What is benign fasciculation syndrome

Benign fasciculation syndrome is also called muscular pain-fasciculation syndrome, is a non-progressive chronic condition characterized by fasciculation, usually in the lower limbs, not associated with any other clinical abnormality ¹. Fasciculations are random muscle twitches that can be observed clinically, are characterized by visible subtle and fast contractions of muscle, even wormlike in movement, by the contraction of a fascicle of muscle fibers ². The clinical pattern of benign fasciculation syndrome frequently includes muscle cramps and local pain, symptoms that may worsen with physical activity and lessen with rest ³. Occasionally, some patients also complain about numbness or tingling ⁴. Fasciculation and cramps without weakness or muscle atrophy are recognized as a benign syndrome ⁵. Long-term follow-up of benign fasciculation syndrome cases ⁶ has verified the benign nature of the condition.

Benign fasciculation syndrome patients usually have fasciculation in their lower limb muscles but no weakness or reflex change. These patients presented in a variety of ways: they had noticed leg muscle twitches and were concerned they might have amyotrophic lateral sclerosis (ALS), non-specific sensory disturbance in the legs or feet and were noted to have fasciculation by referring physicians and leg muscle stiffness thought by referring physicians to represent an upper motor neuron abnormality.

Using the case records of Mayo Clinic patients, 121 patients with a diagnosis of benign fasciculations were identified. All had a normal neurological examination and normal electrophysiological studies, except for fasciculation potentials ⁷. Interviews by telephone were conducted 2 to 32 years after diagnosis. None of the patients developed symptomatic motor neuron disease. Forty individuals were in health care careers. A subset of 19 patients described acute onset of fasciculations following a viral infection. Benign fasciculations are not a preclude to progressive motor neuron disease.

Fasciculations are associated with electrical events recorded by a needle electrode as fasciculation potentials ¹. A fasciculation potential represents the spontaneous discharge of a motor unit or part thereof. Although fasciculation potentials are seen in many conditions, e.g. peripheral neuropathy ⁸, radiculopathy ⁹, peripheral nerve hyper-excitability syndromes ¹⁰ and following the use of depolarizing blocking agents ¹¹; they are of particular importance in the diagnosis of motor neuron diseases. Lambert ¹², in providing the first guidelines for the diagnosis of amyotrophic lateral sclerosis (ALS), asserted that it would be difficult to entertain the diagnosis of ALS without recording fasciculations. Fasciculation potentials also occur in otherwise healthy individuals in the condition termed benign fasciculation syndrome ¹³.

In the benign fasciculation syndrome, fasciculation potentials occur predominantly, but not exclusively, in the distal leg muscles ¹. The origin of these fasciculation potentials is unknown. It has been suggested ¹⁴ that benign fasciculations may arise by ephaptic transmission from irregularly fibrillating fibers. Others suggest that benign fasciculations arise proximally ¹⁵. Study of benign fasciculations in upper limb muscles of three patients ¹⁶ found fasciculation potentials had stable waveforms and a firing rate higher than those in amyotrophic lateral sclerosis. It has also been suggested ¹⁷ that benign fasciculation potentials are more likely to be able to be activated voluntarily than amyotrophic lateral sclerosis fasciculation potentials and have larger amplitudes than voluntary units in the same muscle. There has been no large-scale study, however, examining a wider group of parameters including an assessment of waveform stability, complexity and firing interval distribution in benign fasciculation syndrome.

How long does benign fasciculation syndrome last?

Benign fasciculations (isolated and persistent) can last for months and/or years ².

How common is benign fasciculation syndrome?

There is no data in the prevalence of benign fasciculation syndrome in the general population. In a 1983 study ¹⁸ out of Finland, The extensor digitorum brevis and abductor digiti minimi muscles were examined bilaterally with electromyography in 53 healthy subjects. In 72% of the subjects either fibrillation potentials, positive sharp waves or fasciculation was seen in at least one muscle examined.

Benign fasciculation syndrome vs ALS

ALS is short for amyotrophic lateral sclerosis, which is a group of rare neurological diseases that mainly involve the nerve cells (neurons) responsible for controlling voluntary skeletal muscle movement. Voluntary skeletal muscles produce movements like chewing, walking, and talking. ALS disease is progressive, meaning the symptoms get worse over time. Early symptoms of ALS usually include muscle weakness or stiffness. Gradually all muscles under voluntary control are affected, and individuals lose their strength and the ability to speak, eat, move, and even breathe. Currently, there is no cure for ALS and no effective treatment to halt, or reverse, the progression of the ALS disease.

ALS belongs to a wider group of disorders known as motor neuron diseases, which are caused by gradual deterioration (degeneration) and death of motor neurons. Motor neurons are nerve cells that extend from the brain to the spinal cord and to muscles throughout the body. These motor neurons initiate and provide vital communication links between the brain and the voluntary muscles.

Messages from motor neurons in the brain (called upper motor neurons) are transmitted to motor neurons in the spinal cord and to motor nuclei of brain (called lower motor neurons) and from the spinal cord and motor nuclei of brain to a particular muscle or muscles.

In ALS, both the upper motor neurons and the lower motor neurons degenerate or die, and stop sending messages to the muscles. Unable to function, the muscles gradually weaken, start to twitch (called fasciculations), and waste away (atrophy). Eventually, the brain loses its ability to initiate and control voluntary movements.

In ALS, most fasciculations are thought to be generated in the fine intramuscular axons innervating individual muscle fibers or at motor endplates ¹⁹. First, cutting the nerve supply to a fasciculating muscle ²⁰ or anesthetic blockade of the nerve trunk supplying it ²¹ does not abolish fasciculation. Second, a study of the waveforms of fasciculation potentials shows that sometimes individual fibre components can be recognized that occur in a different order, implying different generator sites in the same motor unit arborization ²². Third, it has been shown that fasciculation potentials evoke an F-response and, by using the fasciculation potential to trigger stimulation of the nerve trunk, blocking of the F-response only occurs when the stimulus is given such that collision occurs distally ²³.

Some fasciculation potentials in ALS however, may arise in more proximal sites ²⁴; it has been shown for instance, that some fasciculation potentials in ALS can be driven by weak transcranial magnetic stimuli to the motor cortex ²⁵. Study of so-called combined fasciculations ²⁶, meaning fasciculation potentials with two or more components that could occur independently, suggested that these could arise at supraspinal sites although it was conceded that multiple distal generators could also explain the phenomenon. Furthermore, a recent multi-electrode surface EMG study ²⁷ has shown that inter-fasciculation intervals may follow either a Poisson distribution, as would be expected from a random rare event, or a more symmetrical distribution of shorter intervals (3–15 ms), generally referred to as double fasciculation potentials. On the basis of the known refractoriness of cell body membrane as opposed to axonal membrane, the former were postulated to be related to spinal motor neuron subexcitability from 50 to 80 ms post-discharge, whereas the latter were thought to occur during the phase of axonal superexcitabilty following the first discharge ²⁸.

Most people with ALS die from respiratory failure, usually within 3 to 5 years from when the symptoms first appear. However, about 10 percent of people with ALS survive for 10 or more years.

Who gets ALS?

In 2016 the Centers for Disease Control and Prevention estimated that between 14,000 – 15,000 Americans have ALS. ALS is a common neuromuscular disease worldwide. It affects people of all races and ethnic backgrounds.

There are several potential risk factors for ALS including:

• Age. Although ALS can strike at any age, symptoms most commonly develop between the ages of 55 and 75.
• Gender. Men are slightly more likely than women to develop ALS. However, as we age the difference between men and women disappears.
• Race and ethnicity. Most likely to develop the disease are Caucasians and non-Hispanics.

Some studies suggest that military veterans are about 1.5 to 2 times more likely to develop ALS. Although the reason for this is unclear, possible risk factors for veterans include exposure to lead, pesticides, and other environmental toxins. ALS is recognized as a service-connected disease by the U.S. Department of Veterans Affairs.

Sporadic ALS

The majority of ALS cases (90 percent or more) are considered sporadic. This means the disease seems to occur at random with no clearly associated risk factors and no family history of the disease. Although family members of people with sporadic ALS are at an increased risk for the disease, the overall risk is very low and most will not develop ALS.

Familial (Genetic) ALS

About 5 to 10 percent of all ALS cases are familial, which means that an individual inherits the disease from his or her parents. The familial form of ALS usually only requires one parent to carry the gene responsible for the disease. Mutations in more than a dozen genes have been found to cause familial ALS. About 25 to 40 percent of all familial cases (and a small percentage of sporadic cases) are caused by a defect in a gene known as “chromosome 9 open reading frame 72,” or C9ORF72. Interestingly, the same mutation can be associated with atrophy of frontal-temporal lobes of the brain causing frontal-temporal lobe dementia. Some individuals carrying this mutation may show signs of both motor neuron and dementia symptoms (ALS-FTD). Another 12 to 20 percent of familial cases result from mutations in the gene that provides instructions for the production of the enzyme copper-zinc superoxide dismutase 1 (SOD1).

ALS symptoms

The onset of ALS can be so subtle that the symptoms are overlooked but gradually these symptoms develop into more obvious weakness or atrophy that may cause a physician to suspect ALS. Some of the early ALS symptoms include:

• fasciculations (muscle twitches) in the arm, leg, shoulder, or tongue
• muscle cramps
• tight and stiff muscles (spasticity)
• muscle weakness affecting an arm, a leg, neck or diaphragm.
• slurred and nasal speech
• difficulty chewing or swallowing.

For many individuals the first sign of ALS may appear in the hand or arm as they experience difficulty with simple tasks such as buttoning a shirt, writing, or turning a key in a lock. In other cases, symptoms initially affect one of the legs, and people experience awkwardness when walking or running or they notice that they are tripping or stumbling more often.

When symptoms begin in the arms or legs, it is referred to as “limb onset” ALS. Other individuals first notice speech or swallowing problems, termed “bulbar onset” ALS.

Regardless of where the symptoms first appear, muscle weakness and atrophy spread to other parts of the body as the disease progresses. Individuals may develop problems with moving, swallowing (dysphagia), speaking or forming words (dysarthria), and breathing (dyspnea).

Although the sequence of emerging symptoms and the rate of disease progression vary from person to person, eventually individuals will not be able to stand or walk, get in or out of bed on their own, or use their hands and arms.

Individuals with ALS usually have difficulty swallowing and chewing food, which makes it hard to eat normally and increases the risk of choking. They also burn calories at a faster rate than most people without ALS. Due to these factors, people with ALS tend to lose weight rapidly and can become malnourished.

Because people with ALS usually retain their ability to perform higher mental processes such as reasoning, remembering, understanding, and problem solving, they are aware of their progressive loss of function and may become anxious and depressed.

A small percentage of individuals may experience problems with language or decision-making, and there is growing evidence that some may even develop a form of dementia over time.

Individuals with ALS will have difficulty breathing as the muscles of the respiratory system weaken. They eventually lose the ability to breathe on their own and must depend on a ventilator. Affected individuals also face an increased risk of pneumonia during later stages of the disease. Besides muscle cramps that may cause discomfort, some individuals with ALS may develop painful neuropathy (nerve disease or damage).

What causes ALS?

The cause of ALS is not known, and scientists do not yet know why ALS strikes some people and not others. However, evidence from scientific studies suggests that both genetics and environment play a role in the development of ALS.

Genetics

An important step toward determining ALS risk factors was made in 1993 when scientists discovered that mutations in the SOD1 gene were associated with some cases of familial ALS. Although it is still not clear how mutations in the SOD1 gene lead to motor neuron degeneration, there is increasing evidence that the gene playing a role in producing mutant SOD1 protein can become toxic.

Since then, more than a dozen additional genetic mutations have been identified and each of these gene discoveries is providing new insights into possible mechanisms of ALS.

The discovery of certain genetic mutations involved in ALS suggests that changes in the processing of RNA molecules may lead to ALS-related motor neuron degeneration. RNA molecules are one of the major macromolecules in the cell involved in directing the synthesis of specific proteins as well as gene regulation and activity.

Other gene mutations indicate defects in the natural process in which malfunctioning proteins are broken down and used to build new ones, known as protein recycling. Still others point to possible defects in the structure and shape of motor neurons, as well as increased susceptibility to environmental toxins. Overall, it is becoming increasingly clear that a number of cellular defects can lead to motor neuron degeneration in ALS.

In 2011 another important discovery was made when scientists found that a defect in the C9ORF72 gene is not only present in a significant subset of individuals with ALS but also in some people with a type of frontotemporal dementia (FTD). This observation provides evidence for genetic ties between these two neurodegenerative disorders. Most researchers now believe ALS and some forms of FTD are related disorders.

Environmental factors

In searching for the cause of ALS, researchers are also studying the impact of environmental factors. Researchers are investigating a number of possible causes such as exposure to toxic or infectious agents, viruses, physical trauma, diet, and behavioral and occupational factors.

For example, researchers have suggested that exposure to toxins during warfare, or strenuous physical activity, are possible reasons for why some veterans and athletes may be at increased risk of developing ALS.

Although there has been no consistent association between any environmental factor and the risk of developing ALS, future research may show that some factors are involved in the development or progression of the disease.

ALS treatment

No cure has yet been found for ALS. However, there are treatments available that can help control symptoms, prevent unnecessary complications, and make living with the disease easier.

Supportive care is best provided by multidisciplinary teams of health care professionals such as physicians; pharmacists; physical, occupational, and speech therapists; nutritionists; social workers; respiratory therapists and clinical psychologists; and home care and hospice nurses. These teams can design an individualized treatment plan and provide special equipment aimed at keeping people as mobile, comfortable, and independent as possible.

Medication

The U.S. Food and Drug Administration (FDA) has approved the drugs riluzole (Rilutek) and edaravone (Radicava) to treat ALS. Riluzole is believed to reduce damage to motor neurons by decreasing levels of glutamate, which transports messages between nerve cells and motor neurons. Clinical trials in people with ALS showed that riluzole prolongs survival by a few months, particularly in the bulbar form of the disease, but does not reverse the damage already done to motor neurons. Edaravone has been shown to slow the decline in clinical assessment of daily functioning in persons with ALS.

Physicians can also prescribe medications to help manage symptoms of ALS, including muscle cramps, stiffness, excess saliva and phlegm, and the pseudobulbar affect (involuntary or uncontrollable episodes of crying and/or laughing, or other emotional displays). Drugs also are available to help individuals with pain, depression, sleep disturbances, and constipation. Pharmacists can give advice on the proper use of medications and monitor a person’s prescriptions to avoid risks of drug interactions.

Physical therapy

Physical therapy and special equipment can enhance an individual’s independence and safety throughout the course of ALS. Gentle, low-impact aerobic exercise such as walking, swimming, and stationary bicycling can strengthen unaffected muscles, improve cardiovascular health, and help people fight fatigue and depression. Range of motion and stretching exercises can help prevent painful spasticity and shortening (contracture) of muscles.

Physical therapists can recommend exercises that provide these benefits without overworking muscles. Occupational therapists can suggest devices such as ramps, braces, walkers, and wheelchairs that help individuals conserve energy and remain mobile.

Speech therapy

People with ALS who have difficulty speaking may benefit from working with a speech therapist, who can teach adaptive strategies to speak louder and more clearly. As ALS progresses, speech therapists can help people maintain the ability to communicate. They can recommend aids such as computer-based speech synthesizers that use eye-tracking technology and can help people develop ways for responding to yes-or-no questions with their eyes or by other nonverbal means.

Some people with ALS may choose to use voice banking while they are still able to speak as a process of storing their own voice for future use in computer-based speech synthesizers. These methods and devices help people communicate when they can no longer speak or produce vocal sounds.

Nutritional support

Nutritional support is an important part of the care of people with ALS. It has been shown that individuals with ALS will get weaker if they lose weight. Nutritionists can teach individuals and caregivers how to plan and prepare small meals throughout the day that provide enough calories, fiber, and fluid and how to avoid foods that are difficult to swallow. People may begin using suction devices to remove excess fluids or saliva and prevent choking. When individuals can no longer get enough nourishment from eating, doctors may advise inserting a feeding tube into the stomach. The use of a feeding tube also reduces the risk of choking and pneumonia that can result from inhaling liquids into the lungs.

Breathing support

As the muscles responsible for breathing start to weaken, people may experience shortness of breath during physical activity and difficulty breathing at night or when lying down. Doctors may test an individual’s breathing to determine when to recommend a treatment called noninvasive ventilation (NIV). NIV refers to breathing support that is usually delivered through a mask over the nose and/or mouth. Initially, NIV may only be necessary at night. When muscles are no longer able to maintain normal oxygen and carbon dioxide levels, NIV may be used full-time. NIV improves the quality of life and prolongs survival for many people with ALS.

Because the muscles that control breathing become weak, individuals with ALS may also have trouble generating a strong cough. There are several techniques to help people increase forceful coughing, including mechanical cough assist devices and breath stacking. In breath stacking, a person takes a series of small breaths without exhaling until the lungs are full, briefly holds the breath, and then expels the air with a cough.

As the disease progresses and muscles weaken further, individuals may consider forms of mechanical ventilation (respirators) in which a machine inflates and deflates the lungs. Doctors may place a breathing tube through the mouth or may surgically create a hole at the front of the neck and insert a tube leading to the windpipe (tracheostomy). The tube is connected to a respirator.

Individuals with ALS and their families often consider several factors when deciding whether and when to use ventilation support. These devices differ in their effect on a person’s quality of life and in cost. Although ventilation support can ease problems with breathing and prolong survival, it does not affect the progression of ALS. People may choose to be fully informed about these considerations and the long-term effects of life without movement before they make decisions about ventilation support.

Benign fasciculation syndrome causes

The precise cause of benign fasciculation syndrome is unknown, and it is not known if it is a disease of the motor nerves, the muscles, or the neuromuscular junction. Benign fasciculation syndrome potential causes ²⁹:

• Coffee ³⁰
• Stress ³¹,
• Anxiety ³¹,
• Cigarettes,
• Corticosteroid use (high dose) ²⁹,
• Strenuous and high intensity exercises ³⁰

Recent studies have found an association between widespread fasciculations and/or paresthesias with small fiber neuropathy in up to 82% of cases which have a normal EMG and nerve conduction study ³². Many patients with benign fasciculation syndrome exhibit a significant decrease in sweat gland nerve fiber density or epidermal nerve fiber density, with the sweat gland nerve fiber density preferentially affected ³².

Benign fasciculation syndrome symptoms

The main symptom of benign fasciculation syndrome is focal fasciculation mainly in forearms, calves and thumb ²⁹ or widespread involuntary muscle activity (twitching), which can occur at random or specific times (or places). Presenting symptoms of benign fasciculation syndrome may include ³³:

• Fasciculations (primary symptom)
  • Blepharospasms (eye spasms)
• Generalized fatigue
• Muscle pain
• Anxiety (which can also be a cause)
• Exercise intolerance
• Globus sensation
• Paraesthesias
• Muscle cramping or spasms

Other symptoms include:

• Hyperreflexia
• Muscle stiffness
• Tremors
• Itching
• Myoclonic jerks

Benign fasciculation syndrome symptoms are typically present when the muscle is at rest and benign fasciculation syndrome patients had normal strength and their EMG showed normal motor unit potential analysis ³⁴. In some benign fasciculation syndrome cases, fasciculations can jump from one part of the body to another. For example, it could start in a leg muscle, then in a few seconds jump to the forehead, then the abdomen, etc. Because fasciculations can occur on the head, this strongly suggests the brain as the generator due to its exclusive non-dependence on the spinal cord. There was no progression to other disorders in the following 2 years ³⁴. Some had associated muscle cramps. No metabolic or medication-related cause was identified.

Benign fasciculation syndrome diagnosis

Benign fasciculation syndrome is a diagnosis of exclusion; that is, other potential causes for the twitching (mostly forms of neuropathy or motor neuron diseases such as ALS) must be ruled out before benign fasciculation syndrome can be assumed. An important diagnostic tool here is electromyography (EMG). Since benign fasciculation syndrome appears to cause no actual nerve damage (at least as seen on the EMG). Electroneuromyography (ENMG) revealed signs of fasciculation potentials, positive waves as well as fibrillations in the various muscle groups tested ³⁵.

Fasciculations require a meticulous clinical and neurologic evaluation in order to look for the cause behind them. The diagnosis frequently is difficult to reach due to the ample range and scope of potential clinical conditions likely to cause them. Additional studies will be necessary in the future.

Other potential causes of fasciculation that will require exclusion before the diagnosis of benign fasciculation syndrome can be made ²⁹:

Neurogenic disorders resulting from fasciculations:

• Amyotrophic Lateral Sclerosis.
• Spinal Muscular atrophies.
• Benign monomelic amyotrophy (Hirayama disease).
• Kennedy Disease
• Multifocal Motor Neuropathy
• Acute Anterior Poliomyelitis
• Radiculopathy
• Peripheral Neuropathies
• Plexopathy
• Syringomyelia
• Creutzfeldt-Jakob Disease
• Spinal amyotrophy of upper limbs (distal)

Fasciculations for metabolic diseases:

• Thyrotoxicosis
• Tetanus

Fasciculations caused by drug use:

• Anticholinergic Drugs
• Use of Steroids (corticosteroids)
• Organophosphates and other insecticides | pesticides (commonly in the acute intoxication).
• Lithium

Fasciculations caused by systemic diseases:

• Infections, mainly viral. (HIV-1, 2, HTLV-1, syphilis)
• Neurosarcoidosis

Another important step in diagnosing benign fasciculation syndrome is checking the patient for clinical weakness. Clinical weakness is often determined through a series of strength tests, such as observing the patient’s ability to walk on his or her heels and toes. Resistance strength tests may include raising each leg, pushing forward and backward with the foot and/or toes, squeezing with fingers, spreading fingers apart, and pushing with or extending arms and/or hands. In each such test the test provider will apply resisting force and monitor for significant differences in strength abilities of opposing limbs or digits. If such differences are noted or the patient is unable to apply any resisting force, clinical weakness may be noted.

Singh et al. ³⁶, in a study of 4 patients who were initially diagnosed with Benign Cramping and Fasciculation Syndrome (SCFB), identified these same patients as progressing to Amyotrophic Lateral Sclerosis. In view of this, the authors warn that a diagnosis of Benign Cramping and Fasciculation Syndrome should not be considered accurate without a 4 to 5 year follow up following onset of clinical symptoms. According to the above-mentioned considerations, a follow up of five years duration was thus requested for the proper characterization of benign fasciculation syndrome ²⁹.

Benign fasciculation syndrome treatment

The treatment of benign fasciculation syndrome is always symptomatic, based especially upon antiepileptic drugs, including carbamazepine, gabapentine, and phenytoin, mostly with only partial clinical control of symptoms ². Recently, gabapentin proved to decrease fasciculations and cramps both in benign syndromes and ALS ³⁷. Gabapentin acts as membrane stabilizer, lessening the excitability of peripheral nerve and modulating neuron receptors. It has an inhibitory effect on the release of dopamine and norepinephrine, rendering an increase of GABAergic concentration in several brain areas. Doses from 300 to 600 mg three times a day are reported to be effective and safe ³. The interpretation of the effect of these drugs concerning their precise mechanism of action is still speculative, although believed to be through the decrease of distal peripheral nerve ending excitability ³⁸.

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