Neuromuscular Disorders
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Neuromyotonia and myokymia …
- Updated 04.15.2024
- Released 01.07.2003
- Expires For CME 04.15.2027
Neuromyotonia and myokymia
Introduction
Overview
Neuromyotonia and myokymia are related disorders of peripheral nerve hyperexcitability. Clinically they manifest as muscle stiffness and twitching. Both conditions are typically related to disorders of the voltage-gated potassium channel and caused by autoimmune, toxic, or genetic processes. Whereas neuromyotonia is specific to these disorders, myokymia can be seen in many neurologic conditions. In this update, the author offers a clinical and electromyographic guide to the diagnosis and treatment of these intriguing syndromes.
Key points
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• Generalized neuromyotonia is usually an autoimmune disease characterized by widespread muscle stiffness and delayed muscle relaxation after voluntary movement. It is accompanied by continuous muscle twitching known as myokymia. | |
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• Electromyography of the affected muscles shows either electrical neuromyotonia (high-frequency trains of decrementing motor unit discharges that start and stop abruptly) or electrical myokymia (grouped discharges recurring semi-rhythmically at a rate of 2 to 10 Hz). | |
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• Neuromyotonia is specific to peripheral nerve hyperexcitability syndromes, whereas myokymia can be seen in a diverse group of neurologic disorders. | |
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• Neuromyotonia may respond to symptomatic treatment with sodium channel-blocking drugs (carbamazepine, phenytoin, mexiletine). If antibodies are identified, it may respond to immune-based therapies (corticosteroids, plasmapheresis, high-dose intravenous human immunoglobulin, rituximab, and other immunosuppressive medications). | |
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• These phenomena also occur in episodic ataxia type 1 and a form of hereditary neuropathy. |
Historical note and terminology
The terms “neuromyotonia” and “myokymia” have both been used to describe clinical phenomena as well as distinct patterns of abnormal electrical discharge recorded during needle electromyography. This dual nomenclature has created confusion over the years, but no other set of clearer definitions has yet been universally accepted. In this review, we will address and distinguish the clinical syndromes of neuromyotonia and myokymia, the electromyographic discharges defined by these terms, and their relationships.
Clinical neuromyotonia is a syndrome of persistent muscle stiffness, delayed muscle relaxation, and continuous muscle twitching due to abnormal electrical discharges of motor nerves. Originally described by Gamstorp and Wohlfart in 1959, it has also been called "Isaacs syndrome" (33) and "myokymia with impaired muscle relaxation" (17), but it is now mostly called "neuromyotonia" (48). Needle EMG recordings from affected muscle show abnormal electrical activity of either the type known as electrical neuromyotonia, or the type known as electrical myokymia, or both. These EMG findings are discussed in this article.
Clinical myokymia refers to the presence of focal or generalized continuous muscle twitching, often exhibiting a rippling, “bag of worms” appearance under the skin. The electrodiagnostic features of myokymia were first described by Denny-Brown and Foley in 1948 (11). Myokymia is the result of spontaneous repetitive discharges from two or more motor units. Needle EMG recordings from the twitching muscle can show either very frequent fasciculations, electrical neuromyotonia, or electrical myokymia.
Clinical manifestations
Presentation and course
Focal neuromyotonia has mainly been reported in the extraocular muscles. Ocular neuromyotonia causes episodic diplopia lasting a few seconds when an ocular muscle contracts spontaneously or remains contracted after voluntary eye deviation (68). There are several reported cases of focal neuromyotonia affecting the third and fourth fingers on one hand, resembling Dupuytren contracture or focal dystonia. Dupuytren contracture is a slow progressive thickening and shortening of the palmar fascia leading to digital contracture. Focal dystonia is a neurologic disorder manifested by involuntary muscle contracture causing abnormal postures. All of the patients had chronic obstructive lung disease and had been treated with a beta-sympathomimetic drug (51; 37; 16). It is possible that in the elderly, a combination of medications such as sympathomimetics and focal trauma or overuse can predispose to this focal spasm resembling a contracture. The identification of this is important as focal neurotoxins can treat it.
In generalized neuromyotonia, there is persistent muscle stiffness that is more pronounced in the distal than in the proximal limbs and occurs more in the limbs than in the trunk or cranial muscles. The hands often have adducted fingers resembling the posture of tetany. The stiffness worsens during activity, and there is delayed muscle relaxation after voluntary movement resembling active myotonia; however, there is no percussion myotonia. Posture may be abnormal with exaggerated kyphosis, and movement is stiff and slow. Weight loss is common. The muscles may be well-developed, and sweating may be prominent, possibly because heat is generated by excessive and constant muscle activity (03). However, direct autonomic nervous system involvement could also explain hyperhidrosis. Dyspnea may result from tightening of the respiratory muscles. Bulbar and laryngeal muscles may be affected. The tongue and jaw become stiff, making swallowing difficult, and the voice turns hoarse (33). In addition to the abnormal stiffness, there is usually continuous muscle twitching (clinical myokymia), which is most pronounced in the distal limbs. This abnormal muscle activity persists during sleep and is not relieved by general anesthesia or spinal anesthesia; it is reduced but not abolished by proximal peripheral nerve blocks and is abolished by curare or botulinum toxin. The discharges are, therefore, thought to arise in the nerve rather than in the perikaryon or neuromuscular junction.
In addition to the above findings, physical examination demonstrates normal or depressed tendon reflexes, sometimes with a mild coexisting sensorimotor peripheral neuropathy. Carpopedal spasm with flexion of the wrist, extension of the fingers, and plantar flexion of the feet may be seen, resembling tetany, but serum calcium and magnesium are normal.
A rare type of generalized neuromyotonia known as Morvan syndrome consists of neuromyotonia, hyperhidrosis, burning pain, and a fluctuating encephalopathy manifest by insomnia, delirium, and hallucinations (44; 06; 45; 41).
In laboratory studies, CSF is normal except for the presence of oligoclonal IgG bands in about half of the cases. Antibodies that immunoprecipitate [125I] alpha-dendrotoxin-labeled voltage-gated potassium channels extracted from mammalian brain tissue (VGKC antibodies) are likewise present in 40% to 50% of cases (55). As explained in the Etiology section, in most cases, the true target of these antibodies is either contactin-associated protein 2 (Caspr2) or leucine-rich glioma inactivated 1 (LGI1), and these antibodies can now be assayed directly (31). Nerve conduction tests may reveal a mild sensorimotor axonal polyneuropathy but may be normal. Adjusting the sensitivity of the nerve conduction study from 5 mV to 200 u and the sweep speed of 100 ms to 1 s per division may identify after discharges. In at least one study, these were more sensitive than EMG and appeared to correlate with clinical improvement (57).
Electromyography shows either electrical neuromyotonia or myokymia (Table 1), or a combination of the two. Electrical neuromyotonia consists of irregular high-frequency (150 to 300 Hz) trains of decrementing single motor unit discharges, which usually start and stop suddenly and can last for up to several seconds. The decrement in amplitude occurs within the train, although the train starts and stops abruptly. When processed and subjected to audio output on an EMG system, these high-frequency discharges can produce sounds ranging from a “ping” to a high-pitched whine. They can occur spontaneously or may be induced by electrical stimulation, nerve ischemia, percussion of the nerve, or needle movement (21; 20). After voluntary activation, there are typically prolonged neuromyotonic after discharges corresponding to the delayed muscle relaxation. Neuromyotonic discharges are more common in distal muscles than in proximal muscles and in legs more than arms (29).
In other cases, EMG reveals electrical myokymia, which consists of rhythmic or semirhythmic bursts of waveforms representing single motor units firing as doublets, triplets, or multiplets. The individual spike frequency within each burst averages from 30 to 40 Hz but ranges from 2 to 62 Hz, and total burst duration is usually 100 to 900 ms. The bursts usually repeat at a frequency of 2 to 10 Hz but may be as slow as 0.05 Hz (one burst every 20 seconds). Myokymic discharges are usually spontaneous and are not affected by electrical stimulation, needle movement, percussion, or sleep and may or may not be precipitated by exercise.
Table 1. EMG Characteristics of Neuromyotonia and Myokymia
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Neuromyotonia |
Myokymia |
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• Single MUAP firing rapidly and irregularly |
• Single MUAP firing as bursts of multiplets |
Clinical myokymia is much more common than clinical neuromyotonia, and it may be either focal or generalized (See Table 2).
Table 2. Causes of Myokymia
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Focal myokymia | ||
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Peripheral nervous system | ||
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• Bell palsy | ||
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Central nervous system | ||
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• Neoplastic/inflammatory meningoradiculitis | ||
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Generalized myokymia | ||
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• Chronic inflammatory demyelinating polyneuropathy | ||
Focal myokymia is associated with diverse syndromes and disorders of both the central and peripheral nervous system. Radiation plexitis, Guillain-Barré syndrome, multiple sclerosis, pontine tumor, timber rattlesnake envenomation, and ocular myokymia due to neurovascular compression are all potential causes of focal myokymia. Myokymia appears in 60% to 70% of radiation-induced brachial or lumbosacral plexopathies; it may involve a few muscles with relatively preserved strength and can persist for many years after irradiation. The presence of myokymia in a symptomatic extremity following radiation of a mass lesion in the vicinity of the plexus favors radiation injury over tumor recurrence, although myokymic discharges may rarely appear with tumor infiltration of the plexus as well. Myokymia occurs from a few weeks to many years after radiation therapy. The presence of pain is an early sign of neoplastic infiltration as well as the presence of Horner syndrome. Transient myokymia occurs in 17% of Guillain-Barré cases and may last up to 6 weeks. It is more common in the face (where it is usually bilateral), involves mildly weak muscles, and is seen more often in women. In multiple sclerosis, myokymia is also more common in the face and is also transient, but it can last up to 3 months. It is usually unilateral, involves nonparetic muscles, can recur on the same or opposite side, and may respond to injection with botulinum toxin type A. In contrast, posterior fossa tumors cause persistent and unilateral myokymia. Although pontine glioma is the most likely neoplasm to cause myokymia, it may also appear with cerebellar astrocytomas, schwannomas, and pontine metastases. Facial myokymia and myokymia in a bitten extremity are also features of timber rattlesnake envenomation. In these cases, facial myokymia is caused by a hematogenous spread of the venom and resolves within several hours of antivenin administration. Myokymia produces an abduction and adduction tremor of the fingers when the arm is bitten or a vertical tremor of the toes when the leg is attacked, each of which typically resolves over 3 days (19). Persistent facial myokymia may also be a focal manifestation of K+ channel antibody syndrome (22).
A case of transient dysarthria due to myokymia in the tongue has been described. The patient had a remote history of stereotactic radiosurgery for retroclival meningioma (07).
Generalized myokymia is present as part of any of the neuromyotonic syndromes. It may be a feature of mercury poisoning, which also causes hyperhidrosis, neuromyotonia, constipation, tremor, and encephalopathy (39). Generalized myokymia can also be seen in timber rattlesnake envenomation, episodic ataxia with myokymia (EA1), and a few cases of chronic inflammatory demyelinating polyneuropathy (19; 08).
Prognosis and complications
Clinical neuromyotonic syndromes (Isaacs and Morvan syndrome), if mild, may be treated with symptomatic therapy alone. If refractory to symptomatic therapy, the condition may remit after immunotherapy and treatment of the comorbid condition. In rare cases it resolves spontaneously (03; 67).
The prognosis of clinical myokymia is dependent on the associated disorder causing it. Myokymia associated with Guillain-Barré syndrome is transient, whereas that associated with multiple sclerosis is also transient, but can recur. Myokymia in brainstem tumors is usually persistent unless antineoplastic therapies are successful. In cases of post irradiation plexopathy, myokymia can persist for many years.
Clinical vignette
Clinical neuromyotonia. For 3 years, starting at 42 years of age, this man noted progressive limb muscle stiffness. At first, there were cramps and twitching in both calves, which gradually spread to involve the arms, trunk, and face. The stiffness was worse with exercise but improved if he continued the activity. His wife reported that the stiffness persisted in sleep, and he was occasionally awakened by the cramps. He complained of excessive fatigue and generalized weakness and had lost 30 pounds. The rigidity made walking difficult; tightening of the chest wall muscles occasionally produced shortness of breath. Speech and swallowing were unaffected. There were no sensory symptoms.
He had no other clinical disorders. He took no medications and had no allergies. He had smoked until 30 years of age, drank alcohol socially, and had never used illicit drugs. No one in his family suffered from any neurologic or autoimmune disorders.
On examination, he had prominently well-developed muscles of the trunk and limbs, which were in a state of constant contraction. Twitching was observed in the thighs and upper arms. He was sweating despite normal ambient temperature. Examination of the cranial nerves was unremarkable. Strength was mildly reduced in the proximal muscles of the arms and legs. Muscles relaxed slowly after contraction, but there was no carpal or pedal spasm. Tendon reflexes were normal. Coordination and sensory examinations were normal. Gait was slow and stiff. Laboratory evaluation revealed normal serum potassium, calcium, and magnesium concentrations. Thyroid studies were normal. Serum creatine kinase was mildly elevated at 260 (less than 195 = normal). Serum anti-voltage-gated potassium channel antibodies were elevated. Oligoclonal bands were present in otherwise unremarkable cerebrospinal fluid. Chest CT showed no evidence of thymoma or tumor of the lung. Nerve conduction studies were normal, but EMG revealed both neuromyotonic and myokymic discharges along with fibrillations and fasciculations in multiple tested muscles of the arms and legs, worse distally.
A course of plasmapheresis (six exchanges over 12 days) resulted in marked improvement in stiffness. He was subsequently given oral prednisone at a dose of 1 mg/kg per day. Symptoms continued to improve, and the dose was slowly tapered over the next 11 months. Eventually, he stopped the steroids entirely without relapse. He remained well 2 years later off all medications.
Clinical myokymia. A 35-year-old woman with relapsing-remitting multiple sclerosis for 7 years presented with a 2-week history of persistent twitching of the right facial muscles. No facial weakness or numbness was reported. There was no double vision; speech and swallowing were unaffected.
She had no medical problems other than multiple sclerosis and had not had any surgeries. She had been on interferon beta 1a for 4 years. Other medications included baclofen for leg spasticity and oxybutynin for a hyperactive bladder. Family history was unremarkable.
Examination revealed continuous fine, worm-like movements of the right facial muscles. The remainder of the cranial nerve examination was normal except for a partial right sixth cranial nerve palsy.
Needle EMG of the right frontalis, orbicularis oculi, nasalis, and orbicularis oris showed myokymic discharges. MRI of the brain showed a small demyelinating lesion in the right pons.
She declined treatment with carbamazepine for fear of side effects. The abnormal movements stopped spontaneously 2 weeks later. They recurred twice, for 3 weeks and 1 week respectively, over the next 2 years.
The facial myokymia in multiple sclerosis occurs with brainstem lesions, which involve the postnuclear facial nerve fascicles. The nucleus of the facial nerve is located in the caudal dorsal pons. The fibers leave the nucleus running through the brainstem to exit ventrally. These fibers are peripheral to the nucleus, which explains the presence of myokymia.
Biological basis
Etiology and pathogenesis
Generalized neuromyotonia is usually a sporadic autoimmune disease (55; 54; 67). A minority of neuromyotonic syndromes are hereditary and occur either in isolation or with periodic ataxia or inherited neuropathies. Most patients with episodic ataxia type I have clinical or electrophysiological neuromyotonia, mainly in facial and hand muscles. This autosomal dominant disorder is caused by mutations in the KCNA1 potassium channel gene (75). An autosomal recessive form of hereditary axonal motor neuropathy associated with neuromyotonia has been linked to loss-of-function mutations of HINT1, which encodes histidine triad nucleotide-binding protein 1, a type of purine phosphoramidase. Mutations of this gene were found in 11% of patients with autosomal recessive peripheral neuropathy, and in 76% of patients with axonal neuropathy plus neuromyotonia (86; 61).
Neuromyotonia is a prominent feature of a rare autosomal recessive genetic disease known as the Schwartz-Jampel syndrome, or chondrodystrophic myotonia. Affected children have a very distinctive appearance, including wry facies, short stature, spondylo-epiphyseal dysplasia, a hunched posture due to muscle stiffness, slow muscle relaxation after voluntary contraction, and percussion myotonia (74). Electromyography demonstrates continuous high-frequency electrical discharges at rest; these are abolished by curare, which also produces muscle relaxation (74). The disorder is caused by mutations of the gene coding for perlecan, the major heparan sulfate proteoglycan of basement membranes. Studies of perlecan-deficient mice suggest that abnormal nerve activity arises in distal motor nerves, perhaps in nerve terminals (05). The presence of percussion myotonia, however, implies that the excitable muscle membrane is also affected (74).
Using [125I] alpha-dendrotoxin immunoprecipitation assay VGKC antibodies are found in 40% to 50% of patients with acquired neuromyotonia (82; 21; 80). However, laboratory investigations have revealed that the antibodies rarely bind to potassium channel subunits. Instead, two main antigen targets have been discovered: leucine-rich glioma-inactivated 1 (LGI1) and contactin-associated protein-2 (Caspr2) (31; 43). Patients with positive LGI1 and Caspr2 antibodies are generally late middle-aged males presenting with limbic encephalitis, neuromyotonia, movement disorders, cardiac involvement, sleep disturbances, and serum hyponatremia. LGI1 is the principal target of VGKC antibodies in patients with limbic encephalitis, whereas Caspr2 is the principal target of VGKC antibodies in patients with neuromyotonia and Morvan syndrome. Of 56 patients with limbic encephalitis attributed to VGKC antibodies in a laboratory, 49 had LGI1 antibodies and 7 had Caspr2 antibodies; of 13 patients with VGKC-antibody neuromyotonia or Morvan syndrome, 10 had Caspr2 antibodies and three had LGI1 antibodies (31). In a study of 29 patients with Morvan syndrome, of whom 93% were male, Irani and colleagues detected VGKC-complex antibodies in 79% (32). Of 24 sera tested, only Caspr2 antibodies were found in six patients, both Caspr2 and LGI1 antibodies in 15 patients, and only LGI1 antibodies in three patients. Tumors, mainly thymoma, were associated with Caspr2 antibodies and a poor prognosis, whereas hyponatremia was associated with LGI1 antibodies. It is not yet known whether antibodies to LGI1 or Caspr2 can be found in the serum of neuromyotonia patients who lack VGKC antibodies.
In a study of 114 patients reported to be positive for VGKC antibodies, only 26.3% had an active or remote solid organ or hematological malignancy (36).
In a 2020 study, Michael and colleagues stated that the evidence from multiple international groups suggests there are no longer clinical reasons to test for VGKC antibodies (50). VGKC antibody radioimmunoassay is not an effective screening test for the key antibody species, and it misses up to 15% of LGI1- or CASPR2-positive antibodies. Many diagnostic centers use fixed cell-based assay. However, live cell-based assay testing has a higher sensitivity and specificity.
Antibodies against netrin-1 receptor (uncoordinated 5A-UNC5A, and deleted in colon carcinoma-DCC) have been described in patients with thymoma, myasthenia gravis, and neuromyotonia (76; 73).
A role for aberrant immunologic activation in acquired clinical neuromyotonia is strongly supported not only by the presence of the aforementioned antibodies in the serum but also by oligoclonal bands in the CSF and by clinical improvement following immunomodulatory therapy with plasmapheresis or IVIg. Further suggestive clinical evidence includes a clear association with thymoma, myasthenia gravis, lung cancer, and neuronal ganglionic anti-acetylcholine receptor antibodies (81; 23). The neurologic disorder appears at the same time or after the diagnosis of myasthenia in patients with clinical neuromyotonia associated with myasthenia gravis, but in patients with lung cancer, the hyperexcitability syndrome may predate the tumor diagnosis by an average of 2 years (23). Passive transfer of clinical neuromyotonia to animals can be achieved by injection of purified IgG from patients with neuromyotonia into mice, in which an antibody-mediated attack on peripheral nerve potassium channels can be demonstrated in vitro (71). The neuromyotonic variant, Morvan syndrome, is also associated clinically with thymoma, myasthenia gravis, psoriasis, and atopic dermatitis, and serologically, it can be associated with antiganglionic-acetylcholine receptor antibodies or anti-voltage gated K channel antibodies (44; 06; 45; 36).
Although most cases of thymoma-related neuromyotonia are associated with VGKC (usually Caspr2) antibodies, one such patient lacking VGKC antibodies was found instead to have ANNA-1 (anti-neuronal nuclear) antibodies (77). After total resection of the tumor, both the antibodies and the neuromyotonia disappeared.
A patient with focal neuromyotonia was reported to have a pathological hexanucleotide repeat in C9ORF72, enlarging the spectrum of motor neuron dysfunctions associated with C9ORF72 (15). The C9ORF72 repeat expansion may act as a risk factor.
The nerve hyperexcitability in neuromyotonia is due to remodeling of voltage-gated cation channels with both increased sodium and decreased potassium conductance.
The C9ORF72 mutation might worsen potassium currents through its known influence on Rab proteins that modulate the Kv1.1 subunit trafficking (12).
Clinical neuromyotonia may also appear because of intoxication with mercury, 2,4-dichlorophenoxyacetic acid, dichlorophenyldichloroethylene, and with drugs such as penicillamine (55) and oxaliplatin (83; 56). VGKC-antibody-positive neuromyotonia has been reported after a wasp sting (78). A patient with MuSK antibodies without myasthenia exhibited frequent fasciculations and neuromyotonia of facial and bulbar muscles, probably originating in hyperactive motor nerve terminals (70). Using acetylcholinesterase inhibitors for patients with myasthenia and positive anti-MUSK antibodies will exacerbate the fasciculations. A few cases of generalized neuromyotonia were reported after human papillomavirus immunization (10; 25; 84). Paraneoplastic neuromyotonia has been reported with thymoma (55), hypernephroma (09), bronchogenic carcinoma, bladder carcinoma (14), testicular seminoma (73), and Hodgkin disease (42). Clinical neuromyotonia has also been described in central pontine myelinolysis, essential thrombocythemia, chronic inflammatory demyelinating polyneuropathy, multifocal motor neuropathy, spinal epidural abscess, amyloidosis, and chronic graft-versus-host disease. A patient with focal neuromyotonia of both legs, especially when walking, was found to have compression of the lumbosacral nerve roots by severe spinal stenosis (64).
A review of the literature on ocular neuromyotonia revealed that 16 of 30 patients had received radiation therapy to the sellar and parasellar regions, and eight cases of ocular neuromyotonia resulted from compressive lesions such as supraclinoid aneurysm, basilar artery dolichoectasia, mucormycosis of the cavernous sinus, arachnoiditis, and Graves disease (85). In a case of ocular neuromyotonia, vascular compression of the oculomotor nerve by the posterior cerebral and superior cerebellar arteries was identified by 3D MRI and successfully treated by surgical microvascular decompression (30). Paroxysmal ocular neuromyotonia involving a single eye muscle has been described in two girls with brainstem demyelinating disease, one with multiple sclerosis and the other with probable neuromyelitis optica (47).
Clinical myokymia, in contrast, most commonly occurs as a component of other disorders (see Table 2). Although it rarely causes serious symptoms directly, it remains important as a possible presenting symptom of a much more serious disease.
Focal myokymia may be caused by multiple sclerosis, pontine tumors, Guillain-Barré syndrome, radiation plexitis, and, rarely, timber rattlesnake envenomation. Facial myokymia may also be seen in Bell palsy, syringobulbia, polyradiculoneuropathy, central pontine myelinolysis, tuberculoma, meningeal carcinomatosis, meningeal sarcoidosis, lymphocytic meningoradiculitis, basilar invagination, phosgene poisoning, and hemifacial spasm. Facial myokymia can also occur spontaneously after brain death (66). Limb myokymia occurs in chronic inflammatory demyelinating polyneuropathy, rare compressive neuropathies, syringomyelia, spinal stenosis, conus medullaris teratoma, radiculopathy, neurocysticercosis, subarachnoid hemorrhage, and following cardiopulmonary arrest.
As we have seen, generalized myokymia is a major feature of clinical neuromyotonia. Myokymia is also an important feature of episodic ataxia type 1, which is caused by mutations of the voltage-gated potassium channel, KCNA1, with high expression in the basket cells of the cerebellum and in the axons of peripheral nerves. Some individuals with this mutation have had isolated neuromyotonia (08; 62). An autosomal dominant familial syndrome of dyskinesia and facial myokymia has also been reported (13). Myokymia of the lower face and tongue, increased by voluntary activation, is a characteristic feature of Kennedy disease or X-linked spinal and bulbar muscular atrophy (58). Myokymic discharges and, occasionally, clinical myokymia may sometimes be seen in other denervating disorders such as neuropathy.
The abnormal electrical activity of neuromyotonia arises from peripheral nerves. The activity takes the form of motor unit potentials or fragments thereof, and the frequency of the discharges (up to 300 Hz) is much higher than can arise from motor neurons. Nerve block experiments suggest that discharges arise at various sites along the nerve because distal nerve blocks tend to reduce the activity to a greater extent than proximal nerve blocks, but only the blockade of neuromuscular transmission with curare or botulinum toxin completely abolishes the activity.
In autoimmune neuromyotonia, it is thought that antibodies directed against Caspr2, LGI1, or other unidentified antigens alter the expression of VGKCs in the plasma membrane of peripheral nerve, preventing potassium efflux and chronically lowering the resting membrane potential, which results in decreased repolarization and neuronal hyperexcitability (71; 55). In Morvan syndrome, the combination of encephalopathy and clinical neuromyotonia suggests that these antibodies may affect VGKCs in both the central and peripheral nervous system (06). Hart and colleagues (24) demonstrated the reactivity of neuromyotonic IgG with dendrotoxin-sensitive VGKCs (“fast” K+ channels), and later patch clamp studies demonstrated that both sera and IgG from patients with neuromyotonia suppressed voltage-gated outward K+ current through indirect mechanisms (52). These findings suggest that the autoantibodies may decrease channel density, either through increased degradation or by decreased expression of VGKCs (02).
Contactin-associated protein-like (Caspr2) is a cell adhesion molecule of the neurexin family and it is expressed on central and peripheral nervous system axons.
Caspr2 is localized to the juxtaparanodal region of both central and peripheral nervous system nodes of Ranvier. At the juxtaparanodes, contactin-2 interacts with Caspr2, and this association is necessary for clustering of voltage-gated potassium channels.
Caspr2 antibodies are frequently IgG4 subtype as are autoantibodies to other cell adhesion molecules expressed on nodes of Ranvier, such as neurofascins and contactin.
Caspr2 autoantibodies disrupt the binding of caspr2 to contactin2, potentially interfering with the clustering of VGKC ay juxtaparanodes, resulting in hyperexcitability of peripheral nerves (60).
Clinical myokymia (focal and generalized) results from the myokymic discharge of one or several motor units, producing brief tetanic contractions 1 to 2 centimeters wide in neighboring muscle segments. These slow, irregular, and independent contractions result in a continuously rippling appearance of the skin overlying the muscle (40). Myokymia may result from disruption of the biochemical microenvironment of an injured axon, causing regional and repetitive membrane hyperexcitability. As with neuromyotonic discharges, the site of origin of myokymic discharges can include virtually any segment of the motor axon, from the perikaryon to the terminal branches. Terminal branch generators are probably less common in myokymia than in neuromyotonia, however, because local nerve block often abolishes these discharges (19). In an animal model, myokymic-like discharges originated in experimentally demyelinated axons at the site of demyelination. A number of mechanisms appeared to contribute to these discharges, including local ephaptic transmission (ie, the abnormal spread of an action potential between two or more injured axons at a point of abnormal physical or electrical contact); a proximal impulse of unidentified source; and spontaneously depolarization of the membrane at the point of demyelination (19).
In humans, local axonal disturbance leading to myokymia may be caused by demyelination (multiple sclerosis, Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, radiation plexopathy), edema (pontine tumors), toxins (rattlesnake envenomation and clozapine administration), and ischemia, but not usually by nerve compression without the above changes. Nerve lesions associated with myokymic discharges are more likely to be chronic than acute.
Epidemiology
Clinical neuromyotonia is uncommon, and neuromyotonic discharges remain extremely rare. Clinical and electrical myokymia are much more common. No specific data about the precise incidence or prevalence of either condition is available in the literature.
Prevention
Apart from the avoidance of known toxins or medications (ie, penicillamine, oxaliplatin, clozapine), there are no known preventative measures for either neuromyotonia or myokymia.
Differential diagnosis
Confusing conditions
The muscle stiffness of neuromyotonia could be confused with stiff-person syndrome, and the delayed muscle relaxation could be mistaken for myotonia. Both diagnoses are easily ruled out on clinical and electromyographic grounds. In stiff-person syndrome, muscle rigidity is usually greatest in the trunk and axial muscles, is accompanied by reflex muscle spasms, is not accompanied by myokymia, and is very painful. The abnormal activity is abolished by spinal anesthesia or peripheral nerve block. On EMG, one observes motor unit discharges at frequencies not exceeding 50 Hz, as would be expected from a central disorder. The delayed muscle relaxation of active myotonia is accompanied by percussion myotonia, as well as by typical myotonic discharges on EMG; percussion myotonia does not occur in neuromyotonia, and the EMG findings are different.
Clinical myokymia (focal and generalized), in its purest form, is usually more easily separated from other disorders, but should be taken seriously as a possible indicator of a more significant, separate disease process, especially when focal. The undulating sensation under the skin may be confused with diffuse fasciculations and motor neuron disease. However, no upper motor neuron signs are present on examination, no muscular atrophy or weakness is noted, and EMG clearly distinguishes myokymia from fasciculation. Facial myokymia may be confused with a variety of other disorders, including blepharospasm (dystonic contractions of the orbicularis oculi muscle) and hemifacial spasm (manifested by tonic and clonic contractions of facial muscles). Hemimasticatory spasm is a similar condition affecting the trigeminal nerve and muscles of mastication. These disorders produce distinctly different findings on EMG, with myokymia demonstrating characteristic bursts of motor unit activation and blepharospasm demonstrating intermittent full contractions indistinguishable from voluntary activation. Hemifacial spasm may be more difficult to distinguish, as it produces irregular, rhythmic bursts of motor unit activity, although most patients with this disorder have more dramatic muscle activation than patients with myokymia. Both myokymia and hemifacial spasm can develop after facial nerve lesions, including Bell palsy. Isolated orbicularis oculi myokymia frequently occurs as a benign phenomenon in otherwise normal individuals, producing twitching of the lower eyelid, exacerbated by stress, sleep deprivation, and the use of caffeine and other stimulants. Tetany (due to hypocalcemia or alkalosis) may resemble myokymia on EMG, but electrolyte measurements and the Trousseau test help to define tetany.
Diagnostic workup
Electromyography is the primary diagnostic tool. The EMG characteristics of neuromyotonia and myokymia have already been defined.
In cases of clinical neuromyotonia, serum studies should include a complete blood count, calcium, magnesium, phosphate, potassium, sedimentation rate, thyroid function tests, and immunologic function tests. Serum creatine kinase activity is usually mildly elevated. Assays for antibodies to VGKC, Caspr2, and LGI1 are commercially available but should be interpreted with caution. If there is a high suspicion for the diagnosis, checking for LGI1 and Caspr2 antibodies is recommended. High levels may be associated with autoimmune disease, whereas low levels are more common in nonautoimmune diseases. The presence of the antibody in general may reflect an associated malignancy and should be checked (36). Although lumbar puncture is not mandatory in all cases, CSF analysis may show elevated gamma-aminobutyric acid levels (65) and oligoclonal bands (40). A CT or MRI of the chest should be performed to rule out a thymoma, lung cancer, or another tumor. Muscle biopsy may be indicated in some cases, depending on the clinical manifestations.
Clinical or electrical myokymia necessitates a search for an underlying etiology. An EMG must be performed. Serum studies should include a complete blood count and serum electrolytes, including calcium and magnesium. Imaging of the brain and spinal cord, usually with contrast, may be necessary to rule out a structural lesion. CSF examination may be needed to search for signs of multiple sclerosis, Guillain-Barré, and other causes of meningeal inflammation.
Neuromuscular ultrasound was performed for a patient with tongue myokymia showing high frequency rotatory, to-and-fro, high amplitude movement of superficial, and deep muscle fascicles more prominent in the proximal muscles (63).
Management
Sodium channel-blocking drugs such as phenytoin, carbamazepine, and mexiletine, which act as membrane-stabilizing agents, are often helpful in reducing muscle stiffness in patients with neuromyotonia. The drugs are not always effective, however, and some patients respond, inexplicably, to centrally acting agents such as valproic acid (03) or baclofen (55). One patient with thymoma-associated generalized neuromyotonia refractory to other treatments responded dramatically to dronabinol, a cannabinoid agent (49).
There are a number of anecdotal reports testifying to the effectiveness of various immunomodulatory treatments for acquired generalized neuromyotonia. These include corticosteroids, azathioprine, mizoribine, plasmapheresis, and intravenous immunoglobulin. None of these treatments has been efficacious in all cases, although plasmapheresis seems to have the best record (04; 71; 55; 35; 26; 79; 53). Although intravenous immunoglobulin has been effective as a sole agent in two cases (27; 01), it was ineffective in one (79) and detrimental in another (35). After immunoglobulin failed in the latter two of these cases, plasmapheresis proved effective. A combination of a sodium channel-blocking drug and immunomodulating therapy may be more effective than either drug alone (55). Rituximab has been shown to be effective in a few case reports (72; 28).
Four patients with acquired neuromyotonia were reported to have a good response with tacrolimus (46).
In a large series of patients with "neuromyotonia," 19 patients treated with intravenous methylprednisolone, 1 gm/day for 5 days, had "significant amelioration of complaints" persisting during follow-up of 1 to 2 years (59). However, the physical findings were not well documented, and although all patients had myokymia, only five had stiffness before treatment. Prolonged remission has been described in other cases (34), but usually lifelong treatment is required.
In a publication, 32 patients with hyperexcitable peripheral nerves disorders, corticosteroids intravenous and oral were the first line of treatment followed by IVIGs or plasmapheresis if symptoms were persistent more than 6 weeks. Rituximab was used after 12 weeks of ongoing symptoms. Azathioprine and mycophenolate mofetil were selected as long-term therapeutic agents. In general, 1 to 3 years of immunotherapy may be sufficient for the majority of patients (38).
Clinical myokymia, either focal or generalized, usually responds to phenytoin and carbamazepine in antiepileptic doses (19). Myokymia alone usually does not pose a functional problem, and many patients may not require treatment. However, a full work-up for an underlying etiology is mandatory.
Special considerations
Anesthesia
Little information is available in the literature about anesthesia in patients with Isaacs syndrome. A patient with neuromyotonia showed increased sensitivity to rocuronium, a nondepolarizing muscle relaxant (18). Shyr and colleagues reported a patient with neuromyotonia who was anesthetized with propofol without effect on the abnormal muscle activity. Administration of the nondepolarizing muscle relaxant atracurium produced complete relaxation. Anesthesia was maintained with propofol and nitrous oxide without any complications (69). Interestingly, although diazepam and baclofen produced no effect on the abnormal muscle activity preoperatively, a small dose of diazepam was effective in the immediate postoperative period.
Clinical and electrical neuromyotonia respond to muscle relaxants working at the neuromuscular junction but not to general or spinal anesthesia.
Media
References
- 01
- Alessi G, De Reuck J, De Bleecker J, Vancayzeele S. Successful immunoglobulin treatment in a patient with neuromyotonia. Clin Neurol Neurosurg 2000;102:173-5. PMID 10996718
- 02
- Arimura K, Sonoda Y, Watanabe O, et al. Isaacs' syndrome as a potassium channelopathy of the nerve. Muscle Nerve 2002;Suppl 11:S55-8. PMID 12116286
- 03
- Auger RG. AAEM Minimonograph #44: diseases associated with excess motor unit activity. Muscle Nerve 1994;17:1250-63. PMID 7935547
- 04
- Bady B, Chauplannaz G, Vial C. Autoimmune etiology for acquired neuromyotonia. Lancet 1991;338:1330. PMID 1682701
- 05
- Bangratz M, Sarrazin N, Devaux J, et al. A mouse model of Schwartz-Jampel syndrome reveals myelinating Schwann cell dysfunction with persistent axonal depolarization in vitro and distal peripheral nerve hyperexcitability when perlecan is lacking. Am J Pathol 2012;180(5):2040-55. PMID 22449950
- 06
- Barber PA, Anderson NE, Vincent A. Morvan’s syndrome associated with voltage-gated K channel antibodies. Neurology 2000;54:771-2. PMID 10680828
- 07
- Bower AS, Fisayo A, Baehring JM, Roy B. Clinical reasoning: a 73-year-old woman with episodic dysarthria and horizontal binocular diplopia. Neurology 2022;98(18):767-72. PMID 35264421
- 08
- Browne DL, Gancher ST, Nutt JG, et al. Episodic ataxia/myokymia syndrome is associated with point mutations in the human potassium channel gene, KCNA1. Nat Genet 1994;8:136-40. PMID 7842011
- 09
- Canovas D, Martinez JM, Viguera M, Ribera G. Association of renal carcinoma with neuromyotonia and involvement of inferior motor neuron. Neurologia 2007;22(6):399-400. PMID 17610170
- 10
- Cerami C, Corbo M, Piccolo G, Iannaccone S. Autoimmune neuromyotonia following human papilloma virus vaccination. Muscle Nerve 2013;47(3):466-7. PMID 23364906
- 11
- Denny-Brown D. Myokymia and benign fasciculations of muscular cramps. Tr A Am Physicians 1948;61:88-96.
- 12
- Farg MA, Sundaramoorthy V, Sultana JM, et al. C9ORF72, implicated in amytrophic lateral sclerosis and frontotemporal dementia, regulates endosomal trafficking. Hum Mol Genet 2014;23(13):3579-95. PMID 24549040
- 13
- Fernandez M, Raskind W, Wolff J, et al. Familial dyskinesia and facial myokymia (FDFM): a novel movement disorder. Ann Neurol 2001;49:486-92. PMID 11310626
- 14
- Forte F, Pretegiani E, Battisti C, Sicurelli F, Federico A. Neuromyotonia as a paraneoplastic manifestation of bladder carcinoma. J Neurol Sci 2009;280(1-2):111-2. PMID 19249799
- 15
- Fortunato F, Bonapace G, Gullace R, et al. Focal neuromyotonia associated with a C9ORF72 expansion mutation. Muscle Nerve 2020;62(4):E63-5. PMID 32578243
- 16
- Gantenbein AR, Wiederkehr M, Meuli-Simmen C, Schwegler G. Focal neuromyotonia: do I love you. J Neurol 2010;257(10):1727-9. PMID 20532908
- 17
- Gardner-Medwin D, Walton JN. Myokymia with impaired muscular relaxation. Lancet 1969;1(7586):127-30. PMID 4180920
- 18
- Ginsburg G, Forde R, Martyn JA, Elkermann M. Increased sensitivity to a nondepolarizing muscle relaxant in a patient with acquired neuromyotonia. Muscle Nerve 2009;40(1):139-42. PMID 19533664
- 19
- Gutmann L. AAEM Minimonograph #37: Facial and limb myokymia. Muscle Nerve 1991;14:1043-9. PMID 1745276
- 20
- Gutmann L, Gutmann L. Myokymia and neuromyotonia 2004. J Neurol 2004;251(2):138-142. PMID 14991346
- 21
- Gutmann L, Libell D, Gutmann L. When is myokymia neuromyotonia. Muscle Nerve 2001a;24:151-3. PMID 11180199
- 22
- Gutmann L, Tellers JG, Vernino S. Persistent facial myokymia associated with K+ channel antibodies. Neurology 2001b;57:1707-8. PMID 11706117
- 23
- Hart IK, Maddison P, Newsom-Davis J, Vincent A, Mills KR. Phenotypic variants of autoimmune peripheral nerve hyperexcitability. Brain 2002;125(Pt 8):1887-95. PMID 12135978
- 24
- Hart IK, Waters C, Vincent A, et al. Autoantibodies detected to expressed K+ channels are implicated in neuromyotonia. Ann Neurol 1997;41(2):238-46. PMID 9029073
- 25
- Hatami M, Förster M, Weyers V, Räuber S, Meuth SG, Kremer D. Neuromyotonia with central nervous system lesions following quadrivalent human papilloma virus vaccination. Vaccines (Basel) 2022;10(7):1132. PMID 35891296
- 26
- Heidenreich F, Vincent A. Antibodies to ion-channel proteins in thymoma with myasthenia, neuromyotonia, and peripheral neuropathy. Neurology 1998;50:1483-5. PMID 9596015
- 27
- Ho WK, Wilson JD. Hypothermia, hyperhidrosis, myokymia and increased urinary excretion of catecholamines associated with a thymoma. Med J Aust 1993;158:787-8. PMID 8341196
- 28
- Horiuchi K, Kudo A, Inoue T, Fujii S, Oshima Y. Rituximab was effective in relieving symptoms of Isaacs syndrome: a case report. Cureus 2022;14(10):e30100. PMID 36381695
- 29
- Hutto SK, Harrison TB. Electrodiagnostic assessment of hyperexcitable nerve disorders. Neurol Clin 2021;39(4):1083-96. PMID 34602216
- 30
- Inoue T, Hirai H, Shimizu T, et al. Ocular neuromyotonia treated by microvascular decompression: usefulness of preoperative 3D imaging. J Neurosurg 2012;117(6):1166-9. PMID 23020768
- 31
- Irani SR, Alexander S, Waters P, et al. Antibodies to Kv1 potassium channel-complex proteins leucine-rich, glioma inactivated 1 protein and contactin-associated protein-2 in limbic encephalitis, Morvan's syndrome and axquired neuromyotonia. Brain 2010;133(9):2734-48. PMID 20663977
- 32
- Irani SR, Pettingill P, Kleopa KA, et al. Morvan syndrome: clinical and serological observations in 29 cases. Ann Neurol 2012;72(2):241-55. PMID 22473710
- 33
- Isaacs H. A syndrome of continuous muscle-fibre activity. J Neurol Neurosurg Psychiatry 1961;24:319-25. PMID 21610902
- 34
- Isaacs H. The syndrome of ‘continuous muscle-fibre activity’ cured: further studies. J Neurol Neurosurg Psychiatry 1974;37:1231-5. PMID 4281819
- 35
- Ishii A, Hayashi A, Ohkoshi N, et al. Clinical evaluation of plasma exchange and high dose intravenous immunoglobulin in a patient with Isaacs’ syndrome. J Neurol Neurosurg Psychiatry 1994;57:840-2. PMID 8021673
- 36
- Jammoul A, Shayya L, Mente K, Li J, Rae-Grant A, Li Y. Clinical utility of seropositive voltage-gated potassium channel-complex antibody. Neurol Clin Pract 2016;6(5):409-18. PMID 27847683
- 37
- Jamora RD, Umapathi T, Tan LC. Finger flexion resembling focal dystonia in Isaacs' syndrome. Parkinsonism Relat Disord 2006;12(1):61-3. PMID 16337423
- 38
- Khadilkar SV, Pandya DC, Dhonde P, et al. Acquired hyperexcitable peripheral nerve disorders: Clinical and laboratory features, therapeutic responses, and long-term follow-up. Muscle Nerve 2024;69(1):48-54. PMID 37936515
- 39
- Khanna L, Agrawal C, Gourie-Devi M, Bhandari AS. Neuromyotonia: a sequel to indigenous medication. Ann Indian Acad Neurol 2022;25(3):513-4. PMID 35936639
- 40
- Kimura J. Electrodiagnosis in diseases of nerve and muscle: principles and practice. 3rd ed. New York: Oxford, 2001:829-36, 931.
- 41
- Kumar PNS, Sajithlal E, Shamsudeen M, Kumar RP. Morvan's syndrome presenting with psychiatric manifestations - a case report and review of the literature. Neurol India 2022;70(3):1207-9. PMID 35864667
- 42
- Lahrmann H, Albrecht G, Drlicek M, et al. Acquired neuromyotonia and peripheral neuropathy in a patient with Hodgkin's disease. Muscle Nerve 2001;24(6):834-8. PMID 11360270
- 43
- Lai M, Huijbers MG, Lancaster E, et al. Investigation of LGI1 as the antigen in limbic encephalitis previously attributed to potassium channels: a case series. Lancet Neurol 2010;9(8):776-85. PMID 20580615
- 44
- Lee EK, Maselli RA, Ellis WG, Agius MA. Morvan’s fibrillary chorea: a paraneoplastic manifestation of thymoma. J Neurol Neurosurg Psychiatry 1998;65:857-62. PMID 9854961
- 45
- Liguori R, Vincent A, Clover L, et al. Morvan’s syndrome: peripheral and central nervous system and cardiac involvement with antibodies to voltage-gated potassium channels. Brain 2001;124:2417-26. PMID 11701596
- 46
- Liu C, Ji S, Bi Z, Shang K, Gao H, Bu B. Tacrolimus as a therapeutic option in patients with acquired neuromyotonia. J Neuroimmunol 2021;355:577569. PMID 33853015
- 47
- Menon D, Sreedharan SE, Gupta M, Nair MD. A novel association of ocular neuromyotonia with brainstem demyelination: two case reports. Mult Scler 2014;20(10):1409-12. PMID 25160126
- 48
- Mertens HG, Zschocke S. Neuromyotonia. Klin Wchnschr 1965;43:917-25. PMID 5863557
- 49
- Meyniel C, Ollivier Y, Hamidou M, Pereon Y, Derkinderen P. Dramatic improvement of refractory Isaacs' syndrome after treatment with dronabinol. Clin Neurol Neurosurg 2011;113(4):323-4. PMID 21144646
- 50
- Michael S, Waters P, Irani SR. Stop testing for autoantibodies to the VGKC-complex: only request LGI1 and CASPR2. Pract Neurol 2020;20(5):377-84. PMID 32595134
- 51
- Modarres H, Samuel M, Schon F. Isolated finger flexion: a novel form of focal neuromyotonia. J Neurol Neurosurg Psychiatry 2000;69:110-3. PMID 10864615
- 52
- Nagado T, Arimura K, Sonoda Y, et al. Potassium current in patients with peripheral nerve hyperexcitability. Brain 1999;122:2057-66. PMID 10545391
- 53
- Nakatsuji Y, Kaido M, Sugai F, et al. Isaacs’ syndrome successfully treated by immunoadsorption plasmapheresis. Acta Neurol Scand 2000;102:271-3. PMID 11071114
- 54
- Newsom-Davis J, Buckley C, Clover L, et al. Autoimmune disorders of neuronal potassium channels. Ann N Y Acad Sci 2003;998:202-10. PMID 14592877
- 55
- Newsom-Davis J, Mills KR. Immunological associations of acquired neuromyotonia (Isaacs’ syndrome). Brain 1993;116:453-69. PMID 8461975
- 56
- Nguyen MC, Patton AJ, Rahnavard AA. Poster 230: acquired neuromyotonia secondary to acute oxaliplatin hyperexcitibility syndrome: a case report. PM&R 2017;9:S205.
- 57
- Niu J, Guan H, Cui L, Guan Y, Liu M. Afterdischarges following M waves in patients with voltage-gated potassium channel antibodies. Clin Neurophysiol Pract 2017;2:72-5. PMID 30214975
- 58
- Olney RK, Aminoff MJ, So YT. Clinical and electrodiagnostic features of X-linked recessive bulbospinal neuronopathy. Neurology 1991;41(6):823-8. PMID 2046924
- 59
- Panagariya A, Kumar H, Mathew V, Sharma B. Neuromyotonia: clinical profile of twenty cases from northwest India. Neurol India 2006;54(4):382-6. PMID 17114847
- 60
- Patterson KR, Dalmau J, Lancaster E. Mechanisms of Caspr2 antibodies in autoimmune encephalitis and neuromyotonia. Ann Neurol 2018;83(1):40-51. PMID 29244234
- 61
- Peeters K, Chamova T, Tournev I, Jordanova A. Axonal neuropathy with neuromyotonia: there is a HINT. Brain 2017;140(4):868-77. PMID 28007994
- 62
- Pessia M, Hanna MG. Episodic Ataxia Type 1. In: Pagon RA, Bird TC, Dolan CR, Stephens K, editors. GeneReviews [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2010 Feb 2009.
- 63
- Prado MB Jr, Moalong KMC, Adiao KJB. Neuromuscular ultrasound findings of myokymia in a young woman with generalized anti-LGI-1 and anti-Caspr2 antibodies negative Isaac syndrome. J Clin Neuromuscul Dis 2023;25(2):81-84. PMID 37962194
- 64
- Raut TP, Garg RK, Chaudhari TS, Malhotra HS, Singh MK. Focal neuromyotonia as a presenting feature of lumbosacral radiculopathy. Ann Indian Acad Neurol 2013;16(4):693-5. PMID 24339612
- 65
- Sakai T, Hosokawa S, Shibasaki H, et al. Syndrome of continuous muscle-fiber activity: increased CSF GABA and effect of dantrolene. Neurology 1983;33:495-8. PMID 6682197
- 66
- Saposnik G, Maurino J, Saizar R. Facial myokymia in brain death. Eur J Neurol 2001;8:227-30. PMID 11328330
- 67
- Sawlani K, Katirji B. Peripheral nerve hyperexcitability syndromes. Continuum (Minneap Minn) 2017;23(5, Peripheral Nerve and Motor Neuron Disorders):1437-50. PMID 28968370
- 68
- Shults WT, Hoyt WF, Behrens M, MacLean J, Saul RF, Corbett JJ. Ocular neuromyotonia. A clinical description of six patients. Arch Ophthalmol 1986;104(7):1028-34. PMID 3729772
- 69
- Shyr MH, Ho AC, Lin CC, Hsu KY, Yang CH, Chen CH. Propofol anesthesia in a patient with Isaacs syndrome – report of a case and literature review. Acta Anesthesiol Sin 1997;35:241-5. PMID 9553241
- 70
- Simon NG, Reddel SW, Kiernan MC, Layzer R. Muscle-specific kinase antibodies: a novel cause of peripheral nerve hyperexcitability. Muscle Nerve 2013;48(5):819-23. PMID 23720161
- 71
- Sinha S, Newsom-Davis J, Mills K, Byrne N, Lang B, Vincent A. Autoimmune etiology for acquired neuromyotonia (Isaacs syndrome). Lancet 1991;338:75-7. PMID 1676468
- 72
- Song J, Jing S, Quan C, et al. Isaacs syndrome with CASPR2 antibody: a series of three cases. J Clin Neurosci 2017;41:63-6. PMID 28438465
- 73
- Spagni G, Modoni A, Primiano G, et al. Clinical, neurophysiological and serological clues for the diagnosis of neuromyotonia and distinction from cramp-fasciculation syndrome. Neuromuscul Disord 2023;33(8):636-42. PMID 37422355
- 74
- Taylor RG, Layzer RB, Davis HS, Fowler WM Jr. Continuous muscle fiber activity in the Schwartz-Jampel syndrome. Electroencephalogr Clin Neurophysiol 1972;33(5):497-509. PMID 4116433
- 75
- Tomlinson SE, Rajakulendran S, Tan SV, et al. Clinical, genetic, neurophysiological and functional study of new mutations in episodic ataxia type 1. J Neurol Neurosurg Psychiatry 2013;84(10):1107-12. PMID 23349320
- 76
- Torres-Vega E, Mancheno N, Cebrian-Silla A, et al. Netrin-1 receptor antibodies in thymoma-associated neuromyotonia with myasthenia gravis. Neurology 2017;88(13):1235-42. PMID 28251919
- 77
- Tsivgoulis G, Mikroulis D, Katsanos AH, et al. Paraneoplastic Isaac's syndrome associated with thymoma and anti-neuronal nuclear antibodies 1. J Neurol Sci 2014;343(1-2):245-6. PMID 24952672
- 78
- Turner MR, Madkhana A, Ebers GC, et al. Wasp sting induced autoimmune neuromyotonia. J Neurol Neurosurg Psychiatry 2006;77(5):704-5. PMID 16614042
- 79
- van den Berg JS, van Engelen BG, Boerman RH, de Baets MH. Acquired neuromyotonia: superiority of plasma exchange over high-dose intravenous human immunoglobulin. J Neurol 1999;246:623-5. PMID 10463372
- 80
- Van Parijs V, Van den Bergh PY, Vincent A. Neuromyotonia and myasthenia gravis without thymoma. J Neurol Neurosurg Psychiatry 2002;73(3):344-5. PMID 12185179
- 81
- Vernino S, Adamski J, Kryzer TJ, Fealey RD, Lennon VA. Neuronal nicotinic Ach receptor antibody in subacute autonomic neuropathy and cancer-related syndromes. Neurology 1998;50(6):1806-13. PMID 9633732
- 82
- Vincent A. Understanding neuromyotonia. Muscle Nerve 2000;23:655-7. PMID 10797387
- 83
- Wilson RH, Lehky T, Thomas RR, Quinn MG, Floeter MK, Grem JL. Acute oxaliplatin-induced peripheral nerve hyperexcitability. J Clin Oncol 2002;20(7):1767-74. PMID 11919233
- 84
- Yang B, Wei W, Duan J, Xiao P, Jing Y, Tang Y. Isaacs syndrome with LGI1 and CASPR2 antibodies after HPV vaccination: a case report. Medicine (Baltimore) 2023;102(44):e35865. PMID 37933002
- 85
- Yuruten B, Ilhan S. Ocular neuromyotonia: a case report. Clin Neurol Neurosurg 2003;105(2):140-2. PMID 12691809
- 86
- Zimon M, Baets J, Almeida-Souza L, et al. Loss-of-function mutations in HINT1 cause axonal neuropathy with neuromyotonia. Nat Genet 2012;44(10):1080-3. PMID 22961002
Contributors
All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.
Author
-
Simona Treidler MD
Dr. Treidler of Stony Brook University Hospital has no relevant financial relationships to disclose.
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Editor
-
Nicholas E Johnson MD MSCI FAAN
Dr. Johnson of Virginia Commonwealth University received consulting fees and/or research grants from AMO Pharma, Avidity, Dyne, Novartis, Pepgen, Sanofi Genzyme, Sarepta Therapeutics, Takeda, and Vertex, consulting fees and stock options from Juvena, and honorariums from Biogen Idec and Fulcrum Therapeutics as a drug safety monitoring board member.
See Profile
Former Authors
- Yevgeny Azrieli MD
- Maria E Alexianu MD PhD
- Clifton L Gooch MD
- Robert Layzer MD
- James Wymer MD PhD
- Michael K Hehir MD
- Emma Ciafaloni MD FAAN
- Christina M Ulane MD PhD
Patient Profile
- Age range of presentation
-
- 0 month to 65+ years
- Sex preponderance
-
- male=female
- Heredity
-
- heredity may be a factor
- Population groups selectively affected
-
- none selectively affected
- Occupation groups selectively affected
-
- none selectively affected
ICD & OMIM codes
- ICD-9
-
- Facial myokymia: 351.8
- ICD-10
-
- Facial myokymia: G51.4
- OMIM
-
- Dyskinesia, familial, with facial myokymia: #606703
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