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Other less conventional forms of treatment for RLS/PLMS Arthur S. Walters, M.D. Professor of Neurology Vanderbilt University Medical School Nashville, Tennessee Antibiotic treatment for RLS There is some previous well established evidence that Irritable Bowel Syndrome is associated with Small Intestinal Bacterial Overgrowth (SIBO). Antibiotic Treatment for RLS Weinstock et al 2008 (Dig Dis Sci 2008) 10/13 patients with both Irritable Bowel Syndrome and RLS showed > 80% improvement in RLS Sx after 10 days of Rifaximin antibiotic therapy 1200 mg/day. 5/10 patients followed long term had 100% resolution of RLS Sx after one month of zinc and bifidobacteria based probiotic and long term tegaserod (mean 139 days). Antibiotic treatment for RLS and the iron hypothesis In substantia nigra, putamen pro-Hepcidin is increased in RLS (Clardy et al J Neurol Sci 2006) Small Intestinal Bacterial Overgrowth (SIBO) ---cytokines and/or translocation of lipopolysaccharides --- increased Hepcidin --- abnormal central processing of iron (Weinstock et al . 2008 (Dig Dis Sci 2008) Antibiotic Treatment for RLS and The immunologic hypothesis Alternatively, RLS may be caused by some immunologic mechanism generated by infection. Antibiotic treatment for RLS and the Immunologic Hypothesis About 15% of RLS patients undergo remissions of a month or more that are independent of therapy. This is reminiscent of Multiple Sclerosis, an immunologically mediated Neurological Disease also characterized by exacerbations and remissions. Antibiotic Treatment for RLS and The immunologic hypothesis • RLS is more common in Rheumatoid Arthritis (up to 1/3) but not osteoarthritis (4%) (Auger et al 2005; Salih et al 1994). • RLS is more common in Multiple Sclerosis (up to 1/3). (Auger et al 2005; Manconi et al 2007). • Multiple Sclerosis and Rheumatoid Arthritis but not osteoarthritis are thought to have an immunologic diathesis. Botulinum Toxin for RLS Rotenberg JS et al J Clin Sleep Med 2006) 3 patients were treated with one day of injections of Botox in the legs and/or lumbar paraspinal muscles. Relief of symptoms for up to 10 weeks. Botulinum Toxin for RLS Botox has previously been used for treatment of Dystonia and facial wrinkles It is derived from the exotoxin of Clostridium botulinum bacteria. Cleaves SNARE proteins causing chemodenervation of cholinergic neurons. Botulinum Toxin for RLS and the dopamine deficiency hypothesis • Botox has also been demonstrated to relieve pain syndromes possibly by reducing peripheral and central sensitization to pain. • This is consistent with the hypothesis of Clemens et al (Neurology) that Dopamine Deficiency - Sympathetic Hyperactivity at the spinal cord level altered muscle spindle activity- altered sensory afferent activity back to the central nervous system - RLS symptoms. Hypothetical spinal cord positive feedback mechanism mediating dopamine responsive Restless Legs Syndrome 1) 2) 3) DA inhibits preganglionic sympathetics, thus, in its absence, basal sympathetic tone may increase. Increased adrenaline via innervation of skeletal muscle, in turn, might irritate muscle spindles. The resulting enhanced input from pain-encoding high threshold muscle afferents in lamina I are insufficiently suppressed in the absence of DA or D2-like receptors. Other cholinergic drugs for RLS • As aforementioned Botox decreases cholinergic activity • Paradoxically physostigmine which has the opposite effect on acetycholine was reported to work in a single case after intravenous administration of 1 mg. Parkinson surgery for RLS • RLS and Parkinson’s Disease (PD) may share a dopaminergic deficit • Both disorders respond well to dopaminergic therapy • it is logical to try to see if patients with both PD and RLS who are undergoing surgery for PD have an improvement in their RLS symptoms. Parkinson surgery for RLS 3 targets have been traditionally chosen for surgery for PD and allied movement disorders such as Dystonia. Globus Pallidus (internal segment) Subthalamic Nucleus Thalamus Parkinson surgery for RLS The impact of surgery upon RLS has been variable and further study is needed in larger numbers of cases. Parkinson surgery for RLS • Rye and Delong Ann Neurol 1999 • Amelioration of SENSORY limb discomfort of RLS by pallidotomy. Parkinson surgery for RLS Okun et al Mov Disord 2005 Deep Brain Stimulation (DBS) in the area of the internal Globus Pallidus improved RLS in a single patient with Dystonia. RLS returned after infection required the removal of one of the devices Parkinson surgery for RLS Driver-Dunckley et al Mov Disord 2006 6 patients with PD who had DBS of Subthalamic Nucleus. Despite a mean drop of levodopa equivalents by 56% they also had a mean improvement in RLS scores by 84%. Parkinson surgery for RLS Kedia et al. Neurology 2004 Observed the opposite. 11 patients had re-emergence of RLS symptoms after Subthalamic Nucleus DBS. However, this occurred in the context of a 74% reduction in Parkinson Medications. Parkinson surgery for RLS Ondo Parkinsonism Relat Disord 2006 Also found the opposite effect. DBS in VIM nucleus of thalamus in 9 patients with Essential Tremor (ET) did not improve RLS Exercise and RLS/PLMS De mello et al. Spinal Cord 2004 + numerous other publications by this group. Exercise was as effective as L-DOPA in reducing PLMS in patients with spinal cord injury Exercise and RLS/PLMS Aukerman et al. J Am Board Fam Med 2006 Two groups – exercise and non-exercise group. End point was improvement in RLS symptoms. Exercise group had a pronounced reduction in IRLS scale compared to the non-exercise group after 12 weeks of exercise. Opioid Hypothesis for RLS and exercise It is well known that exercise increases the release of endogenous opioids (enkephalins and endorphins) The improvement in RLS/PLMS with exercise is compatible with the hypothesis that the endogenous opioid system with its enkephalins and endorphins is hypoactive in RLS. Opioid Hypothesis for RLS and exercise Walters et al (presented at APSS meeting 2008)—done in conjunction with Bill Ondo. Post-mortem study of 5 RLS patients and 5 controls. In thalamus Beta endorphin reduced by 37.5% (p= .006, effect size 2.16). In thalamus Met enkephalin reduced by 26.4% (p =.028, effect size 1.58). Opioid Hypothesis for RLS and exercise Opioid Hypothesis for RLS and exercise Melatonin for PLMS Kunz and Bes Sleep 2001 9 patients with PLMS and no RLS 3 mg melatonin at 10 PM for 6 weeks Reduction of PLMS Melatonin for PLMS -- circadian rhythmicity of RLS/PLMS Hening et al Sleep 1999 Trenkwalder Mov Disord 1999 Both studies showed a circadian rhythmicity to RLS and PLMS independent of body position, sleep or sleep deprivation Melatonin for PLMS -- circadian rhythmicity of RLS/PLMS Melatonin is a well known marker of circadian phase Michaud et al Ann Neurol 2004 Showed that RLS/PLMS has a circadian rhythm that was time locked to melatonin levels. Melatonin for PLMS -- circadian rhythmicity of RLS/PLMS However, changes in melatonin preceded the increase in motor and sensory symptoms of RLS. Michaud et al propose that circadian variations in melatonin levels have a direct impact upon the tendency for RLS symptoms to appear more at night. Vascular Disease and RLS In the 1940’s and 1950’s Ekbom noted that RLS patients have cold feet and used vasodilators to treat RLS. Ware et al and Ancoli-Israel in the 1980’s showed that patients with PLMS have reduced peripheral pulses and cold feet respectively. Vascular Disease and RLS Ware et al used the vasodilator phenoxybenzamine , an alpha-adrenergic blocker to normalize peripheral pulse responses and reduce PLMS. Ancoli-Israel et al used thermal biofeedback to reduce PLMS. Vascular Disease and RLS From this Ancoli-Israel et al and Ware et al respectively hypothesized that decreased circulation and sympathetically mediated vasconstriction contribute to the pathogenesis of PLMS. From Ekbom’s observations, the same hypothesis can be put forward for RLS. Vascular Disease and RLS Vasoconstriction is primarily arterial but veins may also be involved in the pathogenesis of RLS. McDonagh et al Phlebology 2007 174 consecutive patients in a phlebology practice and 174 controls. 36% of patients but only 19% of controls had RLS (P < .05). Vascular Disease and RLS Kanter Dermatol Surg 1995 113 patients with RLS and varicose veins. In 98% the RLS symptoms improved with sclerotherapy. Vascular Disease and RLS Hayes et al Phlebology 2008 35 patients with RLS and varicose veins. Divided in to an operative and non-operative group. Endovenous laser ablation of varicose veins decreased IRLS from 26.9 to 5.5 indicating marked improvement in RLS. Vascular Disease and RLS The aforementioned studies indicate that improvement of arterial and venous abnormalities can lead to improvement of RLS and PLMS. The aforementioned studies therefore suggest that vascular abnormalities may lead to the symptoms and signs of RLS/PLMS. Vascular Disease and RLS Recent studies have shown an allelic association to the Meis 1 gene in RLS/PLMS (Steffansson H et al N Engl J Med 2007; Winkelmann J et al Nat Genet 2007). The Meis 1 gene is also essential for vascular development and this may be one way that vascular anomalies can lead to the signs and symptoms of RLS/PLMS. Stimulation or Compression for RLS/PLMS Montagna et al Acta Neurol Scand 1984–Clonazepam was much more effective than vibratory stimulation of the legs in improving RLS symptomsin a double-blind-crossover trial. Kovacevic-Ristanovich et al Arch Phys Med Rehabil 1991. Electrical stimulation of feet and toes 30 min prior to hs reduced PLMS index from 44.6/hr to 14/hr (p<.01). Stimulation or Compression for RLS/PLMS Ishizu et al. Rinsho Shinkeigaku 2001 A single patient had reduction of RLS/PLMS by wearing a lumbar corset. Eliasson and Lettieri Medicine (Baltimore) 2007. Pneumatic sequential compression devices worn on legs an hour prior to hs for 1-3 months improved RLS in 9 of 10 cases. Stimulation or Compression for RLS/PLMS RLS patients often times tend to spontaneously provide a counter stimulus such as rubbing the legs to eliminate the discomfort or RLS. The neuronal gate theory may apply for both the stimulation provided by devices, compression or spontaneous rubbing of the legs. The body is capable of only appreciating a limited number of stimuli simultaneously. Longer term benefits could be explained by neuronal remodeling or long-term potentiation of neuronal signaling either temporary or permanent as a result of peripheral sensory input. Stimulation or Compression for RLS/PLMS Enhanced External Counter Pulsation (EECP) compresses the legs during diastole and increases cardiac filling pressure and volume. The more forceful contraction during systole creates increased collateral circulation. Has been used to create increased collateral circulation and improvement of symptoms in Angina Vascular impotence Stimulation or Compression for RLS/PLMS If the vascular hypothesis for RLS is true we postulated that increasing collateral circulation by EECP in RLS would result in improvement in RLS symptoms. Stimulation or Compression for RLS/PLMS Rajaram et al. Sleep Med 2006 6 patients with RLS treated with EECP for an hour a day 5 days a week for 7 weeks. Improved RLS and benefits were long-term in open label study. However, double-blind follow-up study was negative. Other less conventional treatments Other Dopaminergic drugs Amantadine –non DA agonist Seligeline– non DA agonist Bupropion -- Antidepressant Apomorphine Implantation of intrathecal pump for delivery of morphine with or without local anesthetic. Other less conventional treatments Acupuncture for RLS Estrogen therapy for PLMS Cognitive-behavioral therapy for PLMS CPAP for RLS in patients with Obstructive Sleep Apnea. Ketamine (NMDA receptor antagonist) for RLS Summary There are many less conventional treatments that have been reported to have some success in the treatment of RLS/PLMS. Further studies of these modalities are needed to prove definite efficacy. The studies of new treatments have led and will lead to new hypotheses for the pathogenesis of RLS/PLMS.