Overview

Isaacs syndrome is a rare disorder affecting the nerves and muscles of the body.^1,2 There have been less than 200 cases reported.³ It is known by many names including:⁴ 

• Isaacs' syndrome
• Isaacs-Mertens syndrome
• Neuromyotonia
• Acquired neuromyotonia
• Continuous muscle fibre activity syndrome
• Quantal squander syndrome

Typically, this disorder tends to affect middle-aged men however, the symptoms of this disorder may start to appear at any time in life and may vary in severity.^5,6 This review will into detail on the causes and symptoms of this rare neuromuscular disorder.

Causes of Issacs syndrome

Isaacs syndrome is a rare nerve disorder discovered in 1961 by Dr Hyam Isaacs.⁶ This disorder causes uncontrollable constant muscle activity and there is ongoing research on understanding the causes of Isaacs syndrome. So far, the two types of Isaacs syndrome are hereditary causes and external causes.⁷

Hereditary causes

It can be caused by genetically inherited factors due to genetic mutations in the DNA that are passed down from generation to generation.³ Recently, Isaacs syndrome associated with hereditary causes has been associated with episodic ataxia and benign familial neonatal epilepsy.² 

However, more research is required to fully understand the heredity causes of Isaacs syndrome. On the other hand, there is more evidence to suggest that Isaacs syndrome is mainly acquired due to external causes.

External causes

The external or acquired forms of the syndrome can develop in connection with an abnormality of the nerves within the peripheral nervous system. This means that the cause is not due to genetics but instead, it is developed over time due to abnormal changes in the way certain parts of the body function.⁸

The nervous system is composed of two parts, the peripheral nervous system, and the central nervous system. The peripheral nervous system is part of the nervous system that lies outside the brain and spinal cord. The brain and spinal cord together are known as our central nervous system. The peripheral nervous system plays an important role in connecting the central nervous system to tissues and organs of the body via a network of nerves.⁸

The nerves within the peripheral nervous system play a key component in the survival of the body as the nerves carry information or signals from the body to the brain (afferent), from the brain to muscles and glands (efferent), or a mix of both.⁹ When the nerves within the peripheral nervous system are overactive, or in other terms overly excited, this leads to involuntary muscle firing. 

This means that the peripheral nerves are damaged, and this is known as peripheral neuropathies. For Isaacs syndrome, the peripheral neuropathies mean that the muscles start to move, jerk^, or better known as twitch uncontrollably. Researchers have tried to discover a better understanding of the cause of involuntary muscle firing.¹⁰

One explanation is that involuntary muscle firing is mostly caused by an autoimmune condition. This means that the body’s immune system produces an elevated amount of antibodies to attack itself, and falsely damage and destroy normal cells, believing that they are foreign to the body.^11,12 Therefore, in the case of Isaacs syndrome, affecting how the nerves and muscles function.^10,13

Common symptoms of Isaacs syndrome

As mentioned earlier, the symptoms of Isaacs Syndrome can start to appear at any age. Some of the symptoms include:^3,7,10,14

• Myokymia: uncontrollable muscle twitching at a slow pace which is also known as quivering of the muscles
• Fasciculations: uncontrollable muscle twitching at a rapid pace 
• Pseudomyotonia: delayed muscle relaxation
• Calf muscle hypertrophy: increased size of calf muscles
• Muscle cramps (spasms)
• Muscle stiffness: Muscles cannot function normally without accompanying pain or muscle spasms
• Muscle fibrillation: rapid and uncontrollable twitching of muscle fibres with little or no movement of the muscle as a whole
• Hyperhidrosis: abnormal excessive sweating in the absence of any stimuli including high temperatures or being in humid environments
• Weight loss
• Distal sensory impairment: decreased sensation in extremities (i.e. the limbs)
• Hyperthermia: increased skin temperature
• Neuropathic pain: nerve pain
• Paraesthesia: abnormal sensations, commonly described as ‘pins and needles’
• Dysautonomia: malfunction of the autonomic system which is involved in controlling vital systems within the body such as the cardiovascular and digestive systems
• Tachycardia: increased heart rate
• Speech and swallowing issues: problems in chewing, talking and breathing 

Some of the uncommon symptoms of Isaacs syndrome include muscle weakness (reduced strength of muscles) and numbness. Symptoms can occur during the day but also during sleep or when under general anaesthesia.^3,15 Unfortunately, every individual with Isaacs Syndrome will have different varieties of the symptoms mentioned above. 

Also, symptoms may start to appear not all at once in a single age range. However, keeping track of when symptoms occur, will help clinicians understand the patient’s situation, and provide the correct diagnosis of Isaacs syndrome.

FAQs

What is the difference between Morvan’s syndrome and Isaacs syndrome?

Morvan’s syndrome also involves uncontrolled muscle activity, but it is life-threatening in comparison to Isaacs syndrome. This is because it is also linked to severe insomnia as well as alterations in personality, hallucinations, confusion, and amnesia.¹⁶

Can Isaac syndrome co-exist with other diseases?

These are some of the other diseases that Isaacs syndrome can also co-exist with^4,17,18:

• Amyotrophic lateral sclerosis (ALS): nervous system disease that affects nerve cells in the brain and spinal cord
• Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP): the body’s immune system attacks the insulative layer that protects the nerves. The insulative layer is called myelin
• Amyloid light-chain amyloidosis: build-up of a protein called amyloid which damages key organs, such as the heart, kidneys, liver, nerves, or digestive system.
• Cancer: radiation treatment is commonly used for treating cancer, and has been associated with the dysfunction of the peripheral nerves after treatment 
• Myasthenia gravis: muscle weakness
• Thymomas: tumour of the thymus (a gland between the lungs that produces cells (called lymphocytes) that are vital to strengthening the body’s immune system)
• Vitamin B12 deficiency: the lack of vitamin B12 leads to the production of unhealthy red blood cells and could lead to the development of anaemia
• Celiac disease: when gluten is consumed, the body’s immune system attacks its tissues
• Haematological malignancy: also known as blood cancer
• Hypoparathyroidism: lack of the parathyroid hormone leads to muscular spasms due to the body being calcium and phosphorus-deficient
• Systemic rheumatic diseases (SRDs): chronic, inflammatory, autoimmune disorders, in which the body’s immune system attacks its own tissues affecting vital organs and systems within the body

Is there a cure for Isaacs syndrome?

Unfortunately, there is no cure, but there are ongoing clinical trials to try to understand the causes of the disorder, and to diagnose individuals earlier. Therefore, taking part in clinical trials aids in providing the necessary treatments to cure the disorder or to prevent symptoms from worsening.⁴

What are some ways to manage symptoms of Isaacs syndrome?

Caution must be taken as there is currently, no cure for Isaacs Syndrome but there are some options available to provide some relief, via the use of:^5,18,19,20

• Anti-seizure medications, also known as anticonvulsants
• Plasma exchange to filter toxins and unhealthy antibodies out of your blood in individuals who have abnormal antibodies, also known as plasmapheresis
• Immunosuppressive treatment might provide short-term relief for individuals with some forms of the acquired disorder

Summary

Isaacs syndrome is a rare condition that causes uncontrollable muscle movements, such as twitching. It can be inherited from generation to generation. Nevertheless, it is mainly acquired from damage to the peripheral nervous system initiating symptoms such as muscle cramps, stiffness, and abnormal excessive sweating (hyperhidrosis). Although Isaacs syndrome is a rare disease, symptoms can develop and progress to anyone at any age.

Advances in research will help to provide more information on the development of Isaacs syndrome. Isaacs syndrome is not curable but clinical trials are ongoing. This will help to improve how individuals are diagnosed and treated. If you think that you have any of the symptoms discussed above, it is best to discuss this further with a doctor.