Isaac’s syndrome
Overview
Isaac's syndrome (also known as neuromyotonia, Isaac-Mertens syndrome, continuous muscle fiber activity syndrome, and quantal squander syndrome) is a rare neuromuscular disorder caused by continuous signaling of the end regions of peripheral nerve fibers that activate muscle fibers (motor neurons). Symptoms, which include progressive muscle stiffness, continuous vibrating or twitching muscles, cramping, increased sweating, and delayed muscle relaxation, occur even during sleep or when patients are under general anesthesia. Many patients develop weakened reflexes and muscle pain, but numbness is relatively uncommon. Although symptoms can be limited to cranial muscles, in most patients stiffness is most prominent in limb and trunk muscles. Speech and breathing may be affected if pharyngeal or laryngeal muscles are involved. Age of onset is between ages 15 and 60, with most patients experiencing symptoms before age 40. There are hereditary and acquired forms of the disorder. The acquired form may develop in association with peripheral neuropathies or as an autoimmune condition
Symptoms
Muscle stiffness associated with the syndrome usually presents during adolescence, although many individuals remain asymptomatic until adulthood. Stiffness results from involuntary muscle contractions (myokymia), or muscles failing to relax after intense activity (myotonia, neuromyotonia). Muscle contraction persists, even during sleep and under general anaesthesia. The condition is visible under the skin as ripples of contractions moving along the muscle. Limb and trunk muscles are particularly affected, and individuals with the syndrome may have a stiff-legged, unsteady gait. Symptoms are more pronounced in the hands and feet than in upper arms and thighs. Apart from stiffness, continuous muscle activity results in fatigued and temporarily weak muscles. Tongue and pharyngeal muscles are sometimes affected, leading to swallowing difficulties and hoarseness. Isaacs’ syndrome patients do not have muscle pain, but approximately one third experience numbness and tingling in the skin. Weight loss may occur and some individuals experience excessive sweating owing to constant muscular activity and increased energy expenditure. Morvan’s syndrome is a variant of Isaacs’ syndrome in which the brain is affected, causing personality changes, sleeping disorders and irritability.
Diagnosis
Electromyography (EMG) is a standard examination in which electrodes measure electrical activity in muscles. In Isaacs’ syndrome, the EMG will show evidence of neuromyotonia and myokymia. Neuromyotonia presents as series of single motor unit potentials discharging at a high frequency (150-300 times/second = 150-300 Hz). Myokymia presents as brief bursts of two, three or multiple discharges recurring rhythmically at 2-10 Hz. Myokymia may present in a number of neurological disorders involving muscle paralysis. When neuromyotonia is confirmed, blood salt concentrations (calcium, magnesium, phosphate and potassium) are measured in order to exclude imbalances between these electrolytes as the underlying cause of the disorder. On suspicion of Isaacs’ syndrome, a blood test should be performed to confirm the presence of VGKC antibodies. As this analysis is not presently available in Sweden, blood samples are sent to England (see under “Research and development”). Spinal fluid analyses will either be normal or show signs of immune system activation. Computer tomography (a CAT scan) or magnetic resonance imaging (MR) should be carried out to exclude thymoma, presenting in approximately 20 per cent of cases. Myasthenia gravis is present in 10-20 per cent of people with the syndrome, particularly in thymoma patients.
Prognosis
There is no cure for Isaac's syndrome. The long-term prognosis for individuals with the disorder is uncertain
Treatment
Anticonvulsants, including phenytoin and carbamazepine, usually provide significant relief from the stiffness, muscle spasms, and pain associated with Isaac's syndrome. Plasma exchange may provide short-term relief for patients with some forms of the acquired disorder.