare the results with other questionnaires recognized as the gold standard in carpal tunnel treatment evaluation. MATERIAL AND METHODS: Patients with electromyographically confirmed carpal tunnel syndrome (n = 317) were enrolled in the study. Participants completed the HFS, Boston Carpal Tunnel Questionnaire (BCTQ), Michigan Hand Outcomes Questionnaire (MHQ), and the Quality-of-Life Scale (QoLS) on their first visit to our clinic. Two weeks later, 84 patients completed the same questionnaires again, and 6-12 months after the operation, we received 90 additional responses. RESULTS: The analysis showed that the HFS questionnaire met the validation criteria and had a strong correlation with the BCTQ questionnaire for the Symptoms Severity Scale (SSS) (Rho = 0.70, p < 0.001) and the Functional Status Scale (FSS) (Rho = 0.89, p < 0.001). CONCLUSIONS: The HFS questionnaire was successfully employed in the subjective assessment of carpal tunnel symptom syndrome severity and the analysis of treatment results, and would complement the clinical assessment of patients during treatment. The questionnaire could also be used in future scientific research.

Efficacy and Safety of DaxibotulinumtoxinA for Injection in Cervical Dystonia: ASPEN-1 Phase 3 Randomized Controlled Trial.

BACKGROUND AND OBJECTIVES: ASPEN-1 was a phase 3, randomized, double-blind, placebo-controlled study to evaluate the efficacy, duration of response, and safety of 2 doses of DaxibotulinumtoxinA for Injection (DAXI), a novel botulinum toxin type A formulation in participants with cervical dystonia (CD). METHODS: Adults (aged 18-80 years) with moderate-to-severe CD (Toronto Western Spasmodic Torticollis Rating Scale [TWSTRS] total score ≥20) were enrolled at 60 sites across 9 countries in Europe and North America. Participants were randomized (3:3:1) to single-dose intramuscular DAXI 125U, 250U, or placebo and followed for up to 36 weeks after injection. The primary end point was change from baseline in TWSTRS total score averaged across weeks 4 and 6. Key secondary end points included duration of effect, Clinical and Patient Global Impression of Change (CGIC, PGIC), TWSTRS subscale scores, and safety. Multiplicity-adjusted intent-to-treat hypothesis tests with multiple imputation were performed using ANCOVA and Cochran-Mantel-Haenszel analyses. RESULTS: Of 444 individuals screened, 301 were randomized to DAXI 125U (n = 125) or 250U (n = 130) or placebo (n = 46). DAXI 125U and 250U significantly improved the mean TWSTRS total score vs placebo (least squares mean [standard error] difference vs placebo: DAXI 125U, -8.5 [1.93], p < 0.0001; DAXI 250U, -6.6 [1.92], p = 0.0006). The median duration of effect (time from treatment until loss of ≥80% of the peak improvement in average TWSTRS total score achieved at weeks 4 and 6) was 24.0 (95% confidence interval 20.3-29.1) weeks with DAXI 125U and 20.3 (16.7-24.0) weeks with DAXI 250U. Significant improvements were also observed with DAXI in CGIC and PGIC responder rates and TWSTRS subscales. Treatment-related treatment-emergent adverse events (TEAEs) were reported by 29.6% of participants with DAXI 125U, 23.8% with DAXI 250U, and 17.4% with placebo, with injection site pain being the most common overall. The most frequently reported treatment-related TEAEs of interest in DAXI 125U, DAXI 250U, and placebo, respectively, were muscular weakness (4.8%, 2.3%, 0%), musculoskeletal pain (2.4%, 3.1%, 0%), and dysphagia (1.6%, 3.8%, 0%). DISCUSSION: This study demonstrated that DAXI, at doses of 125U and 250U, is an effective, safe, long-acting, and well-tolerated treatment for CD. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov identifier (NCT03608397, submitted July 11, 2018) and EU Clinical Trials Register (ClinicalTrialsRegister.eu EudraCT identifier 2018-000446-19, submitted September 13, 2018). First participant enrolled on June 11, 2018. Trial registration was performed in accordance with the Food and Drug Administration Amendments Act (FDAAA 801), which stipulates that the responsible party register an applicable clinical trial not later than 21 calendar days after enrolling the first human participant (42 CFR 11.24). CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that in adults with moderate-to-severe idiopathic cervical dystonia, DAXI reduces dystonia more effectively than placebo.

Spasticity-related pain in children/adolescents with cerebral palsy. Part 2: IncobotulinumtoxinA efficacy results from a pooled analysis.

PURPOSE: This pooled analysis of data from three Phase 3 studies investigated the effects of incobotulinumtoxinA on spasticity-related pain (SRP) in children/adolescents with uni-/bilateral cerebral palsy (CP). METHODS: Children/adolescents (ambulant and non-ambulant) were evaluated for SRP on increasingly difficult activities/tasks 4 weeks after each of four incobotulinumtoxinA injection cycles (ICs) using the Questionnaire on Pain caused by Spasticity (QPS; six modules specific to lower limb [LL] or upper limb [UL] spasticity and respondent type [child/adolescent, interviewer, or parent/caregiver]). IncobotulinumtoxinA doses were personalized, with all doses pooled for analysis. RESULTS: QPS key item responses were available from 331 and 155 children/adolescents with LL- and UL-spasticity, respectively, and 841/444 (LL/UL) of their parents/caregivers. IncobotulinumtoxinA efficacy was evident with the first IC. Efficacy was sustained and became more robust with further subsequent ICs. By Week 4 of the last (i.e. fourth) IC, 33.8-53.3% of children/adolescents reported complete SRP relief from their baseline pain for respective QPS items. Children/adolescents reported reductions in mean LL SRP intensity at levels that surpassed clinically meaningful thresholds. Similarly, parents/caregivers observed complete SRP relief and less frequent SRP with incobotulinumtoxinA. Similar results were found for UL SRP. CONCLUSION: These findings indicate that incobotulinumtoxinA could bring considerable benefit to children/adolescents with spasticity by reducing SRP, even during strenuous activities.

Novel insights into the nervous system affected by prolonged hyperglycemia.

Multiple molecular pathways including the receptor for advanced glycation end-products-diaphanous related formin 1 (RAGE-Diaph1) signaling are known to play a role in diabetic peripheral neuropathy (DPN). Evidence suggests that neuropathological alterations in type 1 diabetic spinal cord may occur at the same time as or following peripheral nerve abnormalities. We demonstrated that DPN was associated with perturbations of RAGE-Diaph1 signaling pathway in peripheral nerve accompanied by widespread spinal cord molecular changes. More than 500 differentially expressed genes (DEGs) belonging to multiple functional pathways were identified in diabetic spinal cord and of those the most enriched was RAGE-Diaph1 related PI3K-Akt pathway. Only seven of spinal cord DEGs overlapped with DEGs from type 1 diabetic sciatic nerve and only a single gene cathepsin E (CTSE) was common for both type 1 and type 2 diabetic mice. In silico analysis suggests that molecular changes in spinal cord may act synergistically with RAGE-Diaph1 signaling axis in the peripheral nerve. KEY MESSAGES: Molecular perturbations in spinal cord may be involved in the progression of diabetic peripheral neuropathy. Diabetic peripheral neuropathy was associated with perturbations of RAGE-Diaph1 signaling pathway in peripheral nerve accompanied by widespread spinal cord molecular changes. In silico analysis revealed that PI3K-Akt signaling axis related to RAGE-Diaph1 was the most enriched biological pathway in diabetic spinal cord. Cathepsin E may be the target molecular hub for intervention against diabetic peripheral neuropathy.

The Feasibility of Surface Electromyography in Monitoring Orbicularis Oculi Recovery after Anterior Approach Levator Aponeurosis Advancement.

INTRODUCTION: In this article, we propose a new application for eyelid surface electromyography (sEMG). By placing the electrode in the mid-pretarsal area of the upper eyelid, one can easily perform a fast examination and achieve repeatable results. We believe that this technique may increase the feasibility of eyelid sEMG in clinical practice. METHODS: 126 sEMG examinations of the upper eyelid were performed by using the above-described method. Thirty-nine controls and 29 ptotic patients were enrolled. The controls underwent one measurement while the ptotic patients were employed for four sessions: Before anterior approach levator aponeurosis advancement (LAA), 2 weeks, 3 months, and more than 6 months after surgery. The relaxation and maximal contraction of the orbicularis oculi muscle (OOM) using root mean square (RMS) values were measured. RESULTS: The results showed a statistically significant decrease in RMS values of the maximal contraction of the OOM 2 weeks after surgery (p < 0.05) and 3 months after surgery (p = 0.03). Six months postoperatively, there were no statistically significant differences in OOM activity compared to preoperative values (p = 0.2). CONCLUSIONS: Eyelid sEMG may be a useful diagnostic tool in post-operative OOM recovery monitoring. sEMG parameters of the maximal contraction of the OOM normalize within 6 months after anterior approach LAA. Electrode placement in the mid-pretarsal area of the upper eyelid offers several advantages and therefore may enhance the feasibility of sEMG in clinical practice.

Role of RAGE in the Pathogenesis of Neurological Disorders.

This review reflects upon our own as well as other investigators' studies on the role of receptor for advanced glycation end-products (RAGE), bringing up the latest information on RAGE in physiology and pathology of the nervous system. Over the last ten years, major progress has been made in uncovering many of RAGE-ligand interactions and signaling pathways in nervous tissue; however, the translation of these discoveries into clinical practice has not come to fruition yet. This is likely, in part to be the result of our incomplete understanding of this crucial signaling pathway. Clinical trials examining the therapeutic efficacy of blocking RAGE-external ligand interactions by genetically engineered soluble RAGE or an endogenous RAGE antagonist, has not stood up to its promise; however, other trials with different blocking agents are being considered with hope for therapeutic success in diseases of the nervous system.

Safety and efficacy of repeat long-term incobotulinumtoxinA treatment for lower limb or combined upper/lower limb spasticity in children with cerebral palsy.

PURPOSE: The open-label phase 3 "Treatment with IncobotulinumtoxinA in Movement Open-Label" (TIMO) study investigated longer-term safety and efficacy of incobotulinumtoxin A in children/adolescents with cerebral palsy (CP). METHODS: Patients on standard treatment, with unilateral or bilateral lower limb (LL) or combined upper limb (UL)/LL spasticity received four incobotulinumtoxinA injection cycles (16 or 20 Units/kg bodyweight total [maximum 400 or 500 Units] per cycle depending on ambulatory status/clinical pattern treated), each followed by 12-16 weeks' observation. Treatment for pes equinus was mandatory; flexed knee or adducted thigh were options for unilateral treatment and/or ULs for unilateral/bilateral treatment. The primary endpoint was safety; changes in Ashworth Scale and Gross Motor Function Measure-66 scores, and Global Impression of Change Scale scores at week 4 of each injection cycle were also evaluated. RESULTS: IncobotulinumtoxinA (≤500 Units for ≤98 weeks) was safe, well-tolerated, and effective across all endpoints for multipattern treatment of LL and combined LL/UL spasticity in ambulant/nonambulant children/adolescents with CP. Treatment effects increased with each injection cycle. No new/unexpected safety concerns were identified. CONCLUSION: IncobotulinumtoxinA showed a good safety and tolerability profile, with efficacy over multiple clinical presentations. As an adjunct treatment, it offers an effective, individualized treatment option for pediatric CP-related spasticity.

Spasticity-related pain in children/adolescents with cerebral palsy. Part 1: Prevalence and clinical characteristics from a pooled analysis.

PURPOSE: A large prospective database from three Phase 3 studies allowed the study of spasticity-related pain (SRP) in pediatric cerebral palsy (CP). METHODS: Baseline (pretreatment) SRP data occurring during different activities in children/adolescents (aged 2-17 years, ambulant/nonambulant) with uni-/bilateral spastic CP was obtained using the Questionnaire on Pain caused by Spasticity (QPS; six modules specific to spasticity level [lower limb (LL) or upper limb (UL)] and type of respondent [child/adolescent, interviewer, or parent/caregiver]). RESULTS: At baseline, 331 children/adolescents with LL- and 155 with UL-spasticity completed at least one key item of their modules; LL/UL QPS modules of parent/caregivers were at least partially completed (key items) by 841/444 parents/caregivers. SRP with at least one activity at baseline was self-reported in 81.9% /69.7% (LLs/ULs) of children/adolescents with spasticity. Parents/caregivers observed LL/UL SRP behaviors in 85.9% /77.7% of their children, with multiple body regions affected. SRP negatively affected the great majority of the children in various ways. Child/adolescent-reported mean SRP intensity and parent/caregiver-observed mean SRP behavior frequencies were higher for LLs than ULs, and the level of SRP increased with more physically demanding activities. CONCLUSION: These data suggest SRP is more common and intense in pediatric CP than generally thought, emphasizing the need for effective, long-term pain management.

Safety Profile and Lack of Immunogenicity of IncobotulinumtoxinA in Pediatric Spasticity and Sialorrhea: A Pooled Analysis.

IncobotulinumtoxinA, a pure botulinumtoxinA formulation, is free of accessory proteins. This analysis provides pooled safety data from phase 3 trials of children/adolescents (2-17 years), investigating incobotulinumtoxinA for the treatment of spasticity associated with cerebral palsy (at doses ≤20 U/kg (max. 500 U) per injection cycle (IC) for ≤6 ICs; three trials) or sialorrhea associated with neurologic disorders (at total doses of 20-75 U per IC for ≤4 ICs; one trial) for ≤96 weeks. Safety endpoints included the incidences of different types of treatment-emergent adverse events (TEAEs) and immunogenicity. IncobotulinumtoxinA dose groups were combined. Of 1159 patients (mean age 7.3 years, 60.4% males) treated with incobotulinumtoxinA, 3.9% experienced treatment-related TEAEs, with the most common being injection site reactions (1.3%) (both indications), muscular weakness (0.7%) (spasticity), and dysphagia (0.2%) (sialorrhea). Two patients (0.2%) experienced a treatment-related treatment-emergent serious adverse event, and 0.3% discontinued the study due to treatment-related TEAEs. No botulinumtoxinA-naïve patients developed neutralizing antibodies (NAbs) after incobotulinumtoxinA. All children/adolescents with known pre-treatment status and testing positive for Nabs at final visit (n = 7) were previously treated with a botulinumtoxinA other than incobotulinumtoxinA. IncobotulinumtoxinA was shown to be safe, with very few treatment-related TEAEs in a large, diverse cohort of children/adolescents with chronic conditions requiring long-term treatment and was without new NAb formation in treatment-naïve patients.

Placebo-Controlled Clinical Trial of IncobotulinumtoxinA for Sialorrhea in Children: SIPEXI.

BACKGROUND AND OBJECTIVES: This prospective phase III study (SIPEXI) investigated efficacy and safety of repeated injections of incobotulinumtoxinA (incoBoNT/A) for treatment of chronic sialorrhea (drooling) associated with neurological disorders (e.g., cerebral palsy, traumatic brain injury) and/or intellectual disability in children/adolescents. METHODS: The study enrolled 2-17-year-olds with sialorrhea due to neurological disorders and/or intellectual disability. Patients received body weight-dependent doses of incoBoNT/A (20 U to 75 U). A main period with 1 injection cycle (placebo-controlled, double-blind, 6-17-year-olds) was followed by an open-label extension with up to 3 further cycles. An additional cohort of 2-5-year-olds received active treatment throughout the study. Co-primary endpoints were the change in unstimulated salivary flow rate (uSFR) from baseline to week 4, and the carers' global impression of change scale (GICS) rating at week 4. Adverse events were recorded. RESULTS: In the main period, 220 patients aged 6-17 years were randomized and treated (148 patients in incoBoNT/A group, 72 patients in placebo group). 35 patients aged 2-5 years received incoBoNT/A (no placebo). 214 patients aged 6-17 years and 33 patients aged 2-5 years continued treatment in the open-label extension period. For the 6-17-year-olds, a significant difference between incoBoNT/A and placebo was seen in the mean uSFR decrease (difference: -0.06 g/min; p = 0.0012) and the carers' GICS rating (difference: 0.28 points; p = 0.032) at week 4, in favor of active treatment. The secondary endpoints consistently supported these results. A sustained benefit was observed during the extension. Incidences of adverse events were comparable between incoBoNT/A and placebo and did not increase notably with repeated injections. The most common adverse events were respiratory infections. Efficacy and safety were also favorable in the uncontrolled cohort of 2-5-year-olds. DISCUSSION: Both co-primary efficacy endpoints were reached and superiority of incoBoNT/A over placebo was confirmed. IncoBoNT/A (up to 75 U, up to 4 cycles) is an effective and well-tolerated treatment for sialorrhea associated with neurological disorders in children. STUDY REGISTRATIONS: Clinicaltrials.gov: NCT02270736 (www.clinicaltrials.gov/ct2/show/results/NCT02270736); EU Clinical Trials Register: 2013-004532-30 (www.clinicaltrialsregister.eu/ctr-search/search?query=2013-004532-30). CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that injection of incobotulinumtoxinA decreases drooling in children aged 6-17 years with neurological disorders.