Motor and respiratory heterogeneity in Duchenne patients: implication for clinical trials.

AIMS: Our objective was to clarify the clinical heterogeneity in Duchenne muscular dystrophy (DMD). METHODS: The French dystrophinopathy database provided clinical, histochemical and molecular data of 278 DMD patients (mean longitudinal follow-up: 14.2 years). Diagnosis was based on mutation identification in the DMD gene. Three groups were defined according to the age at ambulation loss: before 8 years (group A); between 8 and 11 years (group B); between 11 and 16 years (group C). RESULTS: Motor and respiratory declines were statistically different between the three groups, as opposed to heart involvement. When acquired, running ability was lost at the mean age of 5.41 (group A), 7.11 (group B), 9.19 (group C) years; climbing stairs ability at 6.24 (group A), 7.99 (group B), 10,42 (group C) years, and ambulation at 7.10 (group A), 9.25 (group B), 12.01 (group C) years. Pulmonary growth stopped at 10.26 (group A), 12.45 (group B), 14.58 (group C) years. Then, forced vital capacity decreased at the rate of 8.83 (group A), 7.52 (group B), 6.03 (group C) percent per year. Phenotypic variability did not rely on specific mutational spectrum. CONCLUSION: Beside the most common form of DMD (group B), we provide detailed description on two extreme clinical subgroups: a severe one (group A) characterized by early severe motor and respiratory decline and a milder subgroup (group C). Compared to group B or C, four to six times fewer patients from group A are needed to detect the same decrease in disease progression in a clinical trial.

Impact of medical audit on electrodiagnostic medicine in polyneuropathy.

OBJECTIVE: The aim of the study was to investigate whether experienced physicians' electrodiagnostic practice and criteria can be influenced by international collaboration involving peer review medical audit. METHODS: Data was obtained from the ESTEEM project, an ongoing collaboration since 1991 among European neurophysiologists concerned with quality improvement in electrodiagnostic medicine. Three sets of the physicians' polyneuropathy examinations performed with intervals of 2-4 years were analysed. RESULTS: Changes towards increased homogeneity among the physicians were found in (1) the average number of studies performed per patient and the number of abnormal studies required for accepting the diagnosis of polyneuropathy, with the most pronounced changes seen for abnormal motor nerve segments, abnormal F-wave studies, and electromyographic studies, and (2) the agreement on pathophysiological interpretation of nerve conduction studies and classification of polyneuropathy. CONCLUSIONS: Changes towards increased homogeneity contributed to years of participation in peer review medical audit, were seen among a group of experienced physicians. Peer review medical audit as carried out here is however difficult to scale up. Therefore guidelines or minimal criteria should ideally supplement a medical audit process to disseminate the results obtained to a larger audience. SIGNIFICANCE: These results support the role of international peer review medical audit in quality improvement of electrodiagnostic medicine.

Variation in the neurophysiological examination of amyotrophic lateral sclerosis in Europe.

Our objective was to analyse how patients with amyotrophic lateral sclerosis (ALS) are examined neurophysiologically at different European centres in order to identify possible areas with variation or disagreement in the neurophysiological examination of ALS. Ninety-three prospectively collected examinations from six out of seven neurophysiologists in the European ESTEEM project were analysed. All examinations were peer reviewed with an electromyographic consensus diagnosis of motor neuron disease and the diagnosis of ALS confirmed by clinical follow-up. The examinations were analysed for differences among the physicians in EMG techniques and number and distribution of examined and abnormal muscles and nerve segments. Considerable variation was found among the physicians regarding the average numbers of performed and abnormal EMG and nerve conduction studies per patient, the EMG techniques used, and the topographical distribution of the examined muscles. The existence of two different examination approaches, one with quantitative EMG analyses and relatively few muscles studied, and one with more muscles studied using qualitative methods was clearly confirmed in the present study. The large variation among the physicians indicates that different criteria were used, or that criteria were used inconsistently.

Evidence for a dominant negative disease mechanism in cap myopathy due to TPM3.

We report a third patient with typical cap myopathy due to a heterozygous TPM3 mutation, confirming the importance of this causal association. The p.R168C TPM3 mutation we identified has been reported in two previous patients. The histological changes associated with this mutation vary widely from typical cap myopathy with near complete type 1 predominance (two patients), to typical congenital fibre-type disproportion without protein inclusions (one patient). We performed 2D-gel electrophoresis using muscle biopsies from two patients with the p.R168C mutation and show that mutant protein accounts for around 50% of alpha-tropomyosin(slow) in sarcomeres, consistent with a dominant negative mechanism of disease pathogenesis.

Absence of beta-tropomyosin is a new cause of Escobar syndrome associated with nemaline myopathy.

While TPM2 mutations identified so far in muscular diseases were all associated with a dominant inheritance pattern, we report the identification of a homozygous null allele mutation in the TPM2 gene in a patient who presented with a recessive form of nemaline myopathy associated with a non-lethal multiple pterygium syndrome (Escobar-MPS MIM# 265000). The TPM2 mutation led to a complete absence of the skeletal muscle isoform of beta-tropomyosin not compensated by expression of other beta-tropomyosin isoforms. Escobar syndrome has been recently described as a prenatal form of myasthenia associated with recessive mutations in genes of the neuromuscular junction (CHRNG, CHRNA1, CHRND, RAPSN). This observation expands the cause of Escobar variant-MPS to a component of the contractile apparatus. This first report of the clinical expression of the complete absence of TPM2 in human indicated that TPM2 expression at the early period of prenatal life plays a major role for normal fetal movements.

A prospective multicentre study on sural nerve action potentials in ALS.

OBJECTIVE: To evaluate sensory nerve conduction studies in ALS in a prospective multicentre study involving 7 neurophysiologists from 6 European countries. METHODS: Bilateral sural potentials were obtained in 35 ALS patients and 35 age-matched controls according to a standardised examination protocol using antidromic surface technique. The recordings from the right sural nerve of the controls were used for reference values. A reduction from the mean of controls greater than 2 SDs was considered abnormal. RESULTS: Reduced sensory nerve action potential (SNAP) amplitude or reduced conduction velocity (CV), or both, was found in 6 ALS patients (17%). Decrease in CV was the most frequent finding, and was observed in 8 nerves from 5 patients. Reduced SNAP amplitude was found in 2 nerves from 2 patients. All changes were minor ranging from -2.1 to -3.2 SDs. CONCLUSIONS: This is the first standardised multicentre study on sensory potentials in ALS. It confirms that although normal sensory findings should be expected in the majority of ALS patients, minor abnormalities are not uncommon. SIGNIFICANCE: Mild sensory abnormalities do not necessarily exclude a diagnosis of ALS.

Mutations in TPM3 are a common cause of congenital fiber type disproportion.

OBJECTIVE: Congenital fiber type disproportion (CFTD) is a rare form of congenital myopathy in which the principal histological abnormality is hypotrophy of type 1 (slow-twitch) fibers compared with type 2 (fast-twitch) fibers. To date, mutation of ACTA1 and SEPN1 has been associated with CFTD, but the genetic basis in most patients is unclear. The gene encoding alpha-tropomyosin(slow) (TPM3) is a rare cause of nemaline myopathy, previously reported in only five families. We investigated whether mutation of TPM3 is a cause of CFTD. METHODS AND RESULTS: We sequenced TPM3 in 23 unrelated probands with CFTD or CFTD-like presentations of unknown cause and identified novel heterozygous missense mutations in five CFTD families (p. Leu100Met, p.Arg168Cys, p.Arg168Gly, p.Lys169Glu, p.Arg245Gly). All affected family members that underwent biopsy had typical histological features of CFTD, with type 1 fibers, on average, at least 50% smaller than type 2 fibers. We also report a sixth family in which a recurrent TPM3 mutation (p.Arg168His) was associated with histological features of CFTD and nemaline myopathy in different family members. We describe the clinical features of 11 affected patients. Typically, there was proximal limb girdle weakness, prominent weakness of neck flexion and ankle dorsiflexion, mild facial weakness, and mild ptosis. The age of onset and severity varied, even within the same family. Many patients required nocturnal noninvasive ventilation despite remaining ambulant. INTERPRETATION: Mutation of TPM3 is the most common cause of CFTD reported to date.

Using EMG data to constrain optimization procedure improves finger tendon tension estimations during static fingertip force production.

Determining tendon tensions of the finger muscles is crucial for the understanding and the rehabilitation of hand pathologies. Since no direct measurement is possible for a large number of finger muscle tendons, biomechanical modelling presents an alternative solution to indirectly evaluate these forces. However, the main problem is that the number of muscles spanning a joint exceeds the number of degrees of freedom of the joint resulting in mathematical under-determinate problems. In the current study, a method using both numerical optimization and the intra-muscular electromyography (EMG) data was developed to estimate the middle finger tendon tensions during static fingertip force production. The method used a numerical optimization procedure with the muscle stress squared criterion to determine a solution while the EMG data of three extrinsic hand muscles serve to enforce additional inequality constraints. The results were compared with those obtained with a classical numerical optimization and a method based on EMG only. The proposed method provides satisfactory results since the tendon tension estimations respected the mechanical equilibrium of the musculoskeletal system and were concordant with the EMG distribution pattern of the subjects. These results were not observed neither with the classical numerical optimization nor with the EMG-based method. This study demonstrates that including the EMG data of the three extrinsic muscles of the middle finger as inequality constraints in an optimization process can yield relevant tendon tensions with regard to individual muscle activation patterns, particularly concerning the antagonist muscles.

Influence of peer review medical audit on pathophysiological interpretation of nerve conduction studies in polyneuropathies.

OBJECTIVE: To evaluate the possible influence of peer review medical audit on experienced physicians' pathophysiological interpretation of nerve conduction studies in polyneuropathy patients. METHODS: Since 1992, 7 European neurophysiologists have collected samples of their patient examinations for regular review where the physicians interpret each other's cases electronically and subsequently discuss them at regular workshop meetings (i.e. a form of medical audit). Two sets of 100 polyneuropathy examinations interpreted with an interval of 4-6 years were selected. The sets contained 1456 and 1719 nerve conduction studies, each given a pathophysiological test conclusion by each individual physician. Inter-physician agreement on interpretation of demyelination and axonal loss of the nerve, as well as neuropathic and unspecific findings, was estimated using kappa statistics. RESULTS: Increased agreement from set 1 to set 2 was found on interpretation of demyelination of the nerve (set 1: kappa=0.22; set 2: kappa=0.45), and of neuropathic (set 1: kappa=0.46; set 2: kappa=0.64) and unspecific findings (set 1: kappa=0.35; set 2: kappa=0.54). No changes were found on interpretation of axonal loss (set 1: kappa=0.26; set 2: kappa=0.31) and normal findings (set 1 and set 2: kappa=0.90). CONCLUSIONS: Participation in regular peer review medical audit resulted in increased agreement on interpretation of nerve conduction studies for 6 of the 7 participants. The study further highlights the need for better definition of criteria for identification of demyelinating, and in particular, axonal peripheral neuropathies. SIGNIFICANCE: International collaboration involving peer review medical audit may contribute to development of practice guidelines and, in turn, to increased quality of electrodiagnostic medicine.

Estimation of finger muscle tendon tensions and pulley forces during specific sport-climbing grip techniques.

The present work displayed the first quantitative data of forces acting on tendons and pulleys during specific sport-climbing grip techniques. A three-dimensional static biomechanical model was used to estimate finger muscle tendon and pulley forces during the "slope" and the "crimp" grip. In the slope grip the finger joints are flexed, and in the crimp grip the distal interphalangeal (DIP) joint is hyperextended while the other joints are flexed. The tendons of the flexor digitorum profundus and superficialis (FDP and FDS), the extensor digitorum communis (EDC), the ulnar and radial interosseus (UI and RI), the lumbrical muscle (LU) and two annular pulleys (A2 and A4) were considered in the model. For the crimp grip in equilibrium conditions, a passive moment for the DIP joint was taken into account in the biomechanical model. This moment was quantified by relating the FDP intramuscular electromyogram (EMG) to the DIP joint external moment. Its intensity was estimated at a quarter of the external moment. The involvement of this parameter in the moment equilibrium equation for the DIP joint is thus essential. The FDP-to-FDS tendon-force ratio was 1.75:1 in the crimp grip and 0.88:1 in the slope grip. This result showed that the FDP was the prime finger flexor in the crimp grip, whereas the tendon tensions were equally distributed between the FDP and FDS tendons in the slope grip. The forces acting on the pulleys were 36 times lower for A2 in the slope grip than in the crimp grip, while the forces acting on A4 were 4 times lower. This current work provides both an experimental procedure and a biomechanical model that allows estimation of tendon tensions and pulley forces crucial for the knowledge about finger injuries in sport climbing.

Pathophysiology inferred from electrodiagnostic nerve tests and classification of polyneuropathies. Suggested guidelines.

OBJECTIVE: To present criteria for pathophysiological interpretation of motor and sensory nerve conduction studies and for pathophysiological classification of polyneuropathies suggested by a group of European neurophysiologists. METHODS: Since 1992 seven neurophysiologists from six European countries have collected random samples of their electrodiagnostic examinations for peer review medical audit in the ESTEEM (European Standardized Telematic tool to Evaluate Electrodiagnostic Methods) project. Based on existing criteria in the literature, the experience with a patient material of 572 peer reviewed electrodiagnostic examinations, and productive discussions between the physicians at workshops, the collaboration has produced a set of criteria now routinely used at the centres involved in the project. RESULTS: The first part of the paper considers pathophysiology of individual nerve segments. For interpretation of motor and sensory nerve conduction studies, figures showing change in amplitude versus change in conduction velocity/distal latency and change in F-wave frequency versus change in F-wave latency are presented. The suggested boundaries delimit areas corresponding to normal, axonal, demyelinated, or neuropathic nerve segments. Criteria for motor conduction block in upper and lower extremities are schematically depicted using the parameters CMAP amplitude and CMAP duration. The second part of the paper suggests criteria for classification of polyneuropathies into axonal, demyelinating, or mixed using the above-mentioned criteria. CONCLUSIONS: The suggested criteria are developed during many years of collaboration of different centres and may be useful for standardization in clinical neurophysiology. SIGNIFICANCE: Consistent interpretation of nerve conduction studies is an important step in optimising diagnosis and treatment of nerve disorders.

Influence of medical audit on electrodiagnostic evaluation of polyneuropathy. A multicentre study.

OBJECTIVE: Since 1992, 7 European neurophysiologists have participated in the ESTEEM project concerned with improvements in electrodiagnostic medicine. This study assesses whether the collaboration that includes peer review medical audit has influenced the involved physicians' electrodiagnostic criteria for polyneuropathy (PNP) diagnosing and classification. METHODS: Two sets of each physician's PNP examinations performed early and late in the study were examined for changes in (1) number of studies with abnormal electrophysiological findings required for diagnosing PNP, and (2) agreement between the classifications given by the individual physicians and the peer review group. RESULTS: The average number of abnormal motor nerve segments per patient increased from 4.6 to 6.4 during the study. Although most individual changes were minor, the second set of examinations showed an increased homogeneity among the physicians in the number of abnormal motor nerve segments and abnormal F wave studies, and a tendency towards increased homogeneity in the number of abnormal sensory nerve segments. There was also an increased agreement on pathophysiological PNP classification in the second set of examinations compared to the first set. CONCLUSIONS: The participation in the ESTEEM project seems to have impacted the physicians' clinical routine, possibly as they have accustomed themselves to apply criteria more strictly. SIGNIFICANCE: This study support that international collaboration is a useful step towards improvements in electrodiagnostic medicine.

A homozygous splicing mutation causing a depletion of skeletal muscle RYR1 is associated with multi-minicore disease congenital myopathy with ophthalmoplegia.

The ryanodine receptor (RYR1) is an essential component of the calcium homeostasis of the skeletal muscle in mammals. Inactivation of the RYR1 gene in mice is lethal at birth. In humans only missense and in-frame mutations in the RYR1 gene have been associated so far with various muscle disorders including malignant hyperthermia, central core disease and the moderate form of multi-minicore disease (MmD). We identified a cryptic splicing mutation in the RYR1 gene that resulted in a 90% decrease of the normal RYR1 transcript in skeletal muscle. The 14646+2.99 kb A-->G mutation was associated with the classical form of MmD with ophthalmoplegia, whose genetic basis was previously unknown. The mutation present at a homozygous level was responsible for a massive depletion of the RYR1 protein in skeletal muscle. The mutation was not expressed in lymphoblastoid cells, pointing toward a tissue specific splicing mechanism. This first report of an out-of-frame mutation that affects the amount of RYR1 raised the question of the amount of RYR1 needed for skeletal muscle function in humans.

A knowledge-driven agent-centred framework for data mining in EMG.

In this paper, we present a multi-agent framework for data mining in electromyography. This application, based on a web interface, provides a set of functionalities allowing to manipulate 1000 medical cases and more than 25,000 neurological tests stored in a medical database. The aim is to extract medical information using data mining algorithms and to supply a knowledge base with pertinent information. The multi-agent platform gives the possibility to distribute the data management process between several autonomous entities. This framework provides a parallel and flexible data manipulation.