3rd year Caroline Cristofaro investigates restless leg syndrome, a relatively unknown condition that can significantly impact a patient’s qualIty of life.
At first restless leg syndrome may seem like an innocent condition, however, it can be very debilitating for the patient. In addition to the obvious symptom of the patient feeling the uncontrollable desire to move their legs, patients can often suffer from insomnia, parasthesias and various uncomfortable sensations in the lower limbs (Facheris, M., et al., 2010). The goal of this article is to shed light on the symptoms and aetiology of this little known syndrome and what medications are given to treat it.
RLS has been found to have a strong genetic link and most cases are diagnosed as Familial RLS. Secondary RLS can be experienced during pregnancy and renal failure, both of which are associated with iron deficiency (Facheris, M., et al., 2010). Opioid-dependent patients can also experience RLS after stopping opioids as a withdrawal symptom (Ghosh, A. et al., 2014).
Restless Leg Syndrome (RLS) is categorized as both a sensorimotor and sleep disorder with the sensorimotor symptoms being the main complaint in most patients. The sensation is described using a myriad of terms such as itching, burning, crawling, tingling but is relived, albeit only temporarily by movement of the legs (Facheris, M., et al., 2010). Depending on the severity of the patient’s RLS, relief can be by simply stretching out the affected leg(s) or the patient may have to get up and walk around. Although it is fairly obvious why RLS would delay the onset of sleep, the explanation as to why RLS causes disturbed and fragmented sleep is somewhat less evident. Periodic Limb Movements of Sleep (PLMS) are defined as “semirhythmic movements of the limbs which last a few seconds and occur at regular intervals” (Cotter, P. and O’Keeffe, S., 2006), as is indicated by their name. These limb movements are nearly always present in the population suffering from RLS and, in addition, these movements are typically exaggerated and cause patients to awaken leading to patients’ awareness of RLS sensorimotor symptoms, which, of course, makes the task of falling asleep more arduous (Cotter, P. and O’Keeffe, S., 2006).
Whilst the exact cause of RLS has not yet been cemented, two factors have been shown to heavily impact symptoms. These are iron and dopamine levels within the substantia nigra.
Dopamine is a neurotransmitter, which plays an important role in regulating movement. The two main receptors for dopamine in the brain are D1 and D2 receptors and, each via a specific pathway, increase or decrease movement, respectively. In RLS, Positron Emission Tomography (PET) scans have consistently shown decreased activity of the D2 receptor, which normally decreases movement, leading to increased movement (Ruottinen, H.M., 2000). In support of these findings, Connor, JR et al. (2009) demonstrated a 30% reduction in D2 receptors in the basal ganglia using autopsies of patients who had been affected with severe RLS. As RLS occurs in the lower limbs, it is thought that the dopaminergic A11 cell group is mainly affected because they are the only neurones which provide dopaminergic axons to the spinal cord. This hypothesis was strengthened by Clement, S. et al. (2006) demonstrating increased movement in mice with a lesioned A11 dopaminergic cell group.
Iron acts as a coenzyme for tyrosine hydroxylase (an enzyme essential in dopamine synthesis) and it is also related to monoamine oxidase (an enzyme which degrades dopamine) (Facheris, M., et al., 2010). Due to its close relationship with dopamine, the concentration of iron in the brain influences the numbers of dopamine transporters and dopamine receptors (specifically D2 and D4); decreased concentration of iron in the CSF leads to decreased densities of dopamine transporters and receptors which have been attributed to the cause RLS symptoms (Omer, P. et al, 2007). However, a recent study by Conner J.R., et al. (2009) compared the post-mortem tyrosine hydroxylase concentrations of patients who had suffered from RLS to a control group and found no significant difference. Due to conflicting evidence, the previously explained role of dopamine in RLS is considered to be a hypothesis and, as a result, is still referred to as the “Dopamine Hypothesis”.
A critical review conducted by the International Restless Legs Syndrome Study Group in 2013 investigated the efficacy of various drugs to treat long-term RLS. For first line treatment it is recommended to give the patient dopamine-receptor agonists or calcium channel antagonists (pregbalin or gapapentin encarbil) (Gracia-Borreguero, D., et al., 2013). The dopamine agonists recommended are either ergot-based (pergolide and cabergoline) or non-ergot based (pramiprexole, ropinirole, rotigotine, levodopa). Calcium channel antagonists are used mainly when the patient complains of the physical symptoms and act to stop excessive muscle contraction. Iron supplements are also recommended when the patient’s serum ferritin levels are low (Gracia-Borreguero, D., et al., 2013). Together, these treatments decrease muscle contraction, help stabilize the dopaminergic pathways in the brain and increase the patient’s serum iron levels, further stabilizing the concentration of dopamine.
Although RLS may seem like a relatively benign condition at first thought, its constant, intrusive symptoms encroach on nearly every aspect of a patient’s life, making it very difficult to live with. Both its pathophysiology and, consequently, its treatment options draw similarity to Parkinson’s disease, which should also alert you to the seriousness of this syndrome. Unfortunately, none the drugs used to treat the condition have been proven to be effective for more than 1 year (Gracia-Borreguero, D., et al., 2013), which means that we have yet to find a drug that can effectively treat RLS for when the syndrome persists over a year. Hopefully future studies are able to find a concrete link between dopamine and RLS to explain the efficacy of dopamine agonists in treating the condition, or otherwise determine the accurate aetiology of the syndrome to prompt studies of new drugs able to effectively cure RLS.
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