Emmanuel Fournier

Electromyography guides toward subgroups of mutations in muscle channelopathies

Myotonic syndromes and periodic paralyses are rare disorders of skeletal muscle characterized mainly by muscle stiffness or episodic attacks of weakness. Familial forms are caused by mutations in genes coding for skeletal muscle voltage‐gated ion channels. Exercise is known to trigger, aggravate, or relieve the symptoms. Therefore, exercise can be used as a functional test in electromyography to improve the diagnosis of these muscle disorders. Abnormal changes in the compound muscle action potential can be disclosed using different exercise tests. We report the outcome of an inclusive electromyographic survey of a large population of patients with identified ion channel gene defects. Standardized protocols comprising short and long exercise tests were applied on 41 unaffected control subjects and on 51 case patients with chloride, sodium, or calcium channel mutations known to cause myotonia or periodic paralysis. These tests disclosed significant changes of compound muscle action potential, which generally matched the clinical symptoms. Combining the responses to the different tests defined five electromyographic patterns (I–V) that correlated with subgroups of mutations and may be used in clinical practice as guides for molecular diagnosis. We hypothesize that mutations are segregated into the different electromyographic patterns according to the underlying pathophysiological mechanisms. Ann Neurol 2004

Different strategies of modulation can be operative during hypnotic analgesia: a neurophysiological study

&NA; Nociceptive electrical stimuli were applied to the sural nerve during hypnotically‐suggested analgesia in the left lower limb of 18 highly susceptible subjects. During this procedure, the verbally reported pain threshold, the nociceptive flexion (RIII) reflex and late somatosensory evoked potentials were investigated in parallel with autonomic responses and the spontaneous electroencephalogram (EEG). The hypnotic suggestion of analgesia induced a significant increase in pain threshold in all the selected subjects. All the subjects showed large changes (i.e., by 20% or more) in the amplitudes of their RIII reflexes during hypnotic analgesia by comparison with control conditions. Although the extent of the increase in pain threshold was similar in all the subjects, two distinct patterns of modulation of the RIII reflex were observed during the hypnotic analgesia: in 11 subjects (subgroup 1), a strong inhibition of the reflex was observed whereas in the other seven subjects (subgroup 2) there was a strong facilitation of the reflex. All the subjects in both subgroups displayed similar decreases in the amplitude of late somatosensory evoked cerebral potentials during the hypnotic analgesia. No modification in the autonomic parameters or the EEG was observed. These data suggest that different strategies of modulation can be operative during effective hypnotic analgesia and that these are subject‐dependent. Although all subjects may shift their attention away from the painful stimulus (which could explain the decrease of the late somatosensory evoked potentials), some of them inhibit their motor reaction to the stimulus at the spinal level, while in others, in contrast, this reaction is facilitated.

Comparative efficacy of repetitive nerve stimulation, exercise, and cold in differentiating myotonic disorders

The decremental response of the compound muscle action potential (CMAP) to provocative tests is not characterized in genetically verified myotonic disorders. We therefore studied the relationship between decremental responses and mutation type in 10 patients with recessive myotonia congenita (rMC), two with paramyotonia congenita (PMC), nine with myotonic dystrophy type 1 (DM1), four with DM2, and 14 healthy people. CMAPs were measured at rest, just after a short exercise test (SET), and during short, 5‐ and 10‐HZ, repetitive nerve stimulation (RNS) trains at 32°C and at 20°C. The degree of decrement was not related to the severity of clinical myotonia. Controls and PMC patients had similar responses when warm, but with cooling PMC patients had a persistent decrement of CMAPs. In the rMC patients the decremental responses were related to the type of mutation of the CLCN1 gene, as a decrement was encountered in the T268M, R894X, IVS17+1 G>T, K248X, and 2149 del G, but not with the IVS1+3 A>T, F167L, or dominant A313T mutations. In DM1 patients there was no relationship between decrement and CTG repeats. The degree of partial inexcitability in myotonic muscle membrane therefore depends on the mutation type rather than degree of clinical myotonia. RNS at 10 HZ is more sensitive than SET for demonstrating abnormalities in rMC patients when warm; differences are less marked when cold, which is useful to diagnose PMC. Provocative tests are therefore useful in myotonias to demonstrate muscle inexcitability, which depends on the chloride or sodium channelopathy. Muscle Nerve, 2007

Sulfonylurea Therapy Benefits Neurological and Psychomotor Functions in Patients With Neonatal Diabetes Owing to Potassium Channel Mutations

OBJECTIVE Neonatal diabetes secondary to mutations in potassium-channel subunits is a rare disease but constitutes a paradigm for personalized genetics-based medicine, as replacing the historical treatment with insulin injections with oral sulfonylurea (SU) therapy has been proven beneficial. SU receptors are widely expressed in the brain, and we therefore evaluated potential effects of SU on neurodevelopmental parameters, which are known to be unresponsive to insulin. RESEARCH DESIGN AND METHODS We conducted a prospective single-center study. Nineteen patients (15 boys aged 0.1–18.5 years) were switched from insulin to SU therapy. MRI was performed at baseline. Before and 6 or 12 months after the switch, patients underwent quantitative neurological and developmental assessments and electrophysiological nerve and muscle testing. RESULTS At baseline, hypotonia, deficiencies in gesture conception or realization, and attention disorders were common. SU improved HbA1c levels (median change −1.55% [range −3.8 to 0.1]; P < 0.0001), intelligence scores, hypotonia (in 12 of 15 patients), visual attention deficits (in 10 of 13 patients), gross and fine motor skills (in all patients younger than 4 years old), and gesture conception and realization (in 5 of 8 older patients). Electrophysiological muscle and nerve tests were normal. Cerebral MRI at baseline showed lesions in 12 patients, suggesting that the impairments were central in origin. CONCLUSIONS SU therapy in neonatal diabetes secondary to mutations in potassium-channel subunits produces measurable improvements in neuropsychomotor impairments, which are greater in younger patients. An early genetic diagnosis should always be made, allowing for a rapid switch to SU.

Electrophysiological determination of the site involved in generating abnormal muscle responses in hemifacial spasm

In patients with hemifacial spasm (HFS), abnormal muscle responses due to abnormal cross‐transmission are observed in facial muscles. However, the site in the facial nerve responsible for the cross‐transmission remains a matter of controversy. We have developed a model in which by considering the electrophysiological parameters involved in producing the abnormal muscle response, we can determine the site of the abnormal cross‐transmission within the facial nerve. This model was applied to HFS patients with three different etiologies: idiopathic, post‐Bells palsy, and post‐XII‐VII anastomosis. Our data show that: in idiopathic HFS, the cross‐transmission may occur in the facial nerve at the level of the pontocerebellar angle; in post‐Bells palsy, it is inside the petrous bone; and in XII‐VII anastomosis, it must be in the extracranial part of the facial nerve. The possible mechanisms for this cross talk are discussed in terms of ephaptic transmission or of a central hyperexcitability in the facial motor nucleus.

Chronic inflammatory demyelinating polyradiculoneuropathy: search for factors associated with treatment dependence or successful withdrawal

Background About 40% of responders to treatment for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) remain treatment dependent and have a relapse if treatment is interrupted. Objective To look for factors associated with treatment dependence or successful withdrawal in CIDP patients. Methods We retrospectively studied 70 responder CIDP patients comprising 34 patients who remained treatment dependent (treatment-dependent group) and 36 patients whose treatment could be discontinued (treatment withdrawal group). Clinical, biological, electrophysiological and therapeutic features were compared between these groups. Results A multifocal deficit was more frequent in the treatment-dependent group (35%) than in the treatment withdrawal group (8%) (p<0.01). The most frequent effective treatment was intravenous immunoglobulin (IVIG) for the treatment-dependent group (79%). In this group, more patients were resistant to corticosteroids in first-line therapy (93%) than in the treatment withdrawal group (40%) (p=0.002). The delay to effective treatment was significantly shorter for the treatment withdrawal group than for the treatment-dependent group (mean 11.1 vs 31.2 months; p<0.01). The rate of successful withdrawal was lower with IVIG (29%) than with corticosteroids (83%) (p<0.001). Conclusions When compared with the treatment withdrawal group, the treatment-dependent group was more frequently responsive to IVIG, more frequently resistant to corticosteroids in first-line treatment, had a longer delay to effective treatment and was more likely to present a multifocal deficit. The rate of successful withdrawal seems to be higher with corticosteroids, but a prospective study with a long-term follow-up is needed to confirm these features.

Homozygosity for dominant mutations increases severity of muscle channelopathies

Muscle channelopathies caused by mutations in the SCN4A gene that encodes the muscle sodium channel are transmitted by autosomal‐dominant inheritance. We report herein the first cases of homozygous patients for sodium channel mutations responsible for paramyotonia congenita (I1393T) or hypokalemic periodic paralysis (R1132Q). A parallel was drawn between this unprecedented situation and that of myotonia congenita by including patients homozygous or heterozygous for the CLCN1 I556N channel mutation, which is known for incomplete dominance and penetrance. Standardized electromyographic (EMG) protocols combining exercise and cold served as provocative tests to compare homozygotes with heterozygotes for each of the three mutations. Surface‐recorded compound muscle action potentials (CMAPs) were used to monitor muscle electrical activity, and myotonic discharges were evaluated by needle EMG. In heterozygous patients, exercise tests disclosed abnormal patterns of CMAP changes, which matched those previously described for similar dominant sodium and chloride channel mutations. Homozygotes showed much more severe clinical features and CMAP changes. We hypothesized that the presence of 100% defective ion channels in the homozygotes could account for the most severe phenotype. This suggests that the severity of muscle channelopathies depends both on the degree of channel impairment caused by the mutation and on the number of mutant channels engaged in the pathophysiological process. Overall, this study has practical consequences for the diagnosis of muscle channelopathies and raises new questions about their pathophysiology. Muscle Nerve, 2010

Physiological and ultrastructural features of human induced pluripotent and embryonic stem cell-derived skeletal myocytes in vitro

Significance Patients with inherited skeletal muscle diseases are offered little else than symptomatic relief, even when responsible genes have been identified. Access to human skeletal muscle through induced pluripotent stem (iPS) cells has opened new prospects for basic research and drug discovery. Yet the exact nature of iPS-derived skeletal muscle cells needs to be explored to assess their relevance to pathophysiological studies. We show, for the first time to our knowledge, that human iPS-derived skeletal myocytes acquire functional and ultrastructural landmarks of skeletal muscle and reach, in vitro, the same degree of maturity as their embryonic counterparts. This detailed characterization, besides validating the model, paves the way for exploring the pathophysiology and pharmacology of skeletal muscle diseases using patient-derived iPS cells. Progress has recently been made toward the production of human skeletal muscle cells from induced pluripotent stem (iPS) cells. However, the functional and ultrastructural characterization, which is crucial for disease modeling and drug discovery, remains to be documented. We show, for the first time to our knowledge, that the electrophysiological properties of human iPS-derived skeletal myocytes are strictly similar to those of their embryonic stem (ES) cell counterparts, and both are typical of aneural mammalian skeletal muscle. In both cell types, intracellular calcium signaling that links membrane depolarization to contraction occurs in the absence of extracellular Ca2+, a unique feature of skeletal muscle. Detailed analysis of the Ca2+ signal revealed diverse kinetics of the rising phase, and hence various rates in the release of Ca2+ from the sarcoplasmic reticulum. This was mirrored by ultrastructural evidence of Ca2+ release units, which varied in location, shape, and size. Thus, the excitation–contraction coupling machinery of both iPS- and ES-derived skeletal myocytes was functional and specific, but did not reach full maturity in culture. This is in contrast with the myofibrillar network, which displayed the same organization as in adult skeletal muscle. Overall, the present study validates the human iPS-based skeletal myocyte model in comparison with the embryonic system, and provides the functional and ultrastructural basis for its application to human skeletal muscle diseases.

Further evidence for a central reorganisation of synaptic connectivity in patients with hypoglossal-facial anastomosis in man.

In normal subjects, electrical stimulation of trigeminal mucosal afferents (lingual nerve - V3) can elicit a short latency (12.5+/-0. 3 ms; mean+/-S.D.) reflex response in the ipsilateral genioglossus muscle (Maisonobe et al., Reflexes elicited from cutaneous and mucosal trigeminal afferents in normal human subjects. Brain Res. 1998;810:220-228). In the present study on patients with hypoglossal-facial (XII-VII) nerve anastomoses, we were able to record similar R1-type blink reflex responses in the orbicularis oculi muscles, following stimulation of either supraorbital nerve (V1) or lingual nerve (V3) afferents. However, these responses were not present in normal control subjects. Voluntary swallowing movements produced clear-cut facilitations of the R1 blink reflex response elicited by stimulation of V1 afferents. In a conditioning-test procedure with a variable inter-stimulus interval, the R1 blink reflex response elicited by supraorbital nerve stimulation was facilitated by an ipsilateral mucosal conditioning stimulus in the V3 region. This facilitatory effect was maximal when the two stimuli (conditioning and test) were applied simultaneously. This effect was not observed on the R1 component of the blink reflex in the normal control subjects. These data strongly suggest that in patients with XII-VII anastomoses, but not in normal subjects, both cutaneous (V1) and mucosal (V3) trigeminal afferents project onto the same interneurones in the trigeminal principal sensory nucleus. This clearly supports the idea that peripheral manipulation of the VIIth and the XIIth nerves induces a plastic change within this nucleus.

Electrophysiological diagnosis of motor neuron disease and pure motor neuropathy

Abstract 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.