Large-Scale Screening: Phenotypic and Mutational Spectrum in Isolated and Combined Dystonia Genes.

BACKGROUND: Pathogenic variants in several genes have been linked to genetic forms of isolated or combined dystonia. The phenotypic and genetic spectrum and the frequency of pathogenic variants in these genes have not yet been fully elucidated, neither in patients with dystonia nor with other, sometimes co-occurring movement disorders such as Parkinson's disease (PD). OBJECTIVES: To screen >2000 patients with dystonia or PD for rare variants in known dystonia-causing genes. METHODS: We screened 1207 dystonia patients from Germany (DysTract consortium), Spain, and South Korea, and 1036 PD patients from Germany for pathogenic variants using a next-generation sequencing gene panel. The impact on DNA methylation of KMT2B variants was evaluated by analyzing the gene's characteristic episignature. RESULTS: We identified 171 carriers (109 with dystonia [9.0%]; 62 with PD [6.0%]) of 131 rare variants (minor allele frequency <0.005). A total of 52 patients (48 dystonia [4.0%]; four PD [0.4%, all with GCH1 variants]) carried 33 different (likely) pathogenic variants, of which 17 were not previously reported. Pathogenic biallelic variants in PRKRA were not found. Episignature analysis of 48 KMT2B variants revealed that only two of these should be considered (likely) pathogenic. CONCLUSION: This study confirms pathogenic variants in GCH1, GNAL, KMT2B, SGCE, THAP1, and TOR1A as relevant causes in dystonia and expands the mutational spectrum. Of note, likely pathogenic variants only in GCH1 were also found among PD patients. For DYT-KMT2B, the recently described episignature served as a reliable readout to determine the functional effect of newly identified variants. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Somatosensory evoked potentials recorded from DBS electrodes: the origin of subcortical N18.

The different peaks of somatosensory-evoked potentials (SEP) originate from a variety of anatomical sites in the central nervous system. The origin of the median nerve subcortical N18 SEP has been studied under various conditions, but the exact site of its generation is still unclear. While it has been claimed to be located in the thalamic region, other studies indicated its possible origin below the pontomedullary junction. Here, we scrutinized and compared SEP recordings from median nerve stimulation through deep brain stimulation (DBS) electrodes implanted in various subcortical targets. We studied 24 patients with dystonia, Parkinson's disease, and chronic pain who underwent quadripolar electrode implantation for chronic DBS and recorded median nerve SEPs from globus pallidus internus (GPi), subthalamic nucleus (STN), thalamic ventral intermediate nucleus (Vim), and ventral posterolateral nucleus (VPL) and the centromedian-parafascicular complex (CM-Pf). The largest amplitude of the triphasic potential of the N18 complex was recorded in Vim. Bipolar recordings confirmed the origin to be close to Vim electrodes (and VPL/CM-Pf) and less close to STN electrodes. GPi recorded only far-field potentials in unipolar derivation. Recordings from DBS electrodes located in different subcortical areas allow determining the origin of certain subcortical SEP waves more precisely. The subcortical N18 of the median nerve SEP-to its largest extent-is generated ventral to the Vim in the region of the prelemniscal radiation/ zona incerta.

Real-life use of onabotulinumtoxinA reduces healthcare resource utilization in individuals with chronic migraine: the REPOSE study.

BACKGROUND: Chronic migraine (CM) is associated with substantial economic burden. Real-world data suggests that onabotulinumtoxinA treatment for CM reduces healthcare resource utilisation (HRU) and related costs. METHODS: REPOSE was a 2-year prospective, multicentre, non-interventional, observational study to describe the real-world use of onabotulinumtoxinA in adult patients with CM. This analysis examined the impact of onabotulinumtoxinA on HRU. Patients received onabotulinumtoxinA treatment approximately every 12 weeks according to their physicians' discretion, guided by the summary of product characteristics (SPC) and PREEMPT injection paradigm. HRU outcome measures were collected at baseline and all administration visits and included headache-related hospitalizations and healthcare professional (HCP) visits. Health economic data, including family doctor and specialist visits, inpatient treatment for headache, acupuncture, technical diagnostics, use of nonpharmacologic remedies, and work productivity were also collected for patients enrolled at German study centres. RESULTS: Overall, 641 patients were enrolled at 78 study centres across 7 countries (Germany, UK, Italy, Spain, Norway, Sweden, and Russia), 633 received ≥1 onabotulinumtoxinA dose, and 128 completed the 2-year study. Patients were, on average, aged 45 years, 85% were female, and 60% (n = 377) were from Germany. At the end of the 2-year observation period, significantly fewer patients reported headache-related hospitalizations (p < 0.02) and HCP visits (p < 0.001) within the past 3 months than in the 3 months before baseline. In the German population, reductions were observed across all health services at all follow-up visits compared with baseline. The percentage of patients who saw a family doctor decreased from 41.7% at baseline to 13.5% at administration visit 8 and visits to a medical specialist decreased from 61.7% to 5.2% of patients. Inpatient acute treatment and technical diagnostics declined from 6.4% and 19.7% of patients at baseline to 0.0% and 1.0% at administration 8, respectively. The use of nonpharmacologic remedies and medication for the acute treatment of migraine also decreased with continued onabotulinumtoxinA treatment. Work incapacity, disability, absenteeism, and impaired performance at school/work improved with onabotulinumtoxinA treatment for CM over the 2-year observation period. CONCLUSIONS: Real-world evidence from REPOSE demonstrates that onabotulinumtoxinA treatment is associated with decreased HRU and supports the long-term benefits associated with the use of onabotulinumtoxinA for CM in clinical practice. TRIAL REGISTRATION: NCT01686581 . Name of registry: ClinicalTrials.gov. URL of registry: Date of retrospective registration: September 18, 2012. Date of enrolment of first patient: July 23, 2012.

Dysphagia in cervical dystonia patients receiving optimised botulinum toxin therapy: a single-center retrospective cohort study.

To explore the correlations of botulinum toxin (BT) therapy with dysphagia, we wanted to study a group of cervical dystonia (CD) patients with optimised BT therapy during a prolonged period of time to record their dysphagia frequency, severity and duration, to study potential risk factors and try to avoid it by BT application with ultrasound guidance. BT therapy of 75 CD patients (23 males, 52 females, age 60 ± 12 years, BT total dose 303.5 ± 101.5 uMU) was retrospectively analysed for 1 year. BT therapy was optimised prior to the observation period. Dysphagia was noticed by one fifth of the patients. In those patients, it only occurred in about one third of the injection series. It was never associated with a functional deficit and lasted several days to 2 weeks. It was not related to patient age or gender, BT total dose, BT dose in the sternocleidomastoid muscle, BT dose in the sternocleidomastoid and scalenii muscles, by BT therapy with bilateral sternocleidomastoid muscle injections or BT therapy with abobotulinumtoxinA. Ultrasound guidance was not able to prevent it. Further prospective studies will be necessary to study underlying dystonia associated swallowing abnormalities as a potentially predisposing factor.

IncobotulinumtoxinA for hypersalivation in patients with amyotrophic lateral sclerosis: an open-label single-centre study.

The objective of this study is to discover whether incobotulinumtoxinA (inco) can reduce relative hypersalivation in patients with amyotrophic lateral sclerosis (ALS). 14 patients with ALS (8 males and 6 females, age 55.4 ± 16.3 years) received ultrasound-guided injection of inco 100 MU in both parotid glands and inco 50 MU in both submandibular glands. Saliva production was gravimetrically measured with three cotton rolls placed in the mouth. Weight increase after 5 min was measured on an electronic scale. Subjective saliva production was registered with drooling frequency scale (DFS) and drooling severity scale (DSS). Saliva production was gravimetrically reduced at week 4 (p = 0.04), week 8 (p = 0.01) but not after week 12 after BT application. DFS was reduced at week 4 (p = 0.04), week 8 (p = 0.02), but not after week 12. DSS was reduced at week 4 (p = 0.03), week 8 (p = 0.04) and week 12 (p = 0.04). Patients in our study did not experience changes in their swallowing patterns or any other safety-relevant events. Inco is effective and well tolerated for saliva reduction in patients with ALS for 8-12 weeks.

Botulinum toxin type D blocks autonomic cholinergic synapses in humans: discussion of a potential therapeutic use.

Based on epidemiological data it was believed that botulinumtoxin type D (BT-D) may not block human cholinergic synapses. We wanted to investigate BT-D's effect on the autonomic cholinergic synapse in humans. For this, we compared in four volunteers intraindividually the hypohidrotic effect of intradermal BT-D and BT-A in Minor's iodine starch sweat test. Altogether, we studied BT-D in doses of 4, 8, 16 and 32MU and BT-A in doses of 2, 4, 8 and 16MU at weekly intervals throughout a period of 13 weeks. All BT doses were diluted in 0.2 ml 0.9% NaCl/H2O. Overall 704 data points were collected. Combined over all four subjects and all four doses BT-D's hypohidrotic effect intensity was half of BT-A's. BT-D's effect peaked around 5 weeks, BT-A's around 7 weeks. BT-D's effect duration was around 12 weeks, of BT-A's was around 14 weeks. For both BT types the hypohidrotic effect was dose dependent. BT-D, when injected intradermally, can block autonomic cholinergic synapses in humans. Compared to BT-A, BT-D's effect intensity was half and its effect duration was some 2 weeks shorter. With its weaker and shorter effect BT-D does not seem to promise therapeutic effects superior to BT-A.

Quantitative Susceptibility MRI to Detect Brain Iron in Amyotrophic Lateral Sclerosis.

Purpose To investigate the whole-brain landscape of iron-related abnormalities in amyotrophic lateral sclerosis (ALS) by using the in vivo MRI technique of quantitative susceptibility mapping (QSM). Materials and Methods For this prospective study, 28 patients with ALS (mean age, 61 years; age range, 43-77 years; 18 men [mean age, 61 years; range, 43-77 years] and 10 women [mean age, 61 years; range, 47-74 years]) recruited between January 17, 2014, and September 4, 2015, and 39 matched control subjects (mean age, 61 years; age range, 39-77 years; 24 men [mean age, 62 years; range, 39-77 years] and 15 women [mean age, 59 years; range, 39-73 years]) were examined by using structural and susceptibility 3.0-T MRI techniques. Group data were cross sectionally compared with family-wise error (FWE) corrections by using voxel-based morphometry (random-field theory), cortical thickness analysis (Monte Carlo simulated), subcortical volumetry (Bonferroni-corrected Wilcoxon rank-sum testing), and QSM analysis (cluster-enhanced whole-brain permutation testing and Bonferroni-corrected rank-sum testing in regions of interest). In patients with ALS, a potential relationship between diffusion and susceptibility measurements in the corticospinal tracts (CSTs) was also examined by using Spearman rank-correlation tests. Results Conventional structural measures failed to identify atrophy in the present cohort (FWE P > .05). However, QSM identified several whole-brain abnormalities (FWE P < .05) in ALS. Regionally, higher susceptibility (expressed as means in parts per million ± standard errors of the mean) was confirmed in the motor cortex (ALS = 0.0188 ± 0.0003, control = 0.0173 ± 0.0003; P < .001), the left substantia nigra (ALS = 0.127 ± 0.004, control = 0.113 ± 0.003; P = .008), the right substantia nigra (ALS = 0.141 ± 0.005, control = 0.120 ± 0.003; P < .001), the globus pallidus (ALS = 0.086 ± 0.003, control = 0.075 ± 0.002; P = .003), and the red nucleus (ALS = 0.115 ± 0.004, control = 0.098 ± 0.003; P < .001). Lower susceptibility was found in CST white matter (ALS = -0.047 ± 0.001, control = -0.043 ± 0.001; P = .01). Nigral and pallidal QSM values were cross correlated in ALS (ρ2 = 0.42, P < .001), a phenomenon visually traceable in many individual patients. QSM in the CST in ALS also correlated with diffusion-tensor metrics in this tract (ρ2 = 0.25, P = .007). Conclusion Whole-brain MRI quantitative susceptibility mapping analysis is sensitive to tissue alterations in amyotrophic lateral sclerosis that may be relevant to pathologic changes. © RSNA, 2018.

Peripheral nerve atrophy together with higher cerebrospinal fluid progranulin indicate axonal damage in amyotrophic lateral sclerosis.

INTRODUCTION: We aimed to investigate whether sonographic peripheral cross-sectional nerve area (CSA) and progranulin (PGRN), a neuritic growth factor, are related to each other and whether they interact to predict clinical and paraclinical measures in amyotrophic lateral sclerosis (ALS). METHODS: We included 55 ALS patients who had forearm median and ulnar nerve CSA, cerebrospinal fluid (CSF) PGRN, and serum PGRN measures available. CSF PGRN was normalized against the CSF / serum albumin ratio (Qalb ). Using age, sex, height, and weight adjusted general linear models, we examined CSA × CSF PGRN interaction effects on various measures. RESULTS: There was a medium-effect size inverse relationship between CSA and CSF PGRN, but not between CSA and serum PGRN. Lower CSA values together with higher CSF PGRN levels were linked to smaller motor amplitudes. DISCUSSION: In ALS, the constellation of peripheral nerve atrophy together with higher CSF PGRN levels indicates pronounced axonal damage. Muscle Nerve 57: 273-278, 2018.

Strategies to decrease injection site pain in botulinum toxin therapy.

Botulinum toxin is now used for numerous indications including dystonias, spasticity, cerebral palsy, hyperhidrosis, cosmetics and chronic migraine. It has to be injected into its target tissues thus causing injection site pain. We wanted to compare the efficacy of various analgesic interventions suggested for reduction of injection site pain. In 13 healthy controls, pain thresholds in the fingertips II and III bilaterally were determined by the Mechanical Pain Threshold Test and the Repetitive Pain Stimulation Test at baseline and under nitrous oxide/oxygen, ice spray, local anaesthetic cream and forearm ischaemia. All interventions studied produce statistically significant and robust elevations of the pain threshold in both tests. Nitrous oxide/oxygen had stronger effects than the other interventions, although this superiority was statistically significant only in the Repetitive Pain Stimulation Test and not against ice spray. Also considering duration, localisation and penetration depth of analgesic effects, hyperhidrosis treatment may benefit from nitrous oxide/oxygen, ice spray and local anaesthetic cream. In palmar hyperhidrosis, forearm ischaemia is possible and also reduces botulinum toxin washout. Cosmetic indications may also benefit from nitrous oxide/oxygen and local anaesthetic cream. For botulinum toxin therapy of spasticity, dystonia and tremor, only nitrous oxide/oxygen may offer intramuscular analgesic effect. Its systemic and prolonged effect is also an advantage in injections in several body parts. Future studies are necessary to test the influence of penetration depth and combinations of analgesic interventions.

The concept and diagnostic criteria of primary lateral sclerosis.

OBJECTIVES: Primary lateral sclerosis (PLS) is commonly considered as a motor neuron disease (MND) variant which almost exclusively affects upper motor neurons (UMN). There is still no consensus whether PLS should be regarded as an independent disease entity separate from amyotrophic lateral sclerosis (ALS) or as a comparatively slowly progressive variant of ALS. Given these different views, clinical diagnosis of PLS is a challenge. In this multicenter study, we analyzed clinical features of patients diagnosed with PLS in four specialized MND centers. MATERIAL AND METHODS: We retrospectively analyzed clinical, laboratory, imaging, and electrophysiological data of 76 patients with PLS diagnosed in four specialized ALS centers. We analyzed the concept of the disease based on our findings and an extensive review of the literature. RESULTS: We found that 79% of patients showed asymmetrical symptoms, 60% showed clinical or electrophysiological signs of lower motor neuron (LMN) involvement after a mean of 8.4 ± 5.0 years, and extrapyramidal and/or non-motoric symptoms were frequently observed. Interestingly, none of the patients diagnosed with PLS fulfilled the diagnostic criteria proposed by Pringle et al. in 1992. CONCLUSIONS: Our data show that PLS as a disease entity is still not well enough defined and that there are different concepts about its clinical presentation. We believe that further prospective longitudinal studies are needed in order to refine diagnostic criteria to reflect current clinical practice. Furthermore, neuropathological and neuroimaging approaches might help to arrange PLS in the MND spectrum and its classification.

Quantifying disease progression in amyotrophic lateral sclerosis using peripheral nerve sonography.

INTRODUCTION: In this study we investigated whether peripheral nerve sonography could be used as a biomarker to monitor disease progression in amyotrophic lateral sclerosis (ALS). METHODS: In 37 patients, ulnar and median nerve cross-sectional area (CSA) was determined in at least 2 ultrasound sessions; mean follow-up was 14.5 months. Linear mixed-effects models were conducted to analyze time effects on CSA. RESULTS: Ulnar nerve CSA declined significantly at a monthly rate of -0.04 mm(2) (forearm) and -0.05 mm(2) (wrist); the decrease was more pronounced when baseline CSA was greater. To detect a 50% treatment effect on ulnar nerve CSA, 332 patients would need to be entered in a hypothetical randomized, controlled clinical trial. Time had no significant impact on median nerve CSA. CONCLUSIONS: Distal ulnar nerve ultrasound may be a useful biomarker to monitor disease progression in ALS, especially as hypothetical treatment effects on CSA seem to be detectable in manageable cohort sizes. Muscle Nerve 54: 391-397, 2016.

Long-term treatment of chronic migraine with OnabotulinumtoxinA: efficacy, quality of life and tolerability in a real-life setting.

Botulinum toxin was shown to be effective in treatment of chronic migraine. We wanted to explore its efficacy and tolerability in chronic application under real-life conditions. For this, 27 consecutive patients (age 45.6 ± 10.8 years, 25 females, 2 males) received altogether 176 injection series (IS) with 189.7 ± 45.8MU onabotulinumtoxinA (Botox(®)) according to the PREEMPT scheme. During the study period altogether 6.5 ± 2.9 (min 4, max 13) IS were applied per patient (total treatment time of 73.1 ± 36.9 weeks). 96 % of the patients reported benefit. Monthly headache days were reduced from 18.9 ± 3.9 to 8.7 ± 4.5 (p < 0.001, -53.7 %), migraine days from 16.8 ± 4.9 to 7.4 ± 4.6 (p < 0.001, -55.1 %), autonomic days from 8.6 ± 7.5 to 2.7 ± 4.2 (p < 0.001, -71.9 %) and medication days from 14.2 ± 4.6 to 8.3 ± 4.2 (p < 0.001, -71.1 %). Health-related quality of life improved by 0.6-1.5 standard deviations (SD) (Short Form Health Survey), migraine-related quality of life by 1.4-2.0 SD (Migraine-Specific Quality of Life Questionnaire) and by 1.9 SD (Headache Impact Test), depression by 1.1 SD (Beck Depression Inventory). Subjective global clinical improvement was 2.6 ± 0.6 (Global Clinical Improvement Scale). All improvements were stable throughout the entire study period. Adverse effects were infrequent, mild and transient. Botulinum toxin provides highly effective and safe long-term treatment of chronic migraine.

Diagnostic support for selected neuromuscular diseases using answer-pattern recognition and data mining techniques: a proof of concept multicenter prospective trial.

BACKGROUND: Diagnosis of neuromuscular diseases in primary care is often challenging. Rare diseases such as Pompe disease are easily overlooked by the general practitioner. We therefore aimed to develop a diagnostic support tool using patient-oriented questions and combined data mining algorithms recognizing answer patterns in individuals with selected neuromuscular diseases. A multicenter prospective study for the proof of concept was conducted thereafter. METHODS: First, 16 interviews with patients were conducted focusing on their pre-diagnostic observations and experiences. From these interviews, we developed a questionnaire with 46 items. Then, patients with diagnosed neuromuscular diseases as well as patients without such a disease answered the questionnaire to establish a database for data mining. For proof of concept, initially only six diagnoses were chosen (myotonic dystrophy and myotonia (MdMy), Pompe disease (MP), amyotrophic lateral sclerosis (ALS), polyneuropathy (PNP), spinal muscular atrophy (SMA), other neuromuscular diseases, and no neuromuscular disease (NND). A prospective study was performed to validate the automated malleable system, which included six different classification methods combined in a fusion algorithm proposing a final diagnosis. Finally, new diagnoses were incorporated into the system. RESULTS: In total, questionnaires from 210 individuals were used to train the system. 89.5 % correct diagnoses were achieved during cross-validation. The sensitivity of the system was 93-97 % for individuals with MP, with MdMy and without neuromuscular diseases, but only 69 % in SMA and 81 % in ALS patients. In the prospective trial, 57/64 (89 %) diagnoses were predicted correctly by the computerized system. All questions, or rather all answers, increased the diagnostic accuracy of the system, with the best results reached by the fusion of different classifier methods. Receiver operating curve (ROC) and p-value analyses confirmed the results. CONCLUSION: A questionnaire-based diagnostic support tool using data mining methods exhibited good results in predicting selected neuromuscular diseases. Due to the variety of neuromuscular diseases, additional studies are required to measure beneficial effects in the clinical setting.

Amyotrophic lateral sclerosis affects cortical and subcortical activity underlying motor inhibition and action monitoring.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by muscular atrophy, spasticity, and bulbar signs caused by loss of upper and lower motor neurons. Evidence suggests that ALS additionally affects other brain areas including premotor cortex and supplementary motor area. Here, we studied movement execution and inhibition in ALS patients using a stop-signal paradigm and functional magnetic resonance imaging. Seventeen ALS patients and 17 age-matched healthy controls performed a stop-signal task that required responding with a button press to a right- or left-pointing black arrow (go-stimuli). In stop-trials, a red arrow (stop-stimulus) was presented shortly after the black arrow indicating to withhold the prepared movement. Patients had by trend higher reaction times in go-trials but did not differ significantly in their inhibition performance. Patients showed stronger inhibition-related activity in inferior, superior, and middle frontal gyri as well as in putamen and pallidum. Error-related activity, conversely, was found to be stronger in healthy controls, particularly in the insula bilaterally. Patients also showed increased activity in the motor cortex during button presses. The results provide evidence for altered prefrontal and subcortical networks underlying motor execution, motor inhibition, and error monitoring in ALS.

Peripheral nerve ultrasound in amyotrophic lateral sclerosis phenotypes.

INTRODUCTION: In this study we sought to determine the cross-sectional area (CSA) of peripheral nerves in patients with distinct subtypes of amyotrophic lateral sclerosis (ALS). METHODS: Ulnar and median nerve ultrasound was performed in 78 ALS patients [classic, n = 21; upper motor neuron dominant (UMND), n = 14; lower motor neuron dominant (LMND), n = 20; bulbar, n = 15; primary lateral sclerosis (PLS), n = 8] and 18 matched healthy controls. RESULTS: Compared with controls, ALS patients had significant, distally pronounced reductions of ulnar CSA (forearm/wrist level) across all disease groups, except for PLS. Median nerve CSA (forearm/wrist level) did not differ between controls and ALS. CONCLUSION: Ulnar nerve ultrasound in ALS subgroups revealed significant differences in distal CSA values, which suggests it has value as a marker of LMN involvement. Its potential was particularly evident in the UMND and PLS groups, which can be hard to separate clinically, yet their accurate separation has major prognostic implications.

Botulinum toxin therapy for hyperhidrosis: reduction of injection site pain by nitrous oxide/oxygen mixtures.

Injection site pain (ISP) reduces compliance of botulinum toxin (BT) therapy considerably. We wanted to study whether nitrous oxide/oxygen (NOO, Livopan(®), Linde Gas Therapeutics, Unterschleißheim, Germany) can reduce ISP in patients receiving intracutaneous BT injections for axillary or palmar hyperhidrosis (HH). The study followed an open-label design comparing intraindividually ISP in both axillae and/or both palms when NOO was applied or not during BT injections. BT efficacy was measured by the Hyperhidrosis Disease Severity Scale (HDSS) and by a 4-point Self-Assessment Scale. ISP was documented by a Visual Analogue Scale (VAS) and the Verbal Scale of Pain Intensity (VSPI), adverse effects by a Structuralised Interview (SI). Altogether 13 patients (age 34.1 ± 12.4 years, 9 females, 4 males) were studied. 11 BT treatments were for biaxillary and 3 for bipalmar HH. BT reduced biaxillary HH from HDSS 3.7 ± 0.5 to 1.0 ± 0 and bipalmar HH from 3.6 ± 0.6 to 1.0 ± 0. All patients reported ISP reduction by NOO. In axillary HH, NOO reduced ISP from 55.7 ± 12.7 to 12.8 ± 7.5 on the VAS (p < 0.05) and from 4.1 ± 0.3 to 0.7 ± 0.5 on the VSPI (p < 0.05), in bipalmar HH from 60.0 ± 10.0 to 13.3 ± 5.8 on the VAS (p < 0.05) and from 5.0 ± 0 to 1.3 ± 0.5 on the VSPI (p < 0.05). Adverse effects were not identified. NOO is a potent, non-sedative, quickly reversible and safe inhalative analgesic which reduces ISP considerably in patients receiving BT therapy for axillary and palmar HH thus substantially improving compliance of BT therapy.

Safety aspects of incobotulinumtoxinA high-dose therapy.

Botulinum toxin (BT) used for dystonia and spasticity is dosed according to the number of target muscles and the severity of their muscle hyperactivities. With this no other drug is used in a broader dose range than BT. The upper end of this range, however, still needs to be explored. We wanted to do this by a prospective non-interventional study comparing a randomly selected group of dystonia and spasticity patients receiving incobotulinumtoxinA (Xeomin(®)) high-dose therapy (HD group, n = 100, single dose ≥400 MU) to a control group receiving incobotulinumtoxinA regular-dose therapy (RD group, n = 30, single dose ≤200 MU). At the measurement point all patients were evaluated for systemic BT toxicity, i.e. systemic motor impairment or systemic autonomic dysfunction. HD group patients (56.1 ± 13.8 years, 46 dystonia, 54 spasticity) were treated with Xeomin(®) 570.1 ± 158.9 (min 400, max 1,200) MU during 10.2 ± 7.0 (min 4, max 37) injection series. In dystonia patients the number of target muscles was 46 and the dose per target muscle 56.4 ± 19.1 MU, in spasticity patients 35 and 114.9 ± 67.1 MU. HD and RD group patients reported 58 occurrences of items on the systemic toxicity questionnaire. Generalised weakness, being bedridden, feeling of residual urine and constipation were caused by the underlying tetra- or paraparesis, blurred vision by presbyopia. Dysphagia and dryness of eye were local BT adverse effects. Neurologic examination, serum chemistry and full blood count did not indicate any systemic adverse effects. Elevated serum levels for creatine kinase/MB, creatine kinase and lactate dehydrogenase were most likely iatrogenic artefacts. None of the patients developed antibody-induced therapy failure. Xeomin(®) can be used safely in doses ≥400 MU and up to 1,200 MU without detectable systemic toxicity. This allows expanding the use of BT therapy to patients with more widespread and more severe muscle hyperactivity conditions. Further studies-carefully designed and rigorously monitored-are necessary to explore the threshold dose for clinically detectable systemic toxicity.

Blepharospasm: long-term treatment with either Botox®, Xeomin® or Dysport®.

Botulinum toxin (BT) therapy is the treatment of choice for blepharospasm (BPS). Currently available BT type A drugs include Botox(®), Dysport(®) and Xeomin(®). Until now, there are few long-term studies on BT therapy for BPS. This is the first long-term study comparing all three major BT drugs. We collected treatment, efficacy and adverse effect data on BPS patients treated with either Botox(®), Dysport(®) or Xeomin(®) for at least eight consecutive treatments. Two hundred and eighty-eight patients (208 females, 80 males, age 62 ± 12 years) were included in this study. The treatment time was 11.2 ± 4.1 years covering 10,701 injection series. Doses were 47 ± 10 MU for Botox(®), 120 ± 35 MU for Dysport(®) and 62 ± 11 MU for Xeomin(®) (Botox(®) dose vs Xeomin(®) dose: p < 0.001, unpaired t test). 85 % of all patients had stable doses. The onset of the therapeutic effect was after 6.1 ± 3.3 days and its duration lasted 10.2 ± 3.5 weeks. The Global Clinical Improvement (GCI, 0 = no, 1 = slight, 2 = moderate, 3 = marked improvement in severity and function) as estimated by the patient was 2.5 ± 0.6. It was stable in 90% of the patients. Adverse effect frequency was 3.0% (ptosis 2.3%, dry eye 0.5%, diplopia 0.2%). None of these findings was significantly different between Botox(®), Dysport(®) and Xeomin(®). Our study, one of the largest studies on BT therapy of BPS and the study with the longest follow-up, confirms that BT therapy produces robust clinical improvement which is stable throughout the treatment time. Therapeutic effects start after 6.1 days and last for about 10 weeks before they start to vanish. With this, they are approximately 2 weeks shorter than the recommended inter-injection interval. Adverse effects were rare, mild and always transient. BT therapy is a safe and effective treatment for BSP. Shorter inter-injection intervals may improve therapeutic results.

Interaction of physical function, quality of life and depression in Amyotrophic lateral sclerosis: characterization of a large patient cohort.

BACKGROUND: Due to lack of any curative therapy for ALS, symptomatic treatment and maintenance of quality of life (QoL) is very important. We aimed to characterize the affected domains of QoL in ALS patients and to identify factors which are associated with reduced QoL and increased depression. METHODS: 159 ALS patients answered standardized questionnaires (Beck Depression Inventory-II, SF-36 Health Survey questionnaire, revised ALS functional rating scale). Multiple regression analysis was used to identify correlations between clinical features of ALS patients and depression/QoL scores. In addition, QoL data from ALS patients were compared to age-matched reference values representing the German normal population. RESULTS: QoL of ALS patients was reduced in nearly all SF-36-categories. Progression of physical impairment was positively correlated with depression but reduced QoL scores only in items directly related to physical function. However, QoL was considerably influenced by depression, independently from physical impairment. Regarding distinct patient characteristics one of the most interesting findings was that increasing age was correlated with significantly worse QoL results regarding social functioning. CONCLUSIONS: Depressive symptoms had a strong influence on QoL, hence their detection and treatment is of particular importance. Different domains of QoL are differently affected in subgroups of ALS patients. Being aware of these differences can be valuable for both ALS professional and family caregivers and physicians.

Memory deficits in amyotrophic lateral sclerosis are not exclusively caused by executive dysfunction: a comparative neuropsychological study of amnestic mild cognitive impairment.

BACKGROUND: Recent work suggests that ALS and frontotemporal dementia can occur together and share at least in part the same underlying pathophysiology. However, it is unclear at present whether memory deficits in ALS stem from a temporal lobe dysfunction, or are rather driven by frontal executive dysfunction. In this study we sought to investigate the nature of memory deficits by analyzing the neuropsychological performance of 40 ALS patients in comparison to 39 amnestic mild cognitive impairment (aMCI) patients and 40 healthy controls (HC). The neuropsychological battery tested for impairment in executive functions, as well as memory and visuo-spatial skills, the results of which were compared across study groups. In addition, we calculated composite scores for memory (learning, recall, recognition) and executive functions (verbal fluency, cognitive flexibility, working memory). We hypothesized that the nature of memory impairment in ALS will be different from those exhibited by aMCI patients. RESULTS: Patient groups exhibited significant differences in their type of memory deficit, with the ALS group showing impairment only in recognition, whereas aMCI patients showed short and delayed recall performance deficits as well as reduced short-term capacity. Regression analysis revealed a significant impact of executive function on memory performance exclusively for the ALS group, accounting for one fifth of their memory performance. Interestingly, merging all sub scores into a single memory and an executive function score obscured these differences. CONCLUSION: The presented results indicate that the interpretation of neuropsychological scores needs to take the distinct cognitive profiles in ALS and aMCI into consideration. Importantly, the observed memory deficits in ALS were distinctly different from those observed in aMCI and can be explained only to some extent in the context of comorbid (coexisting) executive dysfunction. These findings highlight the qualitative differences in temporal lobe dysfunction between ALS and aMCI patients, and support temporal lobe dysfunction as a mechanism underlying the distinct cognitive impairments observed in ALS.