Neuromyotonia is an autoimmune neuromuscular disease that occurs in response to a malfunction of the potassium ion channels. Pathology develops with myasthenia gravis, Hashimoto’s thyroiditis, collagenoses, and also as a component of paraneoplastic syndrome. The main symptoms include uncontrolled muscle twitching, muscle rigidity, hyporeflexia. Electromyography, muscle biopsy, immunological and genetic studies are used for diagnosis. Treatment includes anticonvulsants to control symptoms, plasmapheresis, administration of immunoglobulins.
ICD 10
G71.1 Myotonic disorders
General information
Neuromyotonia (Isaac’s syndrome) is an orphan disease, the true frequency of which has not been established in the population. Today, about 200 cases of the disease have been described in the medical literature in patients from all over the world. The pathology is named after the neurologist Chaim Isaac, who in 1961 published his own observation of patients with muscle rigidity, fasciculations, progressive myasthenia gravis. The doctor called the disease “the syndrome of continuous activity of muscle fibers” or “armadillo disease”.
Causes
The exact etiological factors of neuromyotonia have not been established. In modern neurology, the role of autosomal recessive mutations in the H1NT1 gene is discussed, although the involvement of the gene in the process of neuromuscular transmission has not yet been disclosed. Other researchers emphasize the role of endogenous and exogenous negative factors, which occurs in all autoimmune processes. Isaac’s disease often occurs against the background of other pathologies, the main of which are:
- Thymoma. Thymus gland tumor is found in 20% of patients with detected neuromyotomy. The risk of developing the syndrome is due to the active participation of thymus cells in the functioning of immune reactions. Also, symptoms of neuromyotonia can manifest in neoplastic syndrome of various etiologies (especially in small cell lung cancer).
- Collagenoses. Systemic connective tissue lesions have an autoimmune nature, therefore they usually become a trigger factor for neuromuscular transmission damage. This group includes systemic lupus erythematosus, dermatomyositis, scleroderma.
- Other autoimmune processes. In some patients, symptoms of neuromyotonia are manifested in Hashimoto’s autoimmune thyroiditis, celiac disease, autoimmune gastritis, accompanied by B12-deficiency anemia.
- Neuromuscular diseases. Isaac’s disease can occur in patients with myasthenia gravis, chronic demyelinating polyneuropathy, hereditary neuropathies.
Pathogenesis
At the present stage, neuromyotonia is considered a type of potential-dependent potassium channelopathy. Violation of the function of ion channels is possible with genetic or autoimmune pathologies. As a result of electrolyte disturbances, hyperexcitability of peripheral nerve fibers is formed, chaotic appearance and propagation of impulses occur, which manifests itself in the form of uncontrolled muscular twitching.
Symptoms of neuromyotonia can be considered as a component of motor-sensory neuropathies — diseases characterized by clinical phenomena of hyperexcitability of muscle fibers. It is believed that they are based on a violation of the posttranslational processing of the H1NT1 gene. As a result, the functions of amino-acyl-tRNA synthetases change, and metabolites toxic to the nervous system accumulate.
Symptoms
The manifestation of pathology occurs in adolescence, although in some patients the first symptoms appear only in adulthood. The main sign of neuromyotonia is considered to be myokemia — a continuous chaotic twitching of different muscle groups, outwardly resembling the movement of a “bag of worms”. Myokemia is not subject to volitional control, it is observed constantly, it persists even in sleep and with the use of general anesthesia.
With neuromyotonia, there is a symptom of increased muscle tension, prolonged tonic contractions of the muscles of the trunk or proximal extremities, which is called the rigid man syndrome. It is characterized by delayed relaxation of the muscles after making a certain movement or volitional effort, for example, the inability to straighten the fingers immediately after squeezing them into a fist.
Symptoms of neuromyotonia include decreased reflex excitability, inability to maintain balance, instability when walking. Large and small motor skills are disturbed, frequent muscle pains are bothering. Vegetative symptoms of Isaac’s disease are represented by increased sweating (hyperhidrosis), palpitations, and heart failure.
Complications
Specific muscle twitches are debilitating, cause a person to feel powerless, cause neurotic or mental disorders. Due to a decrease in motor capabilities, patients experience difficulties during professional activities, performing household tasks. Muscle twitching, which is clearly visible to others, forces patients to limit social contacts.
In 20% of cases, neuromyotonia is accompanied by Morgan’s syndrome. It is manifested by arrhythmia, increased salivation, chronic constipation. Neurological symptoms are represented by memory disorders, personality changes, the appearance of hallucinations. In severe cases, consciousness is oppressed up to a comatose state, which requires emergency medical care.
The spectrum of negative consequences is expanding for those suffering from concomitant diseases. Thymoma is often complicated by Gorner’s syndrome, myasthenic crises, symptoms of hypergammaglobulinemia and aplastic anemia. Collagenoses cause structural and functional changes in the cardiovascular (cardiosclerosis, cardiomyopathy), respiratory systems (pneumofibrosis, respiratory failure).
Diagnostics
Neuromyotonia has typical clinical symptoms, so the assessment of the neurological status at the initial admission is the main way to identify pathology. When examined by a neurologist, the level of preservation of reflexes, muscle strength and tone is established, tests are carried out for coordination of movements and stability of posture. The second stage is an extended laboratory and instrumental diagnostics, in which the following methods are used:
- Electromyography. The study demonstrates the presence of constant activity of motor units, duplets and triplets, the absence of periods of complete muscle relaxation. At the same time, the maximum amplitude of motor unit potentials is increased. The changes are most pronounced in the distal parts of the limbs.
- Chest CT scan. Given the high frequency of thymoma in neuromyotonia, all patients undergo computed tomography to assess the size and structure of the thymus gland. If a suspicious neoplasm is found, a biopsy with histological examination is performed.
- Muscle biopsy. The study of biopsies makes it possible to differentiate neuromyotonia with other neuromuscular diseases, to study the structure of fibers. In Isaac’s disease, the normal structure of myofibrils is observed, which makes it possible to exclude various forms of myopathies.
- Laboratory tests. It is possible to confirm the autoimmune etiology of the pathology when antibodies to the contactin-associated protein Caspr2 are detected. It is also recommended to study the level of gliadin, glutamic acid decarboxylase, antibodies to acetylcholine receptors.
- Genetic testing. Automatic sequencing is performed to confirm or exclude the H1NT1 mutation. According to the indications, prenatal genetic diagnosis is possible using biomaterial obtained by amniocentesis or cordocentesis.
Treatment
Therapy of the disease is complicated by the lack of specific drugs, the inability to eliminate all provoking factors and restore the normal functioning of ion channels. The basis of treatment is the control of symptoms necessary to improve the quality of life of patients. For this purpose, the neurologist draws up a therapeutic scheme individually for the patient, which includes the following groups of drugs and therapeutic methods:
- Anticonvulsants. The main group of drugs that reduce the symptoms of spontaneous muscle activity, reduce the phenomena of myokymia, and relieve pain in the muscles.
- Immunoglobulins. Intravenous administration of immunoglobulins in combination with glucocorticoids or cytostatics is a necessary component of therapy that allows you to control autoimmune processes.
- Plasmapheresis. The objective of the hardware extracorporeal detoxification method is to remove autoantibodies, circulating immune complexes from the blood to reduce autoimmune damage to ion channels.
Further treatment depends on the presence of predisposing tumor or autoimmune diseases. With thymoma, the issue of surgical removal of an enlarged gland, the appointment of chemoradiotherapy in the postoperative period is being resolved. Nonsteroidal anti-inflammatory drugs, corticosteroids are used to stabilize the condition with symptoms of damage to connective tissue elements. The use of hematopoietic stem cells is considered a promising direction of treatment.
Prognosis and prevention
There is no etiotropic treatment of the disease, but with the right selection of medications, it is possible to successfully control the symptoms of the disease. A less optimistic prognosis is for patients who have paraneoplastic syndrome, collagenosis, or Morgan syndrome, since complications often end in the death of the patient. Given the ambiguity of etiopathogenesis, effective preventive measures have not been developed.