- Email: [email protected]
When restless legs syndrome turns malignant
Sleep Medicine 14 (2013) 575–577
Contents lists available at SciVerse ScienceDirect
Sleep Medicine journal homepage: www.elsevier.com/locate/sleep
Brief Communication
When restless legs syndrome turns malignant Eva C. Schulte a,b,c, Nadine Gross a, Helen Slawik d, Juliane Winkelmann a,b,c,⇑ a
Neurologische Klinik und Poliklinik, Klinikum rechts der Isar, Technische Universität München, Ismaningerstr. 22, 81675 München, Germany Institut für Humangenetik, Helmholtz Zentrum München, Ingolstädter Landstr. 1, 85764 Neuherberg, Germany c Institut für Humangenetik, Klinikum rechts der Isar, Technische Universität München, Trogerstr. 32, 81675 München, Germany d Klinik für Psychiatrie und Psychotherapie, Klinikum rechts der Isar, Technische Universität München, Ismaningerstr. 22, 81675 München, Germany b
a r t i c l e
i n f o
Article history: Received 1 December 2012 Received in revised form 5 February 2013 Accepted 24 February 2013 Available online 3 May 2013 Keywords: Restless legs syndrome, Malignant restless legs syndrome Paroxysmal myoclonic attacks Opiate rotation De-escalation of therapy Multidrug therapy
a b s t r a c t Usually symptoms of restless legs syndrome (RLS) respond well to treatment with dopaminergic drugs, opiates, or anticonvulsant medications. Yet sometimes symptoms can be severe and become refractory, even to high-dose combination therapy. Here we present two cases of familial RLS with rigorous and unusual motor and sensory symptoms in the form of episodes of myoclonic hyperkinesias and painful sensations in addition to more characteristic features of RLS. Stepwise reduction of all RLS—and antidepressant medication down to opiate monotherapy—and subsequent opiate rotation led to an improvement of symptoms. Yet in both cases, reintroduction of low-dose dopaminergic drugs was necessary to achieve satisfactory treatment effect. We have termed this form of RLS refractory to multiple combinations of all classes of commonly used drugs malignant RLS. Therapeutically simplification and reduction of the drug scheme and opiate rotation should be considered in malignant RLS. Ó 2013 Elsevier B.V. All rights reserved.
1. Introduction Restless legs syndrome (RLS) is a common sensorimotor disorder characterized by dysesthesias affecting the legs, occurring mostly during the evening and night and triggered by periods of rest and relieved by movement [1]. Age-dependent prevalence of up to 10% were found in the adult populations in Europe [2]. Yet in only 2% of the population, RLS symptoms are severe enough to mandate treatment [2]. Although the pathophysiology is just starting to be uncovered, it is well-established that sensory and motor symptoms are alleviated by dopaminergic drugs (levodopa, dopamine agonists) [3,4], opioidergic [5], and antiepileptic drugs (e.g., pregabalin) [6]. Augmentation, the paradoxic aggravation of RLS symptoms under treatment, represents a conundrum specific to dopaminergic RLS therapy. Rarely, augmentation-like phenomena also have been reported under opiate therapy; five of the reported cases were with the use of tramadol, but none of the 76 individuals treated with methadone for a duration of 10 years experienced augmentation-like phenomena [7–9]. In quotidian practice, both physicians and patients show a tendency to persistently increase medication doses and add drugs to the therapeutic regime in an at-
⇑ Corresponding author at: Neurologische Klinik und Poliklinik, Klinikum rechts der Isar, Ismaningerstr. 22, 81675 München, Germany. Tel.: +49 89 4140 4688; fax: +49 89 4140 4867. E-mail address: [email protected] (J. Winkelmann). 1389-9457/$ - see front matter Ó 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.sleep.2013.02.012
tempt to counteract worsening symptoms. In some cases, RLS symptoms can further deteriorate and become refractory to treatment. Here symptoms can affect the entire body. Dysesthesias can take on painful qualities, and motor symptoms may manifest as episodes of myoclonic hyperkinesias in addition to the commonly seen periodic limb movements (PLMs). Additionally the nocturnal predilection may be replaced by continuous symptoms throughout the day and night [10,11]. 2. Case 1 A 63-year-old woman presented to our RLS clinic. RLS had first been diagnosed at age 54, but intermittent symptoms had been present from her thirties. She described an urge to move with ‘‘electrifying’’ dysesthesias of the legs during the evening hours that improved in response to movement and treatment with levodopa. Over the past 5 years, symptoms had worsened, and symptom control under increasing doses of levodopa monotherapy and dopamine agonists, ropinirole, cabergoline, and pramipexole, was no longer sufficient (International RLS Study Group severity score, 37 of 40 points). Clonazepam (1 mg/d) also did not relieve symptoms. Her medical history included lumbar discal herniation treated conservatively and arterial hypertension treated with bisoprolol, losartan, and hydrochlorothiazide. She had received bupropion, agomelatine, and trimipramine for recurring episodes of depression. Three of her children also had RLS. The patient’s par-
576
E.C. Schulte et al. / Sleep Medicine 14 (2013) 575–577
ents did not report RLS symptoms; however, her father died at the age of 49 years due to unknown cause. Neurologic examination was unremarkable except for bilaterally absent Achilles tendon reflexes. Serum ferritin was 109 ng/ mL, iron was 53 lg/dL, and C-reactive protein levels as well as complete blood cell count and renal parameters were within reference range. At the time of presentation, she reported dysesthesias in all four extremities during the day and night and nightly attack-like 1-hour periods of strong involuntary movements of the arms and legs while on a therapeutic regime of transcutaneous fentanyl 50 lg hourly, long-acting levodopa and benserazide 100 and 25 mg, respectively, once, pramipexole 0.18 mg twice daily, and 50 mg daily of amitriptyline. We slowly discontinued one drug after another over a period of 6 weeks and in parallel rotated fentanyl in a now-reduced dose of 25 lg hourly to two-thirds of the equivalent dosage in oxycodone and naloxone (10 mg and 5 mg, respectively, twice daily). Hyperkinetic attacks shortened to 5 minutes several times a week, though sensory symptoms did not improve as much. After 4 months hyperkinesias gradually recurred and only partially improved after titrating to oxycodone and naloxone 20 mg and 10 mg, respectively, twice daily together with either pregabalin 300 mg daily or ropinirole 1 mg daily.
3. Case 2 A 64-year-old man presented to our clinic with continuous, painful, ‘‘vibrating,’’ and ‘‘cramping’’ sensations affecting his right leg more than the left (International RLS Study Group severity score, 40). He also described nightly episodes of painful hyperkinesias consisting of involuntary movements of all four extremities and intermittent slight vocalizations of up to 4 hours’ duration (video). Symptoms started at the age of 48 years, approximately 2 weeks after the first of seven surgeries for lumbar discal herniations. Initially symptoms consisted of a nightly urge to move the legs in conjunction with ‘‘abnormal’’ sensations largely in his right leg. However, during the 3 years prior to presentation, dysesthesias became near continuous and painful. His medical history comprised peripheral arterial occlusive disease, hyperuricemia treated with allopurinol, chronic pain syndrome following partial gastric resection for a gastric ulcers, and arterial hypertension treated with bisoprolol. Moreover, he had received venlafaxine and mirtazapine for recurring episodes of depression. His father also was diagnosed with RLS. Neurologic examination revealed sensory deficits in line with a known right-sided L3/L4/L5 syndrome. Additionally, all deep tendon reflexes were lively and gait appeared ataxic due to myoclonic hyperkinesias affecting both legs. Serum ferritin was 93 ng/mL, iron was 68 lg/dL, and C-reactive protein levels as well as complete blood cell count and renal parameters were unremarkable. Polysomnography showed an increased index of PLMs while awake (69.3/h, also seen in the video) with only marginally increased PLMs during sleep (13.8/h) as well as a central sleep apnea syndrome (desaturation to 84% and apnea–hypopnea index of 23.8/ h). Diagnostic workup including lumbar puncture, nerve conduction studies, sensory-evoked potentials, electroencephalogram, and cerebral magnetic resonance imaging revealed no abnormalities. Spinal magnetic resonance imaging showed postoperative and degenerative changes of the lumbar vertebrae. Over several years, the therapeutic regime was escalated step by step. Alternative treatments such as amitriptyline 75 mg daily, trimipramin 200 mg daily, and nonsteroidal anti-inflammatory drugs also were unsuccessful. At the time of presentation, he was treated with transcutaneous fentanyl up to 100 lg hourly, levodopa and benserazide 200 mg and 50 mg, respectively, daily, pram-
ipexole 0.535 mg daily, and pregabalin 225 mg daily, and he presented with paroxysmal hyperkinesias. Under the assumption that serotonergic and dopaminergic stimulation may have lead to an exacerbation of RLS symptoms, all RLS, pain, and antidepressant medication (venlafaxine hydrochloride, mirtazapine) were discontinued over several weeks’ duration. In parallel fentanyl was rotated to transcutaneous buprenorphine 52.5 lg hourly. The hyperkinetic episodes stopped. Although less frequent and less severe, intermittent sensory symptoms affecting the entire body including the lips and ears persisted. After 4 months pregabalin 450 mg daily and after 6 months pramipexole 0.35 mg daily were reinstated and further reduced symptom frequency and severity.
4. Discussion Although dopaminergic, opiate, and anticonvulsant drugs are effectively able to control symptoms in many individuals with RLS, medical management can be difficult in some cases. Side effects and the need for frequent therapeutic adjustments with regard to timing and dosage as well as the combinatory treatment with two or more substances often complicate RLS therapy [12]. Yet in some cases, such as the two cases of familial RLS described here severe RLS symptoms may persist and even worsen under high-dose combination therapy. We have termed this continuous worsening of RLS symptoms under different combinations of multidrug therapy malignant RLS. Although dopaminergic imbalance also could represent a possible trigger factor with regard to malignant RLS, in contrast to augmentation in malignant RLS the lack of drug efficacy extends to most if not all classes of RLS drugs. Malignant RLS also has a more gradual onset and further worsening of symptoms if left untreated. It also seems possible that in some individuals with severe RLS and insufficient response to a number of different RLS medications, symptoms may begin to self-propagate and manifest as malignant RLS. Additionally, comorbid depressive symptoms may appear or worsen as RLS symptoms progress and become refractory to treatment. Selective serotonin reuptake inhibitors that frequently are used in an attempt to counteract this course of events sometimes can lead to an exacerbation of RLS symptoms [13]. Moreover, it is possible that the simultaneous dopaminergic and serotonergic stimulation also could play a role in malignant RLS. In our two cases therapeutic reduction of antidepressant and dopaminergic drugs as well as opiate rotation (two-thirds equivalent dose of the original opiate) was able to halt the continuous worsening of symptoms and had an especially beneficial effect on the severe diurnal episodes of hyperkinesias seen in both individuals. Yet in both cases dysesthesias and the urge to move could not be fully alleviated and necessitated additional treatment with pregabalin or a remaining small dose of dopamine agonist. Rotation of opiates is commonly used in cases of chronic pain disorders complicated by loss of drug efficacy, though no formal studies have been conducted. In our experience, opiate rotation often has been successful in cases of RLS that were difficult to treat cases, such as the two cases presented here. However, we also often see that dopaminergic therapy cannot be entirely discontinued and patients still require additional low-dose dopaminergic drugs. One possible explanation could be an adaptation to dopaminergic stimulation. Alternatively it also is conceivable that dopaminergic drugs and opiates have complimentary modes of action in the treatment of RLS symptoms. In cases of RLS that generally are difficult to treat, a reduction of drug dosages and the number of substances should be considered before therapeutic escalation. Next to the development of treatment strategies for malignant cases of RLS and future drug trials specifically assessing drug combinations in the treatment of RLS, deep brain stimulation—thus far
E.C. Schulte et al. / Sleep Medicine 14 (2013) 575–577
only attempted in a single case [14]—also could possibly represent a nonmedical treatment option in the future; however, experience with its use in RLS is limited to date. Further it also will be important to identify factors contributing or predisposing to malignant RLS. To date apart from low serum ferritin levels [15] and certain drugs such as serotonin reuptake inhibitors [13] or dopamine D2 receptor antagonists [16], no factors are known as to which predict disease severity or exacerbation in idiopathic RLS. For now we propose opiate rotation, with additional low-dose levodopa, dopamine agonists, or pregabalin if necessary, to treat persistent or worsening symptoms of malignant RLS. Financial disclosures Dr. Schulte received a postdoctoral fellowship from the Technische Universität München and the German Academic Exchange Service (DAAD) and travel support from the German Society for Neurology (DGN, Stiftung Felgenhauer) and the DAAD. Dr. Gross and Dr. Slawik report no relevant disclosures. Professor Winkelmann serves on a scientific advisory board for UCB and has received speaker honoraria from UCB and Vifor Pharma. She has filed a patent re: Winkelmann et al. Nat Genet 2007 and receives research support from the German RLS foundation, the Deutsche Forschungsgemeinschaft (DFG), and the Fritz Thyssen Foundation. Funding sources The study was funded in its entirety by in-house institutional funding from the Neurologische Klinik and Poliklinik, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.’
Conflict of interest The ICMJE Uniform Disclosure Form for Potential Conflicts of Interest associated with this article can be viewed by clicking on the following link: http://dx.doi.org/10.1016/j.sleep.2013.02.012.
577
References [1] Allen RP, Picchietti D, Hening WA, Trenkwalder C, Walters AS, Montplaisir A, et al. Restless legs syndrome: diagnostic criteria, special considerations, and epidemiology. A report from the restless legs syndrome diagnosis and epidemiology workshop at the National Institutes of Health. Sleep Med 2003;4:101–19. [2] Allen RP, Walters AS, Montplaisir J, Hening W, Myers A, Bell TJ, et al. Restless legs syndrome prevalence and impact: REST general population study. Arch Intern Med 2005;165:1286–92. [3] Scholz H, Trenkwalder C, Kohnen R, Riemann D, Kriston L, Hornyak M. Dopamine agonists for restless legs syndrome. Cochrane Database Syst Rev 2011;3:CD006009. [4] Scholz H, Trenkwalder C, Kohnen R, Riemann D, Kriston L, Hornyak M. Levodopa for restless legs syndrome. Cochrane Database Syst Rev 2011;3: CD005504. [5] Walters AS, Wagner ML, Hening WA, Grasing K, Mills R, Chokroverty S, et al. Successful treatement of the idiopathic restless legs syndrome in a randomized double-blind trial of oxycodone versus placebo. Sleep 1993;16:327–32. [6] Garcia-Borreguero D, Larrosa O, Williams AM, Albares J, Pascual M, Palacios JC, et al. Treatment of restless legs syndrome with pregabalin: a double-blind, placebo-controlled study. Neurology 2010;74:1897–904. [7] Vetrugno R, La Morgia C, D’Angelo R, Loi D, Provini F, Plazzi G, et al. Augmentation of restless legs syndrome with long-term tramadol treatment. Mov Disord 2007;22:424–7. [8] Silver N, Allen RP, Senerth J, Earley CJ. A 10-year, longitudinal assessment of dopamine agonists and methadone in the treatment of restless legs syndrome. Sleep Med 2011;12:440–4. [9] Earley CJ, Allen RP. Restless legs syndrome augmenation associated with tramadol. Sleep Med 2006;7:592–3. [10] Hornyak M, Sohr M, Busse M. 604 and 615 Study groups. Evaluation of painful sensory symptoms in RLS: experience from two clinical trials. Sleep Med 2011;12:186–9. [11] Michaud M, Chabli A, Lavigne G, Montplasir J. Arm restlessness in patients with restless legs syndrome. Mov Disord 2000;15:289–93. [12] Chokroverty S. Long-term management issues in restless legs syndrome. Mov Disord 2011;26:1378–84. [13] Rottach KG, Schaner BM, Kirch MH, Zivotofsky AZ, Teufel LM, Gallwitz T, et al. Restless legs syndrome as side effect of second generation antidepressants. J Psychiatr Res 2008;43:70–5. [14] Ondo WG, Jankovic J, Jimenez-Shahed J. Globus pallidus deep brain stimulation for refractory idiopathic restless legs syndrome. Sleep Med 2012;13:1202–4. [15] Frauscher B, Gschliesser V, Brandauer E, El-Demerdash E, Kaneider M, Rücker L, et al. The severity range of restless legs syndrome (RLS) and augmentation in a prospective patient cohort: association with ferritin levels. Sleep Med 2009;10:611–5. [16] Horiguchi J, Yamashita H, Mizuno S, Kuramoto Y, Kagaya A, Yamawaki S, et al. Nocturnal eating/drinking syndrome and neuroleptic-induced restless legs syndrome. Int Clin Psychopharmacol 1999;14:33–6.
Contents lists available at SciVerse ScienceDirect
Sleep Medicine journal homepage: www.elsevier.com/locate/sleep
Brief Communication
When restless legs syndrome turns malignant Eva C. Schulte a,b,c, Nadine Gross a, Helen Slawik d, Juliane Winkelmann a,b,c,⇑ a
Neurologische Klinik und Poliklinik, Klinikum rechts der Isar, Technische Universität München, Ismaningerstr. 22, 81675 München, Germany Institut für Humangenetik, Helmholtz Zentrum München, Ingolstädter Landstr. 1, 85764 Neuherberg, Germany c Institut für Humangenetik, Klinikum rechts der Isar, Technische Universität München, Trogerstr. 32, 81675 München, Germany d Klinik für Psychiatrie und Psychotherapie, Klinikum rechts der Isar, Technische Universität München, Ismaningerstr. 22, 81675 München, Germany b
a r t i c l e
i n f o
Article history: Received 1 December 2012 Received in revised form 5 February 2013 Accepted 24 February 2013 Available online 3 May 2013 Keywords: Restless legs syndrome, Malignant restless legs syndrome Paroxysmal myoclonic attacks Opiate rotation De-escalation of therapy Multidrug therapy
a b s t r a c t Usually symptoms of restless legs syndrome (RLS) respond well to treatment with dopaminergic drugs, opiates, or anticonvulsant medications. Yet sometimes symptoms can be severe and become refractory, even to high-dose combination therapy. Here we present two cases of familial RLS with rigorous and unusual motor and sensory symptoms in the form of episodes of myoclonic hyperkinesias and painful sensations in addition to more characteristic features of RLS. Stepwise reduction of all RLS—and antidepressant medication down to opiate monotherapy—and subsequent opiate rotation led to an improvement of symptoms. Yet in both cases, reintroduction of low-dose dopaminergic drugs was necessary to achieve satisfactory treatment effect. We have termed this form of RLS refractory to multiple combinations of all classes of commonly used drugs malignant RLS. Therapeutically simplification and reduction of the drug scheme and opiate rotation should be considered in malignant RLS. Ó 2013 Elsevier B.V. All rights reserved.
1. Introduction Restless legs syndrome (RLS) is a common sensorimotor disorder characterized by dysesthesias affecting the legs, occurring mostly during the evening and night and triggered by periods of rest and relieved by movement [1]. Age-dependent prevalence of up to 10% were found in the adult populations in Europe [2]. Yet in only 2% of the population, RLS symptoms are severe enough to mandate treatment [2]. Although the pathophysiology is just starting to be uncovered, it is well-established that sensory and motor symptoms are alleviated by dopaminergic drugs (levodopa, dopamine agonists) [3,4], opioidergic [5], and antiepileptic drugs (e.g., pregabalin) [6]. Augmentation, the paradoxic aggravation of RLS symptoms under treatment, represents a conundrum specific to dopaminergic RLS therapy. Rarely, augmentation-like phenomena also have been reported under opiate therapy; five of the reported cases were with the use of tramadol, but none of the 76 individuals treated with methadone for a duration of 10 years experienced augmentation-like phenomena [7–9]. In quotidian practice, both physicians and patients show a tendency to persistently increase medication doses and add drugs to the therapeutic regime in an at-
⇑ Corresponding author at: Neurologische Klinik und Poliklinik, Klinikum rechts der Isar, Ismaningerstr. 22, 81675 München, Germany. Tel.: +49 89 4140 4688; fax: +49 89 4140 4867. E-mail address: [email protected] (J. Winkelmann). 1389-9457/$ - see front matter Ó 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.sleep.2013.02.012
tempt to counteract worsening symptoms. In some cases, RLS symptoms can further deteriorate and become refractory to treatment. Here symptoms can affect the entire body. Dysesthesias can take on painful qualities, and motor symptoms may manifest as episodes of myoclonic hyperkinesias in addition to the commonly seen periodic limb movements (PLMs). Additionally the nocturnal predilection may be replaced by continuous symptoms throughout the day and night [10,11]. 2. Case 1 A 63-year-old woman presented to our RLS clinic. RLS had first been diagnosed at age 54, but intermittent symptoms had been present from her thirties. She described an urge to move with ‘‘electrifying’’ dysesthesias of the legs during the evening hours that improved in response to movement and treatment with levodopa. Over the past 5 years, symptoms had worsened, and symptom control under increasing doses of levodopa monotherapy and dopamine agonists, ropinirole, cabergoline, and pramipexole, was no longer sufficient (International RLS Study Group severity score, 37 of 40 points). Clonazepam (1 mg/d) also did not relieve symptoms. Her medical history included lumbar discal herniation treated conservatively and arterial hypertension treated with bisoprolol, losartan, and hydrochlorothiazide. She had received bupropion, agomelatine, and trimipramine for recurring episodes of depression. Three of her children also had RLS. The patient’s par-
576
E.C. Schulte et al. / Sleep Medicine 14 (2013) 575–577
ents did not report RLS symptoms; however, her father died at the age of 49 years due to unknown cause. Neurologic examination was unremarkable except for bilaterally absent Achilles tendon reflexes. Serum ferritin was 109 ng/ mL, iron was 53 lg/dL, and C-reactive protein levels as well as complete blood cell count and renal parameters were within reference range. At the time of presentation, she reported dysesthesias in all four extremities during the day and night and nightly attack-like 1-hour periods of strong involuntary movements of the arms and legs while on a therapeutic regime of transcutaneous fentanyl 50 lg hourly, long-acting levodopa and benserazide 100 and 25 mg, respectively, once, pramipexole 0.18 mg twice daily, and 50 mg daily of amitriptyline. We slowly discontinued one drug after another over a period of 6 weeks and in parallel rotated fentanyl in a now-reduced dose of 25 lg hourly to two-thirds of the equivalent dosage in oxycodone and naloxone (10 mg and 5 mg, respectively, twice daily). Hyperkinetic attacks shortened to 5 minutes several times a week, though sensory symptoms did not improve as much. After 4 months hyperkinesias gradually recurred and only partially improved after titrating to oxycodone and naloxone 20 mg and 10 mg, respectively, twice daily together with either pregabalin 300 mg daily or ropinirole 1 mg daily.
3. Case 2 A 64-year-old man presented to our clinic with continuous, painful, ‘‘vibrating,’’ and ‘‘cramping’’ sensations affecting his right leg more than the left (International RLS Study Group severity score, 40). He also described nightly episodes of painful hyperkinesias consisting of involuntary movements of all four extremities and intermittent slight vocalizations of up to 4 hours’ duration (video). Symptoms started at the age of 48 years, approximately 2 weeks after the first of seven surgeries for lumbar discal herniations. Initially symptoms consisted of a nightly urge to move the legs in conjunction with ‘‘abnormal’’ sensations largely in his right leg. However, during the 3 years prior to presentation, dysesthesias became near continuous and painful. His medical history comprised peripheral arterial occlusive disease, hyperuricemia treated with allopurinol, chronic pain syndrome following partial gastric resection for a gastric ulcers, and arterial hypertension treated with bisoprolol. Moreover, he had received venlafaxine and mirtazapine for recurring episodes of depression. His father also was diagnosed with RLS. Neurologic examination revealed sensory deficits in line with a known right-sided L3/L4/L5 syndrome. Additionally, all deep tendon reflexes were lively and gait appeared ataxic due to myoclonic hyperkinesias affecting both legs. Serum ferritin was 93 ng/mL, iron was 68 lg/dL, and C-reactive protein levels as well as complete blood cell count and renal parameters were unremarkable. Polysomnography showed an increased index of PLMs while awake (69.3/h, also seen in the video) with only marginally increased PLMs during sleep (13.8/h) as well as a central sleep apnea syndrome (desaturation to 84% and apnea–hypopnea index of 23.8/ h). Diagnostic workup including lumbar puncture, nerve conduction studies, sensory-evoked potentials, electroencephalogram, and cerebral magnetic resonance imaging revealed no abnormalities. Spinal magnetic resonance imaging showed postoperative and degenerative changes of the lumbar vertebrae. Over several years, the therapeutic regime was escalated step by step. Alternative treatments such as amitriptyline 75 mg daily, trimipramin 200 mg daily, and nonsteroidal anti-inflammatory drugs also were unsuccessful. At the time of presentation, he was treated with transcutaneous fentanyl up to 100 lg hourly, levodopa and benserazide 200 mg and 50 mg, respectively, daily, pram-
ipexole 0.535 mg daily, and pregabalin 225 mg daily, and he presented with paroxysmal hyperkinesias. Under the assumption that serotonergic and dopaminergic stimulation may have lead to an exacerbation of RLS symptoms, all RLS, pain, and antidepressant medication (venlafaxine hydrochloride, mirtazapine) were discontinued over several weeks’ duration. In parallel fentanyl was rotated to transcutaneous buprenorphine 52.5 lg hourly. The hyperkinetic episodes stopped. Although less frequent and less severe, intermittent sensory symptoms affecting the entire body including the lips and ears persisted. After 4 months pregabalin 450 mg daily and after 6 months pramipexole 0.35 mg daily were reinstated and further reduced symptom frequency and severity.
4. Discussion Although dopaminergic, opiate, and anticonvulsant drugs are effectively able to control symptoms in many individuals with RLS, medical management can be difficult in some cases. Side effects and the need for frequent therapeutic adjustments with regard to timing and dosage as well as the combinatory treatment with two or more substances often complicate RLS therapy [12]. Yet in some cases, such as the two cases of familial RLS described here severe RLS symptoms may persist and even worsen under high-dose combination therapy. We have termed this continuous worsening of RLS symptoms under different combinations of multidrug therapy malignant RLS. Although dopaminergic imbalance also could represent a possible trigger factor with regard to malignant RLS, in contrast to augmentation in malignant RLS the lack of drug efficacy extends to most if not all classes of RLS drugs. Malignant RLS also has a more gradual onset and further worsening of symptoms if left untreated. It also seems possible that in some individuals with severe RLS and insufficient response to a number of different RLS medications, symptoms may begin to self-propagate and manifest as malignant RLS. Additionally, comorbid depressive symptoms may appear or worsen as RLS symptoms progress and become refractory to treatment. Selective serotonin reuptake inhibitors that frequently are used in an attempt to counteract this course of events sometimes can lead to an exacerbation of RLS symptoms [13]. Moreover, it is possible that the simultaneous dopaminergic and serotonergic stimulation also could play a role in malignant RLS. In our two cases therapeutic reduction of antidepressant and dopaminergic drugs as well as opiate rotation (two-thirds equivalent dose of the original opiate) was able to halt the continuous worsening of symptoms and had an especially beneficial effect on the severe diurnal episodes of hyperkinesias seen in both individuals. Yet in both cases dysesthesias and the urge to move could not be fully alleviated and necessitated additional treatment with pregabalin or a remaining small dose of dopamine agonist. Rotation of opiates is commonly used in cases of chronic pain disorders complicated by loss of drug efficacy, though no formal studies have been conducted. In our experience, opiate rotation often has been successful in cases of RLS that were difficult to treat cases, such as the two cases presented here. However, we also often see that dopaminergic therapy cannot be entirely discontinued and patients still require additional low-dose dopaminergic drugs. One possible explanation could be an adaptation to dopaminergic stimulation. Alternatively it also is conceivable that dopaminergic drugs and opiates have complimentary modes of action in the treatment of RLS symptoms. In cases of RLS that generally are difficult to treat, a reduction of drug dosages and the number of substances should be considered before therapeutic escalation. Next to the development of treatment strategies for malignant cases of RLS and future drug trials specifically assessing drug combinations in the treatment of RLS, deep brain stimulation—thus far
E.C. Schulte et al. / Sleep Medicine 14 (2013) 575–577
only attempted in a single case [14]—also could possibly represent a nonmedical treatment option in the future; however, experience with its use in RLS is limited to date. Further it also will be important to identify factors contributing or predisposing to malignant RLS. To date apart from low serum ferritin levels [15] and certain drugs such as serotonin reuptake inhibitors [13] or dopamine D2 receptor antagonists [16], no factors are known as to which predict disease severity or exacerbation in idiopathic RLS. For now we propose opiate rotation, with additional low-dose levodopa, dopamine agonists, or pregabalin if necessary, to treat persistent or worsening symptoms of malignant RLS. Financial disclosures Dr. Schulte received a postdoctoral fellowship from the Technische Universität München and the German Academic Exchange Service (DAAD) and travel support from the German Society for Neurology (DGN, Stiftung Felgenhauer) and the DAAD. Dr. Gross and Dr. Slawik report no relevant disclosures. Professor Winkelmann serves on a scientific advisory board for UCB and has received speaker honoraria from UCB and Vifor Pharma. She has filed a patent re: Winkelmann et al. Nat Genet 2007 and receives research support from the German RLS foundation, the Deutsche Forschungsgemeinschaft (DFG), and the Fritz Thyssen Foundation. Funding sources The study was funded in its entirety by in-house institutional funding from the Neurologische Klinik and Poliklinik, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.’
Conflict of interest The ICMJE Uniform Disclosure Form for Potential Conflicts of Interest associated with this article can be viewed by clicking on the following link: http://dx.doi.org/10.1016/j.sleep.2013.02.012.
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