Isaacs syndrome is an autoimmune peripheral nerve disorder that causes neuromuscular manifestations, including continuous muscle twitching (myokymia).
Isaacs syndrome (neuromyotonia) is an autoimmune peripheral nerve hyperexcitability syndrome, thought to be a voltage-gated potassium channelopathy (1). The syndrome sometimes occurs as a paraneoplastic syndrome. It may also accompany other disorders (eg, myasthenia gravis, thymoma, Hashimoto thyroiditis, vitamin B12 deficiency, celiac disease, connective tissue disorders) or can be inherited.
The cause of Isaacs syndrome is unknown. The condition is thought to originate in peripheral nerves because abnormalities are abolished by curare but usually persist after general anesthesia.
General reference
1. Ahmed A, Simmons Z. Isaacs syndrome: A review. Muscle Nerve. 52 (1):5–12, 2015. doi: 10.1002/mus.24632.
Symptoms and Signs of Isaacs Syndrome
The sine qua non of Isaacs syndrome is myokymia—continuous muscle twitching described as bag-of-worms movements, primarily affecting the limbs. Other symptoms include fasciculations, carpopedal spasms, intermittent muscle cramps, stiffness, increased sweating, and pseudomyotonia (impaired relaxation after a strong muscle contraction but without the typical waxing-and-waning electromyography [EMG] abnormality of true myotonia).
Diagnosis of Isaacs Syndrome
History and physical examination
Nerve conduction and EMG studies
Blood tests for specific antibodies
The diagnosis of Isaacs syndrome is based on the above clinical findings and results of nerve conduction and EMG studies, which show characteristic abnormalities. Electrodiagnostic abnormalities include after-discharges on nerve conduction studies and EMG findings of fasciculation potentials, myokymic discharges, neuromyotonic discharges, fibrillation potentials, and cramp discharges, most prominent in distal limb muscles.
Laboratory testing should include tests for antibodies to contactin-associated protein-like 2 (Caspr2), the striational voltage-gated calcium channel, gliadin, glutamic acid decarboxylase (GAD), muscle acetylcholine receptor (AChR), and the voltage-gated potassium channel. About 20% of patients with Caspr2 antibodies have thymoma (1), and many have other solid tumors, which may be diagnosed by chest CT or MRI.
Diagnosis reference
1. van Sonderen A, Ariño H, Petit-Pedrol M, et al. The clinical spectrum of Caspr2 antibody–associated disease. Neurology. 87 (5):521–528, 2016. doi: 10.1212/WNL.0000000000002917
Treatment of Isaacs Syndrome
Medications to relieve symptoms
Plasma exchange or IV immune globulin (IVIG)
Medications that may relieve symptoms of Isaac syndrome include antiseizure medications (carbamazepine, phenytoin, gabapentin, valproate, lamotrigine), mexiletine (experience is limited), clonazepam, and possibly rituximab (Medications that may relieve symptoms of Isaac syndrome include antiseizure medications (carbamazepine, phenytoin, gabapentin, valproate, lamotrigine), mexiletine (experience is limited), clonazepam, and possibly rituximab (1,2).
Plasma exchange and, to a lesser degree, IVIG are usually beneficial (3) and are often used in conjunction with prednisone and azathioprine.) and are often used in conjunction with prednisone and azathioprine.
Treatment references
1. Ahmed A, Simmons Z. Isaacs syndrome: A review. Muscle Nerve. 52 (1):5–12, 2015. doi: 10.1002/mus.24632 Epub 2015 Mar.
2. Horiuchi K, Kudo A, Inoue T, et al. Rituximab Was Effective in Relieving Symptoms of Isaacs Syndrome: A Case Report. Rituximab Was Effective in Relieving Symptoms of Isaacs Syndrome: A Case Report Cureus. 14 (10): e30100, 2022. doi: 10.7759/cureus.30100
3. Newsom-Davis J, Mills KR. Immunological associations of acquired neuromyotonia (Isaacs' syndrome): Report of five cases and literature review. Brain. 116 (Pt 2):453–469, 1993. doi: 10.1093/brain/116.2.453
Key Points
The sine qua non of Isaac syndrome is myokymia—continuous muscle twitching described as bag-of-worms movements, typically in the limbs.
Diagnose based on history, physical examination, results of nerve conduction and EMG studies, and laboratory testing for specific antibody markers.
Treat with medications to relieve symptoms (eg, carbamazepine, phenytoin, gabapentin), plasma exchange, and sometimes IVIG.Treat with medications to relieve symptoms (eg, carbamazepine, phenytoin, gabapentin), plasma exchange, and sometimes IVIG.
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