RLS is a common disease that affects about 10% of the general population [1].

1. What Is the Main Cause of Restless Leg Syndrome?

Although the cause is unknown, it is thought that the main cause of restless leg syndrome (RLS) is associated with an imbalance in the function of the neurotransmitter dopamine due to low levels of iron in the brain and body [1].

Dopamine is an organic chemical involved in the transmission of instructions between neurons to control muscle movements and reward-motivated behavior [2].

Other potential causes involve heredity, pregnancy, attention deficit hyperactivity disorder (ADHD), and medications.

1.1. What Is the Relation Between Restless Leg Syndrome and Heredity?

A role of heredity in RLS is associated with the high frequency of family history of RLS in patients diagnosed with this disease [3].

Monozygotic and dizygotic twin studies confirmed heredity involvement in RLS by showing the existence of a high concordance of RLS in monozygotic twins compared with that in dizygotic twins.

1.2. What Is the Relation Between Restless Leg Syndrome and Pregnancy?

Due to hormonal changes during the third semester of pregnancy, some women may experience RLS which disappears after delivery [4].

These changes involve an increase in the production of hormones, including estrogens, prolactin, progesterone, and thyroid hormone.

A reduction of iron and folate levels during pregnancy also appears to contribute to RLS due to their involvement in the synthesis of dopamine which further highlights the role of dopamine as the main cause of restless leg syndrome.

The prevalence of RLS during pregnancy was estimated to be in the range of 2.9-32% which is about 2-3 times higher than that in non-pregnant women.

1.3. What Is the Relation Between Restless Leg Syndrome and ADHD?

A relation Between Restless Leg Syndrome and ADHD was proposed by a study that showed that 44% of individuals with ADHD also had RLS.

Another important piece of information to add is that both ADHD and RLS have alterations related to dopamine levels in the brain [5].

1.4. What Is the Relation Between Restless Leg Syndrome and Medications?

Certain medications have been associated with restless leg syndrome, such as antidepressants (e.g., SSRIs, Tricyclics), withdrawal from sedative-hypnotic drugs (e.g., benzodiazepines), antiemetics (e.g., anticholinergics), antipsychotics, anticonvulsants, and antihistamines (e.g., diphenhydramine) [6].

Furthermore, alcohol and opioid withdrawal have also been associated with RLS.

2. Who Is Prone to Restless Leg Syndrome?

Restless leg syndrome (RLS) can develop at any age but is more common in women than men. There are also some factors that can increase the risk of RLS:

• Low Iron Levels
• Kidney Failure
• Neuropathy
• Rheumatoid Arthritis
• Diabetes Mellitus
• Celiac Disease
• Alcohol
• Iron Deficiency Anemia
• Parkinson’s Disease

2.1. Low Iron Levels

Iron is an essential cofactor in the production of dopamine and its deficiency can trigger RLS. Low iron levels can be due to blood loss through internal hemorrhage (e.g., gastrointestinal bleeding), excessive menstrual bleeding, frequent blood donations, or malabsorption.

2.2. Kidney Failure

Patients with chronic kidney disease on dialysis have decreased levels of iron due to the depletion of its storage in the blood.

2.3. Neuropathy

Increased levels of glucose in the blood such as during diabetes can lead to damage of nerves resulting in RLS.

2.4. Rheumatoid Arthritis

There is an elevated prevalence of RLS in patients with rheumatoid arthritis reaching between 27.7-31% [7].

2.5. Alcohol

Excessive consumption of alcohol (alcoholism) can lead to damage of nerves leading to RLS.

2.6. Celiac Disease

Celiac disease is an intestinal chronic disease characterized by a loss of appetite, malabsorption, and diarrhea due to gluten intolerance.

Celiac disease can also lead to iron deficiency which may lead to RLS. In fact, a study showed that 40% of studied patients with celiac disease had an iron deficiency [8].

2.7. Parkinson’s Disease

The characteristic dysfunction of dopamine in Parkinson’s Disease may explain why RLS is observed in some PD patients [9].

2.8. Iron Deficiency Anemia

Iron deficiency anemia is caused by a lack of iron in the body resulting in a reduction of the number of red blood cells leading to anemia. This lack of iron can also affect dopamine production.

3. What Symptoms Come with Restless Leg Syndrome?

Restless leg syndrome manifests with the following symptoms:

• An urge to move the legs due unpleasant sensations in the legs.
• An urge to move the legs during periods of rest or inactivity.
• The urge to move the legs may partially or totally be relieved by movement, such as walking or stretching.
• The urge to move the legs is increased in the evening or night than during the day.

4. Is Restless Leg Syndrome Psychological?

Although restless leg syndrome (RLS) is considered a neurological disease, a study that included 38 patients with RLS and 42 non-RLS controls, showed that patients with RLS have a lower internal locus of control (ability to impact its own health) and negative sleep-related personality traits compared to the non-RLS controls [10].

A negative sleep-related personality trait is associated with lower self-confidence, depression, higher mental arousal, and poorer quality of life.

5. How do you get rid of restless legs syndrome?

The treatment of RLS is aimed at relieving the associated symptoms that are caused by underlying physical conditions such as diabetes, celiac disease, or iron deficiency.

Medications to relieve the symptoms of RLS involve the use of dopaminergic drugs to improve dopamine effects, opioids to relieve the symptoms of severe RLS, and benzodiazepines for restful sleep.

Changes in lifestyle such as stopping alcohol, exercising (e.g., aerobics, stretching), taking iron supplements, respecting a regular sleep pattern, can help relieve some of the moderate symptoms.

Conclusion

Restless leg syndrome (RLS) can cause uncomfortable sensations that can affect sleep and the quality of life of the affected individual. The cause is unknown, but many studies highlighted the potential involvement of dopamine as the main cause.

RLS is also associated with several diseases which share with RLS the deficiency in iron which is an essential cofactor in the production of dopamine. However, other diseases and conditions such as diabetes or alcoholism can lead to nerve damage due to high blood levels of glucose or alcohol, respectively.

Although there is no specific treatment for RLS, dealing with this disease involves symptomatic treatments that aim at alleviating or reducing the undesirable and overwhelming manifestations of RLS.

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• AMPA Receptor Antagonists
• Barbiturate antiepileptics
• Benzodiazepine antiepileptics
• Carbamate antiepileptics
• Carbonic Anhydrase Inhibitor antiepileptics
• Dibenzazepine antiepileptics
• Fatty Acid Derivative antiepileptics
• Gamma-Aminobutyric Acid Analogs
• Gamma-Aminobutyric Acid Reuptake Inhibitors
• Hydantoin antiepileptics
• Neuronal Potassium Channel Openers
• Oxazolidinedione antiepileptics
• Pyrrolidine antiepileptics
• Succinimide antiepileptics
• Triazine antiepileptics

1. What Is Epileptic Seizure?

An epileptic seizure is a neurological disorder due to an abnormally excessive, and repetitive neuronal activity in the brain resulting in seizures [1].

It is characterized by uncontrolled shakings caused by convulsions where the muscles of the body contract and relax rapidly and frequently, and loss of consciousness.

The seizures can be focal (only parts of the body) at the beginning and then become generalized to the whole body.

It was estimated that 50 million people worldwide have epilepsy [2]. In the United States, it was estimated that 1.2% of people have active epilepsy including 3 million adults and 470,000 children [3].

2. What Causes a Person to Have Epileptic Seizures?

Epileptic seizures are caused by excessive neuronal activity (hyperexcitation) that is not blocked by the inhibitory mechanisms in the brain.

In physiological conditions, there is always a balance between neuronal excitation and inhibition.

The inhibition of neuron excitation is controlled by a mechanism known as hyperpolarization which involves GABAergic neurons, gamma-aminobutyric acid (GABA) receptors, and potassium channels.

Hyperpolarization results in the inhibition of action potential resulting in the inhibition of the excitation of neurons in the brain.

Therefore, anomalies affecting GABAergic neurons, gamma-aminobutyric acid (GABA) receptors, or potassium channels lead to hyperexcitation of neurons causing seizures.

Seizures can be caused by the following conditions or disorders:

• Metabolic conditions (e.g., low blood pressure, high concentration of sodium in the blood)
• Encephalitis
• Meningitis
• drug overdose (e.g., antidepressants, cocaine, antipsychotics)
• developmental disorders (e.g., venous malformation)
• Hematoma or abscess (due to brain trauma or infections)
• Brain tumors

3. What Are the Types of Antiepileptics drugs?

3.1. What Are AMPA Receptor Antagonists?

The α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA) is a receptor for the neurotransmitter glutamate.

Neurotransmitters are messengers that transmit specific chemical instructions from a neuron to another neuron and from neurons to tissues and organs.

Glutamate is the most abundant chemical messenger that is involved in excitatory neurotransmission which increases nerves impulses (action potential) [4].

AMPA receptor antagonists prevent the binding of glutamate to AMPA receptors which prevents its excitation activity toward neurons.

The most known AMPA receptor antagonist is Perampanel sold under the brand name Fycompa.

3.2. What Are Barbiturate Antiepileptics?

Barbiturates exert their antiepileptics effect through their binding to GABA receptors which inhibit neuron excitation.

They also bind to AMPA receptors which prevent the binding of glutamate and the excitation of neurons.

Barbiturate antiepileptics include drugs such as primidone (Mysoline), phenobarbital (Luminal, Mebaral), and Alphenal (Efrodal, Prophenal).

3.3. What Are Benzodiazepine Antiepileptics?

Benzodiazepines prevent the excitation of neurons by enhancing the effect of GABA on GABA_A receptors.

GABA (Gamma-Aminobutyric acid) is a chemical messenger and the major inhibitor of neurotransmission by reducing nerve impulses (action potential).

Therefore, it has an opposite action to that of glutamate and ensures balanced neurotransmission [5].

Benzodiazepine antiepileptics include drugs such as diazepam (Valium), midazolam (Versed), clonazepam (Klonopin), clobazam (Onfi), lorazepam (Ativan), and clorazepate (Tranxene T-Tab).

3.4. What Are Carbamate Antiepileptics?

Although the mechanism of action of carbamate antiepileptics is not well-known, they may be involved in promoting the activation of GABA_A receptors and the inhibition of AMPA receptors [6][7].

Carbamate antiepileptics include drugs such as Felbamate (Felbatol) and cenobamate (Xcopri).

3.5. What Are Carbonic Anhydrase Inhibitor Antiepileptics?

Carbonic anhydrase inhibitors block the activity of the enzyme carbon anhydrase involved in the maintenance of intracellular (within the cells) homeostasis by catalyzing reversible hydration (adding water) of carbon dioxide (CO2).

Low levels of carbon dioxide have been shown to increase the excitation of neurons, and therefore, the inhibition of carbonic anhydrase block the hyperexcitability of neurons during epileptic seizures [8].

Carbonic anhydrase Inhibitors antiepileptics include drugs such as topiramate, acetazolamide, zonisamide, and topiramate.

3.6. What Are Dibenzazepine Antiepileptics?

Dibenzazepine antiepileptics are inhibitors of voltage-gated sodium channels involved in the action potential of neurons resulting in the blockage of their excitation [9].

Dibenzazepine antiepileptics include drugs such as carbamazepine (Tegretol), oxcarbazepine (Trileptal), and rufinamide (Bansel).

3.7. What Are Fatty Acid Derivative Antiepileptics?

Fatty acid derivative antiepileptics are drugs that inhibit voltage-gated sodium channels and enhance the activity of GABA, resulting in the blockage of neurons excitation [10].

Fatty acid derivative antiepileptics include drugs such as valproic acid (Depakene), and divalproex sodium (Depakote).

3.8. What Are Gamma-Aminobutyric Acid Analogs?

Gamma-aminobutyric acid analogs or GABA analogs share a similar structure to that of GABA, and therefore, are capable to induce the inhibition of neurons excitation [11].

GABA analogs include drugs such as acamprosate (Campral), pregabalin (Lyrica), gabapentin (Neurontin), and gabapentin encarbil (Horizant).

3.9. What Are Gamma-Aminobutyric Acid Reuptake Inhibitors?

GABA reuptake inhibitors block GABA reuptake by gamma-aminobutyric acid transporters which increase extracellular neuronal concentrations of GABA leading to increased inhibition of neurons excitation [12].

GABA reuptake inhibitors include drugs such as tiagabine (Gabitril), and stiripentol (Diacomit).

3.10. What Are Hydantoin Antiepileptics?

Hydantoin antiepileptics are drugs that block voltage-gated sodium channels which prevents action potentials resulting in the inhibition of neurotransmission [13].

Hydantoin antiepileptics include drugs such as phenytoin (Phenytek), ethotoin (Peganone), fosphenytoin (Sesquient), and mephenytoin (mesantoin).

3.11. What Are Neuronal Potassium Channel Openers?

Neuronal potassium channel openers are drugs that activate voltage-gated potassium channels of the Kv7 subfamily which results in the hyperpolarization neurons and the inhibition of their excitation [14].

Neuronal potassium channel openers include drugs such as ezogabine (Potiga).

3.12. What Are Oxazolidinedione Antiepileptics?

Although oxazolidinedione antiepileptics reduce neurons excitation, their mechanism of action is unknown. These drugs also appear to cause birth defects due to maternal exposure during pregnancy [15].

Oxazolidinedione antiepileptics include drugs such as trimethadione (Tridione).

3.13. What Are Pyrrolidine Antiepileptics?

Although the mechanism by which pyrrolidine antiepileptics inhibit neurons excitation is not well known, it was suggested that the mechanism may be associated with the inhibition of presynaptic calcium channels through which reduces neurotransmission [16].

Pyrrolidine antiepileptics include drugs such as levetiracetam (Keppra), and brivaracetam (Briviact).

3.14. What Are Succinimide Antiepileptics?

Succinimide antiepileptics are drugs that reduce neurons excitation by blocking low voltage calcium channels (T-type calcium channels) involved in action potentials [17].

Succinimide antiepileptics include drugs such as Ethosuximide (Zarontin) and methsuximide (Celontin).

3.15. Triazine Antiepileptics

Triazine antiepileptics are drugs that inhibit neurons excitation by blocking voltage-gated sodium channels involved in the action potentials [18].

Triazine antiepileptics include drugs such as lamotrigine (Lamictal).

Conclusion

Although these categories of drugs are used for the treatment of epileptic seizures, they have also other activities that were not discussed in this article and will be discussed in another article.

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