Published online Mar 27, 2018. doi: 10.4254/wjh.v10.i3.379
Peer-review started: October 31, 2017
First decision: December 26, 2017
Revised: December 27, 2017
Accepted: January 23, 2018
Article in press: January 23, 2018
Published online: March 27, 2018
Processing time: 147 Days and 17.3 Hours
Restless legs syndrome (RLS) remains a clinical diagnosis based on confirming the four essential diagnostic features of RLS, including: (1) An urge to move the legs, usually but not always accompanied by or felt to be caused by uncomfortable and unpleasant sensations in the legs; (2) the urge to move, as any accompanying unpleasant sensation begins or worsens during periods of rest or inactivity, such as lying down or sitting; (3) the urge to move, as any accompanying unpleasant sensation is partially or totally relieved by movement, such as walking or stretching; and (4) the urge to move, as any accompanying unpleasant sensation during rest or inactivity only occurs or is worse in the evening or night compared to during the day. Chronic medical situations (dialysis, end-stage renal disease and rheumatologic disorders) have a higher prevalence of RLS.
An increased prevalence of RLS has been described in patients with liver cirrhosis in the United States and Japan. Very recently, RLS has been described in India in a series of chronic hepatic failure patients. Data in hepatic patients are limited.
According to neurological exams, the diagnosis of RLS was suggested by the Johns Hopkins questionnaire and verified by fulfillment of the diagnostic criteria by Allen. Iron-free level, ferritin, folate and vitamin B12 and vitamin D-OH25 were measured in all patients. Drugs used to treat RLS belong to many different pharmacological classes, such as the dopaminergic agents, opioids, benzodiazepines and antiepileptic drugs. We decided to avoid the employment of opioids and benzodiazepine due to the hepatic conditions. Therefore, the first-choice drug was pramipexole, a dopamine agonist. The second-choice drug was gabapentin, due to its beneficial properties and to the limited hepatic side effects. Neurological examinations and laboratory tests were performed at the beginning, after 2 wk, at the 28th, 75th, 105th, 135th and 165th day, and at the final day of the follow-up, the 205th day. Another aim of this study was to define the augmentation phenomenon in the liver patients.
The study included 267 adult patients with chronic liver disease, referred to our Neurological Unit by the Liver Unit of the University of Trieste, for three complaints, including sleep disturbances, painful leg sensation, and daily sleepiness not correlated to hepatic encephalopathy. Patients with chronic liver disease included primary liver tumor and liver cirrhosis cases. We excluded 13 patients with chronic and persistent significant alcohol intake, 25 patients with recent worsening of clinical condition, and 12 patients with hepatitis C virus infection. All the other 211 patients were followed up by a neurologist for at least 24 mo. At baseline, patients were tested with the Hamilton rating scale for depression, sleep quality assessment (PSQI), Epworth sleepiness scale (ESS), International Restless Legs Syndrome Study Group (IRLSSG) evaluation, and international RLS severity (IRLS) scoring system. Alterations in titration, side effects, augmentation phenomenon and laboratory test findings were checked and reported. The first-choice drug was pramipexole, a dopamine agonist. If major side effects induced by the neurological therapy occurred, such as nausea, vomiting, somnolence, hypotension or optical illusions, the pramipexole was stopped. The second-choice drug was gabapentin, due to its beneficial properties and to the limited hepatic side effects. Another aim of this study was to define the augmentation phenomenon in the liver patients.
Patients included in the study fulfilled the IRLSSG criteria for RLS; they were moderately depressed, with evident nocturnal sleep problems and a concomitant daily sleepiness. Of the 211 RLS patients, 22 considered their symptoms as mild, according to IRSL, but 189 found them moderate to very severe. A Spearman’s rank correlation analysis showed the following: (1) a positive correlation between IRLSSG fulfillment criteria and poor nocturnal sleep quality (PSQI); (2) a positive correlation between IRLSSG fulfillment criteria and excessive diurnal sleepiness (ESS); (3) a positive correlation between IRLSSG fulfillment criteria and Hamilton’s score; (4) a positive correlation between the four levels of IRSL and PSQI; and (5) no correlation between ammonium level and ESS or PSQI. At the beginning, all patients were prescribed pramipexole at an average dosage of 0.18 mg, to be taken in the evening for the first 2 week. Titration was standard; we duplicated the dosage for 2 more weeks, up to 0.36 mg, till the 75th day. At the 75th day, we prescribed 0.7 mg daily, which was then increased to 0.88 mg daily at the 105th day. Forty-one patients reported heavy side effects at the 135th day and decided to stop the pramipexole therapy. The remaining 170 patients were prescribed 1.4 mg daily, which seemed quite appropriate in respect of their average body mass index. At the 205th day, 110 patients (52%) continued to feel good with the 1.4 mg daily dosage; on the other hand, 60 patients (48%) reported the augmentation symptoms and were titrated at 0.7 mg daily. The 41 patients who abandoned pramipexole, after 2 wash-out weeks, were administered gabapentin, at increasing dosages. Considering the 170 patients who completed the 205 d of follow-up with pramipexole, the results were rather satisfactory, with an evident and constant amelioration of depression, of sleep quality and of daily sleepiness, as far as Wilcoxon signed rank test within-group comparison (vs baseline) showed. At the final visit, their subjective feeling of the intensity of RLS disturbances was perceived as mild to moderate in 155 patients and severe in 15 of them. Nobody declared a very severe score. The 41 patients who abandoned pramipexole, due to side effects, were treated with gabapentin, reporting a slight worsening of nocturnal sleep quality and an increase of daily sleepiness. All the 41 patients who took gabapentin reported abdominal weight gain at the final visit. As far as the augmentation phenomenon was concerned, a logistic regression analysis to identify factors associated with the augmentation were performed with independent variables, including age, body mass index, IRLS alcohol abuse, iron-free levels, folate, vitamin B12 and D-OH25 levels, alanine and aspartate aminotransferase, treatment duration of pramipexole, and daily pramipexole doses. Univariate and multivariate logistic regression analyses were performed and the Wald test was used to assess the significance of each variable. Daily pramipexole dose, the duration of the treatment, previous alcohol abuse, iron-free levels as well as lower levels of B12, D-OH25 and folate were significantly associated with augmentation in univariate analysis. On the other hand, abuse of alcohol, dose of pramipexole and its duration, level of vitamin B12 and D-OH25 and of folate, in the multivariate regression analysis, seemed to be significantly associated with augmentation.
In this study, we found that patients with chronic liver disease, such as liver cirrhosis or primitive tumors, who were referred for sleep disorders might have RLS as well. The presence of RLS was not associated with sex, and cause or severity of the liver disease was in line with what has been demonstrated by the few other studies. As previously reported, in our study, many causative factors induce RLS in hepatic chronic disease patients, such as low iron levels, high ferritin levels, and associated low folate and vitamin B12 levels. Our study confirms an effective and rapid benefit for the use of dopamine agonist (as is well-recognized and reported in the literature). On the other hand, RLS is a hyperdopaminergic condition with an apparent postsynaptic desensitization that overcompensates during the circadian low point of dopaminergic activity in the evening and night. This overcompensation leads to the RLS symptoms that in turn often lead to increasing postsynaptic desensitization and augmentation of the RLS. In fact, patients with RLS with mood and stress states may be at greater risk of developing compulsive behaviors while receiving standard dosage treatment of dopamine agonists (but also of other drugs, such as tramadol). Augmentation seems rather precocious in our patients (135th day), and more frequent (35%) than previously described by the most important study on the topic (8.3%-9.1%). The dosage of dopamine agonists reported in our study to be associated with augmentation appears to be in range with the literature. Previous intake of alcohol and lower levels of vitamins were related to the phenomenon in our study.
It appears evident that RLS remains a still confounding, not immediately recognized condition requiring rapid diagnosis and treatment. Despite the fact that RLS is a very common disorder, it is frequently undiagnosed in primary care, and therefore inadequate therapy may be prescribed. Additional neurophysiologic studies and more extended clinical trials are strenuously needed to explain some crucial pathologic mechanisms of the syndrome, in order to better employ common therapeutic agents and to find novel ones.