Isaacs syndrome (ORPHA:84142)
Isaac's syndrome is an immune-mediated peripheral motor neuron disorder characterized by continuous muscle fiber activity at rest resulting in muscle stiffness, cramps, myokymia, and pseudomyotonia.
Epidemiology
Prevalence is unknown but 100 -200 cases have been reported so far.
Clinical description
The age of disease onset ranges from infancy to the sixth decade, with a peak incidence between forty and sixty. Isaac's syndrome is characterized by continuous muscle fiber activity at rest (even during sleep), resulting in cramps, muscle stiffness and weakness, pseudomyotonia, muscle twitching (visible myokymia), and fasciculation. Hyperhidrosis, muscle hypertrophy and hyporeflexia are also observed. Stiffness without severe pain is more remarkable in the distal than proximal muscles. In 20% of cases Isaac's syndrome is associated with malignancy (thymoma and small cell lung cancer) (see these terms). It is mainly associated with myasthenia gravis (see this term), but has incidentally been associated with other immune mediated diseases such as chronic inflammatory demyelinating polyneuropathy (CIDP), rheumatoid arthritis, Guillain-Barré syndrome, and systemic lupus erythematosus (see these terms). Some patients may present with a variant form known as Morvan syndrome (see this term) which is characterized by muscle activity and excessive perspiration and neurological findings with symptoms including personality changes, hallucinations, mood swings and sleeping disorders.
Etiology
The etiology for this disorder remains unknown. However, a role for the voltage-gated potassium channel complex (VGKC) in terminal nerve fibers has been implicated by the discovery of VGKC-complex antibodies. These antibodies are not against VGKC itself, but against Caspr2 and to a lesser extent in neuromyotonia against LGI1. These antibodies down-regulate VGKC leading to repeated action potentials. The precise meaning of increased levels of VGKC-complex antibodies without Caspr2 or LGI1 antibodies is currently controversial, as is the use of immunotherapy in this specific group.
Diagnostic methods
Diagnosis of Isaac's syndrome relies on history, physical findings, and electromyography (EMG). Typical findings are doublet, triplet or multiplet ('myokymic') motor unit discharges and fasciculations. 35-40% of patients have elevated levels of anti-VGKC-complex antibodies, which is more frequent in Morvan syndrome than in Isaac's syndrome.
Differential diagnosis
Differential diagnosis includes hereditary neuromyotonia or myokymia (with/without episodic ataxia) syndromes, cramp-fasciculation syndrome, motor neuron diseases (progressive spinal muscle atrophy, neuropathy, amyotrophic lateral sclerosis (ALS) (see this term), intoxication (gold, mercury, toluene, insecticides) and tetanus (see this term).
Management and treatment
Peripheral nerve hyperexcitability in Isaacs' syndrome can be treated with membrane-stabilizing drugs such as phenytoin, valproic acid, carbamazepine or lamotrigine, alone or in combination if necessary. If response is insufficient, oral corticosteroid (prednisolone) may be prescribed. The addition of non-steroid immunosuppressive drugs such as azathioprine and methotrexate may also be considered. Daily treatment with acetazolamide may improve twitching/writhing movements and eliminate episodes of loss of tone. Plasma exchange or intravenous immunoglobulin is indicated for severe neuromyotonia and for patients with Morvan's syndrome. In the paraneoplastic form, treatment of malignancy is warranted.
Prognosis
There is no cure for Isaac's syndrome although it is not fatal. Morvan's syndrome has a more severe course and can be fatal. The long-term prognosis for individuals with paraneoplastic Isaac's syndrome is dependent on the tumor course.

                            Last update: 
                            July 2013


                            - Expert reviewer(s): 
                            Dr M.J. [Maarten] TITULAER