Isaacs' Syndrome; Syncope
Patient #2 is a 39 year old male who was referred to our Center with a history of difficulty gripping things with his hands, "jumping muscles", slurred speech, and weight loss. The referring physicians were concerned about the possibility of Amyotrophic Lateral Sclerosis and the patient had been referred to evaluate this possibility. On clinical examination, the patient had good proximal strength with slight distal weakness. He did not appear to have the characteristic random muscle twitches which jump from place to place which would be characteristic of fasciculations. The movements were undulating in character like "worms moving under the skin", which is characteristic of myokymia. The EMG confirmed the absence of fasciculations and showed the presence of doublets, widespread irregular grouped motor unit discharges, and complex repetitive discharges with mixed widespread myotonic discharges which was consistent also with a diagnosis of Isaacs' syndrome or neuromyotonia. The patient's father also had a history of cramps, but the patient probably did not have the familial form of the disease because of the good response he had to treatment with plasma exchange, as outlined later.
The patient also did not have any problems with swallowing and had only slight dysphonia which was of unclear cause. The patient's symptoms of syncope were investigated by cardiology and their workup included an echocardiogram, Holter monitor and tilt table testing. Patients with Isaacs' can have autonomic involvement but the patient was on many antihypertensive medications and their role in producing these symptoms could not be ruled out. There was no evidence of an autonomic neuropathy. The patient's lab tests also showed a slightly high CSF protein with an IgG synthesis rate of 2.4 (normal range for Methodist Hospital 0.00-2.00). Isaacs' syndrome is thought to be an autoimmune disorder and elevations of IgG synthesis may be seen in the CSF of these patients.
The patient was admitted to the hospital and received six courses of plasma exchange. He was subsequently started on oral prednisone and cyclophosphamide and during his hospital stay noticed a marked improvement in the myokymia and muscle strength. The myotonia improved as well. The patient was then discharged and was to be followed in clinic.
The syndrome was described by Hyam Issacs in 1961 in a paper published in the Journal of Neurology, Neurosurgery and Psychiatry. He described two cases of a disease which was characterized by "increasing muscle stiffness, fasciculations, cramping and hyporeflexia". The EMG studies that he performed showed continuous motor activity which persisted despite a local nerve block and administration of pentothal, but disappeared after infiltrating the muscle with procaine or after administering paralytic agents such as curare and succinyl choline. Cases with similar characteristics had been described before, but Isaacs is acknowledged for linking the disorder to the peripheral nerves. The syndrome has also been called a variety of other names such as "Quantal Squander", "The syndrome of continuous motor activity", "Pseudomyotonia" and "Neuromyotonia".
The condition is extremely rare and has therefore never been studied in a controlled fashion. A recent review of all reported cases by Jamieson and Katiriji in 1994 suggests an equal incidence in both sexes. The disease appears to present earlier in life with most patients being less than 40 years of age at the time of symptom onset. A study of three families by Ashizawa et al in 1983 suggested a dominant mode of inheritance in the familial form of the disease.
The etiology of the disease remains unclear. Isaacs in 1961 was the first person to localize the disorder to the peripheral nerves. Pharmacological localization of the generator of the myokymia seems to confirm the initial observations of Isaacs. More exact localization has been less fruitful. The electrical activity appears to originate from multiple sites in the axon. There is some evidence to suggest the role of autoimmunity and, specifically, antibodies against the potassium channel in motor nerve terminals. The potential importance of circulating antibodies is supported by the fact that plasma exchange is effective in treatment of some patients with this disease. A recent case has been reported in which a patient met criteria for both Isaacs' syndrome and CIDP, another potential autoimmune disease.
Muscle and nerve biopsies tend to be normal in the majority of cases. Axonal loss and demyelination have been described. EM studies have shown multiple expansion of the terminals and hypertrophy of the synaptic clefts. In a study by Nagashima et al in 1985, a complex consisting of CPK (MM) and IgA was seen deposited in the motor end plates and membranes of muscle fibers, supporting a possible immune etiology for the disease.
Most patients are below the age of 40 years at the time of disease onset. Progressive stiffness, cramping, and weakness are prominent features of the disease. As opposed to fasciculations, patients complain of constant writhing movements of the muscles under the skin. This is corroborated on examination which reveals continuous "rippling" movements of the muscle. These persist during sleep. Hyporeflexia is also seen in a large percentage of patients. Weakness, when present, tends to be in the distal lower extremities. Autonomic involvement may also be seen with hyperhidrosis and tachycardia. Calf hypertrophy has been described in some patients. "Action" or grip myotonia may be seen. However, percussion myotonia is rare. There may be an associated neuropathy.
No routine laboratory test is available to detect the antibodies which have been described in research studies. EMG - is the most valuable diagnostic test. As in the original description by Isaacs, continuous motor activity is present. There are spontaneous discharges and there is rhythmical and continuous firing. The configuration of the wave forms varies, representing either motor units or single fiber discharges. Myokymia is seen electrically. This motor activity persists during sleep.
The diagnosis is made by the characteristic history of cramping and stiffness, which persists during sleep and the EMG findings of continuous spontaneous discharges and myokymia in the affected muscle groups. The differential diagnosis includes Stiffman's Syndrome, which also has prominent muscle stiffness. However, the stiffness goes away during sleep and EMG does not show myokymia. Also the anti-GAD antibodies seen in Stiffman's syndrome are not seen in neuromyotonia. Benzodiazepines are helpful in Stiffman's syndrome, but have no effect in Isaacs'. Phenytoin and Carbmezepine help the stiffness in Isaacs' syndrome, while there is no effect in Stiffman's syndrome. Another disease to be considered in the differential is the Schwartz-Jampal syndrome or osteochondromuscular dystrophy. This is an autosomal recessive disorder with short stature, muscular hypertrophy, diffuse bone disease, ocular and facial anomalies.
Several different treatments have been tried. Phenytoin has been used with a great deal of success in many different reports. Most patients have marked improvement in the weakness, stiffness and myokymia. There are also reports on the use of tegretol and depakote with similar benefits. In a study by Ishii et al the effects of plasma exchange were compared to IV IgG. Plasma exchange was thought to have significant benefit, while the IV IgG made the symptoms worse. Quinidine, diazepam, calcium, steroids and barbiturates have been used without success.
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