Respuesta clínica y neurofisiológica a la efedrina en un paciente con síndrome miasténico congénito de canal lento / Clinical and neurophysiological response to ephedrine in a patient affected with slow-channel congenital myasthenic syndrome

INTRODUCCIÓN: El síndrome miasténico congénito de canal lento, o síndrome de canales lentos, es un trastorno neuromuscular progresivo hereditario, autosómico dominante, causado por una activación anormal de los receptores de la acetilcolina en la unión neuromuscular. La alteración histopatológica característica es la degeneración selectiva de la placa terminal y la membrana postsináptica debido a la sobrecarga de calcio. La piridostigmina debe evitarse en este síndrome, y la quinidina o la fluoxetina son las terapias recomendadas actualmente. CASO CLÍNICO: Niña de 11 años con un fenotipo de cinturas de síndrome miasténico congénito de canal lento que presenta debilidad y fatiga lentamente progresivas desde los 8 años. Tras un empeoramiento clínico con piridostigmina, iniciado empíricamente antes de que los resultados de la secuenciación del exoma estuvieran disponibles, se observó una respuesta espectacular y sostenida con efedrina en monoterapia. La secuenciación del exoma reveló una mutación heterocigota de novo en el gen CHRNB1: c.865G>A; p.Val289Met (NM_000747.2). El estudio electromiográfico con estimulación repetitiva en el nervio peroneo mostró una disminución anormal en la amplitud (23,9%) y también la génesis de un segundo potencial de acción muscular compuesto más pequeño después del pico de la onda M principal en los nervios motores mediano, cubital y peroneo. CONCLUSIÓN: Aunque se han documentado respuestas favorables a agonistas adrenérgicos en asociación con la fluoxetina, ésta representa la primera aportación que documenta una respuesta clínica relevante con efedrina en monoterapia en un paciente con síndrome miasténico congénito de canal lento. Los agonistas adrenérgicos pueden considerarse una opción terapéutica en pacientes con este síndrome

INTRODUCTION: Slow-channel congenital myasthenic syndrome is an autosomal dominant inherited progressive neuromuscular disorder caused by abnormal gating of mutant acetylcholine receptors in the neuromuscular junction. Its pathological hallmark is selective degeneration of the endplate and postsynaptic membrane due to calcium overload. Pyridostigmine should be avoided in this syndrome, being quinidine or fluoxetine the current recommended therapies. CASE REPORT: An 11-year-old girl with a limb-girdle phenotype of slow-channel congenital myasthenic syndrome presenting with a slowly progressive fatigable weakness at the age of 8 years. After a clinical worsening with pyridostigmine, empirically started before the exome sequencing results were available, a dramatic and sustained response to ephedrine monotherapy was observed. Whole exome sequencing revealed a de novo heterozygous mutation in CHRNB1 gene: c.865G>A; p.Val289Met (NM_000747.2). An abnormal decrement in amplitude (23.9%) from the first to fifth intravollley waveform was revealed after repetitive peroneal nerve stimulation at low frequencies. In addition, a second smaller compound muscle action potential after the peak of the main M-wave in median, ulnar and peroneal motor nerves was observed. CONCLUSION: Favorable responses to adrenergic agonists added to fluoxetine had been reported. However, to the best of our knowledge this is the first report on effective monotherapy with ephedrine in a slow-channel congenital myasthenic syndrome patient. Adrenergic agonists may be considered as a therapeutic option in patients with this syndrome

A Retrospective Analysis of the Safety Profile of Intravenous Immunoglobulin in 1176 Patients Receiving Home Infusion Therapy.

OBJECTIVES: This analysis assessed the safety of intravenous immunoglobulin (IVIg) in the treatment of patients with neuroimmunological and immunological disorders in a home-based setting. METHODS: Adverse reactions (ARs) were assessed in a retrospective review of 1176 patients receiving 28,677 home-based IVIg infusions between 1996 and 2013. RESULTS: Of 1176 patients, 648 (55.1%) experienced IVIg-related ARs; 536 (45.6%) were mild, 78 (6.6%) moderate, and 34 (2.9%) severe. Thirty-seven (3.1%) patients were hospitalized because of ARs; of these, headache was most common (51.4%). Mean number of ARs per patient increased from 1.4 (low dose) to 3.6 (high dose). Incidence of ARs increased from 41% in the first 5-year moving average in 2003 to 65% in 2008. The number of ARs correlated with the number of infusions (ρ = 0.24; P < 0.001) and the average IVIg dose (ρ = 0.10; P < 0.001). CONCLUSIONS: Low- and high-dose IVIg were safe and well tolerated with a few serious ARs in patients with neuroimmunological and immunological disorders.

Neuroleptics as therapeutic compounds stabilizing neuromuscular transmission in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a rapidly progressing, fatal disorder with no effective treatment. We used simple genetic models of ALS to screen phenotypically for potential therapeutic compounds. We screened libraries of compounds in C. elegans, validated hits in zebrafish, and tested the most potent molecule in mice and in a small clinical trial. We identified a class of neuroleptics that restored motility in C. elegans and in zebrafish, and the most potent was pimozide, which blocked T-type Ca2+ channels in these simple models and stabilized neuromuscular transmission in zebrafish and enhanced it in mice. Finally, a short randomized controlled trial of sporadic ALS subjects demonstrated stabilization of motility and evidence of target engagement at the neuromuscular junction. Simple genetic models are, thus, useful in identifying promising compounds for the treatment of ALS, such as neuroleptics, which may stabilize neuromuscular transmission and prolong survival in this disease.

Chronic TrkB agonist treatment in old age does not mitigate diaphragm neuromuscular dysfunction.

Previously, we found that brain-derived neurotrophic factor (BDNF) signaling through the high-affinity tropomyosin-related kinase receptor subtype B (TrkB) enhances neuromuscular transmission in the diaphragm muscle. However, there is an age-related loss of this effect of BDNF/TrkB signaling that may contribute to diaphragm muscle sarcopenia (atrophy and force loss). We hypothesized that chronic treatment with 7,8-dihydroxyflavone (7,8-DHF), a small molecule BDNF analog and TrkB agonist, will mitigate age-related diaphragm neuromuscular transmission failure and sarcopenia in old mice. Adult male TrkBF616A mice (n = 32) were randomized to the following 6-month treatment groups: vehicle-control, 7,8-DHF, and 7,8-DHF and 1NMPP1 (an inhibitor of TrkB kinase activity in TrkBF616A mice) cotreatment, beginning at 18 months of age. At 24 months of age, diaphragm neuromuscular transmission failure, muscle-specific force, and fiber cross-sectional areas were compared across treatment groups. The results did not support our hypothesis in that chronic 7,8-DHF treatment did not improve diaphragm neuromuscular transmission or mitigate diaphragm muscle sarcopenia. Taken together, these results do not exclude a role for BDNF/TrkB signaling in aging-related changes in the diaphragm muscle, but they do not support the use of 7,8-DHF as a therapeutic agent to mitigate age-related neuromuscular dysfunction.

Preservation of neuromuscular function in symptomatic SOD1-G93A mice by peripheral infusion of methylene blue.

In mutant superoxide dismutase 1 (SOD1) mouse models of familial amyotrophic lateral sclerosis (fALS) some of the earliest signs of morphological and functional damage occur in the motor nerve terminals that innervate fast limb muscles. This study tested whether localized peripheral application of a protective drug could effectively preserve neuromuscular junctions in late-stage disease. Methylene blue (MB), which has mitochondria-protective properties, was infused via an osmotic pump into the anterior muscle compartment of one hind limb of late pre- symptomatic SOD1-G93A mice for ≥3weeks. When mice reached end-stage disease, peak twitch and tetanic contractions evoked by stimulation of the muscle nerve were measured in two anterior compartment muscles (tibialis anterior [TA] and extensor digitorum longus [EDL], both predominantly fast muscles). With 400µM MB in the infusion reservoir, muscles on the MB-infused side exhibited on average a ~100% increase in nerve-evoked contractile force compared to muscles on the contralateral non-infused side (p<0.01 for both twitch and tetanus in EDL and TA). Pairwise comparisons of endplate innervation also revealed a beneficial effect of MB infusion, with an average of 65% of endplates innervated in infused EDL, compared to only 35% on the non-infused side (p<0.01). Results suggested that MB's protective effects required an extracellular [MB] of ~1µM, were initiated peripherally (no evidence of retrograde transport into the spinal cord), and involved MB's reduced form. Thus peripherally-initiated actions of MB can help preserve neuromuscular structure and function in SOD1-G93A mice, even at late stages of disease.

Congenital myopathies with secondary neuromuscular transmission defects; a case report and review of the literature.

Congenital myopathies are a clinically and genetically heterogeneous group of disorders characterized by early onset hypotonia, weakness and characteristic, but not pathognomonic, structural abnormalities in muscle fibres. The clinical features overlap with muscular dystrophies, myofibrillar myopathies, neurogenic conditions and congenital myasthenic syndromes. We describe a case of cap myopathy with myasthenic features due to a mutation in the TPM2 gene that responded to anticholinesterase therapy. We also review other published cases of congenital myopathies with neuromuscular transmission abnormalities. This report expands the spectrum of congenital myopathies with secondary neuromuscular transmission defects. The recognition of these cases is important since these conditions can benefit from treatment with drugs enhancing neuromuscular transmission.

Current pharmacologic management in selected neuromuscular diseases.

For generations, the neuromuscular disorder care community has focused on establishing the correct diagnosis and providing supportive care. As the pathophysiology and genetics of these conditions became better understood, novel treatments targeting the disease mechanism were developed. This has led to some significant disease-modifying and supportive treatments for several neuromuscular disorders. The current treatments for amyotrophic lateral sclerosis (ALS), neuromuscular junction disorders, inflammatory myopathies, and myotonia are reviewed. Additionally, investigational treatments for ALS, Duchenne muscular dystrophy, and spinal muscular atrophy are discussed.

Signaling and aging at the neuromuscular synapse: lessons learnt from neuromuscular diseases.

The neuromuscular junction (NMJ) is a specialized synapse between motor neurons and skeletal muscle with a complex signaling network that assures highly reliable neuromuscular transmission. Diseases of the NMJ cause skeletal muscle fatigue and include inherited and acquired disorders that affect presynaptic, intrasynaptic or postsynaptic components. Moreover, fragmentation of the NMJ contributes to sarcopenia, the loss of muscle mass during aging. Studies from recent years indicate that the formation and stabilization of NMJs differs between various muscles and that this difference affects their response under pathological conditions. This review summarizes the most important mechanisms involved in the development, maintenance and dysfunction of the NMJ and it discusses their significance in myasthenic disorders and aging and as targets for possible future treatment of NMJ dysfunction.

Neuromuscular abnormality and autonomic dysfunction in patients with cerebrotendinous xanthomatosis.

BACKGROUND: Cerebrotendinous xanthomatosis (CTX) is a rare lipid-storage disease. Neuromuscular abnormality and autonomic system (ANS) dysfuction in CTX are rarely examined in large-scale studies in the literature. We studied the peripheral nervous system, myopathology, and autonomic system of four CTX patients and performed a literature review of the reported CTX patients with peripheral neuropathy. METHODS: Four biochemically and genetically confirmed CTX patients, belonging to two families, were included for study and all received nerve conduction study (NCS), muscle biopsy for histopathologic and ultrastructural study, skin biopsy for intraepidermal nerve fiber (INEF) density measurement, autonomic testings including sympathetic skin response, R-R interval variation and head-up tilt test using an automated tilt table to record the changes of blood pressure and heart rate in different postures. The Q-Sweat test was also applied for the detection of sweat amount and onset time of response. The clinical characteristics, study methods and results of 13 studies of peripheral neuropathy in CTX patients in the literature were also recorded for analysis. RESULTS: The results of NCS study showed axonal sensory-motor polyneuropathy in three CTX cases and mixed axonal and demyelinating sensor-motor polyneuropathy in one. The myopathological and histopathologic studies revealed mild denervation characteristics, but the ultrastructural study revealed changes of mitochondria and the membranous system, and increased amounts of glycogen, lipofuscin and lipid deposition. The ANS study revealed different degrees of abnormalities in the applied tests and the INEF density measurement showed small fiber neuropathy in three of the four CTX patients. The literature review of peripheral neuropathy in CTX revealed different types of peripheral neuropathy, of which axonal peripheral neuropathy was the most common. CONCLUSIONS: Peripheral neuropathy, especially the subtype of axonal sensori-motor neuropathy, is common in patients with CTX. Evidence of lipid metabolic derangement in CTX can be reflected in ultrastructural studies of muscles. With an adequate multi-parametric evaluation, a high incidence of ANS abnormalities can be seen in this rare lipid-storage disease, and a high incidence of small fiber involvement is also reflected in the IENF density measurement of skin biopsies.

Guidelines for treatment of autoimmune neuromuscular transmission disorders.

BACKGROUND: Important progress has been made in our understanding of the autoimmune neuromuscular transmission (NMT) disorders; myasthenia gravis (MG), Lambert-Eaton myasthenic syndrome (LEMS) and neuromyotonia (Isaacs' syndrome). METHODS: To prepare consensus guidelines for the treatment of the autoimmune NMT disorders, references retrieved from MEDLINE, EMBASE and the Cochrane Library were considered and statements prepared and agreed on by disease experts. CONCLUSIONS: Anticholinesterase drugs should be given first in the management of MG, but with some caution in patients with MuSK antibodies (good practice point). Plasma exchange is recommended in severe cases to induce remission and in preparation for surgery (recommendation level B). IvIg and plasma exchange are effective for the treatment of MG exacerbations (recommendation level A). For patients with non-thymomatous MG, thymectomy is recommended as an option to increase the probability of remission or improvement (recommendation level B). Once thymoma is diagnosed, thymectomy is indicated irrespective of MG severity (recommendation level A). Oral corticosteroids are first choice drugs when immunosuppressive drugs are necessary (good practice point). When long-term immunosuppression is necessary, azathioprine is recommended to allow tapering the steroids to the lowest possible dose whilst maintaining azathioprine (recommendation level A). 3,4-Diaminopyridine is recommended as symptomatic treatment and IvIG has a positive short-term effect in LEMS (good practice point). Neuromyotonia patients should be treated with an antiepileptic drug that reduces peripheral nerve hyperexcitability (good practice point). For paraneoplastic LEMS and neuromyotonia optimal treatment of the underlying tumour is essential (good practice point). Immunosuppressive treatment of LEMS and neuromyotonia should be similar to MG (good practice point).

Impairment of diaphragm muscle force and neuromuscular transmission after normothermic cardiopulmonary bypass: effect of low-dose inhaled CO.

Cardiopulmonary bypass (CPB) is associated with significant postoperative morbidity, but its effects on the neuromuscular system are unclear. Recent studies indicate that even relatively short periods of mechanical ventilation result in significant neuromuscular effects. Carbon monoxide (CO) has gained recent attention as therapy to reduce the deleterious effects of CPB. We hypothesized that 1) CPB results in impaired neuromuscular transmission and reduced diaphragm force generation; and 2) CO treatment during CPB will mitigate these effects. In adult male Sprague-Dawley rats, diaphragm muscle-specific force and neuromuscular transmission properties were measured 90 min after weaning from normothermic CPB (1 h). During CPB, either low-dose inhaled CO (250 ppm) or air was administered. The short period of mechanical ventilation used in the present study ( approximately 3 h) did not adversely affect diaphragm muscle contractile properties or neuromuscular transmission. CPB elicited a significant decrease in isometric diaphragm muscle-specific force compared with time-matched, mechanically ventilated rats ( approximately 25% decline in both twitch and tetanic force). Diaphragm muscle fatigability to 40-Hz repetitive stimulation did not change significantly. Neuromuscular transmission failure during repetitive activation was 60 +/- 2% in CPB animals compared with 76 +/- 4% in mechanically ventilated rats (P < 0.05). CO treatment during CPB abrogated the neuromuscular effects of CPB, such that diaphragm isometric twitch force and neuromuscular transmission were no longer significantly different from mechanically ventilated rats. Thus, CPB has important detrimental effects on diaphragm muscle contractility and neuromuscular transmission that are largely mitigated by CO treatment. Further studies are needed to ascertain the underlying mechanisms of CPB-induced neuromuscular dysfunction and to establish the potential role of CO therapy.

Novel anti-idiotype antibody therapy for lipooligosaccharide-induced experimental autoimmune neuritis: use relevant to Guillain-Barré syndrome.

Campylobacteriosis is a frequent antecedent event in Guillain-Barré syndrome (GBS), inducing high-titer serum antibodies for ganglioside antigens in the peripheral nervous system (PNS). Molecular mimicry between the lipooligosaccharide (LOS) component of Campylobacter jejuni and human peripheral nerve gangliosides is believed to play an important role in the pathogenesis of GBS. Conventional treatment strategies for patients with GBS include plasmapheresis, intravenous immunoglobulin (IVIG), and immunosuppression, which are invasive or relatively ineffective. In this study, we used our animal model of GBS, in which Lewis rats were immunized with GD3-like LOS isolated from C.jejuni. The animals developed anti-GD3 ganglioside antibodies and manifested neuromuscular dysfunction. To develop novel therapeutic strategies, we treated the animals by intraperitoneal administration of an anti-GD3 antiidiotype monoclonal antibody (BEC2) that specifically interacts with the pathogenic antibody. The treated animals had a remarkable reduction of anti-GD3 antibody titers and improvement of motor nerve functions. The results suggest that ganglioside mimics, such as antiidiotype antibodies, may be powerful reagents for therapeutic intervention in GBS by neutralizing specific pathogenic antiganglioside antibodies.

Physiology and biology of neuromuscular transmission in health and disease.

The introduction of powerful and contemporary research techniques has allowed for an increasingly detailed understanding of neuromuscular transmission. The classic model of nerve signaling to muscle using acetylcholine has been well described. Newer discovery points toward a more complex signaling system with adaptive receptor physiology and a multifaceted action response scheme for muscle relaxants. Although adding complexity, these newer discoveries help align experimentally derived knowledge with clinical observations. In this review, new concepts relative to neuromuscular transmission in health and disease are discussed, including a detailed discussion of acetylcholine and acetylcholine receptor physiology. Recent elucidations of the pathophysiologic responses to neuromuscular injury and its clinical implications are also detailed.

[Human calcium channelopathies. Voltage-gated Ca(2+) channels in etiology, pathogenesis, and pharmacotherapy of neurologic disorders]. / Kalziumkanalopathien des Menschen. Spannungsgesteuerte Ca(2+)-Kanäle in Atiologie, Pathogenese und Pharmakotherapie neurologischer Krankheitsbilder.

Voltage-gated calcium channels are key components in a variety of physiological processes. Within the last decade an increasing number of voltage-gated Ca(2+) channelopathies in both humans and animal models has been described, most of which are related to the neurologic and muscular system. In humans, mutations were found in L-type Ca(v)1.2 and Ca(v)1.4 Ca(2+) channels as well as the non-L-type Ca(v)2.1 and T-type Ca(v)3.2 channels, resulting in altered electrophysiologic properties. Based on their widespread distribution within the CNS, voltage-gated calcium channels are of particular importance in the etiology and pathogenesis of various forms of epilepsy and neuropsychiatric disorders. In this review we characterise the different human Ca(2+) channelopathies known so far, further illuminating basic pathophysiologic mechanisms and clinical aspects.

Irritable bowel syndrome: update on colonic neuromuscular dysfunction and treatment.

Recent discoveries regarding the relatively autonomous workings of the enteric nervous system have expanded our understanding of the pathophysiology of irritable bowel syndrome (IBS). However, the heterogeneity of the pathogenesis of IBS continues to create unique challenges for clinicians who care for these patients. Advances in our understanding of the structure and functions of the brain-gut axis and its interplay with other potentially important factors, such as genetic predisposition, inflammation, and psychological unrest, have led to new developments in the field of targeted pharmacotherapy for IBS sufferers. Therapies designed specifically to modulate gut motility, secretion, and/or sensation have been created and introduced into the marketplace in recent years, and additional designer formulations are in various stages of development. Concurrently, new discoveries of potentially beneficial effects of agents approved for other, often non-gastroenterologic, conditions continue to be reported. This article reviews the accumulating body of evidence supporting the importance of neuromuscular dysfunction as a central cause of IBS symptoms and provides a rationale for the discussion of current and future drug development.

Acetazolamide acts on neuromuscular transmission abnormalities found in some migraineurs.

Mild subclinical impairment of neuromuscular transmission can be detected with single-fibre electromyography (SFEMG) in subgroups of patients suffering from migraine and could be due to dysfunctioning Ca2+-channels on motor axons controlling stimulation-induced acetylcholine release. Acetazolamide, which is thought to ameliorate ion channel function, was shown effective in familial hemiplegic migraine and episodic ataxia type 2, both of which are associated with mutations of the neuronal Ca2+-channel gene CACNA1A, as well as in aura status. We treated therefore in an open pilot study five non-hemiplegic migraineurs showing mild SFEMG abnormalities with acetazolamide for several weeks. This was followed by a normalization of SFEMG recordings in all patients and by clinical improvement in four. These results support the assumption that the subclinical impairment of neuromuscular transmission found in certain migraineurs might be due to dysfunctioning Ca2+-channels.

In vivo analysis of end-plate noise of human extensor digitorum brevis muscle after intramuscularly injected botulinum toxin type A.

To evaluate changes occurring in the neuromuscular junction after injection with botulinum neurotoxin type A (BoTx), three healthy volunteers were injected with 10 U BoTx in the right extensor digitorum brevis muscle. In agreement with previous observations, amplitude of compound muscle action potential (CMAP) decreased to approximately 30% of the initial value at approximately day 8 and slowly returned to baseline values around day 250. Values of the acetylcholine receptor (AChR) open time were determined by spectral analysis of end-plate noise and from single exponential fits to the decay phase of individual miniature end-plate potentials (MEPPs). At baseline, the mean channel open times determined by end-plate noise analysis and the exponential fits were 1.1 +/- 0.2 ms and 1.20 +/- 0.04 ms, respectively. After BoTx injection, initially no end-plate noise could be recorded. From day 9 onwards, however, a gradual recurrence of end-plate noise was observed, with mean channel open times of approximately 2-5 ms, being maximal between days 20 to 140. In addition, the shape of many recorded MEPPs was different from the typical fast rising MEPPs observed at baseline. After day 80, end-plate noise gradually returned to normal and mean channel open times decreased slowly to baseline values. Our findings reflect the changed AChR characteristics of newly formed neuromuscular junctions, which are created after BoTx injection and gradually removed after restoration of the original neuromuscular junctions.