H. Jurgen Schelhaas

Normal values for quantitative muscle ultrasonography in adults.

Ultrasonography can detect structural muscle changes caused by neuromuscular disease. Quantitative analysis is the preferred method to determine if ultrasound findings are within normal limits, but normative data are incomplete. The purpose of this study was to provide normative muscle ultrasonography data for muscle thickness and echo intensity for five different muscle groups in adults. Bilateral scans of the sternocleidomastoid, biceps brachii/brachialis, forearm flexor group, quadriceps femoris, and tibialis anterior were made in 95 volunteers, aged 17–90 years. Both muscle thickness and echo intensity showed gender differences and a muscle‐specific non‐linear correlation with age. The muscles of the upper extremities showed right–left differences. These data demonstrate the effect of age on muscle characteristics and provide normative values that can be used in clinical practice. Muscle Nerve, 2010

Randomized sequential trial of valproic acid in amyotrophic lateral sclerosis

To determine whether valproic acid (VPA), a histone deacetylase inhibitor that showed antioxidative and antiapoptotic properties and reduced glutamate toxicity in preclinical studies, is safe and effective in amyotrophic lateral sclerosis (ALS) using a sequential trial design.

Muscle ultrasonography: a diagnostic tool for amyotrophic lateral sclerosis.

OBJECTIVE In a prospective study we tested whether muscle ultrasonography can differentiate between amyotrophic lateral sclerosis (ALS) and mimics. Furthermore, we assessed the ability of ultrasonography to identify subclinical lower motor neuron involvement. METHODS In 59 patients, suspected for adult onset motor neuron disease, ultrasound scans were made of 12 different muscle groups. Echo intensity was determined and each muscle was screened for fasciculations. Ultrasonography was considered diagnostic for ALS when echo intensity was 1.5 SD above normal in at least two muscles and fasciculations were present in at least four muscles. RESULTS Ultrasonography differentiated between ALS and mimics with 96% sensitivity and 84% specificity. In the 27 ALS patients, ultrasonography detected 15 regions with lower motor neuron involvement that were negative using either clinical examination or needle EMG. CONCLUSIONS Muscle ultrasound can differentiate between amyotrophic lateral sclerosis and mimics with high sensitivity and specificity, and is a sensitive tool to screen for regional lower motor neuron involvement. SIGNIFICANCE Muscle ultrasonography is a promising tool in the diagnostic work up of ALS.

Muscle changes in amyotrophic lateral sclerosis: A longitudinal ultrasonography study

OBJECTIVE We performed a longitudinal study to assess structural muscle changes in amyotrophic lateral sclerosis (ALS) using ultrasonography. METHODS During a follow-up of 6 months, ultrasonography parameters (muscle thickness, echo intensity and fasciculations) were obtained from 6 muscle groups in 31 ALS patients, together with strength and scores on the revised ALS functional rating scale (ALSFRS-r). RESULTS At baseline, we found an increased echo intensity and decreased thickness, and these parameters correlated with lower strength. Moreover, ultrasound abnormalities were also detected in muscles with preserved strength. Longitudinal changes in echo intensity, muscle thickness and fasciculations showed large variations between patients. Rates of change in ultrasound parameters did not correlate with changes in ALSFRS-r or strength. CONCLUSION In patients with ALS ultrasound abnormalities can be found in muscles with preserved strength. The pattern of ultrasonographic muscle changes in ALS is highly variable and shows no evident correlation with functional measures. SIGNIFICANCE Ultrasonography is not suitable to monitor disease progression in ALS.

Lithium lacks effect on survival in amyotrophic lateral sclerosis: a phase IIb randomised sequential trial.

Objectives To determine the safety and efficacy of lithium for the treatment of amyotrophic lateral sclerosis (ALS) in a randomised, placebo controlled, double blind, sequential trial. Methods Between November 2008 and June 2011, 133 patients were randomised to receive lithium carbonate (target blood level 0.4–0.8 mEq/l) or placebo as add-on treatment with riluzole. The primary endpoint was survival, defined as death, tracheostomal ventilation or non-invasive ventilation for more than 16 h/day. Secondary outcome measures consisted of the revised ALS Functional Rating Scale and forced vital capacity. Analysis was by intention to treat and according to a sequential trial design. Results 61 patients reached a primary endpoint, 33 of 66 in the lithium group and 28 of 67 patients in the placebo group. Lithium did not significantly affect survival (cumulative survival probability of 0.73 in the lithium group (95% CI 0.63 to 0.86) vs 0.75 in the placebo group (95% CI 0.65 to 0.87) at 12 months and 0.62 in the lithium group (95% CI 0.50 to 0.76) vs 0.67 in the placebo group (95% CI 0.56 to 0.81) at 16 months). Secondary outcome measures did not differ between treatment groups. No major safety concerns were encountered. Conclusions This trial, designed to detect a modest effect of lithium, did not demonstrate any beneficial effect on either survival or functional decline in patients with ALS. Trial registration number NTR1448. Name of trial registry: Lithium trial in ALS.

A frameshift mutation in LRSAM1 is responsible for a dominant hereditary polyneuropathy

Despite the high number of genes identified in hereditary polyneuropathies/Charcot-Marie-Tooth (CMT) disease, the genetic defect in many families is still unknown. Here we report the identification of a new gene for autosomal dominant axonal neuropathy in a large three-generation family. Linkage analysis identified a 5 Mb region on 9q33-34 with a LOD score of 5.12. Sequence capture and next-generation sequencing of the region of interest identified five previously unreported non-synonymous heterozygous single nucleotide changes or indels, four of which were confirmed by Sanger sequencing. Two sequence variants co-segregated with the disease, and one, a 2 bp insertion in the last exon of LRSAM1, was also absent in 676 ethnicity-matched control chromosomes. This frameshift mutation (p.Leu708Argfx28) is located in the C-terminal RING finger motif of the encoded protein. Ubiquitin ligase activity in transfected cells with constructs carrying the patient mutation was affected as measured by a higher level of abundance of TSG101, the only reported target of LRSAM1. Injections of morpholino oligonucleotides in zebrafish embryos directed against the ATG or last splice site of zebrafish Lrsam1 disturbed neurodevelopment, showing a less organized neural structure and, in addition, affected tail formation and movement. LRSAM1 is highly expressed in adult spinal cord motoneurons as well as in fetal spinal cord and muscle tissue. Recently, a homozygous mutation in LRSAM1 was proposed as a strong candidate for the disease in a family with recessive axonal polyneuropathy. Our data strongly support the hypothesis that LRSAM1 mutations can cause both dominant and recessive forms of CMT.

RISE AND FALL OF SKELETAL MUSCLE SIZE OVER THE ENTIRE LIFE SPAN

history of coronary heart disease. The mean Epworth Sleepiness Scale score was 14.4 in persons with sleep apnea, compared with 10.3 in persons without sleep apnea. After controlling for variables associated with falls, sleep apnea, but not snoring, witnessed apnea, or an Epworth Score above 10, was associated with a greater risk of two or more falls during the previous 12 months (odds ratio (OR) 5 2.23, 95% confidence interval (CI) 5 1.11–4.47). Sleep apnea was also associated with a higher Geriatric Depression Scale score (third tertile vs rest, OR 5 2.26, 95% CI 5 1.14–4.48), and inclusion of the depression variable into the model attenuated the relationship between sleep apnea and falls. Including the MMSE score did not substantially alter these results (Table 1). To our knowledge, this is the first study examining the relationship between sleep apnea and falls in older persons. We demonstrated a doubling of the likelihood of falls in older persons with a previous diagnosis of sleep apnea. Hypoxemia and sleep disruption from sleep apnea are related to daytime functional impairments in executive function, vigilance, alertness, fine motor coordination, and psychological disturbance, which may be likely mechanisms. In our population, depression attenuated the magnitude of the association between sleep apnea and falls, suggesting that psychological disturbance may be one of the intermediary factors in the association between sleep apnea and falls. A relationship was not demonstrated between falls and our measure of daytime sleepiness, the Epworth Sleepiness Score, although this score does not differentiate underlying causes resulting in daytime sleepiness. Confirmation of our findings in other elderly populations would be useful, given aging population trends and the high burden from recurrent falls on health and community services.

TDP-43 plasma levels are higher in amyotrophic lateral sclerosis

Abstract Our objective was to investigate TDP-43 plasma levels in patients with amyotrophic lateral sclerosis (ALS). TDP-43 has been identified as a major component of protein inclusions in the brain of patients with ALS; mutations in the corresponding gene (TARDBP) have also been identified. Although increased TDP-43 levels have been reported in the cerebrospinal fluid, plasma levels have not yet been assessed in patients with ALS. TDP-43 levels were quantified by sandwich ELISA in plasma of 219 patients and 100 controls. In addition, we sequenced exon 6 of TARDBP, and performed longitudinal TDP-43 plasma measurements in a subset of patients. Results showed that TDP-43 plasma levels were significantly increased in patients with ALS (p = 0.023) and we found a positive correlation with age in patients and controls. Longitudinal measurements of TDP-43 plasma levels showed an increase in only one patient, with stable levels in five others. Three TARDBP variations were identified in the ALS group (1.7%), but the association with TDP-43 plasma levels was ambiguous. In conclusion, our data indicate that TDP-43 plasma levels may have potential as a marker for ALS. A genotype-phenotype relationship could not, however, be established in this cohort.

Acute Deterioration of Bulbar Function After Botulinum Toxin Treatment for Sialorrhoea in Amyotrophic Lateral Sclerosis

Transcutaneous botulinum toxin injection in the salivary glands was introduced in 2000 as a new treatment for sialorrhoea in amyotrophic lateral sclerosis (ALS). We describe an ALS patient who developed serious complications of botulinum toxin treatment for sialorrhoea, and we review the relevant literature. A 64-yr-old woman with bulbar ALS for 6 mos was treated for disabling sialorrhoea. She had moderate dysphagia, but she was able to swallow. The submandibular and parotid glands were injected transcutaneously, under ultrasound guidance, with botulinum toxin (Dysport), 80 U on each side. Four days later, her bulbar function rapidly deteriorated, resulting in complete aphagia and anarthria on the fifth day. A PEG catheter was placed. Although according to the literature this treatment can be made safer by cautiously increasing the dosage and injecting the parotid glands first, BTX should not be the first-line treatment of sialorrhoea in ALS; comparative studies of BTX, amitryptiline, scopolamine, and radiation should be performed first.

BSCL2 mutations in two Dutch families with overlapping Silver syndrome-distal hereditary motor neuropathy

Mutations in the BSCL2 gene have recently been identified in families with (SPG17-linked) Silver syndrome-type hereditary spastic paraparesis as well as in families with distal hereditary motor neuropathy (HMN). We describe the first two Dutch families with BSCL2 mutations and corroborate the phenotypic variability of this gene mutation, as features compatible with Silver syndrome, variant Silver syndrome (with predominant foot rather than hand muscle involvement), distal HMN type II, or distal HMN type V were all encountered.