UPDATE: DIAGNOSIS & MANAGEMENT OF RLS

Transcription

1 UPDATE: DIAGNOSIS & MANAGEMENT OF RLS Beenish K. Khwaja, D.O. Legacy Medical Group--Neurology & Sleep Medicine Director, Legacy Mt. Hood Sleep Center

2 Outline Definition & Diagnostic Criteria Epidemiology of RLS Pathophysiology of RLS Etiology of RLS Differential Diagnosis of RLS Diagnosis of RLS in Adults and Children Clinical Course & Complication of RLS Impact of RLS Management Approach & Treatment of RLS

3 Essential Features Urge to move or the unpleasant leg sensation begins or worsens during periods of rest or inactivity such as lying down or sitting. Patients describe exacerbation of symptoms in situations such as watching television, driving or flying long distances, or attending meetings. Symptoms also worsen in association with a decrease in central nervous system (CNS) activity that leads to a decrease in alertness.

4 Essential Features Patients with RLS report an urge to move associated with dysesthesia when they are at rest. Some say that the sensations are uncomfortable and unpleasant, and others use specific terms such as creepycrawly, jittery, internal itch, or shock-like feelings. Up to 50% of RLS patients describe their sensations as painful. Some people, however, describe only an urge to move, and they are unaware of a sensory component.

5 Essential Features Symptoms are usually felt over large areas of the thighs or calves (or both) and are usually experienced as coming from deep within the legs rather than as superficial. The disorder can also involve the arms and other body parts. Symptoms in the legs usually precede involvement of the arms by several years. Arm paresthesias have been associated with a higher severity of the disorder. The involvement of the arms without any involvement in the legs rarely occurs.

6 Essential Features Urge to move and the unpleasant leg sensations are relieved by activity. When symptoms occur, patients may move their legs vigorously, flexing, stretching, or crossing them one over the other. In severe cases, they might walk around for hours in the evening or during the night to relieve the discomfort. The relief is generally described as beginning immediately or soon after the activity begins and this relief usually persists as long as the activity continues.

7 Essential Features Symptoms are worse in the evening. Three factors that can contribute to this phenomena are: Increased sleepiness in the evening compared to the daytime. Decrease in motor activity in the evening compared to the daytime. There is a manifestation of an intrinsic circadian rhythm in RLS symptoms.

8 Supportive Clinical Features Positive Family History Positive response to dopaminergic therapy. Nearly all patients with RLS show at least an initial positive therapeutic response to either L-dopa or dopamine receptor agonist. Presence of periodic limb movements (PLM) Occur in 80% of people with RLS. PLM in sleep are also common in some other disorders and among the elderly and are not specific for RLS. Recent genetic studies suggest that there may be a strong genetic connection between PLM and RLS and in the future, a specific form of RLS with PLM may be described.

9 Epidemiology Prevalence of RLS is approximately 5% to 10%. Most common movement disorder and among the most common sleep-related disorders. Most studies have also shown notable gender differences Women 9% v. Men 5.4% Has been found to occur across most every population (less so in Asians). Can begin at any age even young children. Up to 25% of primary care patients have RLS symptoms. Prevalence of severe RLS (at least moderate symptoms 3 or more times a week): 2.7% Women 3.7% v. Men 1.7% Increases in each decade of life

10 RLS and Age

11 Pathophysiology Dopamine Has been hypothesized as the main neurotransmitter in the pathophysiology because dopaminergic mechanisms are involved in spinal flexor reflex control and dopamine agonists provide symptomatic relief of RLS and PLMD. However, imaging studies (PET and SPECT ) scrutinizing either the dopamine type 2 (D 2 )-receptor or dopamine transporter have yielded mixed results, with three demonstrating reduced synaptic activity and two showing no difference from controls.

12 Pathophysiology Proteins involved in dopamine transmission exhibit circadian rhythms, possibly providing an explanation for the circadian character of RLS. The similarities in treatment response suggest a potential shared pathophysiology between RLS and Parkinson's disease. However, current evidence does not convincingly show more than a casual association.

13 Pathophysiology Iron Given the similar circadian rhythms of serum iron levels, the proteins involved in dopamine transmission, and RLS symptoms, it is difficult not to hypothesize a connection. Iron is a cofactor for tyrosine hydroxylase, the rate-limiting enzyme for dopamine synthesis. Decrease in iron may decrease dopamine synthesis. However, studies in iron-deficient animals have also demonstrated a decrease in D 1 - and D 2 -receptor, a decrease in dopamine transporter function, but an elevation in extra-cellular dopamine. Clearly, if there is an iron-dopamine connection in RLS, it is complex and it will need to be elucidated.

14 Etiology of RLS Primary (Idiopathic) RLS Accounts for most cases 50% of all cases are familial Inheritance is autosomal dominant with 5 genetic loci identified Seen in younger patients, or patients have a history of onset at a young age. Secondary RLS Pregnancy 11-33% Iron Deficiency Anemia 25% Peripheral Neuropathy 36% ESRD 20-57% Parkinson s Disease 21% Other Metabolic Deficiencies: B12, Folate, Thyroid

15 Secondary RLS Iron Deficiency Recent studies have shown that decreased iron stores (indicated by serum ferritin levels below 50 ng per ml [50 μg per L] can exacerbate RLS symptoms. Patients with newly diagnosed RLS or RLS patients with a recent exacerbation of symptoms should have their serum ferritin levels measured. Neurologic Lesions RLS has been reported in association with spinal cord and peripheral nerve lesions, although an exact pathologic mechanism has not been identified. RLS also may occur in patients with vertebral disk disease/radiculopathy. Other Neurologic Conditions Associate with RLS: Parkinson s CMT 2 SCA 1-2-3

16 Secondary RLS Pregnancy 20-25% of pregnant women experience RLS. If new onset (more than half) generally occur in last half of pregnancy. Symptoms stop soon after or even before delivery. Speculated etiologies include iron deficiency, folate deficiency, hormonal changes. May be a risk factor for later development of RLS. The more # of children a woman has, the higher the risk of RLS.

17 Secondary RLS Uremia Renal failure patient have a higher prevalence of RLS than general population: %. Associated with anemia and peripheral neuropathy or independently. Dialysis does NOT markedly improve RLS symptoms; in fact, may dialysis patients discontinue dialysis due to RLS. Kidney transplantation has a strong and positive influence on RLS symptoms in hemodialysis patients.

18 Secondary RLS Drug-Induced RLS symptoms may be induced or exacerbated by medications such as: Tricyclic antidepressants Selective serotonin reuptake inhibitors (SSRIs) Lithium Dopamine antagonists (e.g. Raglan, Compazine and Antipsychotics) Alcohol Antihistamines Caffeine Nicotine

19 Differential Diagnosis of RLS Disorders of Restlessness Neuroleptic-induced akathisia Positional discomfort Nervous leg shaking Involuntary leg movements (PLM, priopriospinal myoclonus at sleep onset, rhythmic movement disorder) Disorders of Leg Discomfort Peripheral Neuropathy Nocturnal Leg Cramps Intermittent Claudication or arterial insufficiency Arthritic leg discomfort Painful myopathies Varicose veins or venous insufficiency Deep vein thrombosis Fasciculations Disorders of Both Restlessness and Leg Discomfort Painful legs and moving toes Hypnic jerks

20 Diagnosing RLS History: main method of diagnosis Neurologic examination: normal in idiopathic; mainly used to look for secondary causes Lab testing: CBC, serum ferritin, percent iron saturation Added testing for peripheral neuropathy: B12, Chemistries (BUN, Cr), Glucose/A1c, EMG/NCS Consider PSG (not required or recommended) Insufficient sleep and sleep disorders such as sleep apnea might exacerbate symptoms of RLS.

21

22

23 RLS in Children 4 essential adult criteria + description in child s own words consistent with leg discomfort (urge to move is not enough) OR 4 essential adult criteria + 2 supportive criteria Supportive criteria in children: Sleep disturbance for age Biological parent or sibling with RLS Sleep study documenting PLM index > 5/hr Studies have found that RLS/PLMS in children is more prevalent in ADHD and vice versa. Treatment of RLS in Children: Gabapentin Clonazepam Clonidine (may be a good choice in patient with RLS and ADHD)

24 Clinical Course The intensity of sensory and motor symptoms varies greatly from one case to another; it also fluctuates throughout a patient's lifetime. Onset of RLS in patients younger than 30 tends to be more insidious and may not become troublesome until middle or later age. When the age of onset is 50 years or older, symptoms often appear more abruptly. Sudden remissions, lasting for months or even years, are as difficult to explain as are relapses, which appear without any apparent reason.

25 Complications of RLS Discomfort and pain Major cause of sleep disturbance (e.g. difficulty initiating and maintaining sleep) May lead to daytime fatigue/sleepiness Poor functioning at home or job due to restlessness Impaired social interactions Feelings of frustration, anxiety, depression, embarrassment

26 Impact of RLS REST Study: looked at epidemiology and impact of RLS People with RLS have impaired quality of life comparable to other chronic conditions. Wisconsin Sleep Cohort Study: People with RLS symptoms every night are much more likely to have cardiovascular disease. National Sleep Foundation in America Poll 2005: Those with RLS symptoms are more likely to report drowsy driving and missing social events due to discomfort.

27 Treatment of RLS Intermittent : RLS that is troublesome enough when present to justify treatment but does not occur frequently enough to necessitate daily therapy. Symptoms when not treated would occur on average <2/week for the past year with at least 5 lifetime events. Daily : RLS that is frequent and troublesome enough to require daily therapy. Symptoms when not treated would occur on average at least 2x/week for the past year. Refractory : Daily RLS treated with at least one dopamine agonist at usual dose with one or more the following outcomes: Inability to achieve a satisfactory response. Response that has become unsatisfactory with time despite increasing doses. Intolerable adverse effects. Augmentation that is not controllable with adjustment of agonist doses.

28 Target Symptoms for RLS Therapy Dysesthesia: reduce to the lowest level possible throughout the 24 hours. Sleep: normalize sleep onset, sleep maintenance, and daytime alertness. Periodic Leg Movements: reduce to asymptomatic level for patients and bed partner. Timing of treatment before significant onset of symptoms. Side Effects should be minimized.

29 Behavior Modification for RLS Avoid caffeine, chocolate, and MSG Aerobic exercise, but before 7:00 PM Limit use of centrally active stimulants: decongestants, antihistamines, nicotine, appetite suppressants, etc. Avoid SSRI anti-depressants, unless only effective treatment (possibly better: bupropion or nefazodone). Counter stimuli: socks, stretching, hot baths or showers, ice pack etc.

30 Pharmacologic Treatment for RLS Pharmacologic treatment options FDA Approved Medications Levadopa Dopamine Agonists Pramiprexole (Mirapex) Ropinirole (Requip) Non-FDA Approved Medications Anticonvulsants (GBP, Carbamazepine, Lyrica) Opioids (Codeine, Propoxyphene, Oxycodone, Tramadol, Hydrocodone, Methadone) Benzodiazepines (Clonazepam, Oxazepam, Triazolam) Iron Therapy

31 Treatment of RLS: Levodopa Several open-label and placebo-controlled studies have documented the short-term efficacy and long-term benefit of levodopa, given with carbidopa, in idiopathic RLS and RLS associated with uremia. Several adverse effects were reported including: Nausea/vomiting Tachycardia Orthostatic hypotension Hallucinations Insomnia Daytime fatigue Daytime sleepiness

32 Treatment of RLS: Levodopa 2 adverse effects were more specifically studied including morning rebound and RLS augmentation. Morning rebound is characterized by the presence of RLS symptoms occurring de novo as a consequence of evening or nighttime treatment. Augmentation is characterized by an earlier onset of symptoms by at least 4 hours or by an earlier onset between 2 and 4 hours plus at least one of the following: shorter latency to symptoms when at rest, extension of symptoms to other body parts, greater intensity of symptoms, and shorter duration of relief from treatment. One group found augmentation in 81% patients treated with levodopa. Increased severity of RLS and higher dosage of levodopa were associated with higher risk of developing augmentation. Mild augmentation may be treated by earlier administration of the drug, but in severe cases the medication should be discontinued.

33 Treatment of RLS: Dopamine Agonists Dopamine agonists are now considered the firstline treatment for RLS. More effective and produce fewer adverse effects (especially augmentation). Sleepiness might be seen during treatment with dopamine agonists, but it is much less problematic than in Parkinson's disease, and no cases of sudden onset of sleep have been reported. Small percentage of RLS patients treated with dopaminergic medications have noted increased urges and time spent gambling and increased sexual desire, a side-effect previously reported in Parkinson's disease.

34 Treatment of RLS: Opioids Opioids are often prescribed for severe cases, especially in patients unresponsive to other treatments. Opioids are also very useful during withdrawal from dopaminergic agents in patients who have developed severe augmentation. Opioids should also be used cautiously in patients who snore and are at risk for having sleep apnea syndrome.

35 Treatment of RLS: Anticonvulsants Studies of anticonvulsants have focused on gabapentin. Several open-label trials and one placebo-controlled study showed subjective improvements with gabapentin at doses of 300 to 2400 mg a day. Gabapentin is considered more potent and produces fewer adverse effects than dopaminergic agonists, except for mild daytime somnolence. Recommended for the treatment of neuropathic RLS and in general for patients who use pain as a descriptor for their leg sensations.

36 Treatment of RLS: Benzodiazepines Several studies showed that benzodiazepines improve the quality of sleep and reduce PLMS and associated arousals. However, the therapeutic effects of benzodiazepines on subjective ratings of RLS symptoms were either modest or not significant. Therefore benzodiazepines are mostly used to improve sleep continuity in patients with RLS. Because dopaminergic agents often have a stimulating effect and worsen insomnia, benzodiazepines are often used as an adjunctive treatment.

37 Treatment of RLS: Iron Supplementation Ferritin < 18, percent saturation < 16% However, ferritin levels less than 50ng/ml have been associated with increased symptoms The goal of therapy maintain ferritin > 50 ng/ml Treatment: Ferrous Sulfate 325 mg PLUS 100mg Vitamin C 1 hour or at least 2 hours after a meal up to 3x/daily Severe iron deficiency Ferritin <10 ng/ml Treatment: IV iron infusions of mg at least 2 days apart Iron dextran has higher anaphylactic risk than iron sucrose, iron gluconate or ferumoxytol However, the dextran maintains high peripheral iron availability much longer than does the sucrose. Optimal parental iron therapy is unclear.

38 Treatment of RLS & Pregnancy 1 st option is to increase iron, vitamin B12, folate, and magnesium levels. 2 nd option is oxycodone 5mg in 2 nd and 3 rd trimester. Pramipexole and GBP are pregnancy category C. Gabapentin can be used during breastfeeding as there is very little penetration into breast milk. Other options in breast feeding including benzodiazepines like Clonazepam, Diazepam or even Methadone (monitor the infant for sedation and poor suckling). Oxycodone and codeine can enter breast milk. Dopamine agonists suppress prolactin production.

39 Case Study # 1 54 y/o woman with 20+ year history of RLS. PMHx: CKD with creatinine of 2.1, stable. Hospitalized for major depression 4 yrs ago; currently taking fluoxetine at 40 mg/d. My legs are driving me nuts. Inside they crawl and hurt. I just have to move them. I can t live this way any longer. I would be better off dead. Taking carbidopa/levodopa ER 50/200 qid for 8 months. Relief of 1-2 hours, otherwise 24-hour RLS.

40 Case Study # 1 Did anything help you? I slept with oxycodone (taken for 3 days after dental work). Sinemet CR helped for 2 months and then it wouldn t last so I took more. Re-check of creatinine, hemoglobin and hematocrit, B12, folate, and Ferritin. No changes were found.

41 Augmentation Shift of RLS symptoms by two or more hours to an earlier onset compared to the patient s baseline. Levodopa produces augmentation in 30-85% of RLS patients (onset typically at 1-3 months). Dopamine agonists (DA) estimated to produce augmentation in 15-35% of patients (onset typically >6-12 months).

42 Management Options for Augmentation Change the schedule of drug administration. For example, split the dose in two first dose at about 6pm and the second half at bedtime. For levodopa, taper off then switch to a dopamine agonist. If DA, consider earlier dosing (as above). Observe for further augmentation. In the severe patient, shift to high potency opiate. Consider gabapentin, clonazepam or other therapy.

43 Case Study # 1: Treatment Approach Taper carbidopa/levodopa ER 50/200 by one tablet every 2 days, beginning in the evening, to prevent augmentation. To reduce augmentation, substitute ropinirole 0.25 mg for each of the doses every 2 days. Oxycodone 5 mg p.o. h.s. for acute symptom relief and to improve sleep. Emphasize complexity, need for daily contact.

44 Treatment Course Day 1-10 Day 1: I slept 5 hours. Day 6: The legs are 30% better, but I m only sleeping 4 hours or so. Response: Increase ropinirole doses # 3 & 4 to 0.50 mg. Day 10: My legs are OK until about 11:00 and then they act up. The medicine makes me really sick (nauseated). Response: Nausea should get better. Increase ropinorole at noon to 0.5 mg.

45 Treatment Course Day Day 11: I m sick all day. I didn t sleep. Response: Discontinue a.m. ropinirole. Day 12: You got to do something. Response: Reduce ropinirole to 0.25 mg noon & 6:00 pm, continue 0.5 mg at 10:00 pm. Day 14: I m not as sick but my legs are worse. Is this ever going to get better? Response: Add oxycodone 5 mg at 6:00 p.m. (and h.s.). Reduce ropinirole to 0.25 mg TID.

46 Treatment Course Day Day 21: I m 50 % better. I even slept 6 hours one night. RL starts at about noon. Response: Increase ropinirole to 0.5 mg with lunch. Day 24 That stuff makes me sick. I decreased it (back to 0.25 mg at noon). My legs were getting puffy. Response: Checked chemistries and renal function. No acute changes.

47 Treatment Course Day Day 26: Doc, I think the dope works the best. The fluid was making my legs hurt. Response: Stopped ropinirole Changed oxycodone to METHADONE 5 mg at 6:00 p.m. and 10:00 p.m. Day 35: Doc, it s amazing. I don t feel my legs jumping and I slept for five nights straight. Edema resolved.

48 Treatment Course Day 35 + Depression remained moderate with low energy & motivation; moderate sadness. PCP agreed to my request to discontinue Prozac. Wellbutrin SR 150 mg was started and increased to a.m. and noon one week later. Four weeks later, clonazepam 0.5 mg h.s. was added due to feeling a bit nervous. At eight weeks, he slept >6 hours nightly and said I feel pretty good. He has remained so for 3+ years on methadone, buproprion XL and clonazepam.

49 Conclusions Treat symptoms identified as problems by patient. Treat iron deficiency. Dopamine agonists are the first line. Target therapy before the onset of syptoms. Carbidopa Levodopa causes augmentation. Best used prn. [Arbitrary limit: 3 tabs of 25/100)] Opiates reserved for severe patients. High potency agents can be used (methadone, hydromorphone) but caution for EDS and SDB. Gabapentin is variably effective. Best with pain. Depression and anxiety are common and require treatment when present. Buproprion preferred.

50

51

52

53