Isaacs Syndrome Diagnosis And Treatment

Overview

Isaacs’ syndrome is a rare neuromuscular disorder that is caused by continuous neuronal firing from the peripheral nerve cells. It is an autoimmune disorder where the muscles become overactive due to the continuous activation of nerve cells. Patients may present with muscle stiffness and muscle cramps.

Isaacs’ syndrome is also known as:

• Isaacs-Mertens syndrome
• Neuromyontonia
• Continuous muscle fibre activity syndrome
• Quantal squander syndrome.

Although there is no cure for Isaacs’ syndrome, the disease is progressive. Therefore, seeking a diagnosis and undergoing treatment is important in improving quality of life.^1,2

Understanding Isaacs’ syndrome

Characteristics

Isaacs’ syndrome falls under peripheral nervous excitability syndrome. It is caused by continuous muscle overactivity. The key characteristics of the disease are:

• Muscle stiffness
• Muscle twitching which is also known as myokymia
• Delayed muscle relaxation
• Muscle cramps
• Fatigue
• Excessive sweating
• Speech and breathing difficulties occur when pharyngeal and laryngeal muscles are affected by muscle hyperactivit.^1,2

Pathophysiology

The movement of potassium into and out of the nerve cell plays a key role in muscle activation. This occurs through voltage-gated potassium channels. 50% of patients with Isaacs’ syndrome have antibodies that target these potassium channels. This type of Isaacs syndrome is known as an autoimmune condition. This is because the body's defense mechanism i.e. the antibodies attacks the potassium ion channels as if they were foreign bodies. This is also known as the acquired form of Isaacs’ disease. There is also a hereditary form which is inherited.²

Epidemiology and prevalence

A study has shown that the average age of onset is the mid-40s. The disease was found to occur in more men than women by a ratio of approximately 2:1. More research, involving larger sample sizes needs to be conducted to corroborate whether the disease is more prevalent in a specific gender. This may prove difficult due to the rarity of the disease.

Isaacs’ syndrome may be associated with diseases such as:

• Myasthenia gravis
• Thymoma
• Addison disease
• Hashimoto thyroiditis
• Vitamin B₁₂ deficiency
• Coeliac disease
• Connective tissue disorders
• Guillain-Barré syndrome
• Cancer 

Symptoms

Patients with Isaacs’ syndrome may present with:

• Muscle stiffness is mostly experienced in the limbs and chest muscles, however, it may also be present in muscles in other parts of the body
• Muscle cramps- Patients may complain of muscle cramps that worsen with voluntary muscle contraction
• Muscle twitching (myokymia)-Persistent widespread muscle twitching is commonly experienced by patients. It can be described as wavelike motions on the muscle surface
• Weakness and fatigue-although this is uncommon in patients
• Distal sensory loss-another uncommon symptom
• Muscle hypertrophy- This is when muscle mass increases. It occurs when the muscle is very active. The hyperactivity of the muscles is relative to muscle hypertrophy
• Slow relaxation of muscles after voluntary contraction-Also known as pseudomyotonia, is seen in approximately one-third of patients. It generally occurs during a handgrip or after closing the eye or jaw^1,2

Differential diagnosis

Due to the similarities in the clinical presentation of various muscle disorders, additional tests are required to rule out other potential diseases. The differential diagnosis of Isaacs’ syndrome includes:

• Myotonia congenita-Patients with this disease present with muscle weakness, stiffness, muscular hypertrophy and delayed muscle relaxation. Unlike Isaacs’ syndrome, the disease is present at birth and is caused by a genetic mutation
• Stiff person syndrome- This is a rare neurological disorder where patients present with muscle stiffness and painful muscle spasms. The muscle spasms may be triggered by sudden noise or changes in light. It may also be triggered by internal stimuli. The exact causes are unknown, however, it is believed to be an autoimmune disorder 
• Motor neuron disease- more specifically amyotrophic lateral sclerosis (ALS) is caused by the degeneration and eventual death of nerve cells. Symptoms may include muscle stiffness and cramps, however unlike Isaacs’ syndrome it progresses to weakness and the muscles begin to waste away 
• Hallervorden-Spatz syndrome-This is a neurodegenerative disorder where the nervous system deteriorates over time. Symptoms include muscular rigidity, involuntary muscle spasms, difficulty in walking and speech problems
• Hereditary spastic paraplegia-This is an inherited neurological disorder. Symptoms include paraplegia, increased muscle tone and rigidity of leg muscles. Walking may progressively become difficult
• Schwartz-Jampel syndrome- This is a rare genetic disorder, symptoms include delayed relaxation of muscles after contraction, muscle spasms and permanent bending or extension of joints
• Progressive spinal muscle atrophy- This inherited disease is caused by the progressive degeneration of the horn cells in the spinal cord. Symptoms include muscle weakness, paralysis, muscle atrophy, cramps, tremors and joint pain^3,4

Diagnosis

Diagnosis of Isaacs’ syndrome involves multiple examinations. This includes assessment of nerve conduction, clinical presentation of the disease, electromyography (EMG) and serological testing. 

• Clinical evaluation- A medical examination should be conducted to understand the patient's symptoms and determine whether they represent symptoms that are characteristic of Isaacs’ syndrome. This may include muscle twitching, muscle cramps and stiffness. Also, checking whether the patient experiences prolonged muscle relaxation after voluntary muscle contractions. Lastly, determining whether any factors exacerbate the patient's symptoms, such as physical or mental stress
• Electromyography- This test records the electrical activity of muscles. In a patient with Isaacs’ syndrome, an EMG may show irregular bursts of discharges with high frequencies. The doublet or triplet firing pattern which may occur spontaneously or after voluntary muscle contraction is characteristic of Issacs’ syndrome
• Nerve conduction studies- This test is usually normal in patients with Issacs’ syndrome. However, it can be used to eliminate other diseases
• Blood tests- This can be used to test for VGKC antibodies which may be present in patients with Isaacs’ syndrome. Tests for other autoimmune conditions may also be conducted to rule out other disorders
• Imaging studies- An MRI of the brain and spinal cord may prove useful in eliminating other neuromuscular disorders^1,2 

Treatment

Currently, there is no cure for Isaacs’ syndrome. Treatment focuses on managing the symptoms and improving the quality of life for patients. Treatments include:

• Anticonvulsants- Medications such as carbamazepine, phenytoin, or gabapentin may help alleviate muscle stiffness and muscle cramps
• Sodium channel blockers- Mexiletine or lamotrigine may help to inhibit nerve impulses to reduce muscle hyperexcitability
• Intravenous Immunoglobulin (IVIg)- IVIg therapy may have been effective in some cases, however, there are no long-term studies to corroborate this. It is not generally used as a first response, but rather as an alternative when other treatments have been unsuccessful^1,2
• Plasmapheresis- This involves removing antibodies attacking the potassium ion channels from the blood plasma. This may improve the patient's symptoms
• Physiotherapy- This may help in improving strength, flexibility and coordination⁵
• Occupational Therapy- This may help the patient with their day-to-day living. It may help them in finding strategies to overcome challenges they may face when doing daily activities⁶
• Regular checkups- Patients should be regularly monitored to enable the physician to manage any changes in symptoms or detect whether there are any underlying diseases
• Surgical Intervention- Rarely, Isaacs syndrome could be caused by a tumour pressurizing the nerves. Therefore surgical removal may be required^1,2

Prognosis

Despite the challenges patients with Isaacs’ syndrome face, they can still lead fulfilling lives as long as the disease is managed. The correct treatment alongside close monitoring can help alleviate symptoms and improve the patient's quality of life. 

Summary

Isaacs’ syndrome is a neuromuscular disorder that causes muscle hyperactivity. It is an autoimmune disease that causes the body to attack itself. In this case, the voltage-gated potassium ion channels are targeted. There are both hereditary and acquired forms of the disease. Patients may experience symptoms including muscle cramps, stiffness and muscle twitching. There are various diseases that must be ruled out when diagnosing Isaacs’ syndrome, due to their similar clinical presentations. A diagnosis is determined based on symptoms, electromyography, blood tests, nerve conduction studies and imaging studies. 

There is no cure for Isaacs’ syndrome. Treatment involves alleviating symptoms to improve quality of life. Medical professionals may put patients on medication, they may undergo plasmapheresis or intravenous immunoglobulin therapy as well as physiotherapy and occupational therapy. The patient needs to receive regular checkups as those with Isaacs’ syndrome may be more susceptible or may have other underlying diseases. If you are experiencing any of the symptoms above and are concerned, please ensure to consult a healthcare professional.