Acquired neuromyotonia is a rare inflammatory disease where peripheral nerve cells become overstimulated and repeatedly fire, causing muscle fibres to activate. This leads to gradual muscle stiffness, continuously contracting or twitching muscles, cramping, increased sweating, and delayed muscle relaxation.1 Understanding this rare disorder can help improve and transform the lives of others. Acquired neuromyotonia is also known as Isaacs syndrome.²

What causes acquired neuromyotonia?

Acquired neuromyotonia is an autoimmune disorder. This is when your immune system attacks normal cells, identifying them as foreign instead of self. 40% of those affected were found to have antibodies that target voltage-gated potassium channels (VGKC).

Potassium channels are significant as they contribute to the regulation of vascular smooth muscle contraction. Allowing for relaxation and contraction of muscles. They regulate cell membrane potential.¹² This influences the places where nerve fibre signals contact the muscle cells (neuromuscular junction).

Further targets have been discovered where pathogenic antibodies target leucine-rich glioma inactivated protein 1 (LGI1) and contactin-associated protein-like 2 (CASPR2).³ These are potassium channel-associated proteins where the antibodies will bind to one or both, causing acquired neuromyotonia.⁴ In most cases, they are associated with autoantibodies targeting CASPR2.⁵ 

Binding to these proteins prevents the potassium channel from functioning correctly, as CASPR2 is responsible for the proper localisation of voltage-gated potassium channels.¹⁸ LGI1 is a secreted protein mainly present in the hippocampus and temporal cortex. It is crucial for connecting pre- and postsynaptic signals.¹⁷

Antibody targets for several different conditions, including Morvan syndrome, have some overlap, suggesting the involvement of other targets that may not be identified yet.^3,6

The disease often manifests between the ages of 15 and 60, with the majority of symptoms occurring in those in their 40s. Despite this, acquired neuromyotonia has been shown in even younger people.

What are the symptoms of acquired neuromyotonia?

There are various symptoms associated with the disease. Common signs and symptoms include:

• Involuntary muscle twitching (myokymia)¹
• Myokymia of the limbs, face, and tongue¹
• Muscle Stiffness 
• Cramps⁴
• Pain
• Excessive sweating (hyperhidrosis)¹
• Rapid heartbeat (tachycardia)
• Weakness⁴
• Weight loss¹
• Hypertrophy (increase in muscle size) of the muscles can occur because of continuous muscle activity¹

These symptoms might occur during sleep, resulting in fatigue and insomnia. Because of this illness, you may experience pain in your muscles and impaired reflexes. Speech and breathing may be compromised if throat muscles are involved.

How is acquired neuromyotonia diagnosed? 

Acquired neuromyotonia is typically diagnosed through observations of the symptoms mentioned above, under the supervision of a specialist. Following physical examinations for clinical symptoms,² further tests are undertaken, including:

• Electromyograms (EMGs) to see the electrical activity of your muscles and spot any abnormal activity⁷
• Blood tests to identify specific antibodies present in people with acquired neuromyotonia
• Imaging studies such as CT scans or MRI scans can also be used to check for any tumours and thymomas

Voltage-gated potassium channel antibodies may be found in the blood of a person suffering from this disease. Antibody serum tests can also be conducted as another way to diagnose acquired neuromyotonia.⁴

A typical diagnosis will show an EMG where there is a continuous firing of motor unit potentials, even at rest. 

EMG recording from a person with acquired neuromyotonia, where continuous muscle activity can be seen. Taken from https://www.thaiscience.info/Journals/Article/JMAT/10401805.pdf 

What are some other diseases associated with acquired neuromyotonia? 

The disease has been linked to other conditions, such as:

• Cancer³
• Hashimoto’s disease⁸
• Lupus⁹
•  Myasthenia gravis⁹
• Peripheral neuropathy
• Thymoma⁹

This condition is often associated with cancer. This link with cancer suggests that acquired neuromyotonia can arise via paraneoplastic mechanisms.³

Paraneoplastic syndrome is a set of symptoms that develops when substances released by cancer cells interfere with the normal function of surrounding cells and tissues.

What are the differences between acquired neuromyotonia and other similar diseases?

Diagnosing acquired neuromyotonia can prove difficult based on the symptoms, due to overlapping similarities with other disorders. Below is a table with some of the common muscle hyperexcitability disorders.

What are the treatment options for acquired neuromyotonia? 

While there is no cure, you can use certain medications to improve your symptoms:

• Anticonvulsant drugs can be used to stop abnormal impulses and prevent symptoms from reoccurring¹
• Plasma exchange filters toxins and unhealthy antibodies out of your blood⁴
• Immunosuppressive medications⁴
• Intravenous immunoglobulin to normalise your immune system⁴

Examples of common anticonvulsant drugs taken to treat acquired neuromyotonia include carbamazepine, phenytoin, and acetazolamide. These have proven effective in controlling muscle spasms and twitches. ¹

How to manage acquired neuromyotonia long-term?

Managing acquired neuromyotonia in the long term is possible through treatment using immunosuppressants. In addition, constant monitoring for paraneoplastic causes and treating these can also improve the condition. The treatment for paraneoplastic instances will depend on the type of cancer that is underlying.¹

Severity of the disorder depends on the underlying cause, treatment effectiveness, and any associated medical conditions. With time, the symptoms may get worse, limiting movement and making daily tasks more difficult.

Understanding ‌the basic mechanisms of the disease is important. Most patients respond well to treatment, which usually provides significant relief of symptoms.

Over time, it is possible that acquired neuromyotonia can develop into CNS disorders like Morvan’s syndrome.

Some have had success with managing the physical and psychological effects of acquired neuromyotonia by:

• Joining counselling sessions where you can learn coping mechanisms
• Establishing connections with other people who share the condition
• Meditating and practising yoga
• Walking

Current and future directions

Acquired neuromyotonia remains a rare disorder that is often overlooked. As a result, additional research is needed to address symptoms and poor treatment efficacy where treatments like anticonvulsants and plasma exchanges are not effective for all patients. 

There is a need for larger studies to better understand the disease’s complexities and identify novel treatments for patients. Understanding specific autoantibody targets and clarifying the association with cancer will be essential to aid in the development of targeted therapeutics.³

FAQs

What is the difference between genetic and acquired neuromyotonia?

Genetic means that the disorder is inherited; you are born with it, whilst acquired develops after birth over time.

Are Isaacs’ syndrome and acquired neuromyotonia the same?

Yes, these are called the same thing. Isaac syndrome is the original name, which was named after Dr Hyam Isaacs, who originally reported a ‘syndrome of continuous muscle fibre activity’.³

Can you live with acquired neuromyotonia?

Although there is no cure, it is not, by itself, fatal, and treatments can be used to deal with the symptoms.

Is acquired neuromyotonia progressive?

Muscles can become progressively stiffer.

What cancers are associated with acquired neuromyotonia?

Thymoma, small-cell lung carcinoma, or lymphoma.

Summary

Acquired neuromyotonia is an autoimmune disease caused by antibodies attacking the CASPR2 or LGI1-associated proteins of the VGKC’s. The major symptoms include constant muscle twitching, muscle stiffness, and excessive sweating. Diagnosis includes observation of these symptoms, followed by electromyography to measure electrical activity of muscles, blood tests to see antibody levels, and CT scans and MRI’s scans. Difficulty in diagnosis can arise from similar disorders, so time must be taken to perform the necessary tests. The disorder is not curable but can be managed with anticonvulsant drugs, plasma exchanges, and in some cases immunosuppressants. Further studies are needed to provide more treatments, as some treatments are not effective in all patients. However, yoga, meditation, and walking have been shown to help manage acquired neuromyotonia long-term.