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International audience; CROUZIER, M., K. TUCKER, L. LACOURPAILLE, V. DOGUET, G. FAYET, M. DAUTY, and F. HUG. Force-sharing within the Triceps Surae: An Achilles Heel in Achilles Tendinopathy. Med. Sci. Sports Exerc., Vol. 52, No. 5, pp. 1076–1087, 2020. Purpose: The primary aim of this study was to determine whether the distribution of force between the three heads of the triceps surae differs between people with Achilles tendinopathy and controls. We also aimed to determine the effect of this force distribution on subtendon strain. Methods: Data were collected for 21 participants with Achilles tendinopathy and 21, case-wise paired, asymptomatic controls. Ultrasonography was used to measure muscle volume, fascicle length, pennation angle and subtendon length at rest. Muscle activation was estimated using surface electromyography during maximal and submaximal isometric plantarflexion tasks. The product of normalized activation, physiological cross-sectional area, and the cosine of the pennation angle was considered as an index of individual muscle force. Displacement of the distalmyotendinous junction of each muscle was measured during the submaximal contractions. Results: The contribution of the gastrocnemius lateralis to the overall triceps surae physiological cross-sectional area and activation was 8.5% (P = 0.047, d = 0.75) and 24.7% lower (main effect group P = 0.009, d = 0.67) in people with Achilles tendinopathy than in the controls, respectively. Consequently, gastrocnemius lateralis contributed approximately 28% less (main effect group P = 0.025, d = 0.62) of the triceps surae force in people with Achilles tendinopathy. The contribution of gastrocnemius medialis and soleus was not different between groups. Subtendon strain was not different between groups (P = 0.835). Conclusions: These results provide evidence for a difference in force-sharing strategy within the triceps surae in people with Achilles tendinopathy compared with the controls. Whether this altered strategy is a cause or a consequence of Achilles tendinopathy should be explored further.

Objective To demonstrate the causal role in disease of the MT-TP m.15992A>T mutation observed in patients from 5 independent families. Methods Lactate measurement, muscle histology, and mitochondrial activities in patients; PCR-based analyses of the size, amount, and sequence of muscle mitochondrial DNA (mtDNA) and proportion of the mutation; respiration, mitochondrial activities, proteins, translation, transfer RNA (tRNA) levels, and base modification state in skin fibroblasts and cybrids; and reactive oxygen species production, proliferation in the absence of glucose, and plasma membrane potential in cybrids. Results All patients presented with severe exercise intolerance and hyperlactatemia. They were associated with prominent exercise-induced muscle swelling, conspicuous in masseter muscles (2 families), and/or with congenital cataract (2 families). MRI confirmed exercise-induced muscle edema. Muscle disclosed severe combined respiratory defect. Muscle mtDNA had normal size and amount. Its sequence was almost identical in all patients, defining the haplotype as J1c10, and sharing 31 variants, only 1 of which, MT-TP m.15992A>T, was likely pathogenic. The mutation was homoplasmic in all tissues and family members. Fibroblasts and cybrids with homoplasmic mutation had defective respiration, low complex III activity, and decreased tRNAPro amount. Their respiratory complexes amount and tRNAPro aminoacylation appeared normal. Low proliferation in the absence of glucose demonstrated the relevance of the defects on cybrid biology while abnormal loss of cell volume when faced to plasma membrane depolarization provided a link to the muscle edema observed in patients. Conclusions The homoplasmic MT-TP m.15992A>T mutation in the J1c10 haplotype causes exercise-induced muscle swelling and fatigue.

Introduction Vincristine is an antimitotic agent used for treatment of leukemia, lymphomas, and cancers. Its main side effect is a dose-related, length-dependent (LD) axonal neuropathy. Methods We performed electrodiagnostic (EDx) examinations in 17 children who had been treated with vincristine and who presented with the clinical picture of a peripheral neuropathy. Results The mean dose of vincristine was 8.5 ± 4.0 mg/m2. Clinical motor symptoms were more frequent and more severe than sensory ones. Thirteen children presented with a motor deficit, 4 of whom could no longer walk. EDx examination showed an axonal neuropathy with a non–length-dependent (NLD) pattern in 9 children and an LD pattern in 8. A major motor predominance was encountered in 12 patients. Conclusions The electrophysiological and clinical motor predominance described differs from the mainly sensory neuropathy reported in adults. Incomplete myelination due to young age may have resulted in greater sensitivity of some nerves to neurotoxic agents. Muscle Nerve, 2015

Introduction Guillain–Barre syndrome (GBS) has some specific characteristics in children. Methods In this study we reviewed the clinical, laboratory, electrophysiological, and prognosis features of the 19 children diagnosed with GBS at Nantes University Hospital from 2000 to 2011. Results Gait disturbance and leg pain were the most frequent presenting symptoms. Electrophysiological examinations revealed significant abnormalities even when performed within the first week after onset. Decreased distal CMAP amplitude was noted in 89% of cases. The pattern indicated an acute inflammatory demyelinating polyneuropathy in 95% of cases and acute motor axonal neuropathy in the remaining 5%. About two-thirds of the children were treated with intravenous immunoglobulin. After >1 year of follow-up, 17 patients had complete recovery. Conclusion Gait disorder, leg pain, a high rate of distal conduction block, and a good prognosis are among the main specific features of GBS in childhood. Muscle Nerve, 48: 247–251, 2013

Background The treatment of depression remains a challenge since at least 40% of patients do not respond to initial antidepressant therapy and 20% present chronic symptoms (more than 2 years despite standard treatment administered correctly). Repetitive transcranial magnetic stimulation (rTMS) is an effective adjuvant therapy but still not ideal. Intermittent Theta Burst Stimulation (iTBS), which has only been used recently in clinical practice, could have a faster and more intense effect compared to conventional protocols, including 10-Hz high-frequency rTMS (HF-rTMS). However, no controlled study has so far highlighted the superiority of iTBS in resistant unipolar depression. Methods/design This paper focuses on the design of a randomised, controlled, double-blind, single-centre study with two parallel arms, carried out in France, in an attempt to assess the efficacy of an iTBS protocol versus a standard HF- rTMS protocol. Sixty patients aged between 18 and 75 years of age will be enrolled. They must be diagnosed with major depressive disorder persisting despite treatment with two antidepressants at an effective dose over a period of 6 weeks during the current episode. The study will consist of two phases: a treatment phase comprising 20 sessions of rTMS to the left dorsolateral prefrontal cortex, localised via a neuronavigation system and a 6-month longitudinal follow-up. The primary endpoint will be the number of responders per group, defined by a decrease of at least 50% in the initial score on the Montgomery and Asberg Rating Scale (MADRS) at the end of rTMS sessions. The secondary endpoints will be: response rate 1 month after rTMS sessions; number of remissions defined by a MADRS score of

Summary Background Somatosensory evoked potentials (SSEPs) are increasingly performed for the assessment of peripheral neuropathies, but no practical guidelines have yet been established in this specific application. Study aim To determine the relevant indication criteria and optimal technical parameters for SSEP recording in peripheral neuropathy investigation. Methods A survey was conducted among the French-speaking practitioners with experience of SSEP recording in the context of peripheral neuropathies. The results of the survey were analyzed and discussed to provide recommendations for practice. Results SSEPs appear to be a second-line test when electroneuromyographic investigation is not sufficiently conclusive, providing complementary and valuable information on central and proximal peripheral conduction in the somatosensory pathways. Conclusions Guidelines for a standardized recording protocol, including the various parameters to be measured, are proposed. Clinical relevance We hope that these proposals will help to recognize the value of this technique in peripheral neuropathy assessment in clinical practice.

Increased susceptibility to apoptosis has been shown in many models of mitochondrial defects but its relevance to human diseases is still discussed. We addressed the presence of apoptosis in muscle from patients with mitochondrial DNA (mtDNA) disorders. Taking advantage of the mosaic pattern of muscle morphological anomalies associated with heteroplasmic mtDNA alterations, we have used an in situ approach to address the relationship between apoptosis and respiratory defect, mitochondrial proliferation and mutation load. Different patterns of mitochondrial morphological alterations were provided by the analysis of muscles with large mtDNA deletion (16 cases) or with the MELAS mutation (4 cases). The patient's age at biopsy ranged from 0.4 to 66 years and the muscle mutant mtDNA proportion from 32 to 82%. Apoptotic muscle fibres were observed in a small proportion of muscle fibres of 16 out of the 20 biopsies by three different detection methods for different steps of apoptosis: caspase 3 activation, fragmentation of nuclear DNA [terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling (TUNEL) assay] or overexpression of the pro-apoptotic factor Bax. Analysis of apoptotic features in parallel to cytochrome c oxidase (COX) and succinate dehydrogenase activity of more than 34,000 individual muscle fibres showed that apoptosis occurred only in muscle fibres with mitochondrial proliferation (ragged red fibres, RRF) irrespective of their COX activity. Molecular analyses of single muscle fibres evidenced that, as expected, the presence of COX defect was associated with higher proportion of mutant mtDNA and lower amount of normal mtDNA. Within COX-defective fibres, the presence of mitochondrial proliferation was associated with increase of the mtDNA content but without change in the ratio between normal and mutant mtDNA molecules, thus showing that mitochondrial proliferation was accompanied by similar amplification of normal and mutant mtDNA molecules. Within RRF, apoptosis was associated with higher mutation proportion, suggesting that it was provoked by severe respiratory defect in the same time as increased mitochondrial mass. In conclusion, apoptosis most probably contributes to mitochondrial pathology. It is tightly linked to mitochondrial proliferation and high mutation load. When considering training therapeutics, one will have to take into account the possibility to induce apoptosis in parallel to mitochondrial proliferation.

Introduction Motor unit number index (MUNIX), est une technique permettant d’estimer le nombre d’unites motrices fonctionnelles pour un muscle donne, procurant ainsi un marqueur de perte motoneuronale. Objectifs Le but de l’etude etait d’appliquer la technique MUNIX aux neuropathies peripheriques a anti-myelin associated glycoprotein (MAG) et notamment de pouvoir estimer la perte axonale probablement sous-estimee dans cette pathologie. Patients et methodes Onze patients ont ete recrutes au sein de la cohorte nantaise de patients atteints de neuropathie a anti-MAG lors de leur visite bisannuelle au centre de reference des maladies neuromusculaires. Les enregistrements ont ete realises sur Natus Keypoint. La technique MUNIX a ete realisee selon le protocole d’etudes deja publiees dans ce domaine sur les muscles jambier anterieur (JA) et court abducteur du pouce (CAP). Resultats Une perte du nombre d’unites motrices, environ de moitie comparee aux donnees de la litterature, a ete retrouvee aux membres superieurs et inferieurs chez les patients recrutes. MUNIX semble etre une technique plus sensible que la stimulo-detection standard pour rechercher l’atteinte axonale. Le MUNIX est diminue chez des patients presentant une amplitude conservee de leur potentiel d’action (amplitude moyenne sur le nerf median de 6,75 mV, pour un MUNIX moyen de 102,5 ; norme du MUNIX pour le CAP a 203). Discussion MUNIX permet de confirmer l’existence d’une atteinte axonale precoce dans les neuropathies a anti-MAG. Celle-ci a deja ete decrite en histologie, mais sa physiopathologie n’est pas clairement etablie dans la litterature. Elle est possiblement liee a l’inflammation locale sans lien de cause a effet direct avec l’anticorps anti-MAG. Conclusion MUNIX permet une evaluation de la perte axonale des neuropathies anti-MAG plus precise que la mesure de l’amplitude du potentiel d’action moteur. Informations complementaires Remerciements au Pr Pereon pour m’avoir propose ce sujet de memoire, au Dr Magot pour son encadrement et son aide precieuse pour le recrutement des patients, au Dr Fayet pour sa relecture attentive. Pas de financement declare.

Although mitochondrial DNA deletions have been shown to accumulate in cytochrome c oxidase deficient muscle fibres of ageing muscle, this has not been demonstrated for point mutations. In this study, we investigated the occurrence of mitochondrial DNA alterations (point mutations and deletions) in cytochrome c oxidase deficient muscle fibres from 14 individuals, without muscle disease, aged 69-82 years. Immunohistochemical investigation showed that the majority of the cytochrome c oxidase deficient muscle fibres expressed reduced levels of subunit II of cytochrome c oxidase, which is encoded by mitochondrial DNA, whereas there was normal or increased expression of subunit IV of cytochrome c oxidase, which is encoded by nuclear DNA. This pattern is typical for mitochondrial DNA mutations causing impaired mitochondrial translation. Single muscle fibres (109 cytochrome c oxidase deficient and 109 normal fibres) were dissected and their DNA extracted. Mitochondrial DNA point mutations were searched for in five tRNA genes by denaturing gradient gel electrophoresis while deletions were looked for by polymerase chain reaction amplification. High levels of clonally expanded point mutations were identified in eight cytochrome c oxidase deficient fibres but in none of the normal ones. They included the previously described pathogenic tRNALeu(UUR)A3243G and tRNALysA8344G mutations and three original mutations: tRNAMetT4460C, tRNAMetG4421A, and a 3-bp deletion in the tRNALeu(UUR) gene. Four different large-scale mitochondrial DNA deletions were identified in seven cytochrome c oxidase deficient fibres and in one of the normal ones. There was no evidence of depletion of mitochondrial DNA by in situ hybridisation experiments. Our data show that mitochondrial DNA point mutations, as well as large-scale deletions, are associated with cytochrome c oxidase deficient muscle fibre segments in ageing. Their focal accumulation causes significant impairment of mitochondrial function in individual cells in spite of low overall levels of mitochondrial DNA mutations in muscle.

We report a case of a 32-year-old male patient who suffered from bipolar depression complicated by severe alcohol dependence and chronic cannabis abuse. No medication could help him to control a strong craving leading to frequent relapse until off-label treatment by baclofen at high dosage (300 mg/day). The subject became completely abstinent in alcohol for several months. Thymic evaluation showed a major depressive episode with Beck Depression Inventory (BDI) score at 13/39. Treatment by quetiapine was then introduced at 300 mg/day. Motor cortical excitability was assessed before starting quetiapine and after 4 weeks of stable intake. A complete remission of depressive state was observed according to the BDI score at 2/39. Before quetiapine and under chronic and stable baclofen and cannabis consumption, we observed: – hugely lengthening of CSP in both hemispheres (right more than left), probably due both to baclofen and cannabis use; – absent SICI in left hemisphere and present SICI in right hemisphere in agreement with a major depressive disorder. Baclofen could also have accentuated SICI decrease via presynaptic inhibition action; – present ICF in left hemisphere and absent ICF in right side. These results may be consequence of SICI abnormalities described above. After quetiapine, we observed bilateral CSP shortening, SICI restoration in left hemisphere, and ICF restoration in right hemisphere. In summary, we observed for the first time normalization of cortical excitability associated with bipolar depression (i.e. deficit in motor cortical gabaergic transmission in left hemisphere) due to pharmacological intervention. This case shows the feasibility and the physiological insight of pharmaco-TMS, even in complex “real-life” clinical situations.

Introduction Le corps calleux (CC) est atteint dans de nombreuses maladies neurologiques. La periode de silence corticale ipsilaterale (iSP) permet d’evaluer l’etat fonctionnel des fibres inhibitrices transcalleuses. Objectifs L’iSP est une interruption totale mais transitoire du signal electromyographique secondaire a l’activation du cortex moteur ipsilateral declenche par une stimulation magnetique. L’objectif etait d’analyser l’iSP chez des sujets porteurs de pathologies centrales. Patients et methodes Six temoins et 4 sujets atteints de maladies neurologiques decrites comme associees a une atteinte du corps calleux dont la SEP et la SLA ont ete etudies. Les mesures de l’iSP (latence, duree) ont ete obtenues dans le muscle 1er interosseux dorsal de chaque main apres une stimulation magnetique transcrânienne a 2 niveaux d’intensite. Les seuils moteurs corticaux de repos et les temps de conduction centraux (TCC) ont ete egalement obtenus pour chaque hemisphere. Resultats Chez les temoins, la latence de l’iSP etait stable et parfois asymetrique entre les 2 hemispheres. La duree de l’iSP augmentait avec l’intensite de stimulation. Les patients SEP presentaient parfois une augmentation de la latence de l’iSP et/ou une perte partielle ou totale de l’iSP sur au moins un des 2 hemispheres. Le patient SLA presentait une perte quasi-totale de l’iSP sur l’hemisphere droit. Les anomalies de l’iSP etaient associees a un allongement du TCC. Discussion Cette etude preliminaire a permis de detecter un dysfonctionnement transcalleux chez deux patients SEP et chez un patient SLA. L’atteinte se manifestait soit par un retard soit par une perte de l’inhibition transcalleuse (IT) ce qui pourrait traduire des alterations morphologiques differentes. La perte d’IT pourrait participer a la levee d’inhibition corticale du faisceau corticospinal observe dans ces deux affections. Conclusion Nous proposons en routine la mesure de l’iSP comme outil simple et indolore d’aide diagnostique aux maladies neurologiques associees a un dysfonctionnement du CC.

Guillain-Barré syndrome (GBS) has some specific characteristics in children.In this study we reviewed the clinical, laboratory, electrophysiological, and prognosis features of the 19 children diagnosed with GBS at Nantes University Hospital from 2000 to 2011.Gait disturbance and leg pain were the most frequent presenting symptoms. Electrophysiological examinations revealed significant abnormalities even when performed within the first week after onset. Decreased distal CMAP amplitude was noted in 89% of cases. The pattern indicated an acute inflammatory demyelinating polyneuropathy in 95% of cases and acute motor axonal neuropathy in the remaining 5%. About two-thirds of the children were treated with intravenous immunoglobulin. After1 year of follow-up, 17 patients had complete recovery.Gait disorder, leg pain, a high rate of distal conduction block, and a good prognosis are among the main specific features of GBS in childhood.

Exercise intolerance may be suggestive of metabolic myopathy or mitochondrial disorders. We report a family where 7 female subjects presented with various degree of exercise intolerance since childhood. A common and original feature shared by affected members was the increased volume of the masseter muscle systematically occurring after feeding, making them looking like a hamster. Limb muscle size was not affected by effort. Patients also complained of keloid scars and for some of them of congenital cataract. The index case underwent full examination including clinical assessment, electromyography, electro-retinography, muscle biopsy, pulmonary function testing, exercise test, genetic testing. Clinical and EDX examinations were normal. Exercise test was brief due to muscle fatigue but induced an important increase of lactates and lactate/pyruvate ratio. Morphological analysis and standard immunochemistry of the muscle biopsy were normal but analysis of the respiratory chain complexes from the muscle biopsy displayed a combined defect in the complexes I, III, and IV encoded by mitochondrial DNA, associated with an increase of complex II and citrate synthase. An increased number of muscle mtDNA copies was observed reflecting a probable mitochondrial proliferation. Whole mtDNA sequencing revealed the homoplasmic m.15992A > T variant in the mitochondrial tRNA (Pro) gene (MT-TP). This mutation does not affect the codon reading but modifies the efficiency of aminoacylation or of post-transcriptional modification, leading to less efficient translation. It was also found in 3 affected members apart from index case and is very likely to be pathological. The relationships between the gene mutation and the unusual clinical phenotype are not clear but are worthy of interest.

We describe a lethal mitochondrial disease in a 10-month-old child who presented with encephalomyopathy. Histochemical and electron microscopy examinations of skeletal muscle biopsy revealed abnormal mitochondria associated with a combined deficiency of complexes I and IV. After excluding mitochondrial DNA deletions and depletion, direct sequencing was used to screen for mutation in all transfer RNA (tRNA) genes. A T-to-C substitution at position 5693 in the tRNA{sup Asn} gene was found in blood and muscle. Microdissection of muscle biopsy and its analysis revealed the highest level of this mutation in cytochrome c oxidase (COX)-negative fibres. We suggest that this novel mutation would affect the anticodon loop structure of the tRNA{sup Asn} and cause a fatal mitochondrial disease.

Mutations in the human mitochondrial MT-ATP6 gene, encoding ATP synthase subunit a, are causing different neurological disorders such as Neurogenic Ataxia and Retinitis Pigmentosa (NARP), Leigh’s syndrome, Charcot-Marie-Tooth neuropathy, and more recently paralysis episodes. The deleterious consequences of these MT-ATP6 mutations are still the matter of debate with respect to their cellular impact and influence of the nuclear background. To investigate the primary molecular mechanisms independently from the impact of nuclear genome, we constructed cybrids with homoplasmic levels of the MT-ATP6 m.9185T > C mutation previously associated with each type of clinical presentation encountered with MT-ATP6 mutations. Using cDNA microarray analysis (31,142 probes) coupled with bioinformatics and functional gene annotations studies, we compared 7 samples from four independent homoplasmic mutant 143B cybrid cells to 9 samples from four independent control cybrids with different wild type mtDNA. Hierarchical clustering revealed 6 main gene clusters. The significant Gene Ontology up-regulated terms in the mutant cybrids as compared to controls notably involved reactive oxygen species, monocarboxylic acid transport, activity and/or regulation of adaptive and/or inflammatory responses, MAP-kinases pathway, striated development muscle, tissue remodelling, extracellular matrix, cell cycle pathway and organelle fission. The significant Gene Ontology down-regulated terms in the mutant cybrids as compared to controls notably involved DNA replication, RNA splicing and a decrease of actin cytoskeleton regulation. These results will be discussed with respect to functional respiratory chain and cellular analyses searching for primary molecular pathways associated to MT-ATP6 mutations.

Among congenital myopathies, X-linked recessive myotubular myopathy is one of the most severe forms. The majority of patients present with severe hypotonia at birth and respiratory insufficiency and most of them die in the first year of life. However, there is phenotypic variability. Here, we report two patients carrying a missense mutation in MTM1 gene and presenting with a mild phenotype. The first boy was born on time with respiratory insufficiency and generalised hypotonia. He required ventilator support for 3 weeks, and then he went home without specific care. He walked at 11 month. He is now 24 and can run, practices canoe and works as a salesperson. At the exam, he presents mild proximal weakness and restrictive syndrome with no ventilator support (VC = 57%). His brother was born on time with respiratory insufficiency and hypotonia. He stayed in intensive care unit for 6 weeks, then went home without support. He walked at 18 months. Respiratory involvement was more severe than his brother with a severe restrictive syndrome (VC = 33%) but the young man refused non-invasive night-time ventilation proposed at the age of 16. Being now 20, he can walk without any difficulty but cannot run. Clinical exam reveals a mild proximal weakness. Both patients underwent muscle biopsy showing the typical centronuclear myopathy pattern. Molecular analysis of MTM1gene found a hemizygous mutation c.575A>G in exon 8 leading to a missense p.Tyr192Cys. A decreased level of the MTM1 protein was observed by western blot analysis on lymphoblasts. To date, about 300 different mutations in around 540 families have been identified in MTM1 gene, including point mutations, insertions and small and large deletions and duplication. Around 70% of patients presenting with a mild or moderate phenotype carries a missense mutation, which is also the most frequent type of mutation. Another patient has been described with the same mutation (c.575A>G) and presented also with a mild phenotype.

A quantitative analysis of deltoid muscle biopsy specimens was performed by light microscopy in 26 males and 25 females aged 50-79 years without known neuromuscular disease. Muscle fibre size, fibre type distribution and increase in mitochondrial content in muscle fibres were examined using a semi-automatic image analysis system. This study showed significant age- and gender-related differences. In females, there was marked atrophy of type II fibres with increasing age, specially of type IIb fibres, but no significant change in muscle fibre type distribution. In males, there was diminution in the relative proportion of type IIb fibres with increasing age but no significant muscle fibre atrophy. Mitochondrial aggregates increased with age, and this increase was observed earlier in females than in males. The gender-related morphological changes observed in the present study differ somewhat from those reported in the literature. The differences between males and females may be partially related to gender differences in muscular activity and may reflect an earlier decline in deltoid muscle strength in females. The existence of these age and gender changes should be taken into account in the interpretation of muscle biopsies of aged individuals.

Many different pathogenic mutations in the mitochondrial (mt) transfer RNA (tRNA) genes have been reported for patients with mitochondrial encephalomyopathy. Although some of them are recurrent, most have only been described once and appear to be restricted to one patient or to one family. The incidence of mt tRNA gene alterations is not known, even though the frequency of some recurrent mutations has been analysed both in patients and in the general population. In this study, we describe the results of stepwise screening for sequence variations in the mt tRNA genes of 166 patients selected according to several criteria. Extensive sequence analysis of the tRNA genes was performed using denaturing gradient gel electrophoresis. A total of 31 patients (19%) were found to harbour significant levels of a pathogenic mutation, thus confirming the importance of mt tRNA mutations in human pathology. Forty-three different sequence variations were found, illustrating the great diversity of the mtDNA sequence in humans. The functional assessment of all these sequence variations represented a difficult task; it was mostly based on indirect data, such as the phylogenetic conservation of modified nucleotides and the proportions of variant species in different tissues of the index case or in blood of maternal relatives. Direct demonstration of a correlation between the proportion of heteroplasmic sequence variations and the cytochrome c oxidase defect was performed at the single muscle-fibre level. Eleven heteroplasmic sequence variations were found, six of which are new mutations. One is a known Caucasian polymorphism but the other 10 are pathogenic. Two of them are the well-known pathogenic MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes) (A3243G) and MERRF (myoclonic epilepsy with ragged-red fibres) (A8344G) point mutations. They were found in 23 patients. The eight other mutations were restricted to one patient. The pathogenic nature of these mutations was demonstrated directly for five of them and hypothesized from indirect arguments for the other three. Thirty-two homoplasmic sequence variations were found. Twenty-nine were considered to be polymorphisms, even though 15 of these were found for the first time in our patients and two others had been reported previously as pathogenic. The pathogenic nature of three homoplasmic variants remains questionable.

Neurogenic motor evoked potential (NMEP) monitoring, which basically represents a monitoring of both motor and somatosensory tracts, has been proposed as a warning system in preventing neural damage during spinal surgery. The aim of this study was to report our clinical experience in 112 consecutive patients undergoing surgery for spinal deformity, and to emphasize the interest of NMEP monitoring. NMEPs were elicited in each patient by electrical stimulation of the spinal cord via needle electrodes placed by the surgeon in the rostral part of the surgical field, and recorded from the right and left sciatic nerves. Concomitantly, somatosensory evoked potentials (SSEPs) were obtained using a standard method. No false-negative cases of intra-operative spinal cord damage were reported. In 3 patients, both NMEPs and SSEPs suddenly disappeared during specific surgical manipulations of the vertebral implants. In these patients, the level of the lesion was easily recognized by moving the stimulating electrodes of NMEPs along the spinal cord, allowing the surgeon to perform laminectomy at the appropriate vertebral level. Spinal cord decompression was a success in two patients, the last unfortunately being paraplegic. Two additional patients exhibited transient reduction in NMEP amplitude at the insertion of a rod while SSEPs did not change significantly. In these two cases, the surgeon modified his procedure according to the NMEP changes, possibly avoiding a neurological complication. Each time evoked potentials were significantly altered, significant information was more rapidly acquired with NMEPs than with SSEPs. These results suggest that NMEPs can be used as primary choice for detecting impeding lesion of the spinal cord during critical steps of spinal surgery.

Background Most techniques used to monitor spinal cord tracts are sensitive to the effects of anesthesia, particularly to volatile anesthetic agents. The aim of this prospective study was to show that evoked potentials recorded from the peripheral nerves after spinal cord stimulation, so-called neurogenic motor evoked potentials, are resistant to clinical concentrations of isoflurane or desflurane, compared with somatosensory-evoked potentials. Methods Twenty-three patients were studied during surgery to correct scoliosis. The background anesthetic consisted of a continuous infusion of propofol. Isoflurane (n = 12) or desflurane (n = 11) were then introduced to achieve 0.5 and 1.0 end-tidal minimum alveolar concentrations (MAC), both in 50% oxygen-nitrous oxide and in 100% oxygen. Somatosensory-evoked potentials were elicited and recorded using a standard method, defining cortical P40 and subcortical P29. Neurogenic motor-evoked potentials were elicited by electric stimulation of the spinal cord via needle electrodes placed by the surgeon in the rostral part of the surgical field. Responses were recorded from needle electrodes inserted in the right and left popliteal spaces close to the sciatic nerve. Stimulus intensity was adjusted to produce a supramaximal response; that is, an unchanged response in amplitude with subsequent increases in stimulus intensity. Measurements were obtained before introducing volatile agents and 20 min after obtaining a stable level of each concentration. Results Isoflurane and desflurane in both 50% oxygen-nitrous oxide and 100% oxygen were associated with a significant decrease in the amplitude and an increase in the latency of the cortical P40, whereas subcortical P29 latency did not vary significantly. Typical neurogenic motor-evoked potentials were obtained in all patients without volatile anesthetic agents, consisting of a biphasic wave, occurring 15 to 18 ms after stimulation, with an amplitude ranging from 1.3 to 4.1 microV. Latency or peak-to-peak amplitude of this wave was not significantly altered with isoflurane and desflurane, either in the presence or in the absence of nitrous oxide. Conclusions Compared with cortical somatosensory-evoked potentials, neurogenic motor-evoked potential signals are well preserved in patients undergoing surgery to correct scoliosis under general anesthesia supplemented with isoflurane or desflurane in concentrations as great as 1 MAC.

beta A4 deposits occur in the brain of some individuals over 50 years of age. It could be a part of the aging process or indicate a disease found frequently in the elderly. To address this question, beta A4 immunocytochemistry was performed on the brain of 15 nondemented and 5 demented centenarians, some of whom were affected by Alzheimer's disease. We found beta A4 deposits in the parahippocampal and the superior temporal gyri of all the cases, whatever the clinical state. The hippocampus was frequently spared. The lesion density was not correlated with the severity of the mental deterioration. The constant deposition of beta A4 protein in the brain of very old people indicates that this process does not spare a large proportion of this population. This result favors beta A4 accumulation in the brain being an ineluctable age-related process.