Isaacs Syndrome

What is Isaacs Syndrome?

Isaacs Syndrome is a resultant of hyperexcitability of peripheral nervous system and affects neuromuscular system. The progressive neuromuscular disorder provides several characteristic features.

This is a rare disorder, which may involve hereditary factors, however, some cases also provide the evidence that the Isaacs Syndrome also has acquired form. Usually, the outcome of this disease appears at the age between 15 to 60 years old, but most affected individual develops their symptoms within 40 years of their age^1,2,3.

Signs & Symptoms

• The characteristic feature of Isaacs Syndrome is mainly involved neuromuscular disorders, that can generate constant involuntary activity in muscular fiber. This continuous over-activity leads to muscular stiffness and affected muscle also has delayed relaxation. Accompanying these symptoms, the affected nerve becomes undulate and muscle twitching is also common muscular symptoms. Altogether these muscular defects cause impaired voluntary muscle coordination, walking difficulty (ataxia) and body balancing problem, which causes difficulty to perform the daily routine activity.
• Progressive muscle stiffness, muscular cramping, and weakness in muscular tissues are attributing features of Isaacs Syndrome. The patient often complains that muscles under their skin are continuously rippling, which cannot stop during sleeping time also. The impaired muscular reflex action causes delaying of the muscle movement and that can observe as affected individual unable to immediately open their eyes or fist after tightly closing them.
• Isaacs Syndrome affected patients also frequently have profuse sweating, fast heartbeat, and unexplained weight loss.
• A rare group of symptoms is accompanied with Isaacs Syndrome, which includes excessive salivation, arrhythmias, hallucinations, confusion, memory loss, personality disorder, disturbed sleep, and constipation. The combination of these symptoms along with other symptoms of Isaacs Syndrome is termed as Morvan syndrome. Approximately 20% of Isaacs Syndrome affected patients Morvan syndrome.
• In some individual with Isaacs Syndrome also have a thymoma (a tumor of the thymus gland). This combination of disorders also affects almost 20% of the patients. This association of disorder can lead to different autoimmune disorders like myasthenia gravis, as thymus gland is responsible for autoimmune functioning².

Causes

The exact cause of Isaacs Syndrome progression is not clear. However, it has been found that voltage-gated potassium channel complex (VGKC) involvement in the nervous fibers terminal end may appear due to VGKC-complex antibodies are formed. These antibodies are not acts against VGKC itself, but acting against Caspr2 and less significantly affects neuromyotonia against LGI1.

In the case of hereditary involvement, genetic transportation of the impaired gene is a responsible factor. But in the case of non-inheritor factors involvement, several associated co-morbidity like thymoma, thyroiditis, myasthenia gravis, peripheral neuropathies, Hashimoto, malignancies, celiac disease, vitamin B12 deficiency, connective tissue disorders influence the Isaacs Syndrome progression. Autoimmune disorders also provide a positive influence to generate Isaacs Syndrome^1,4,.

Diagnosis

The initial diagnostic approach of Isaacs’ syndrome depends upon symptomatic analysis. In addition, differential diagnosis requires conducting for excluding the risk of other disorders, such as autoimmunity, malignancy etc. The included diagnostic tests are:

• Specialized Blood tests and Urine test are conducted. The findings of  anti-VGKC-complex antibodies is more prominent in Morvan syndrome than in Isaac’s syndrome
• CT scan and MRI provide images which can very important to determine the underlying cause
• Electromyography to detect the muscles and the nerves condition^1,4

Treatment

• Membrane-stabilizing medicines like valproic acid, phenytoin, carbamazepine etc usually prescribed as a single therapy or in combination to control hyperexcitability of the peripheral nerve.
• An oral corticosteroid such as prednisolone needs to prescribe in the case of unresponsive patients.
• Azathioprine and methotrexate are non-steroid immunosuppressive drugs may need to prescribe for some uncontrolled cases.
• Regular acetazolamide dosing administration can provide recovery from twitching movements and eradicate periodic event of muscular tone loss.
• Plasma exchange is another treatment approach for treating patients with acquired Isaacs’ syndrome. It has been noticed that this therapy can provide short-term symptomatic relief. In this method, total blood volume from the body is totally eliminated to proceed separation of cellular components including red and white blood cells from the liquid component (plasma) of the blood. Then without the plasma, the blood cells are returned to the patient body for quick physiological replacement.
• Intravenous immunoglobulin administration assists in controlling severe neuromyotonia. This treatment is also prescribed for patients with Morvan’s syndrome.
• Malignancy treatment is required for paraneoplastic form of Isaac’s syndrome.^1,2,5

Prognosis

Isaac’s syndrome is not provided a life-threatening outcome, however, no treatment yet available to completely cure the syndrome. Morvan’s syndrome can be fatal, as it is a severe course of the disease. The prognosis of paraneoplastic Isaac’s syndrome varies, as the tumor course varied from patient to patient^1,4.

References:

1. Isaacs’ syndrome; Genetic and Rare Diseases Information Center; Retrieve from https://rarediseases.info.nih.gov/diseases/6793/isaacs-syndrome
2. Acquired Neuromyotonia; National Organization for Rare Disorder; Retrieve from https://rarediseases.org/rare-diseases/acquired-neuromyotonia/
3. Michael Rubin; Isaacs Syndrome; MSD Manual; Retrieve from http://www.msdmanuals.com/home/brain,-spinal-cord,-and-nerve-disorders/peripheral-nerve-disorders/isaacs-syndrome
4. Isaac syndrome; Orpha.net ; Retrieve from http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=84142
5. Michael Rubin; Isaacs Syndrome; Merck Manual; Retrieve from http://www.merckmanuals.com/professional/neurologic-disorders/peripheral-nervous-system-and-motor-unit-disorders/isaacs-syndrome