Life Extension Magazine

Life Extension Magazine May 2012

Abstracts

Restless leg syndrome

The effect of sclerotherapy on restless legs syndrome.

BACKGROUND: Restless Legs syndrome (RLS) is a disorder of unknown etiology characterized by relentless leg discomfort when stationary, which compels voluntary leg movement to obtain temporary relief. We have received anecdotal reports of coincidental relief from symptoms of RLS in patients following sclerotherapy for varicose vein disease. OBJECTIVE: To prospectively evaluate the concomitant occurrence of RLS and varicose veins in a population seeking treatment for varicose veins, and to assess the therapeutic response of RLS to sclerotherapy. METHODS: One thousand three hundred and ninety-seven patients were screened for RLS symptoms by questionnaire and interview, and for saphenous vein disease by clinical examination, including continuous-wave Doppler. Sclerotherapy with sodium tetradecyl sulphate was performed on 113 RLS patients. RESULTS: RLS symptoms were present in 22% (312/1,397), with a Doppler-negative to Doppler-positive ratio of 3:2. One hundred and eleven of the 113 treated patients (98%) reported initial relief from RLS symptoms. Follow-up thus far shows a recurrence rate of 8% and 28% at 1 and 2 years, respectively. CONCLUSIONS: RLS is common in patients with both saphenous and nontruncal varicose vein disease, and can respond frequently and rapidly to sclerotherapy. This subpopulation of RLS sufferers should be considered for phlebological evaluation and possible treatment before being consigned to chronic drug therapy.

Dermatol Surg. 1995 Apr;21(4):328-32

Restless legs syndrome in patients with chronic venous disorders: an untold story.

OBJECTIVES: To prospectively study the profile of restless leg syndrome (RLS) in patients presenting to a phlebology practice. METHODS: The study uses prospective questionnaire and clinical observation study. In all, 174 consecutive patients and 174 matched controls were evaluated in detail. The diagnosis of restless legs syndrome (RLS) was established by the International RLS study group (IRLSSG) criteria. Detailed clinical, systemic and Duplex ultrasound evaluations were done to establish the presence of chronic venous disorders (CVD) (reflux > 0.5 s on augmentation manoeuvers and revised clinical, aetiological, anatomical and pathological [CEAP] criteria). RESULTS: Of the 174 consecutive subjects studied (22M: 152F), 63 (36%) had evidence of RLS compared with only 34 of 174 of the controls (19%, P < 0.05). Sixty-two (98%) of these RLS-positive study subjects were subsequently diagnosed with CVD. In comparison, 31 (91%) of the RLS-positive control subjects (n = 34) were found to have CVD. This prevalence of CVD was comparable with RLS-positive study subjects, but was significantly higher than the prevalence in CVD in RLS-negative controls (P < 0.01). Only three (9%) of the controls had RLS without CVD. RLS-positive subjects were typically women above the age of 40 years (P < 0.01 vs. men, P < 0.01 vs. below 40 years). A significant difference in clinical presentation in the study subjects was the high prevalence of leg cramps in the RLS-positive subjects (P < 0.01). None of the patients with RLS in this series gave history of anaemia, chronic renal failure or an established psychiatric or neurological disease as found pathognomic for RLS by others. CONCLUSIONS: RLS appears to be a common overlapping clinical syndrome in patients with CVD. Prospective blinded therapeutic trials are planned to study the influence of definitive treatments for CVD on sequential RLS scores.

Phlebology. 2007;22(4):156-63

Pharmacological agents in the treatment of venous disease: an update of the available evidence.

Varicose veins and the complications of venous disease are thought to affect over a quarter of the adult population and the management of these conditions are a major cause of health service expense. Advances in the understanding of venous pathophysiology have highlighted numerous potential targets for pharmacotherapy. This review considers the evidence for pharmacological agents used for the treatment of chronic venous disease. A literature search using Pubmed, Embase and Cinahl databases was performed. The initial search terms ‘varicose vein’, ‘venous ulcer’ and ‘venous disease’ were used with appropriate search limits to identify prospective studies of pharmacotherapy in venous disease. A wide range of venoactive and non-venoactive drugs have been studied in patients with venous disease. The use of micronized purified flavonoid fraction (Daflon) can reduce symptoms of pain, heaviness and oedema in patients with venous reflux and a recent meta-analysis concluded that Daflon improves healing in patients with venous ulceration treated with compression. Pentoxifylline may be a useful adjunct to compression therapy for patients with venous ulceration. Oxerutins and calcium dobesilate may be of benefit in reducing oedema and rutosides may help to relieve the symptoms of varicose veins in pregnancy. The clinical benefits of other medications remain unproven. Although numerous pharmacological agents have been proposed and studied, Daflon has demonstrated the greatest clinical benefits in patients with venous disease. Further research is needed to define the role of venoactive drugs in clinical care and improve our understanding of the pathophysiology of venous disease to help identify new therapeutic avenues.

Curr Vasc Pharmacol. 2009 Jul;7(3):303-8

Phlebotonics for venous insufficiency.

BACKGROUND: Chronic venous insufficiency (CVI) is a common condition caused by inadequate blood flow through the veins, usually in the lower limbs. It can result in considerable discomfort with symptoms such as pain, itchiness and tiredness in the legs. Sufferers may also experience swelling and ulcers. Phlebotonics are a class of drugs that are often used to treat CVI. OBJECTIVES: To assess the efficacy of oral or topical phlebotonics. SEARCH STRATEGY: We searched the Cochrane Peripheral Vascular Diseases Group trials register (April 2005), the Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 2, 2005), MEDLINE (January 1966 to April 2005), EMBASE (January 1980 to April 2005) and reference lists of articles. We also contacted pharmaceutical companies. SELECTION CRITERIA: Randomised, double blind, placebo-controlled trials (RCTs) assessing the efficacy of rutosides, hidrosmine, diosmine, calcium dobesilate, chromocarbe, centella asiatica, disodium flavodate, french maritime pine bark extract, grape seed extract and aminaftone in CVI patients at any stage of the disease. DATA COLLECTION AND ANALYSIS: Two reviewers independently extracted data and assessed trial quality. The effects of treatment were estimated by relative risk (RR) or by standardised mean differences (SMD) by applying a random effects statistical model. Sensitivity analyses were also performed. MAIN RESULTS: Fifty-nine RCTs of oral phlebotonics were included, but only 44 trials involving 4,413 participants contained quantifiable data for the efficacy analysis: 23 of rutosides, ten of hidrosmine and diosmine, six of calcium dobesilate, two of centella asiatica, one of french maritime pine bark extract, one of aminaftone and one of grape seed extract. No studies evaluating topical phlebotonics, chromocarbe, naftazone or disodium flavodate fulfilled the inclusion criteria. Outcomes included oedema, venous ulcers, trophic disorders, subjective symptoms (pain, cramps, restless legs, itching, heaviness, swelling and paraesthesias), global assessment measures and side effects. The results of many variables were heterogeneous. Phlebotonics showed some global benefit (i.e. oedema reduction) (relative risk 0.72, 95% confidence interval 0.65 to 0.81). The benefit for the remaining CVI signs and symptoms must be evaluated by phlebotonic group. There were no quantifiable data on quality of life. AUTHORS’ CONCLUSIONS: There is not enough evidence to globally support the efficacy of phlebotonics for chronic venous insufficiency. There is a suggestion of some efficacy of phlebotonics on oedema but this is of uncertain clinical relevance. Due to the limitations of current evidence, there is a need for further randomised, controlled clinical trials with greater attention paid to methodological quality.

Cochrane Database Syst Rev. 2005 Jul 20;(3):CD003229

Veno-active drugs in the management of chronic venous disease. An international consensus statement: current medical position, prospective views and final resolution.

BACKGROUND: Veno-active drugs (VAD) have effects on edema and symptoms related to chronic venous disease (CVD), especially so-called venous pain. VAD’s effectiveness, although well established, is regularly debated. OBJECTIVE: Our purpose was to select all randomized controlled trials (RCTs) and meta-analyses devoted to VAD and symptoms in CVD, to submit them to a group of international experts in CVD and to vote with secrete ballot to determine the level of efficacy of each drug, according to EBM (Evidence-Based Medicine) rules and critical analysis. METHODS: Publications in any language devoted to VAD and venous symptoms were searched for in different databanks and submitted to the experts prior to the meeting. RESULTS: 83 papers were analyzed, including 72 RCTs or meta-analyses. Experts determined the level of EBM of each drug, according to the literature and personal experience, using 3 levels of recommendation, A, B and C (from large RCTs to non-randomized trials). CONCLUSIONS: VAD are effective and may be applied in CVD when symptomatic, from C0s to C6s. However, etiological treatment of venous reflux and venous hypertension has always priority. In some cases VAD may replace compression and/or complement its effects. If respecting these prerequisites, VAD are safe and effective.

Clin Hemorheol Microcirc. 2005;33(4):309-19

Surgical correction of varicose vein disease under micronized diosmin protection (results of the Russian multicenter controlled trial DEFANS).

The paper presents the results of DEFANS trial (Detralex - assessment of efficacy and safety for combined phlebectomy). The study enrolled 245 patients with varicose vein disease, who underwent unilateral combined phlebectomy. The main group (n=200) received micronized diosmin (Detralex, 1000 mg/day) for 2 weeks before and 30 days after the procedure; control group (n=45) did not receive Detralex in pre- and postoperative period. Pain severity by 10-point visual analog scale (VAS), an area of subcutaneous hemorrhage in the zone of femoral great saphenous vein resection (by original 12-point scale) and subjective feelings of limb heaviness and fatigability were evaluated 7, 14 and 30 days after the procedure. Subjective symptoms and the area of subcutaneous hemorrhage were significantly lower in the main group, then in control: 7 days after the procedure VAS score was 2.9 and 3.5, respectively; hemorrhage area - 3.4 and 4.6 points, respectively. The same trend was observed for limb heaviness and fatigability, evidencing the better exercise and orthostatic tolerance among patients of the main group in early postoperative period. Quality of life assessment by CIVIQ failed to reveal statistically significant difference between main and control groups in 4-weeks postoperative follow-up. Micronized diosmin in pre- and postoperative period after plebectomy helps to attenuate pain syndrome, to decrease postoperative haematomas and accelerate their resorption, to increase exercise tolerance in early postoperative period.

Angiol Sosud Khir. 2007;13(2):47-55

Medicamentous treatment of chronic venous insufficiency using semisynthetic diosmin—a prospective study.

INTRODUCTION: Chronic venous insufficiency (HVI) is manifested by the progressive signs of venous stasis. This disorder is treated by: compressive bandaging, medicaments, sclerotherapy, surgery, etc. AIM: Prospective study of the effects of semisynthetic diosmin (clinical signs, quality of life, local biochemical parameters) on patients with HVI to whom no other method of treatment has previously been administered. METHOD APPLIED: This prospective study analysed the presence of risk factors and personal history of 80 patients with HVI. Diagnosis of HVI was based on the clinical apperance and the color duplex scan. Each patient’s clinical signs (pain, oedma, feeling of heaviness and tightness in the lower leg), quality of life (physical, social, and psychological), and CEAP stage were assessed prior to and 30 days after the treatment with Phlebodia 600. For 15 patients with unilateral varicose veins, local values of lactates and gass analysis were taken under the conditions before and following the static load, and venous control samples were taken from the healthy leg. The acquired data were processed by means of descriptive statistics, while the significance of nonparametric features was measured by Wilcoxon test. RESULTS: HVI is somewhat more frequent among females than among mails, on the left than on the right leg, and at the average age of 52.3 +/- 10.5. The patients with HVI are basicly engaged in professions with static load and have positive family history. The patients mainly started medical treatment 12.5 +/- 8.6 years after the first symptoms of the disease. Clinical improvement was recorded on the state of 65/80 patients. After the treatment numerical values of some of the clinical signs were statisticaly lower compared to the values before the administration of semisynthetic diosmin: oedema (0.94:1.50), pain (1.10:1.84), feeling of heaviness (1.20:1.96), and tightness (1.14:1.78). After the administration of the tested medication, parameters of physical, social, and psychological quality-of life were significantly improved (p<0,0001), accompanied with significantly improved (p<0,0001) CEAP stage of HVI (3.00:3.40). Local biochemical parameters had not been significantly changed. CONCLUSION: Administration of semisynthetic diosmin during 30 days results in significant improvement of clinical signs, quality of life and CEAP stage of HVI.

Acta Chir Iugosl. 2008;55(4):53-9

Restless legs syndrome: pathophysiology, clinical presentation and management.

Restless legs syndrome (RLS) is a somatosensory network disorder that is clinically diagnosed according to four main criteria: an urge to move the legs, usually associated with unpleasant leg sensations; induction or exacerbation of symptoms by rest; symptom relief on activity; and diurnal fluctuations in symptoms with worsening in the evening and at night. Genetic variants in four chromosomal regions have been identified that increase the risk of RLS. In addition, various different lesions, ranging from peripheral neuropathies to spinal cord lesions or alterations of brain metabolism, are implicated in RLS. In most cases, sleep disorders with frequent sleep fragmentation and characteristic periodic limb movements during sleep can be identified during a polysomnographic recording. The first-line drugs for RLS are dopaminergic agents, which are effective in low to moderate doses. Alternative or additional treatments include opioids and anticonvulsants. Augmentation-paradoxical worsening of symptoms by dopaminergic treatment-is the main problem encountered in difficult-to-treat patients. Iron deficiency must be identified and treated by supplementation, both to improve RLS symptoms and to potentially lower the risk of augmentation. Here, we review the latest studies pertaining to the pathophysiology, clinical presentation and management of RLS.

Nat Rev Neurol. 2010 Jun;6(6):337-46

Epidemiology of restless legs syndrome in French adults: a nationwide survey: the INSTANT Study.

OBJECTIVE: To evaluate the prevalence, characteristics, and treatment of restless legs syndrome (RLS) in France. METHODS: In this population-based survey, face-to-face home interviews were conducted among a random sample of 10,263 French adults. A French translation of the four features defined by the International RLS Study Group in 1995 was used to assess the prevalence of symptoms consistent with a diagnosis of RLS. Data on severity of symptoms and their management were also collected. RESULTS: The 12-month prevalence of RLS symptoms in the French adult population was estimated to be 8.5% (95% CI 8.0%, 9.0%), with a higher prevalence (p < 0.001) observed in women (10.8%) than in men (5.8%). Prevalence increases with age until 64 years and decreases thereafter in both sexes. Half of the identified subjects reported symptoms once a week at least. Symptoms were more severe in subjects reporting symptoms once a week at least compared to subjects with less frequent symptoms. In this group, half of the subjects reported a family history, the age at onset was earlier, and severity of symptoms higher. RLS had been previously diagnosed in only 5.3% of the subjects who reported previous medical diagnosis, and recommended RLS drug treatment was received by 3.4% of the 28.7% currently treated subjects. CONCLUSIONS: Restless legs syndrome (RLS) occurred in 10% of women and 5% of men. RLS prevalence decreases after the age of 64. RLS is often underdiagnosed and few subjects receive recommended RLS drug treatment.

Neurology. 2005 Jul 26;65(2):239-46

Abnormally increased CSF 3-Ortho-methyldopa (3-OMD) in untreated restless legs syndrome (RLS) patients indicates more severe disease and possibly abnormally increased dopamine synthesis.

BACKGROUND: Abnormally high CSF 3-OMD occurs frequently for RLS patients indicating either increased l-dopa synthesis, limitations in l-dopa decarboxylation or increased MAT/COMT activity, or some combination of these. Increased tyrosine hydroxylase activity was found on both the RLS autopsy and the rodent iron-deprivation model of RLS, suggesting increased DA synthesis in RLS. We, therefore, hypothesized elevated 3-OMD in RLS results from increased DA synthesis and that this should occur accordingly with increased HVA. It would then also reflect both the more severe iron insufficiency pathology of RLS and greater clinical severity, shown by the objective measure of PLMS/hr. METHODS: Patients off RLS medications and matched controls had lumbar punctures at either 10 a.m. or 10 p.m.; RLS patients were grouped by normal or abnormally high 3-OMD (>10 nmol/l). RESULTS: Forty-nine RLS patients (30 high, 19 normal 3-OMD) and 36 age- and gender-matched controls, analyzed separately by time of CSF collection, did not significantly differ in age or gender. RLS patients with high 3-OMD had significantly higher CSF HVA, while those with normal 3-OMD had consistently lower CSF HVA than controls. CSF ferritin was consistently lower compared to controls for the high 3-OMD but not the normal 3-OMD RLS patients. The PLMS/hr was significantly higher for RLS patients with high compared to normal 3-OMD, indicating high 3-OMD patients had more severe RLS. CONCLUSIONS: Abnormal elevation in 3-OMD for RLS patients may reflect increased dopamine synthesis for more severe but perhaps not mild RLS. These differences in the putative dopamine pathology of RLS may indicate different phases or expression of RLS biology or different underlying disease processes.

Sleep Med. 2009 Jan;10(1):123-8