IPF is a progressive, chronic, fibrotic lung disease with a bleak overall prognosis of 2-3 years and multiple comorbidities, including cardiovascular disease, chronic obstructive pulmonary disease (COPD), gastroesophageal reflux disease (GERD), lung cancer but also sleep disorders such as nocturnal hypoventilation or obstructive sleep apnea syndrome (OSAS) (47,48). In a debuting, recent study by Varone et al a cohort of 50 IPF patients was evaluated for the presence of RLS using the validated 5-item criteria, its severity using the IRLSSG rating scale and the PSQI to assess the quality of their sleep (1). The results revealed a 2.5 higher prevalence of RLS in IPF patients compared with the controls, compounding the RLS effect on the already poor sleep quality of the patients (1). The study thus identified RLS as a new, frequent comorbidity to IPF with a devastating effect on the sleep quality of the patients, making the dopaminergic medication or other forms of therapy a possible solution to improved sleep and life-quality of the IPF patients (1).

RLS has an important prevalence (up to 68%) in the ESRD population with dire implications ranging from low sleep and quality of life to comorbid anxiety, depression and, if left untreated, to potentially lethal cardiovascular diseases (49-51).

Ohayon et al revealed ethnic and age-related differences within the ESRD population with the RLS comorbidity comprised of a higher prevalence of RLS in European and American populations compared with Asians, as well as an age-related increase in prevalence for Europeans and Americans that is not is not found in the Asian population (52). Nevertheless, the whole spectrum of chronic kidney disease (CKD) patients, especially those undergoing hemodialysis (HD) and continuous ambulatory peritoneal dialysis (CAPD) have higher prevalence of RLS compared with the general population. Several studies have tried to identify parameters (such as age, weight, BMI or even serum hemoglobin or ferritin levels) that would predict an increased risk for RLS in ESRD but failed to render consistent results (53-55). Not even the severity of renal failure could be singled out as a predicting factor for RLS because not all ESRD patients that received renal transplants were relieved of RLS subsequently (56). A single study has identified as predictors of the risk for RLS/WED both the positive family history for RLS and reduced/absent renal function and peripheral neuropathy (57).

With RLS related to ESRD being considered a secondary form of RLS, there are no differences in clinical manifestation between primary and secondary forms of RLS. There are some clinical aspects to be considered when diagnosing RLS in ESRD: Uremic and diabetic neuropathy are frequent in ESRD patients manifesting as prickling sensations in the lower extremities with little circadian variability, thus clinicians/doctors should be aware not to misdiagnose them by resorting to neurological examinations (2). Moreover, the evaluation of respiratory events (such as apnea) and motor events (such as limb movements) is assisted through a polysomnography recording considering that sleep apnea is highly comorbid with ESRD (2).

Before therapeutic interventions, one should note that numerous substances, mainly psychotropic medication (neuroleptics, tricyclics, SSRIs, SNRIs) can induce or worsen RLS and are frequently prescribed for the psychiatric complications of ESRD (2).

Regarding the pharmacological treatment in ESRD patients with RLS, the list of drugs used is similar to that for primary RLS/WED consisting of: levodopa, dopamine agonists, GABA agonists and intravenous iron (2). In two different studies gabapentin proved superior to levodopa, despite the not very stringent study design (58,59). As far as the time of administration, 2 h before bedtime proved optimal for all drugs except for intravenous iron and gabapentin, that was administered in an improved way after HD sessions, 3 times per week (2). Apart from these conventional medications, previous studies investigating antioxidant vitamin supplementation with vitamin C, E or both revealed positive results, with an increase in the IRLS score up to 50% (60,61).

A non-pharmacological researched approach identified that intradialytic aerobic exercise training during HD 3 times per week can be as effective as a low-dosage dopamine agonist for RLS (2,62).

IBS represents a bowel disorder mainly affecting the function of the bowel, with no current tools at the disposal of physicians to detect any structural or biochemical abnormalities of this condition. Patients usually describe the following symptoms: Discomfort or even pain in the abdominal area, a different color pattern and regularity of stool and frequent bloating. The severity of the symptoms may vary, from completely debilitating, to moderate or mild symptoms. The irritable bowel syndrome is usually associated with other comorbidities (non-psychiatric/psychiatric) such as: RLS, pain syndromes, headaches, migraines and overactivity of the bladder. The psychiatric evaluation includes: depression and anxiety. The prevalence of IBS is high (~12%) and the disorder highly affects the quality of life (63). Revealing the link between IBS and RLS can improve our understanding of the pathophysiology of IBS, especially since it represents a somewhat mystery of the neuro-gastroenterology field and it is also the most common functional bowel disorder.

ADHD occurs before the age of 12 and is an inherited neurological developmental disorder that has a common pathology with RLS in the central nervous system. Previous studies correlating sleep disorders with ADHD pathology have led to the identification of functional cortical areas involved in both pathologies: Attention (64), inhibition (65) and working memory. Moreover, there is a positive correlation between ADHD and sleep disorders, including the manifestation of similar symptoms (66).

Children who are diagnosed with both RLS and ADHD appear to face a certain spectrum of symptoms that overlap such as: Alterations of the diurnal activities, inattention (if the child is diagnosed with attention deficit disorder (ADD), the hyperactivity symptom is not present), difficulties in mood regulation, paroxysms of hyperactivity and all leading, in most cases, to poor school performance.

The same studies correlate sleep disorders caused by RLS with attention deficits as a secondary factor for these conditions or assume the existence of molecular mechanisms involved in both disorders. Furthermore, the dopaminergic deficit should be taken into consideration when it comes to the pathogenesis of both RLS and ADHD.

The International Classification of Sleep Disorders-Third Edition (ICSD-3) defines insomnia as: ‘Difficulty initiating sleep, maintaining sleep, or waking up too early; presence of these symptoms despite adequate opportunity for sleep; and daytime deficits’. The difference between acute and chronic insomnia lays in the period of time of which patients experience the aforementioned symptoms. In the case of acute insomnia, the symptoms last less than three months and more than three months for chronic insomnia (occurring more than three times a week). Acute insomnia is usually linked to a stressor or event that led to insomnia in the first place (67).

The symptoms that appear in the RLS, such as uncontrollable urges to move the limbs that get worse at rest usually appear during the night time or the evening. The fact that the symptoms appear during the second part of the day, mainly at nighttime affects the ability to initiate or continue the sleep cycle. RLS is considered to be the fourth leading cause of insomnia.

The individualization of the treatment in RLS must respect the following principles: It starts from the minimum effective dose, and this will be increased with caution and only if necessary, with knowledge on the personality structure of these patients, clinical interference with neuromuscular pathology, receptor sensitivity, as well as the sensitive elements of personality, which render the individual in question more receptive to side effects. The second principle is that medication should be initiated early enough after diagnosis to prevent habituation to suffering and self-induction of a pattern that, at the limit, resembles hypochondria. The third principle is related to the cyclicity of sleep, the doses being necessary to be administered in the evening, in a single dose or in two divided doses, the first one frequently before the evening meal and the second late in the night to ensure the quality of sleep, shortening REM periods and controlling the nocturnal aggravation phenomenon. The fourth principle is established when it is necessary to give up monotherapy and supplementation with a second pharmaceutical agent with different receptor action (3).

Unfortunately, the current pharmacological approaches are focused on symptomatology, when new lines should be opened in the direction of modulatory therapies and those that address causation. The risks that may occur in the long term are generated by the natural progression of the disease itself, the development of drug tolerance and by the psychological management, with characteristics including depression, increased sensitivity and emotional lability, feeling helpless, feelings of uselessness and incurability, which can evolve to comorbidity with a depressive episode of moderate or severe intensity. Subjects complain throughout life of the accumulation of extra time spent in suffering and occasionally of therapeutic alliances that decrease in intensity because specialists become discouraged with the patient if they fail to control RLS and its main comorbidities including hypochondria and depression (68).

Medication needs to be instituted when the symptoms are clinically significant, when they occur with frequency and severity affecting quality of life. What has been previously described belongs to the chronic form of RLS as opposed to the occasional form, when treatment could be taken intermittently (9,11). Of choice are the dopaminergic agonists aforementioned, pramipexol and ropinirole, which are also used in Romania. The specialized literature also mentions use of the rotigotine patch with which there is no experience in Romania. Dopaminergic agonists act quickly by minimizing the symptoms even at low doses, but, paradoxically, if the aspect of control escapes the care of the patient or specialist, in the sense of an unjustified increase, the worsening of the severity of the disease will be faced. Pramipexol and ropinirole are commonly used to treat Parkinson's, but the doses addressed in RLS are markedly lower (5).

The administration of iron should not be neglected and its dosage should be gradually increased (69). Serum iron is routinely measured (a more complex battery that includes ferritin, sideremy, transferrin and iron-binding capacity), but what really matters in RLS is not the level of blood iron but the amount of iron in the synaptic cleft being directly related to RLS symptoms. However, usual dosages claim that if serum ferritin ≤75 µg/l or the transferrin and iron-binding capacity is <20% it becomes imperative to administer oral iron therapy. In case of gastric intolerance, nausea or fever, intravenous iron preparations such as ferric carboxymaltose in high doses or low molecular weight dextran iron can be used (4,70,71). Specialists should be careful when considering iron therapy, checking the ratio of serum ferritin measured in µg/l to the age of the patient. In other words, iron should be given if the ferritin value is less than the age of the patient (21). The iron used intravenously must be chosen at the right time, namely when the ferritin is not extremely low, so that the total iron-binding capacity can fulfill its function and the absorption of iron in the intestinal transit is efficient. Under normal physiological conditions, even if the patient receives unjustified iron medication, there is an endogenous regulation in terms of oral absorption of iron, which prevents its accumulation in excess (69,71-73).

In 1982 Akpinar et al revolutionized RLS management by discovering the effectiveness of levodopa (74). This is a carboxylase doping inhibitor that immediately and markedly relieves symptoms (3,75). Following the study by Akpinar et al, which investigated patients diagnosed with intermittent RLS, another study (75) was performed with multiple dopaminergic agents, which were considered effective in RLS and peripheric limb movement disorder. Levodopa is well tolerated in subjects with RLS, and dyskinesias induced in Parkinson's patients are not found in subjects with RLS. If dopaminergic treatment lasted >5 years, nigrostriatal binding capacity was normalized according to PET-type studies performed with 18F-Fluorodopa (76). The aforementioned research confirmed the additional safety of this long-term medication. Unfortunately, the negative aspects remain: The risk of relapse (regardless of how long the pharmacological treatment lasted), as well as the risk of developing tolerance, in other words the need to increase the doses. Relapse can be considered a consequence of the fact that levodopa is a medicine with a short half-life. Patients themselves end up shortening their time between doses gradually to 5 h, then to 4 h, which potentiates tolerance and early recurrence of symptoms. The problem could be solved by supplementing the medication with a prolonged-release medicine. It would be desirable to administer it in the morning, although the effectiveness of the protocol is not yet fully supported by enough evidence-based medicine studies (3,77).

Modern changes have occurred in the pharmacological approach related to the use of levodopa, which in the past was considered the treatment of choice, and currently proves effective only in patients with intermittent symptoms (even if they are severe) (3). Orientation to other medicines to the detriment of levodopa is based on the following clinical considerations: Up to 80% of patients treated exclusively with levodopa for RLS exhibit increased symptoms within several months, of which one third of them reach severe symptoms that curl depression as comorbidity or hypochondriac concerns or suicidal ideation. This imposes a firm need to change the therapy (78). The need to increase doses is a serious problem that involves the following aspects: Symptoms appear earlier in the day, become more severe, rest time is significantly reduced, new areas of the body appear in which symptoms are felt and which were not previously involved.

In principle, dopaminergic drugs are at risk of increasing doses, but of these, the phenomenon is most common in levodopa (up to 73%) and less common in dopamine agonists. In the last-mentioned case, the need to increase doses occurs in 10% of cases requiring short-term medication and in 42-68% in patients with over 10 years of treatment (69,70). Short-acting dopamine agonists, such as ropinirole and pramipexole, have a higher risk of short-term dose escalation compared with those with a longer half-life (transdermal rotigotine). In the case of the second category (dopaminergic agonists with a longer half-life) a lower circadian fluctuation of serum dopamine levels is observed. In other words, dopaminergic receptors are stimulated, but in a less pulsating manner, allowing downward regulation of dopamine receptors, which in turn reduces circadian variation (69,70,79-81). A pertinent question remains whether the continuous administration of a dopaminergic antagonist for 24 h treats the symptom or simply masks the symptoms or does nothing but risk the development of tolerance and require the body to increase the doses.

Due to the existence of multiple comorbidities, numerous of them psychiatric, the increase can be performed gradually or in a sudden manner in a hospital, if the severity of symptoms requires it (82) and with an efficient management of the therapeutic alliance. Meetings of 30-min duration are preferred, in which the subjects are listened to with their somatic complaints, in an active and empathetic manner, without being contradicted; the depressive component can be recognized and brought into discussion, without denying their moral and physical suffering and without appealing to the notion of hypochondria. In critical moments, such meetings must be reserved for a few days. If the suffering of the patient is mild to moderate, and the patient is already being treated with dopaminergic agents, the following strategies are possible: Increase the dose or administer it earlier or split it into two doses, both administered in the evening. If the suffering is clinically significant, transition from a short-acting dopamine agonist to an α2δ ligand is suggested. In the case of severe RLS, an attempt is made to relieve the patient of previous medication, as fast as possible, which should not exceed 10 days. Subsequently, the transition will be made from a long-acting dopamine agonist to one with an even longer-lasting action or to an α2δ ligand (83). If ferritin is <100 µg/l then these are characterized as severe cases that require intravenous iron infusion and if the clinical symptoms bring with them a pain that is difficult to tolerate, opioids are selected, which act on GABAergic receptors and have a quick response; among the beneficial effects, along with the removal of pain is a relative state of euphoria.

For a first stage, non-pharmacological treatments are desired; it is considered that performing moderate to intense physical activities, with attention to the risk of abdominal trauma and at the chosen time of day, when physical exercises should be performed (if sport is practiced in the evening, it can cause insomnia, which in turn will aggravate the symptoms of RLS) have an important role (80,84). From the pharmacological point of view, oral supplementation with iron is selected, or the intravenous method if the ferritin level falls <75 µg/l. If the aforementioned are not sufficient to alleviate the symptoms, the carbidopa/levodopa dopaminergic combination will be used as a necessary option in a daily dose of 20/100 to 50/200 mg. Opting for a prolonged-release formula reduces the risk of developing tolerance on the medication. Dopaminergic agonists are contraindicated in pregnancy. Due to the inhibition of prolactin, breastfeeding is not triggered because the dopaminergic mechanisms are inhibited by medication. However, if the treatment is interrupted, this aspect is reversible (80,84).

A randomized study on the effectiveness of ameliorating paresthesia and reducing the number of RLS attacks, demonstrates the effectiveness of carbamazepine at a dose of 100-400 mg, which is given at bedtime, to demonstrate its effectiveness at night (44,85). Although the effectiveness of carbamazepine is certain, given the side effects which are mainly of hepatic involvement (with up to a 3 times increase in transaminases), but also the risk of spinal cord depression, recently, gabapentin is preferred, which also appears to be effective and tolerated in an improved way (86). Pregabalin, lamotrigine or topiramate may also have a special role in patients who report painful paresthesia or underlying neuropathies. The use of antiepileptics in RLS is performed at lower doses compared with those in bipolar affective disorders and significantly lower than those in seizures (87).

Opioids were first described as being used in RLS in a double blinded study, by Walters et al. This research group conducted a controlled study on oxycodone that improved the quality of life of patients by its symptomatic action, reducing periodic limb movement disorder (88). It is well known that opioids also have a high risk of addiction and should be avoided in patients whose personality structure has such inclinations or who risk using them to instantly eliminate depression and feelings of euphoria. Thus, this class of drugs remains preserved for refractory cases (89).

Unfortunately, double-blind cross-over studies have been performed on a small number of patients (90). Clonazepam has been considered the first choice due to the mechanism that acts on the one hand, as a muscle relaxant and on the other, as a hypno-inducer (91). The risks of sedation and nocturnal falls should not be overlooked if therapeutic doses are not well controlled, if the patient is elderly, or at risk of addiction or uses poly-medication.

In a first stage they can be applied singularly, and in a later stage they will remain in the background, in various pharmacological combinations, to relieve the symptoms. Roundly, the general instructions are based on the following indications: The combination of alcohol, caffeine, nicotine or activator-type antidepressants should be minimized. Exercise should remain at a moderate level. The body must be given proper care by applying warmth or hot baths, massage at the lower and/or upper limbs, maintaining healthy habits in terms of inducing sleep by maintaining a regular schedule, learning relaxation and meditation exercises to be used at night and avoidance of forced sleep at any cost. Subjects are advised to engage in motivational coaching and/or cognitive-behavioral therapy and to develop their own warning strategies when their own behavior becomes sedentary. Pneumatic foot compression, near-IR light spectroscopy (NIRS) have also been used, although there is insufficient evidence of their efficacy as adjuvants to pharmacological treatments (67,69,92). Complementary therapies such as acupuncture, transcranial magnetic stimulation, vibration equipment applied to muscles during exercise, cryotherapy and aromatherapy should not be overlooked (67,93,94). Antipsychotics have the potential to increase the symptoms of RLS or periodic limb movement disorder and upon pertinent evaluation, the clinician is required to make an effective differential diagnosis with hypochondria (or even delusional somatic disorder) to avoid this group of drugs (3). Even antihistamines can worsen RLS symptoms. Unfortunately, exclusive non-pharmacological approaches are presented in randomized studies without well-defined control groups and suffer from a lack of clarity in the objective analysis of the result. To all these aforementioned symptoms, poor sleep quality is also added (67,94). Non-pharmacological options remain effective for mild cases (68,69).