Botulinum toxin therapy improves masseter spasticity in Amyotrophic Lateral Sclerosis.

Fifteen ALS patients, with troublesome symptoms linked to masseter spasticity, benefited from BoNT-A injections in each masseter. Based on the medical records of patients, the effect of the first injection was assessed one month later. We retrospectively collected information for 12 patients. Eight of them reported a beneficial effect after the injection for the following symptoms: trismus, tongue, lip and cheek biting, and jaw clonus. Five patients indicated that dental care was easier after injection. Our study showed that injections of BoNT-A unequivocally reduced masseter spasticity in ALS patients who subsequently enjoyed greater comfort in their daily living.

Quantitative brainstem and spinal MRI in amyotrophic lateral sclerosis: implications for predicting noninvasive ventilation needs.

BACKGROUND: Respiratory complications resulting from motor neurons degeneration are the primary cause of death in amyotrophic lateral sclerosis (ALS). Predicting the need for non-invasive ventilation (NIV) in ALS is important for advance care planning and clinical trial design. The aim of this study was to assess the potential of quantitative MRI at the brainstem and spinal cord levels to predict the need for NIV during the first six months after diagnosis. METHODS: Forty-one ALS patients underwent MRI and spirometry shortly after diagnosis. The need for NIV was monitored according to French health guidelines for 6 months. The performance of four regression models based on: clinical variables, brainstem structures volumes, cervical spinal measurements, and combined variables were compared to predict the need for NIV within this period. RESULTS: Both the clinical model (R2 = 0.28, AUC = 0.85, AICc = 42.67, BIC = 49.8) and the brainstem structures' volumes model (R2 = 0.30, AUC = 0.85, AICc = 40.13, BIC = 46.99) demonstrated good predictive performance. In addition, cervical spinal cord measurements model similar performance (R2 = 0.338, AUC = 0.87, AICc = 37.99, BIC = 44.49). Notably, the combined model incorporating predictors from all three models yielded the best performance (R2 = 0.60, AUC = 0.959, AICc = 36.38, BIC = 44.8). These findings are supported by observed positive correlations between brainstem volumes, cervical (C4/C7) cross-sectional area, and spirometry-measured lung volumes. CONCLUSIONS: Our study shows that brainstem volumes and spinal cord area are promising measures to predict respiratory intervention needs in ALS.

Mutations selected in the hepatitis C virus NS3 protease domain during sequential treatment with boceprevir with and without pegylated interferon alfa-2b.

Treatment with hepatitis C virus (HCV)-NS3-protease inhibitors lead to the selection of resistant variants. Viral kinetics and resistance profiles in patients who are re-treated with the same protease inhibitor are unknown. Viral kinetics and NS3-resistance mutations obtained by clonal sequencing of the NS3-protease were analyzed in nine HCV-genotype-1-infected nonresponder patients who were sequentially treated with boceprevir (400 mg t.i.d.) for 1 week, peginterferon-alfa-2b for 2 weeks and combination of the two for 2 weeks in varying order. In addition to predominant wild-type isolates, previously described boceprevir-resistant mutations (V36, T54, R155, A156, V170) were observed. Furthermore, two resistant mutations (Q41, F43) were detected for the first time in vivo. In three patients, mutations selected after initial treatment with boceprevir were re-selected during subsequent boceprevir exposure. However, mutational patterns after the first and second exposure to boceprevir were different in five patients. In one patient, a viral variant (V55A) known to reduce susceptibility to boceprevir was the predominant variant observed at baseline and throughout treatment and was associated with a shallow viral decline. Different resistance mutations were selected during treatment with boceprevir ± peginterferon. Sequential short-term dosing of boceprevir was not associated with accumulation of resistant variants but pre-existing variants may impair virologic response.

[Primary lateral sclerosis: the era of international diagnosis criteria]. / La sclérose latérale primitive : l'avènement de critères consensuels internationaux.

Since Charcot's first description, primary lateral sclerosis (PLS) remains a rare clinical syndrome, a neuropathological phenotype of motor system degeneration. In turn, PLS has been described as belonging to the large spectrum of motoneuron diseases or to the diverse degenerative diseases of the nervous system. Clinically, it is characterized by progressive pyramidal involvement in patients who present insidiously progressive gait disorders and, on examination, have relatively symmetrical lower limb weakness, increased muscle tone, pathologic hyper-reflexia, and exaggerated extensor plantar responses. Pinprick, light touch, and temperature sensations are preserved. Viewed in another way, PLS mimicks progressive hereditary spastic paraparesis (HSP) and the "central" phenotype of amyotrophic lateral sclerosis (ALS). PLS is considered "idiopathic" and, depending on the presence or absence of similarly affected family members, the syndrome of idiopathic HSP and ALS are labeled "hereditary" or "apparently sporadic". The juvenile form of PLS and early age at onset in cases of HSP complicate our understanding of the relationship between these two disorders. Guidelines for diagnosis and genetic counseling have been published for HSP and ALS. Recently, since the first international workshop, guidelines for diagnosis of PLS propose a classification system, e.g. for heterogeneous HSP into "pure PLS", complicated or "plus PLS", symptomatic PLS and upper motor neuron-dominant ALS. However, when reviewing known cases of PLS drawn from the literature, rigorous retrospective application of these new PLS criteria raises an unanswered question: does pure PLS exist?

[Parkinson disease and amyotrophic lateral sclerosis. Tauopathies, TDP-43 and SOD mutations]. / Syndromes parkinsoniens et sclérose latérale amyotrophique Tauopathies, TDP-43 et mutations SOD.

In addition to a large number of clinical descriptions of atypical cases, recent pathological, biochemical and genetic studies challenge the view that amyotrophic lateral sclerosis (ALS) is a disorder restricted to the pyramidal motor system. Relations between ALS, Parkinson disease, fronto-temporal dementia, progressive supranuclear paralysis, and cortico-basal degeneration have now been identified. We propose a review of the topic and discuss the contribution of various clinical and pathological features leading to consider motoneuron diseases as neurodegenerative processes included in a broad spectrum of tauopathies.

Type A competitiveness traits correlate with downregulation of c-Fos expression in patients with type 1 diabetes.

AIM: Type A personality has been associated with increased survival in people with type 1 diabetes (T1D). Systemic low-grade inflammation may play a critical role, as suggested in recent reports, although the links between the inflammatory circulating transcriptome and Type A remain unknown. This prompted our exploration of the potential associations between Type A personality and c-Fos gene expression, a candidate gene closely linked to inflammatory processes, in T1D. METHODS: Type A personality was assessed by Bortner questionnaire in patients with T1D, and two subscales - 'speed' and 'competitiveness' - were used to measure these specific dimensions of Type A. Expression of the c-Fos gene was assessed by a quantitative real-time polymerase chain reaction technique. RESULTS: This pilot study included 20 men with T1D. Multivariable analyses showed an independent inverse association between Type A competitiveness score and c-Fos expression, while a regression model adjusted for age, body mass index and HbA1c levels revealed a significant inverse relationship between c-Fos transcripts and Type A competitiveness (P = 0.003). CONCLUSION: This strong association between Type A competitiveness and reduced c-Fos expression is in line with recent data suggesting a psychobiological influence of the Type A profile in T1D via inflammatory pathways.

Effect of inhaled iloprost plus oral sildenafil in patients with primary pulmonary hypertension.

BACKGROUND: The application of iloprost, a stable prostacyclin analogue, by inhalation has been shown to improve hemodynamic variables in patients with primary pulmonary hypertension. However, repetitive inhalations are required due to its short-term effects. One potential approach to prolong and increase the vasorelaxant effects of aerosolized iloprost might be to combine use with phosphodiesterase inhibitors. METHODS AND RESULTS: The short-term effects of 8.4 to 10.5 microgram of aerosolized iloprost, the phosphodiesterase type 5 inhibitor sildenafil, and the combination thereof were compared in 5 patients with primary pulmonary hypertension. Aerosolized iloprost resulted in a more pronounced decrease in mean pulmonary arterial pressure (PAP) than sildenafil alone (9.4+/-1.3 versus 6.4+/-1.1 mm Hg; P<0.05). The reduction in mean PAP after sildenafil was maximal after the first dose (25 mg). The combination of sildenafil plus iloprost lowered mean PAP significantly more than iloprost alone (13.8+/-1.4 versus 9.4+/-1.3 mm Hg; P<0.009). No significant changes in heart rate or systemic arterial pressure were observed during any treatment. The treatments were well tolerated, without major adverse effects. CONCLUSIONS: Sildenafil caused a long-lasting reduction in mean PAP and pulmonary vascular resistance, with a further additional improvement after iloprost inhalation. These data suggest that small doses of a phosphodiesterase type 5 inhibitor may be a useful adjunct to inhaled iloprost in the management of pulmonary hypertension.

Influence of inhaled iloprost on transpulmonary gradient of big endothelin in patients with pulmonary hypertension.

BACKGROUND: The pulmonary circulation is an important site for the production and clearance of endothelin (ET)-1, a potent vasoactive and mitogenic peptide. In healthy individuals, 40% to 50% of circulating ET-1 is removed on each passage through the lungs resulting in an arteriovenous ratio of <1, whereas many patients with pulmonary arterial hypertension (PAH) have ratios >1, indicating reduced clearance or increased release of endothelin. The influence of inhaled prostanoids on endothelin clearance is unknown. METHODS AND RESULTS: In a prospective investigation, plasma concentrations of big endothelin-1 (big ET-1, Elisa) were measured in 15 patients with pulmonary hypertension undergoing right heart catheterization with iloprost inhalation (4 m, 11 f, aged 35 to 75 years, mean pulmonary arterial pressure (PAPm) 54+/-2.3 mm Hg, pulmonary vascular resistance (PVR) 1061+/-141 dyn x sec x cm(-5)). There was a significant transpulmonary gradient for big ET-1 with 31% +/-11% higher concentrations in the radial artery than in the pulmonary artery (P<0.001). After inhalation of iloprost a significant decrease in the AV-ratio from 1.31+/-0.11 to 0.92+/-0.06 (P<0.007) was observed. The pulmonary net release of 3.10+/-0.65 pmol/min big ET-1 at baseline decreased to -1.24+/-1.32 pmol/min (P=0.013) within 15 minutes indicating a restored balance. Patients under long-term treatment with iloprost (n=7) tended to have a lower net release and AV-ratio for big ET-1 than patients without pretreatment. CONCLUSION: An increase in pulmonary clearance of big-ET could be a mechanism contributing to the beneficial effects of inhaled prostanoids in the treatment of PAH.

Electrically-induced muscle fatigue affects feedforward mechanisms of control.

OBJECTIVE: To investigate the effects of focal muscle fatigue induced by electromyostimulation (EMS) on Anticipatory Postural Adjustments (APAs) during arm flexions performed at maximal velocity. METHODS: Fifteen healthy subjects performed self-paced arm flexions at maximal velocity before and after the completion of fatiguing electromyostimulation programs involving the medial and anterior deltoids and aiming to degrade movement peak acceleration. APA timing and magnitude were measured using surface electromyography. RESULTS: Following muscle fatigue, despite a lower mechanical disturbance evidenced by significant decreased peak accelerations (-12%, p<.001), APAs remained unchanged as compared to control trials (p>.11 for all analyses). CONCLUSION: The fatigue signals evoked by externally-generated contractions seem to be gated by the Central Nervous System and result in postural strategy changes which aim to increase the postural safety margin. SIGNIFICANCE: EMS is widely used in rehabilitation and training programs for its neuromuscular function-related benefits. However and from a motor control viewpoint, the present results show that the use of EMS can lead to acute inaccuracies in predictive motor control. We propose that clinicians should investigate the chronic and global effects of EMS on motor control.

APOE: a potential marker of disease progression in ALS.

Although documented in AD, the role of APOE remains unclear in ALS. APOE phenotype and plasma levels were measured in 403 patients with ALS and were correlated with clinical parameters and survival time. No correlations were observed between the APOE phenotype and these variables. In contrast, APOE plasma levels were correlated with both rate of deterioration and survival time and appeared to be an important risk factor for decreased survival time with a relative risk of 0.647 (95% CI: 0.465 to 0.901; p = 0.01).

Neuroplasticity as a basis for therapeutics in spinal cord injuries and diseases.

The concept of neuroplasticity in the adult is now well accepted. Amongst the most striking neuroplastic phenomena are those that systematically follow a lesion in the neural system itself. The work reported in this symposium emphatically illustrates the plasticity of neurons participating in spinal cord networks in various conditions that involve axonal lesions and neuronal degeneration. The purpose of this paper is to evaluate the potential for post-lesion neuroplastic changes to serve as a basis for future therapeutics with specific emphasis on two important pathologies observed in humans: spinal cord injuries and degenerative motoneuronal diseases. Spontaneous attempts at axonal regeneration and growth of axotomized neurons can be seen after a spinal trauma although the number of neurons involved is often low and variable from one population to another. In any case, axons fail to cross the scar tissue, most probably due to specific neurono-glial interactions. Successful recovery of neural systems (and therefore possible functional recovery) that can be expected as a result of these spontaneous attempts at regeneration of axotomized axons is, overall, very poor. Innumerable attempts have been made to provide severed axons in the spinal cord with a suitable substrate. Altogether, the results obtained when regeneration is facilitated in the adult through a series of different ways point to several remarkable conclusions: (i) adult neurons are indeed able to grow an axon; (ii) the failure to grow an axon after axotomy which is normally observed depends, at least in part, on an unsuitable substrate; (iii) growth ability seems to be much more restricted for neurons with large myelinated axons than for neurons with unmyelinated ones. Several therapeutic avenues can be considered that can be grouped in three different endeavors: to fill in the gap, and to change the nature of the gap, to protect fibers that have not been directly injured. An additional possibility is that compensation of lost inputs by transplants of monoaminergic neurons below the level of the lesion can be of therapeutic value. Experimental models of spinal neurodegeneration have been less intensely studied than those of spinal cord injuries. Data suggesting the existence of spontaneous neuronal plasticity in the aftermath of motoneuronal loss are, however, available. Two types of neuronal attempts at regeneration can be considered: sprouting of surviving motoneurons leading to the reoccupation of vacant motor endplates and possible attempts to grow by afferents that have been deprived of their postsynaptic target cells. These attempts may be facilitated experimentally by the use of growth factors and fetal neural transplants. The use of growth factors may be of therapeutic value and preliminary studies are presently in progress. The therapeutic value of neural transplants to replace lost motoneurons in amyotrophic lateral sclerosis or spinal muscular atrophies is not easily determined. It seems excluded that transplanted motoneurons replace lost neurons at all levels of the neuraxis. In contrast, neural transplantation may be interesting to replace a specific set of motoneurons, namely those controlling respiratory muscles.

Electrophysiological diagnosis of motor neuron disease and pure motor neuropathy.

Motor neuron disease (MND) is a group of disorders in which there is degeneration of upper and lower motor neurons to a variable degree. Amyotrophic lateral sclerosis is the most frequent form of the disease, presenting with both upper and lower motor neuron involvement. Frequently, especially in the early stages of the disease, only lower motor neuron signs are present. In these conditions, some pure motor neuropathies may resemble MND. The diagnosis is of importance because some of these motor neuropathies are "dysimmune" disorders and may respond to immune therapies. In such diseases the multifocal motor neuropathy with conduction block appears to be the more frequent. In MND and pure motor neuropathies, the electrophysiological examination is the most decisive test. In MND, it is of diagnostic importance. In addition, it is useful in the assessment of disease severity and progression, in the evaluation of therapeutic trials and in the understanding of etiopathogenesis of the disease. In pure motor neuropathies, the presence of conduction block leads to immune treatment with good response in more than 50% of the cases.

The effects of muscular fatigue on the coordination of a multijoint movement in human.

The purpose of the present experiment was to investigate the adaptation to fatigue in a multijoint movement. The subjects' task was to throw a ball towards one of three targets in two conditions of no fatigue and fatigue. Results showed that the number of successful trials decreased with fatigue. Analysis of these successful trials showed that, without fatigue, the final hand velocity resulted from a 'summation of speed' principle from the elbow to the hand joint. With fatigue, a new inter-segmental organization was necessary in order to maintain a good motor performance. This compensating strategy was characterized by the absence of a temporal delay between the elbow and hand peak velocity suggesting that, with fatigue, movement organization was similar to that of a rigid system. In other words, the 'summation of speeds' principle was no more respected.

Primary lateral sclerosis: further clarification.

Primary lateral sclerosis (PLS) has been defined as a rare. Non-hereditary disease characterized by progressive spinobulbar spasticity, related to the exclusive involvement of precentral pyramidal neurons, with secondary pyramidal tract degeneration and a preservation of anterior horn motor neurons, the latter allowing PLS to be distinguish from amyotrophic lateral sclerosis (ALS). However, a clear distinction between the two diseases remains a subject of debate. With this in mind, we assessed patients with meeting the previously published criteria for PLS in a prospective, longitudinal study. At regular intervals, we analyzed various clinical and electrophysiological parameters in nine patients with a diagnosis of PLS. We made a deltoid muscle biopsy and PET study.Our results provide evidence that degeneration in PLS is not restricted to the upper motor neurons but also affects the lower motor neurons. The distinction between ALS and PLS is related to the degree and stability of lower motor neuron involvement. In view of the similarities with ALS, we consider that PLS may represent a slowly progressive syndrome closely related to this disease.

[Electrophysiologic study, diagnosis and cases of acquired sensory polyneuropathy]. / Etude électrophysiologique, diagnostic et causes des polyneuropathies sensitives acquises.

Sensory neuropathies encompass a group of neuropathies affecting solely or predominantly peripheral sensory nerves. They are rarely encountered in clinical practice. The authors review sensory nerve conduction studies and compare the various recording technics. Values of compound sensory action potential amplitude and sensory nerve conduction velocity are analyzed. On the basis of clinical and electrophysiological sensory impairment, three types of neuropathies can be proposed: neuropathies with either large, small or total myelinated fibers involvement. Lastly definable causes of sensory neuropathies are reviewed.

[True neurological thoracic outlet syndrome]. / Syndrome du défilé thoraco-brachial à forme neurologique.

The thoracic outlet syndrome (TOS) encompasses various clinical entities affecting the neurovascular bundle crossing the thoracic outlet. Unfortunately, this term often proves to be confusing because many of these entities have little in common beyond their known or presumed lesion site. Neurogenic TOS (true TOS) is caused by compression of the lower trunk in the brachial plexus, the cervical ribs or fibrous band. This syndrome is extremely rare. We consider that this neurological form of TOS is a clearly defined neurological syndrome. We report 10 patients with true TOS. All were females. Stating the onset was difficult because symptoms were progressive and insidious. Pain was the most frequently reported symptom. Sensory deficit was slight or absent. All patients showed unilateral severe atrophy of the thenar muscles. Wasting and weakness developed later. A reduced amplitude of ulnar and median compound muscle action potential associated with a normal amplitude of median sensory nerve action and a reduced amplitude of ulnar sensory nerve action potential were indicative of a chronic axon loss in the lower trunk of the brachial plexus. In all cases, we performed medial antebrachial cutaneous sensory nerve action potential, a C8-T1 innervated nerve. The absence of the medial antebrachial cutaneous sensory nerve action potential in 9 patients and a reduction in amplitude of 50 p. 100 compared to the unaffected side in the other patient, indicated the diagnostic value of this easy and reproductible test. It confirmed a C8-T1 post-ganglionic radicular lesion or a lower brachial plexus neuropathy. Radiography showed a rudimentary bilateral cervical rib or an elongated C7 transverse process in all cases. Surgery was performed in the affected side in 7 patients and in each case the lower part of the brachial plexus was found to be stretched and angulated over a fibrous band, which was removed. Pain was relieved after 1 to 4 weeks. A minimal motor improvement was observed after one year. Electrophysiological results were unchanged.

[Charcot-Marie-Tooth disease: electromyography is still useful in diagnosis and classification]. / Maladie de Charcot-Marie-Tooth: l'électromyogramme reste utile au diagnostic et à la classification.

Genetic heterogeneity was known for a long time in Charcot-Marie-Tooth disease (CMT). The recent findings in molecular biology emphasized the distinction in different types of the disease. Nevertheless, electrophysiological examinations are of a great interest to detect asymptomatic patients, to classify the different forms and to make correlations with the clinical and histological features. Current classification is based on genetic and electrophysiologic data. CMT1, or hypertrophic form in which mutations or a duplication were found on chromosome 17 is the most frequent (CMT1A), CMT2 is the neuronal form, CMT3 is termed the Dejerine-Sottas disease, CMT4 recessive forms, CMT5 a form with associated pyramidal features, and CMTX. The electrophysiologic aspects of these different types are reported.

[What's new in primary lateral sclerosis?]. / Qu'en est-il de la sclérose latérale primitive ?

Primary lateral sclerosis as a nosological entity distinct from amyotrophic lateral sclerosis has been the subject of controversy since it was first described in the nineteenth century. Primary lateral sclerosis has been defined as a rare, non-hereditary disease characterized by highly progressive spinobulbar spasticity, related to the exclusive loss of precentral pyramidal neurons, with secondary pyramidal tract degeneration and preservation of anterior horn motor neurons. We carried out a study in nine patients with a diagnosis of primary lateral sclerosis. Our clinical, electrophysiological and pathological investigations provide evidence that the disease has a heterogeneous clinical presentation and that degeneration is not restricted to the central motor system but also affects the lower motor neuron. In view of this similarity with amyotrophic lateral sclerosis, primary lateral sclerosis may represent a slowly progressive syndrome closely related to motor neuron disease and amyotrophic lateral sclerosis.