Acquired Neuromyotonia

Resumen

Acquired neuromyotonia is an inflammatory disorder characterized by abnormal nerve impulses from the peripheral nerves that result in continuous muscle fiber activity. Affected individuals often experience progressive muscle stiffness and cramping especially in the hands and feet, increased sweating (hyperhidrosis) and delayed muscle relaxation. Symptoms may persist even during sleep or under general anesthesia.

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Sinónimos

Isaacs-Merten syndrome
Isaacs' syndrome
continuous muscle fiber activity syndrome

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Signos y Síntomas

Acquired neuromyotonia is characterized by involuntary continuous muscle fiber activity (fasciculations, doublet and triplet discharges on electromyography) that cause stiffness and delayed relaxation in the affected muscles. Muscle twitching with a rippling appearance (myokymia) may occur along with these symptoms. Affected individuals may, at times, be unable to coordinate voluntary muscle movement and have difficulty walking (ataxia). Other symptoms may include staggering and reeling (titubation), stiffness and lack of balance in response to being startled. There may be diminished spontaneous gross motor activity.

The disorder is characterized by progressive stiffness, cramping and weakness. Muscle activity is constant, and patients describe the feeling of continuous writhing or rippling of muscles under the skin. These movements continue during sleep. Diminished reflexes are also frequently a sign of this disorder. In some instances, muscle relaxation following voluntary muscle movement is delayed (grip myotonia) in the affected muscles. For example, affected individuals may not be able to open their fists or eyes immediately after closing them tightly for a few seconds.

Affected individuals frequently have excessive sweating (hyperhidrosis), rapid heartbeats (tachycardia) and weight loss. Symptoms of pain are common.

In slightly fewer than 20% of patients, a set of symptoms, including arrhythmias, excessive salivation, memory loss, confusion, hallucinations, constipation, personality change and sleep disorders, are found. In such cases the disorder may be referred to as Morvan syndrome.

Approximately 20% of affected individuals have a tumor of the thymus gland (thymoma). The thymus glands are the source of a number of specialized cells associated with autoimmune functions. The disorder is also associated with peripheral neuropathies and autoimmune diseases including myasthenia gravis in some individuals. It has also been reported following infections and radiation therapy.

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Causas y Herencia

Acquired neuromyotonia is an autoimmune disease in which the immune system malfunctions so that it damages parts of a person’s own body. Approximately 40% of affected individuals have antibodies to voltage-gated potassium channels (VGKC’s) that affect the points at which the signals from the nerve fiber meet the muscle cell (neuromuscular junction).

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Frecuencia

Aquired neuromyotonia is a rare disorder affecting males and females but is slightly more common among males. Disease onset is usually between the ages of 15 and 60 years but has also been reported in childhood.

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Enfermedades con síntomas similares

Symptoms of the following disorders can be similar to those of acquired neuromyotonia. Comparisons may be useful for a differential diagnosis:

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is the most common treatable chronic neuropathy worldwide, with a prevalence ranging up to 9 cases per 100,000. CIDP typically presents as either a relapsing or progressive neuropathy with proximal and distal weakness which develops over at least an 8-week period. Similar to acquired neuromyotonia, CIDP is an autoimmune disorder in which an aberrant immune response is directed towards components of the peripheral nerve causing demyelination and axonal damage, resulting in weakness, altered sensation and coordination difficulties.

Multifocal motor neuropathy (MMN) typically presents with asymmetrical distal weakness and wasting, without sensory impairment which is slowly progressive and has an upper limb predilection. Weakness may be out of proportion to muscle wasting and involvement of wrist or finger extension at onset should prompt consideration of MMN as a potential diagnosis. Positive features such as twitching, cramping and spasm are relatively common in MMN and may be the presenting symptom. Bulbar and respiratory involvement are not typical.

Amyotrophic lateral sclerosis (ALS) is one of a group of disorders known as motor neuron diseases. ALS is characterized by the progressive degeneration and eventual death of nerve cells (motor neurons) in the brain, brainstem and spinal cord that facilitate communication between the nervous system and voluntary muscles of the body. Ordinarily, motor neurons in the brain (upper motor neurons) send messages to motor neurons in the spinal cord (lower motor neurons) and then to various muscles. ALS affects both the upper and lower motor neurons (Gold Coast consensus diagnostic criteria, Shefner et al., 2020) so that the transmission of messages is interrupted, and muscles gradually weaken and waste away. As a result, the ability to initiate and control voluntary movement is lost. Ultimately, ALS leads to respiratory failure because affected individuals lose the ability to control muscles in the chest and diaphragm. ALS is often called Lou Gehrig’s disease. (For more information on these disorders, choose “ALS” as your search terms in the Rare Disease Database.)

Neurodegeneration with brain iron accumulation (NBIA) type 1 (Hallervorden-Spatz syndrome) is a rare, inherited, neurological movement disorder characterized by the progressive degeneration of the nervous system (neurodegenerative disorder). Individuals with NBIA1 have iron accumulation in the brain along with a progressive movement disorder. Individuals can plateau for long periods of time and then undergo intervals of rapid deterioration. Symptoms may vary greatly from person to person. Common features include an abnormality in muscle tone (dystonia), muscular rigidity and sudden involuntary muscle spasms (spasticity). These features can result in clumsiness, walking problems, difficulty controlling movement and speech problems. Another common feature is degeneration of the retina, resulting in progressive night blindness and loss of peripheral (side) vision. Approximately 50% of individuals with a clinical diagnosis of NBIA1 have variants in the PANK2 gene, which helps to metabolize vitamin B5. (For more information on these disorders, choose “NBIA” as your search terms in the Rare Disease Database.)

Hereditary spastic paraplegia (HSP) is a group of inherited neurological disorders characterized by progressive weakness (paraplegia), increased muscle tone and spasticity of leg muscles. The age of onset and severity of symptoms may be extremely variable from person to person, including among individuals within the same family. Symptoms usually develop during early to mid-adulthood. Initial findings typically include stiffness and relatively mild weakness of leg muscles, balance difficulties, unexplained tripping and falls and an unusually “clumsy” manner of walking. As the disorder progresses, walking may become increasingly difficult, however, complete loss of the ability to walk is relatively rare. (For more information on this disorder, choose “paraplegia” as your search term in the Rare Disease Database.)

Stiff-person syndrome (SPS) is a rare acquired neurological disorder characterized by progressive muscle stiffness (rigidity) and repeated episodes of painful muscle spasms. Muscular rigidity often fluctuates and usually occurs along with the muscle spasms. Spasms may occur randomly or be triggered by a variety of different events including a sudden noise or light physical contact. In most affected individuals, other neurological signs or symptoms do not occur. The severity and progression of SPS varies from one person to another. If left untreated, SPS can potentially progress to cause difficulty walking and significantly impact a person’s ability to perform routine, daily tasks. Although the exact cause of SPS is unknown, it is believed to be an autoimmune disorder and sometimes occurs along with other autoimmune disorders. (For more information on this disorder, choose “SPS” as your search term in the Rare Disease Database.)

Episodic ataxia type 1(EA1) is an autosomal dominant genetic disorder characterized by muscle cramps and stiffness, muscle twitching with a rippling appearance, spastic contraction of skeletal muscles of the head, arms and legs, and loss of motor coordination and balance. EA1 is caused by variants in the KCNA1 gene.

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Diagnóstico

The diagnosis of acquired neuromyotonia is based on the presence of continuous muscle contractions (myokymia), especially in the face and hands, rhythmic tics or twitches (fasciculations) and muscle cramps. The diagnosis is confirmed by studies of the electrical signs of muscle activity (electromyography). Serum investigations include autoimmune serology and specifically testing for the presence of anti-VGKC.

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Tratamiento

Treatment
Acquired neuromyotonia may be treated with anticonvulsant drugs such as phenytoin or carbamazepine, which may stop the abnormal impulses and prevent the symptoms from reoccurring. Plasma exchange (plasmapheresis) and intravenous immune globulin have been effective although no long term, controlled, clinical studies have been carried out.

Testing for acetylcholine receptor antibodies (ACHr-Ab) as well as muscle-specific kinase (MUSK) antibodies should be done if thymoma is suspected. The thymus gland should be surgically removed if thymoma is present.

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Investigaciones

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]

Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/

For information about clinical trials sponsored by private sources, contact: www.centerwatch.com.

For information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/

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Referencias

JOURNAL ARTICLES
Park SB, Thurbon R, Kiernan MC. Isaacs syndrome: the frontier of neurology, psychiatry, immunology and cancer. J Neurol Neurosurg Psychiatry. 2020:91:1243-1244.

Shefner JM, Al-Chalabi A, Baker MR, Cui LY, de Carvalho M, Eisen A, Grosskreutz J, Hardiman O, Henderson R, Matamala JM, Mitsumoto H, Paulus W, Simon N, Swash M, Talbot K, Turner MR, Ugawa Y, van den Berg LH, Verdugo R, Vucic S, Kaji R, Burke D, Kiernan MC. A proposal for new diagnostic criteria for ALS. Clin Neurophysiol. 2020;131(8):1975-8.

Noto Y, Simon NG, Selby A, Garg N, Shibuya K, Shahrizaila N, Kiernan MC. Ectopic impulse generation in peripheral nerve hyperexcitability syndromes and amyotrophic lateral sclerosis. Clinical Neurophysiology. 2018;129(5):974-80.

Vincent A, Pettingill P, Pettingill R, Lang B, Birch R, Waters P, Kiernan MC. Association of leucine-rich glioma inactivated protein 1, contactin-associated protein 2, and contactin 2 antibodies with clinical features and patient-reported pain in acquired neuromyotonia. JAMA Neurol. 2018 Dec 1;75(12):1519-1527.

Garg N, Park SB, Vucic S, Yiannikas C, Spies J, Howells J, Huynh W, Matamala JM, Krishnan AV, Pollard JD, Cornblath DR, Reilly MM, Kiernan MC. Differentiating lower motor neuron syndromes. Journal of Neurology, Neurosurgery & Psychiatry. 2017;88(6):474-83.

Mathey EK, Park SB, Hughes RAC, Pollard JD, Armati PJ, Barnett MH, Taylor BV, Dyck PPJ, Kiernan MC, Lin CS. Chronic inflammatory demyelinating polyradiculoneuropathy: from pathology to phenotype. Journal of Neurology, Neurosurgery and Psychiatry. 2015;86:973-85.

Kiernan MC, Vucic S, Cheah BC, et al. Amyotrophic lateral sclerosis. The Lancet. 2011;377:942-955.

Vucic S, Cheah BC, Yiannikas C, Vincent A and Kiernan M. Corticomotoneuonal function and hyperexcitability in acquired neuromyotonia. Brain. 2010:133;2727-2733.

Imam I, Edwards, S and Hanemann CO. Acquired neuromyotonia following upper respiratory tract infection: a case report. Cases Journal. 2009:2:7982.

Gonzelez G, Barros G, Russi ME, Nunez A and Scavone C. Acquired neuromyotonia in childhood: case report and review. Ped Neurol. 2008:38;61-63.

Vernino S, Lennon VA. Ion channel and striational antibodies define a continuum of autoimmune neuromuscular hyperexcitability. Muscle Nerve. 2002;26:702-07.

Daube JR. Myokymia and neuromyotonia. Muscle Nerve. 2001;24:1711-12.

Liguori R, Vincent A, Clover L, et al. Morvan’s syndrome: peripheral and central nervous system and cardiac involvement with antibodies to votage-gated potassium channels. Brain. 2001;124:2417-26.

Hayat GR, Kulkantrakorn K, Campbell WW, et al. Neuromyotonia: autoimmune pathogenesis and response to immune modulating therapy. J Neurol Sci. 2000;181:38-43.

Nakatsuji Y, Kaido M, Sugai F, et al. Isaacs’ syndrome successfully treated by a immunoadsorption plasmapheresis. Acta Neurol Scand. 2000;102:271-73.

Alessi G, De Reuck J, De Bleecker, et al. Successful immunoglobulin treatment in a patient with neuromyotonia. Clin Neurol Neurosurg. 2000;102:173-75.

Van den Berg JS, van Engelen BG, Boerman RH, et al. Acquired neuromyotonia: superiority of plasma exchange over high-dose intravenous immunoglobulin. J Neurol. 1999;57:623-25.

INTERNET
Isaac’s syndrome Information Page. NINDS. Last Update Nov 28, 2023. https://www.ninds.nih.gov/health-information/disorders/isaacs-syndrome#:~:text=Issacs%20syndrome%20(also%20known%20as,fire%20causing%20muscle%20fibers%20to Accessed May 22, 2024.

Hasan SM, D’Adamo MC. Episodic Ataxia Type 1. 2010 Feb 9 [Updated 2018 Nov 1]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: https://www.ncbi.nlm.nih.gov/books/NBK25442/ Accessed May 22, 2024.

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