Overview
Isaacs syndrome (also known as Neuromyotonia) is an extremely rare neuromuscular condition which causes overactivity of the nerves that control the muscles of the body. This is referred to as hyperexcitability and leads to symptoms such as muscle stiffness and twitching.1
Our nerves communicate with each other through chemicals they transmit to one another. The transmission of these chemicals is controlled in part by various channels (think of those as gates) found at the end of each nerve. Different factors control the opening and closing of each channel, with voltage being one example.
Voltage-gated potassium channels play a role in signalling at the junctions between nerves.1 Their healthy functioning is vital to the precise control of muscle contraction, which is needed for voluntary movement and reflex actions. When someone has Isaacs syndrome, these channels are impaired by an auto-immune disease or a genetic alteration which causes hyperexcitability of the peripheral nervous system.1,2 This suppresses the outward flow of positive ions from the neuron and stops the neuron from returning to its resting state.1 This stops the nerve cell (also known as a neuron) from returning to its resting state, meaning that the neurons that control our muscles are kept in an excited state for longer than usual, causing spontaneous and excessive muscle contractions.
Why are potassium channels important in Isaacs syndrome?
Potassium channels are involved in the complex signalling system that which allows for the precise control of movement. These channels play a vital role in stopping a neuron from signalling. This means that when potassium channel function is disrupted in Isaacs syndrome,1 the neurons which carry signals to the muscles are overexcited, and individuals experience muscle twitching and stiffness.
The role of potassium channels in muscle contraction
The brain transmits messages using electrical impulses which are sent down the neurons of the spinal cord to the peripheral nervous system (PNS). The neurons of the peripheral nervous system then relay these electrical signals to our muscles.7 The healthy function of this system allows us to contract and relax our muscles to precisely control our voluntary movement.8 The peripheral nervous system also relays signals to and from the spinal cord to cause reflexes without input from the brain. These reflexes allow us to quickly withdraw a body part from something painful, or make us step out to stabilise ourselves if we trip.
Electrical impulses are passed between neurons using chemical messengers called neurotransmitters.11 Where two neurons meet, they form a synapse. This is a gap where neurotransmitters can travelbe passed from the end of one neuron to the start of the next neuron to ‘excite’ (activate) the neuron and transmitpass on the electrical signal. At these endings, neurons also have many different channels which allow ions (electrically charged particles) in and out of the neurons at the same time.9 This also contributes to the precise control of signalling between neurons.9 These channels control the flow of ions (electrically charged particles)ion flow very precisely and thereby the electrical signal because ions are charged, and having too many ions that stimulate positive charge in the neuron will prolong the electrical signal. Voltage- gated potassium channels usually allow positively charged potassium ions out of the neuron in healthy signalling, allowing the neuron to return to its resting state after passing on the electrical signal to the next neuron.1,9
However, in Isaacs syndrome, the function of these potassium channels is disrupted by the body’s immune system or by a genetic alteration.1 This disrupts the outward flow of positive potassium ions, meaning that the neuron remains in an excited state for longer. This causes hyperexcitability of peripheral neurons, causing them to spontaneously fire and cause the motor symptoms seen in Isaacs syndrome.
Causes of Isaacs syndrome
It is thought that Isaacs syndrome can be both acquired and hereditary. Acquired Isaacs syndrome refers to the development of the syndrome where the exact cause remains unknown, but is often associated with an auto-immune disease.2
In a healthy immune system, antibodies bind to unwanted foreign organisms (such as viruses and bacteria) to help remove them from the body. However, if someone has an auto-immune disease, the body’s immune system creates antibodies which bind to healthy cells by mistake, causing damage to the body’s healthy tissue.3 In Isaacs syndrome, these antibodies target voltage-gated potassium channels at nerve endings, which causes overactivity of the neurons that control our muscles.1
There are over 80 different types of auto-immune diseases,3 and several have been associated with Isaacs syndrome, such as:2,12
- Myasthenia gravis
- Guillain-Barré syndrome
- Rheumatoid arthritis
- Chronic inflammatory demyelinating polyneuropathy (CIDP)
Acquired Isaacs syndrome has also been associated with neuropathic pain.2 Cancer is also associated with Isaacs syndrome; however, the exact cause of the syndrome remains unknown.4 Some cancers such as thymoma (a tumour of the thymus) can cause immune system dysfunction through tumour-associated antigens, which may affect the nervous system.4 These are substances produced by the tumor that trigger an immune response. On the other hand, treatments for cancer such as radiotherapy, immunotherapy and chemotherapy can also compromise the body’s immune system. In both cases, the immune system is impaired, which can increase the risk of Isaacs syndrome.
On the other hand, some cases of Isaacs syndrome are inherited and are thought to occur due to genetic alterations of the voltage-gated potassium channel genes.2 Individual and family case studies have identified mutations in the KCNA1 gene in patients with Isaacs syndrome.5 A mutation in this gene is thought to affect potassium channel function, thereby causing the symptoms of Isaacs syndrome.10
Symptoms of Isaacs syndrome
As Isaacs Syndrome is a condition affecting the body’s peripheral nervous system (the nerves which control our muscles), the symptoms are primarily muscular,2,6,8,12 and include:
- Muscle stiffness
- Increased sweating
- Myokymia – frequent muscle twitching and contractions
- Prolonged muscle contraction – contraction is sustained for a longer time, and muscles take longer to relax after contraction
- Weaker reflexes
- Muscle cramping and pain
- Ataxia – poor coordination due to loss of muscle control
- Increased heart rate
- Weight loss
- Muscle hypertrophy – an increase in muscle mass
Other less common symptoms of Isaacs syndrome include mood disorders and a decline in the ability to control the muscles of the mouth and throat which we use to talk, breathe, and swallow.2
Diagnosis
Diagnosising Isaacs syndrome can be difficult, as the syndrome is extremely rare, which means that doctors may not have seen it before. Muscular symptoms such as muscle twitching and contracting (myokymia) can be an indicator that there is something going on in the neurons controlling the muscles, and so needle electromyography may be used to investigate the electrical activity of the muscles at rest.6,12 This test is used for many neuromuscular conditions and can be used to identify spontaneous and excessive electrical activity in the muscles, which characterises Isaac syndrome. A blood test may be performed and analysed for specific amounts or types of immune cells which can indicate an auto-immune disease that may be associated with Isaacs syndrome.1,12
What are the treatments for Isaacs syndrome?
Anticonvulsant medications, such as carbamazepine, can be used in severe cases of Isaacs syndrome to relax the muscles and relieve muscle cramping and stiffness, which can become painful.12 This can provide short-term symptomatic relief.2
Therapeutic plasma exchange is another treatment which may be offered in Isaacs syndrome.2,12 A plasma exchange involves the patient's own blood passing through a machine which separates the red blood cells from the plasma. Since the plasma contains defective immune cells, the patient’s plasma is removed and exchanged for a replacement fluid that is then combined with their own red blood cells and returned to the patient’s body.
Some patients may also receive an immunosuppressant as a long-term treatment, such as methotrexate.12 This type of medication decreases the activity of the immune system to prevent it from attacking the body’s healthy tissue. Intravenous steroids may also be given alongside immunosuppressants to reduce inflammation in the short-term.12
These treatments may be given separately or in combination to combat the symptoms of Isaacs syndrome whilst attempting to manage the body’s immune response.
FAQs
Are there other names for Isaacs syndrome?
There are many names given to Isaacs syndrome including:2,13
- Acquired neuromyotonia
- Acquired autoimmune neuromyotonia
- Neuromyotonia
- Continuous muscle fibre activity syndrome
- Quantal squander syndrome
- Isaacs-Mertens syndrome
- Idiopathic generalised myokymia
Are the symptoms of Isaacs syndrome only physical?
There are some reports of mood disorders related to Isaacs disease, such as anxiety and depression. It is not exactly known what might cause these changes.4 Insomnia is another symptom reported to occur in some cases of Isaacs syndrome. This may be due to motor symptoms occurring during the night, which may disturb sleep in some patients.2
Isaac syndrome and misdiagnosis
There are multiple conditions which may present with symptomssimilar to those seen in Isaacs syndrome. This can sometimes lead to misdiagnoses. These include:
- Stiff person syndrome:14 Stiff person syndrome is also characterised by rigidity and muscle cramping but has additional symptoms that can affect gait and vision. It is also thought to be an autoimmune disorder, but is related to the loss of neurotransmitters that usually inhibit neuronal signalling
- Rippling muscle disease (RMD):15 RMD also is characterised by muscle cramps and stiffness, alongside repetitive muscle contractions. However, this is caused by mutations of the caveolin-3 (CAV3) gene which codes for a protein that makes up part of muscle cells, and is different from Isaacs syndrome
Summary
Isaacs syndrome is a very rare condition in which hyperexcitability of the peripheral nervous system causes spontaneous or uncontrolled muscle twitching and cramping. Isaacs syndrome is sometimes associated with auto-immune disorders, but may also be inherited and caused by genetic alterations. The syndrome is thought to be caused by disruptions to the voltage-gated potassium channels which contribute to restoring a neuron’s resting state. This means that muscles remain contracted for longer than they usually would, or may contract spontaneously. Current treatments include immunosuppressants and plasma exchange to reduce the body’s immune response, alongside anticonvulsants to relax muscles and provide short term relief from symptoms.
References
- Arimura K, Sonoda Y, Watanabe O, Nagado T, Kurono A, Tomimitsu H, et al. Isaacs’ syndrome as a potassium channelopathy of the nerve. Muscle Nerve Suppl. 2002; 11:S55-58.
- Isaacs Syndrome | National Institute of Neurological Disorders and Stroke [Internet]. [cited 2024 Apr 4]. Available from: https://www.ninds.nih.gov/health-information/disorders/isaacs-syndrome.
- Autoimmune Diseases. National Institute of Environmental Health Sciences [Internet]. [cited 2024 Apr 4]. Available from: https://www.niehs.nih.gov/health/topics/conditions/autoimmune.
- Park SB, Thurbon R, Kiernan MC. Isaacs syndrome: the frontier of neurology, psychiatry, immunology and cancer. J Neurol Neurosurg Psychiatry [Internet]. 2020 [cited 2024 Apr 4]; 91(12):1243–4. Available from: https://jnnp.bmj.com/content/91/12/1243.
- Kinali M, Jungbluth H, Eunson LH, Sewry CA, Manzur AY, Mercuri E, et al. Expanding the phenotype of potassium channelopathy: severe neuromyotonia and skeletal deformities without prominent Episodic Ataxia. Neuromuscular Disorders [Internet]. 2004 [cited 2024 Apr 4]; 14(10):689–93. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0960896604001749.
- Isaacs’ Syndrome. UK HealthCare [Internet]. [cited 2024 Apr 4]. Available from: https://ukhealthcare.uky.edu/kentucky-neuroscience-institute/conditions/neuromuscular-disorders/isaacs-syndrome.
- The Peripheral Nervous System | SEER Training [Internet]. [cited 2024 Apr 4]. Available from: https://training.seer.cancer.gov/anatomy/nervous/organization/pns.html.
- Involuntary Movements: Types, Causes, and Examples, Stanford 25. Stanford Medicine 25 [Internet]. [cited 2024 Apr 4]. Available from: https://stanfordmedicine25.stanford.edu/the25/involuntary-movements-and-tremors.html.
- Voltage-Gated Potassium Channel - an overview | ScienceDirect Topics [Internet]. [cited 2024 Apr 4]. Available from: https://www.sciencedirect.com/topics/neuroscience/voltage-gated-potassium-channel#:~:text=Biomedical%20Sciences%2C%202017-,Potassium%20Channels,and%20a%20reduction%20in%20excitability.
- Smith M. Chapter 8 - Epilepsy and movement disorders. In: Smith M, editor. Mechanisms and Genetics of Neurodevelopmental Cognitive Disorders [Internet]. Academic Press; 2021 [cited 2024 Apr 4]; p. 195–224. Available from: https://www.sciencedirect.com/science/article/pii/B9780128219133000093.
- Grider MH, Jessu R, Kabir R. Physiology, Action Potential. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 [cited 2024 Apr 4]. Available from: http://www.ncbi.nlm.nih.gov/books/NBK538143/.
- Isaacs’ Syndrome: Causes, Symptoms, Prognosis & Treatment. Cleveland Clinic [Internet]. [cited 2024 Apr 4]. Available from: https://my.clevelandclinic.org/health/diseases/22665-isaacs-syndrome.
- Katirji B. Chapter 17 - Peripheral nerve hyperexcitability. In: Levin KH, Chauvel P, editors. Handbook of Clinical Neurology [Internet]. Elsevier; 2019 [cited 2024 Apr 4]; bk. 161, p. 281–90. Available from: https://www.sciencedirect.com/science/article/pii/B9780444641427000540.
- Stiff Person Syndrome (SPS) [Internet]. 2024 [cited 2024 Apr 4]. Available from: https://www.hopkinsmedicine.org/health/conditions-and-diseases/stiff-person-syndrome-sps.
- Rippling muscle disease. rarediseases.info.nih.gov [Internet]. Genetic and Rare Diseases Information Center; n.d. Available from: https://rarediseases.info.nih.gov/diseases/9164/rippling-muscle-disease.