Behavioral & Cognitive Disorders
Dementia associated with amyotrophic lateral sclerosis
Aug. 11, 2023
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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.
• 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.
• 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).
• Neuromyotonia is specific to peripheral nerve hyperexcitability syndromes, whereas myokymia can be seen in a diverse group of neurologic disorders.
• 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).
• These phenomena also occur in episodic ataxia type 1and a form of hereditary neuropathy.
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" (47). 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.
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 (66). 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 (50; 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 the excessive and constant muscle activity (03). However, direct autonomic nervous system involvement could also explain the 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 (43; 06; 44; 40).
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 (54). 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 (56).
Electromyography shows either electrical neuromyotonia or myokymia (Table 1), or a combination of the 2. 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 (1 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.
• 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).
Peripheral nervous system
• Bell palsy
Central nervous system
• Neoplastic/inflammatory meningoradiculitis
• 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 (38). 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).
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; 65).
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 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 (6 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.
Generalized neuromyotonia is usually a sporadic autoimmune disease (54; 53; 65). A minority of neuromyotonic syndromes is hereditary and occurs 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 (72). 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 (82; 60).
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 (71). Electromyography demonstrates continuous high-frequency electrical discharges at rest; these are abolished by curare, which also produces muscle relaxation (71). 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 (71).
Using [125I]alpha-dendrotoxin immunoprecipitation assay VGKC antibodies are found in 40% to 50% of patients with acquired neuromyotonia (79; 21; 77). 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; 42). 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 (49). 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 were described in patients with thymoma, myasthenia gravis, and neuromyotonia (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 (78; 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 (69). 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 (43; 06; 44; 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 (74). 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 as a consequence of intoxication with mercury, 2,4-dichlorophenoxyacetic acid, dichlorophenyldichloroethylene and with drugs such as penicillamine (54) and oxaliplatin (80; 55). VGKC-antibody positive neuromyotonia has been reported after a wasp sting (75). A patient with MuSK antibodies without myasthenia exhibited frequent fasciculations and neuromyotonia of facial and bulbar muscles, probably originating in hyperactive motor nerve terminals (68). Using acetylcholinesterase inhibitors for patients with myasthenia and positive anti-MUSK antibodies will exacerbate the fasciculations. A case of generalized neuromyotonia was reported after human papilloma virus immunization (10; 25). Paraneoplastic neuromyotonia has been reported with thymoma (54), hypernephroma (09), bronchogenic carcinoma, bladder carcinoma (14), and Hodgkin disease (41). 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 (62).
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 (81). 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 (46).
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 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 (64). 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; 61). 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 (57). 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 (69; 54). 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 (51). 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 (59).
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 (39). 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.
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 are available in the literature.
Apart from the avoidance of known toxins or medications (ie, penicillamine, oxaliplatin, clozapine), there are no known preventative measures for either neuromyotonia or myokymia.
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 exam, 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.
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 (63) and oligoclonal bands (39). 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.
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 (54). One patient with thymoma-associated generalized neuromyotonia refractory to other treatments responded dramatically to dronabinol, a cannabinoid agent (48).
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; 69; 54; 35; 26; 76; 52). Although intravenous immunoglobulin has been effective as a sole agent in two cases (27; 01), it was ineffective in one (76) 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 (54). Rituximab has been shown to be effective in a few case reports (70; 28).
Four patients with acquired neuromyotonia were reported to have a good response with tacrolimus (45).
In the largest 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 (58). 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.
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.
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 (67). 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.
All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.
Simona Treidler MD
Dr. Treidler of Maimonides Medical Center has no relevant financial relationships to disclose.See Profile
Michael K Hehir MD
Dr. Hehir of University of Vermont Medical Center received a consulting fee from Immunovant, Janssen, and UCB Pharma.See Profile
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