Neuromyotonia Research Articles

1607 Isaacs syndrome: case report

ObjectiveTo analyze the clinical features and pathogenesis mechanism of Isaacs syndrome.MethodsA case with Isaacs syndrome was reporttedResults and ConclusionIsaacs syndrome is characterized by the occurrence of spontaneous and continuous muscle fiber activity, associated with muscle cramps, pseudomyotonia and myokymia, stiffness and delayed relaxation of the muscle. The stiffness and myokymia are present at rest and during sleep. Isaacs syndrome has been recently suggested to be produced through an immune-mediated mechanism in which voltage-gated potassium channels may be targeted by auto-antibodies.

Acquired Neuromyotonia in Association With Systemic Lupus Erythematosus

Acquired neuromyotonia (NMT) is a rare condition resulting from a dysfunction of motor nerves. Current literature suggests acquired NMT is an antibody-mediated channelopathy. We present a case of acquired NMT in a patient with systemic lupus erythematosus. This association has not been previously reported.

The stiff-man syndrome and related disorders

The stiff-man syndrome (SMS) is characterised by rigidity and spasm of predominantly axial and proximal limb muscles. The cause of the condition is unknown but the finding of antibodies to glutamic acid decarboxylase (GAD) in approximately 60% of patients has suggested an autoimmune basis. Pathological findings are limited to a small number of cases which are reviewed in this paper. In some, evidence of an inflammatory aetiology has been found, and there appears to be overlap with progressive encephalomyelitis with rigidity (PER) which may present with a similar clinical picture. The spontaneous muscle activity in SMS and PER is of central origin, related to release of polysynaptic spinal and brainstem reflexes. The SMS is readily distinguished from the continuous muscle activity, spasm and cramps of Isaac's syndrome and neuromyotonia which originate in the peripheral nervous system. Fasciculations, myokymia, myotonia and complex repetitive discharges are characteristic of these peripheral neuromuscular disorders.

Un caso de síndrome de Isaacs asociado a dextrocardia

Isaacs syndrome is a disorder of unknown etiology characterized by muscular rigidity, cramps and myokymias. Described by Isaacs in 1961 and called by him as continuous muscular activity syndrome. There are few reports in Latino american countries.A 31 year-old man with sustained muscular contractions in lower limbs and diffuse myokymias since he was eighteen-year old. Dextrocardia was disclosed on clinical examination.We report the case of a patient with Isaacs syndrome and dextrocardia.

Neuromyotonia: autoimmune pathogenesis and response to immune modulating therapy

Background: Neuromyotonia (NMT) has been postulated to be an autoimmune channelopathy, probably by affecting voltage gated potassium channels (VGKC) leading to excitation and abnormal discharges [Sinha et al., Lancet 338 (1991) 75]. Objective: To report three patients with NMT who had other associated immune-mediated conditions, i.e., myasthenia gravis, thymoma and various types of peripheral neuropathies. One patient had peripheral neuropathy and involvement of pre- and post-synaptic neuromuscular junction. Results: All three patients had evidence of polyneuropathy and neuromyotonic discharges on electrodiagnostic studies. Elevated acetylcholine receptor antibodies were noted in all patients and malignant thymoma was found in two patients with metastasis. All three patients showed moderate to marked response to plasma exchange. Conclusions: These findings strongly suggest a humoral autoimmune pathogenesis of NMT, probably by K + channel involvement, affecting acetylcholine quantal release and postsynaptic membrane. Clinicians should be aware of this association of immune-mediated conditions in NMT patients and marked improvement with plasma exchange.

Two Curious Cases of Finger-Flexion Deformity

Neuromyotonia is a motor-nerve hyperactivity syndrome characterized by muscle contraction at rest and delayed muscle relaxation, sometimes accompanied

Autoantibodies in thymoma-associated myasthenia gravis with myositis or neuromyotonia.

About 50% of patients with thymoma have paraneoplastic myasthenia gravis (MG). Myositis and myocarditis or neuromyotonia (NMT) will also develop in some. Patients with thymoma-associated MG produce autoantibodies to a variety of neuromuscular antigens, particularly acetylcholine receptor (AChR), titin, skeletal muscle calcium release channel (ryanodine receptor [RyR]), and voltage-gated potassium channels (VGKC). To examine whether neuromuscular autoantibodies in patients with thymoma correlate with specific clinical syndromes. Serum and plasma samples from 19 patients with thymoma-associated MG, of whom 5 had myositis and 6 had NMT, underwent testing for antibodies to AChR, titin, RyR, and VGKC. Antibodies to AChR and titin were found in 19 and 17 patients, respectively. Antibodies to RyR correlated with the presence of myositis (P = .03); they were found in all 5 patients with myositis and in only 1 patient with NMT, but also in 4 of 8 patients with neither disease. Antibodies to VGKC were found in 4 patients with NMT, 1 of 3 patients undergoing testing for myositis, and 2 of 7 patients undergoing testing with neither comorbidity. Presence of RyR antibodies correlated with high levels of titin antibodies. The results appear to distinguish partially between 3 groups of patients with thymoma-associated MG: the first with RyR antibodies and myositis or myocarditis, the second with NMT without RyR antibodies, and the third without RyR antibodies, myositis, or NMT. Differences in the thymoma may underlie these pathologic associations.

Acquired Neuromyotonia: A New Autoantibody-Mediated Neuronal Potassium Channelopathy

INeuromyotonia (Isaacs syndrome) is a rare and heterogenous syndrome of continuous motor unit activity of peripheral nerve origin that manifests as various combinations of muscle stiffness, cramps, twitching, weakness, and delayed muscle relaxation. Although neuromyotonia may accompany an assortment of inherited diseases, most cases are acquired. The observation that the cquired form is often associated with an autoimmune disorder, and the demonstration that some cases improve after plasma exchange, has led to a search for an immune-mediated etiology. This review summarizes the recent immunological and electrophysiological evidence that autoantibodies to voltage-gated potassium channels produce the peripheral motor nerve hyperexcitability that characterizes neuromyotonia and thus establishes acquired neuromyotonia as an autoantibody-mediated disorder. In the nervous system, ion channels and neurotransmitter receptors that function as ligand-gated ion channels seem to be favored targets for autoantibody attack, and neuromyotonia can now be added to the growing list of autoimmune channelopathies.

Acquired neuromyotonia: a new autoantibody-mediated neuronal potassium channelopathy.

Neuromyotonia (Isaacs syndrome) is a rare and heterogenous syndrome of continuous motor unit activity of peripheral nerve origin that manifests as various combinations of muscle stiffness, cramps, twitching, weakness, and delayed muscle relaxation. Although neuromyotonia may accompany an assortment of inherited diseases, most cases are acquired. The observation that the acquired form is often associated with an autoimmune disorder, and the demonstration that some cases improve after plasma exchange, has led to a search for an immune-mediated etiology. This review summarizes the recent immunological and electrophysiological evidence that autoantibodies to voltage-gated potassium channels produce the peripheral motor nerve hyperexcitability that characterizes neuromyotonia and thus establishes acquired neuromyotonia as an autoantibody-mediated disorder. In the nervous system, ion channels and neurotransmitter receptors that function as ligand-gated ion channels seem to be favored targets for autoantibody attack, and neuromyotonia can now be added to the growing list of autoimmune channelopathies.

Potassium current suppression in patients with peripheral nerve hyperexcitability.

Acquired neuromyotonia (Isaac's syndrome) is considered to be an autoimmune disease, and the pathomechanism of nerve hyperexcitability in this syndrome is correlated with anti-voltage-gated K(+) channel (VGKC) antibodies. The patch-clamp technique was used to investigate the effects of immunoglobulins from acquired neuromyotonia patients on VGKCs and voltage-gated Na(+) channels in a human neuroblastoma cell line (NB-1). K(+) currents were suppressed in cells that had been co-cultured with acquired neuromyotonia patients' immunoglobulin for 3 days but not for 1 day. The activation and inactivation kinetics of the outward K(+) currents were not altered by these immunoglobulins, nor did the immunoglobulins significantly affect the Na(+) currents. Myokymia or myokymic discharges, with peripheral nerve hyperexcitability, also occur in various neurological disorders such as Guillain-Barré syndrome and idiopathic generalized myokymia without pseudomyotonia. Immuno-globulins from patients with these diseases suppressed K(+) but not Na(+) currents. In addition, in hKv 1.1- and 1.6-transfected CHO (Chinese hamster ovary)-K1 cells, the expressed VGKCs were suppressed by sera from acquired neuromyotonia patients without a change in gating kinetics. Our findings indicate that nerve hyperexcitability is mainly associated with the suppression of voltage-gated K(+) currents with no change in gating kinetics, and that this suppression occurs not only in acquired neuromyotonia but also in Guillain-Barré syndrome and idiopathic generalized myokymia without pseudomyotonia.

Strength‐duration properties of peripheral nerve in acquired neuromyotonia

The strength-duration time constant (SDTC) of a myelinated axon is a property of the nodal membrane and is sensitive to changes in membrane potential. Strength-duration time constants for motor axons and cutaneous afferents of the median nerve were measured in 9 patients with acquired neuromyotonia (NMT), a condition of peripheral nerve hyperexcitability, and 15 control patients. Mean motor axon time constants were significantly prolonged (344 ± 100 μs) in patients compared to healthy controls (264 ± 34 μs; P = 0.038), but sensory axon time constants were not significantly different. Motor axon time constants were longer than sensory axon time constants in 4 of the patients with neuromyotonia, suggesting that the nodal membrane was depolarized by an ectopic focus at the site of nerve stimulation at the wrist, ionic conductances were altered at the node, or that the size of the node was increased, possibly as a result of immune-mediated damage. The anti–voltage-gated potassium channel antibodies thought to generate peripheral nerve hyperexcitability in acquired neuromyotonia may be indirectly responsible for changes in motor axon nodal membrane properties. © 1999 John Wiley & Sons, Inc. Muscle Nerve 22: 823–830,1999

Strength-duration properties of peripheral nerve in acquired neuromyotonia.

The strength-duration time constant (SDTC) of a myelinated axon is a property of the nodal membrane and is sensitive to changes in membrane potential. Strength-duration time constants for motor axons and cutaneous afferents of the median nerve were measured in 9 patients with acquired neuromyotonia (NMT), a condition of peripheral nerve hyperexcitability, and 15 control patients. Mean motor axon time constants were significantly prolonged (344 +/- 100 micros) in patients compared to healthy controls (264 +/- 34 micros; P = 0.038), but sensory axon time constants were not significantly different. Motor axon time constants were longer than sensory axon time constants in 4 of the patients with neuromyotonia, suggesting that the nodal membrane was depolarized by an ectopic focus at the site of nerve stimulation at the wrist, ionic conductances were altered at the node, or that the size of the node was increased, possibly as a result of immune-mediated damage. The anti-voltage-gated potassium channel antibodies thought to generate peripheral nerve hyperexcitability in acquired neuromyotonia may be indirectly responsible for changes in motor axon nodal membrane properties.

The therapeutic potential for targetting potassium channels: Are dendrotoxins a suitable basis for drug design?

Voltage-dependent potassium ion channels have been implicated in several diseases of genetic or autoimmune origin. There are genetic defects of specific potassium channel genes in episodic ataxia with myokymia, long QT syndrome, Jervell–Lange–Nielsen syndrome, and familial hyperinsulinemic hypoglycemia of infancy. Antibodies against voltage-gated potassium channels have been detected in Isaacs syndrome (acquired neuromyotonia). Voltage-gated potassium channels have also been regarded as therapeutic targets for immunosuppressants (targetting Kv1.3 channels) and in some neurodegenerative diseases (targetting Kv1.1 or 1.2 channels). Specific blockers of potassium channels may be designed from an understanding of the molecular recognition properties of highly specific potassium channel blocking toxins such as dendrotoxin. The dendrotoxin family of toxins and their genetic relatives in the Kunitz family of proteinase inhibitors have been studied extensively in recent years. Structural studies and functional studies with mutated toxins provide information that should help the rational design of analogues with the desired properties.

4-25-02 Acquired neuromyotonia (Isaac's syndrome) in intrathoracic pathology. Electrophysiological findings

4-25-02 Acquired neuromyotonia (Isaac's syndrome) in intrathoracic pathology. Electrophysiological findings

4-34-06 Isaac's syndrome associated with myasthenia gravis. Case report

4-34-06 Isaac's syndrome associated with myasthenia gravis. Case report

Repetitive CMAPs: Mechanisms of neural and synaptic genesis

Repetitive compound muscle action potentials (R-CMAPs) occur when a single nerve shock excites muscle fibers repeatedly. “Double discharges” are due to intramuscular nerve reexcitation. “Synaptic” R-CMAPs, due to excess acetylcholine in the neuromuscular synapse, can occur in congenital myasthenia, the slow-channel syndrome, and acetylcholinesterase inhibition. Secondary nerve excitation can reexcite muscle fibers. Synaptic R-CMAPs in a patient consisted of two discharges. The second diminished during repetitive stimulation and began 3.5–4.0 ms after the first, which is slightly longer than the synapse-muscle refractory period. Neural R-CMAPs, due to ectopic nerve activity, occur in neuromyotonia (NMT). R-CMAPs in a patient consisted of about 20 discharges at 200–300 Hz. Studies in healthy subjects showed that such trains represent added single CMAPs. Impulse frequency in the patient lies close to the threshold of refractoriness. Refractoriness of the synapse-muscle cell assembly determines the characteristics of R-CMAPs regardless of the primary cause. © 1996 John Wiley & Sons, Inc.

Repetitive CMAPs: Mechanisms of neural and synaptic genesis

Repetitive compound muscle action potentials (R-CMAPs) occur when a single nerve shock excites muscle fibers repeatedly. "Double discharges" are due to intramuscular nerve reexcitation. "Synaptic" R-CMAPs, due to excess acetylcholine in the neuromuscular synapse, can occur in congenital myasthenia, the slow-channel syndrome, and acetylcholinesterase inhibition. Secondary nerve excitation can reexcite muscle fibers. Synaptic R-CMAPs in a patient consisted of two discharges. The second diminished during repetitive stimulation and began 3.5-4.0 ms after the first, which is slightly longer than the synapse-muscle refractory period. Neural R-CMAPs, due to ectopic nerve activity, occur in neuromyotonia (NMT). R-CMAPs in a patient consisted of about 20 discharges at 200-300 Hz. Studies in healthy subjects showed that such trains represent added single CMAPs. Impulse frequency in the patient lied close to the threshold of refractoriness. Refractoriness of the synapse-muscle cell assembly determines the characteristics of R-CMAPs regardless of the primary cause.

Neuromyotonia: Antibodies against K channels

Neuromyotonia: Antibodies against K channels

Cold-induced neuromyotonia

Cold-induced neuromyotonia

Decrement/increment phenomenon in a case of idiopathic generalized myokymia (Isaac's syndrome)

Decrement/increment phenomenon in a case of idiopathic generalized myokymia (Isaac's syndrome)