There have been substantial amount of research carried out in the last 20 years that are aimed at narrowing down the causes of RLS to more specific factors.
Just like many diseases and health conditions, RLS can also be related to environmental factors and genes.
The specific causes of RLS are still generally unknown, but scientists have been able to identify a few risk factors that may lead to RLS.
RLS has been linked to a genetic component that is common in families where symptoms are noticed before the age of 40 years.
Apart from genetic factors, scientists have also identified iron deficiency in the brain, which is one of the leading causes of RLS.
Iron deficiency (as in Low total body iron status) accounts for about 20% of all diagnosed RLS cases.
In 2007, scientific research was published which detected distinct RLS features in 34% of people who have iron deficiency against 6% of the control population.
Other conditions associated with RLS include venous reflux, magnesium deficiency, folate deficiency, fibromyalgia, hernia, sleep apnea, peripheral neuropathy, diabetes, uremia, peripheral neuropathy, thyroid disease, Parkinson’s disease, and some autoimmune diseases such as celiac disease, Sjogren’s syndrome, and rheumatoid arthritis.
RLS is also known to get worse during pregnancy.
Iron deficiency
Iron deficiency remains the single largest known environmental factor that may develop before birth, during pregnancy, during infancy or later in life.
As mentioned earlier the role that iron levels play in the development of RLS is quite obvious and cannot be overlooked.
Iron deficiency remains the most investigated factor responsible for RLS.
Professor Nordlander discovered the link between iron deficiency and RLS, he also reported that the treatment of iron deficiency had a significant effect by improving or eliminating symptoms of RLS.
Despite the strong link between serum iron deficiency and RLS, it was found that only about 15% of the clinical population had peripheral iron deficiency.
In order to account for this gap in the research, Professor Nordlander stated in his hypothesis “It is possible…that there can exist an iron deficiency in the tissues in spite of normal serum iron.”
This hypothesis generated a lot of interest among scientist who went on to examine whether it was possible for the brain to be deficient in iron with normal serum iron measurements.
Further studies have since embraced the concept of low brain iron levels in patients who have RLS even when their blood samples indicate normal iron levels when tested.
Studies employing the use of MRI scans have shown a deficiency of iron in the substantia nigra, which is one of the primary regions in the brim where cells that produce dopamine are found.
Other studies using MRI have also identified a relationship between iron concentrations in the substantial nigra and the intensity or severity of RLS symptoms.
Genetics
Understanding the roles that genes play in our well-being can be extremely complex.
A damaged gene can lead to abnormal protein or lack of protein which can be responsible for diseases such as sickle cell anemia and hemophilia.
Other diseases such as Alzheimer’s, heart diseases, high blood pressure, and RLS, may be caused by a damaged gene or as a result of the interaction of several genes under certain conditions.
For instance, a person born with a normal heart can develop certain health conditions due to the interactions with several environmental factors (high cholesterol, aging, smoking, diabetes, increased blood pressure) and genes.
Scientist have explored the genetics of RLS in order to see how much influence it has in the pathogenesis of the disorder, especially when the condition is observed from a very young age.
Recently, a series of research have described a vulnerability to RLS that is being shown by three loci
Found in Italian and French-Canadian families in chromosomes 9q, 12q and 14q, which emphasizes an autosomal dominant manner of inheritance.
The three loci have been tagged RLS1, RLS2, RLS3 respectively.
However, the causative have remained quite elusive and there has been no linkage analysis identified in the candidate genes that have been investigated.
Interaction between Iron, Genetics and RLS
While low iron levels may have been resolved long before a person begins to develop or notice RLS symptoms, but the condition could create a domino effect where certain conditions that may eventually lead to RLS may be set in motion.
For instance, slight variations in several genes (TOX3, BTBD9, MAP2K5/LBXCOR1, MEIS1, PTPRD) has been established as a high risk factor for the development of RLS.
The change in the gene BTBD9 which is associated in with and increased risk of developing RLS is flu d in about 75% of patients with RLS, but is also present in 65% of patients who have never had the condition.
Studies have revealed that there is a point at which the interaction between iron and several genes occur, which further support the research concept that there is indeed an interaction between iron levels and several genes at one point in one’s life which may be responsible for the onset of RLS.
Other Causes
The Relationship Between ADHD,RLS and Dopamine levels in the Brain
Scientists have carried out observations that identified an association between attention deficit hyperactivity disorder (ADHD) and RLS. Both RLS and ADHD have clear indications that they have links to dysfunctions that are related to the neurotransmitter dopamine, such that medications for both RLS and ADHD tend to affect the levels of dopamine in the brain.
A 2005 research identified that up to 44% of people who have ADHD also had coexisting RLS, while 26% of people who have RLS had presented ADHD or symptoms of the condition. This research justifies the relationship between both conditions and the dopamine levels of the brain.
Medications
There are several medications that may cause or worsen the symptoms of RLS.
These medications may cause it secondarily in addition to other factors that are responsible for secondary RLS in people who from the age of 40 and above.
People below the age of 40 may also develop RLS or experience worse symptoms such as an increase in sensations in their limbs or frequency of occurrence.
Medications that have been identified as possible causes of RLS include:
- Many antidepressants including older tricyclic antidepressants and newer Selective serotonin reuptake inhibitors
- Antidopaminergic antiemetics – these are drugs that are used for treating nausea and vomiting
- Sedating first generation Antihistamines that are commonly found in over-the-counter medications for cold
- Anticonvulsants and antipsychotic drugs
- Alcohol Withdrawal is associated with RLS and other similar conditions such as parkinsonism and akathisia
- Caffeine
- Beta blockers
- Lithium
- Serotonin-norepinephrine reuptake inhibitors (SNRIs)
- Opioid withdrawal is associated with worsening or causing RLS
- Withdrawal from sleeping pills or benzodiazepine tranquilizers
Injury Related Causes
Recent studies and research have revealed that surgeries of any kind can cause or worsen both primary and secondary RLS. These include back surgeries or injuries.
It has not been established that conditions such as lack of exercise, excess weight, depression and other related mental illnesses can cause RLS. However, symptoms associated with RLS such as loss of sleep, or common medications for treating certain conditions could cause or worsen RLS.