We have read with great interest the case description of Mehta et al. [1] that highlighted an unusual clinical manifestation of restless legs syndrome (RLS) in the neurology intensive care unit. RLS is a still underdiagnosed chronic sleep-related movement disorder with a wide range of severity, including uncommon cases with severe and abrupt clinical presentation. The presentation of RLS in an emergency room setting has been almost neglected in the literature. The case reported by Mehta et al. concerns a patient with a history of undiagnosed RLS and an acute exacerbation of symptoms likely secondary to promethazine. Herein we report a similar case that underlines the possibility that RLS can present as an acute emergency, and adds the observation that this may even occur in patients with a well-established RLS diagnosis and treatment for RLS. A 57-year-old man with chronic renal failure due to inherited collagenopathy underwent renal transplantation after 1 year of peritoneal dialysis. Two years before, RLS associated with renal insufficiency had been diagnosed and treatment with pramipexole was initiated. The patient had suffered from RLS since the age of 10 years and reported a positive family history of RLS. Before surgery he was successfully treated with extended release pramipexole 1.125 mg plus clonazepam 0.5 mg, because of progressive worsening of the symptoms during the past year. For reasons that were not well specified, probably related to standard safety pre-surgical procedures, the surgeons decided to withdraw pramipexole and clonazepam the day before the operation. Surgery proceeded without complications, but about 2 h after awakening from anesthesia the patient started to show severe ‘akathisia’ characterized by continuous leg and arm stretching movements associated with confusion. Symptoms worsened during the following 2 h, and the patient started to insist that he needed to move and repeatedly tried to stand up and walk to relieve symptoms. Physicians and nurses attempted to restrain him in order to avoid post-surgical complications due to the intense motor activity. Physicians then decided to inject haloperidol 10 mg intra-muscularly, which worsened the symptoms and induced an unusual aggressive behavior in the patient. Main hemodynamic and laboratory parameters were within the normal range, and a diagnosis of psychomotor agitation due to an abnormal response to anesthesia was suspected. Although confused, the patient screamed repetitively the name of the sleep expert who was treating him for RLS. Finally, physicians contacted the sleep expert who advised against giving any other neuroleptic, and suggested to administer morphine intravenously (10 mg), and to subsequently continue with the pre-surgery RLS treatment. With morphine, RLS symptoms rapidly resolved and the patient was able to stay in bed. We think that in this case the complete and rapid RLS drug withdrawal before surgery and possibly the anesthesia triggered RLS symptoms, and that haloperidol with its anti-dopaminergic effect significantly worsened the symptoms. Anesthesia might trigger new or worsen a pre-existing RLS [2], and already Karroum et al. [3] described a series of patients who experienced a perioperative acute exacerbation of their RLS symptoms with negative consequences and complications during surgery and followup. In our case, we decided to administer opioids and observed an immediate effect, which had previously also been described by Vahedi et al. [4] in another case of severe RLS admitted as an emergency. This case and others described in the literature are in support of a recent proposal of the Medical Advisory Board of the RLS Foundation that suggested to provide all patients with RLS with a pocket card containing information regarding the diagnosis, its treatment and the contact details of the treating physician in case of emergencies. Finally, we think that increased knowledge of and attention to RLS symptoms by emergency room personnel may disclose a significant number of diagnosed or undiagnosed exacerbated RLS cases otherwise misdiagnosed as unknown psychomotor agitation.

Restless legs syndrome in the emergency room.

Das Restless-legs-Syndrom (RLS) ist eine der haufigsten neurologischen Erkrankungen. Kardinalsymptom ist der Bewegungsdrang, v. a. in den Beinen. Perioperativ kann ein RLS neu auftreten, oder die Symptome eines vorhandenen RLS konnen exazerbieren. Schwerer Schlafentzug, forcierte Immobilisation und akuter Eisenmangel sind haufige Ausloser. Eine medikamentose Therapie kann einen wichtigen auslosenden und exazerbierenden Faktor darstellen. Arzneimittel, die dopaminantagonistische, serotonerge oder opioidantagonistische Wirkungen besitzen, sollten vermieden werden. Die medikamentose Dauertherapie des RLS sollte so kurz wie moglich unterbrochen und falls notig nicht oral uberbruckt werden. Bei Krankheiten, die mit einem sekundaren RLS assoziiert sein konnen, ist besonders an die mogliche Provokation oder Exazerbation eines RLS zu denken. Dies gilt speziell fur M. Parkinson, Diabetes mellitus, terminale Niereninsuffizienz, Ruckenmarkschaden oder bei Schwangeren. Bisher gibt es keine ausreichende Evidenz, dass irgendeine Anasthesieform das RLS negativ beeinflusst.

Perioperatives Vorgehen bei Restless-legs-Syndrom

The side effects of drugs annuals form a series of volumes in which the adverse effects of drugs and adverse reactions to them are surveyed. The series supplements the contents of Meyler's Side Effects of Drugs: The International Encyclopedia of Adverse Drug Reactions and Interactions. This review of the January 2015–January 2016 publications on antihistamines (H1 receptor inverse agonists) covers bilastine, cetirizine, chlorphenamine, diphenhydramine, doxylamine, ebastine hydroxyzine, ketotifen, levocetirizine, oxatomide, promethazine and rupatadine.

Antihistamines (H1 Receptor Antagonists)

Sir, We read with great interest the case descriptions by Mehta et al. [1] and Manconi and Fulda [2] and appreciated the highlight on restless legs syndrome (RLS) as a clinical manifestation in emergency. We report a similar, although less dramatic, case. We evaluated in the emergency department a 60-year-old male referred for severe worsening of RLS lasting continuously for 2 days and leading to severe insomnia and leg restlessness. The patient had a history of bipolar depression and impulse control disorder and was treated with valproate 900 mg/day. RLS symptoms started 2 years before but, since they were mild and sporadic, no treatment was suggested. Owing to severe insomnia and worsening of depressive symptoms, mirtazapine 30 mg at bedtime was added. Immediately after, RLS symptoms dramatically worsened. On the second night, pramipexole 0.25 mg in the evening was started with no benefit. In the third afternoon the patient came to the emergency department with severe agitation and restlessness, being unable to sit down without moving. We immediately decided to stop mirtazapine and, due to the anxiety symptoms and previous psychiatric history, we preferred not to use high dosage dopamine agonists and shifted the treatment to tramadol 25 mg and gabapentin 300 mg. The patient refused to be admitted into our ward. However, the next morning he reported an impressive improvement of the symptoms. In the first month, tramadol was gradually discontinued and gabapentin was increased to 600 mg/day. After more than 4 years of follow-up, RLS and bipolar symptoms appear still controlled with gabapentin 600 mg in the evening, valproate CR 300 mg TID and imipramine 12.5 mg TID. This case report is a further example of how RLS could become a real emergency. A drug-related worsening, or occurrence, of RLS symptoms should always be considered in the differential diagnosis of agitation. In this case, although psychiatric history and symptoms of anxiety were confounding factors, correct identification of RLS symptoms (both during the previous years and currently) together with a recent change in antidepressant therapy led to the correct diagnosis. The successful treatment was based on therapy with alpha-delta ligand, but probably even more so on the discontinuation of mirtazapine. It should be underlined that mirtazapine has the highest risk for RLS among second-generation antidepressants [3], typically within the first week, and provokes periodic limb movements even in healthy subjects [4]. However, a similar case report had been described with citalopram [5]. Thus, we would suggest that a list of contraindicated drugs should be diffused to general practitioners, other specialists and also to patients to help the correct treatment of comorbidities in RLS.

Exacerbation of restless legs syndrome presenting as a psychiatric emergency.

The side effects of drugs annuals forms a series of volumes in which the adverse effects of drugs and adverse reactions to them are surveyed. The series supplements the contents of Meyler's Side Effects of Drugs: The International Encyclopedia of Adverse Drug Reactions and Interactions. This review of the January 2013–January 2015 publications on antihistamines (H1 receptor inverse agonists) covers alcaftadine, bepotastine, bilastine, cetirizine and levocetirizine, chlorphenamine, diphenhydramine, dimetindene maleate, doxylamine, hydroxyzine, olopatadine, promethazine and rupatadine.

Chapter 15 – Antihistamines (H1 Receptor Antagonists)

Sir, Restless legs syndrome (RLS) is a common sensorimotor disorder with a prevalence of up to 10% in the general population [1]. Despite increasing awareness and education regarding this condition, there remain a sizeable number of patients who suffer from the typical symptoms of RLS but still remain undiagnosed and untreated for this condition [2]. Medications that exacerbate RLS symptoms are generally avoided in a patient diagnosed with RLS [3]. However, these drugs may be inadvertently prescribed for an undiagnosed patient with RLS, leading to a severe worsening and an acute/emergent presentation. We present a previously undiagnosed patient with an explosive presentation of RLS symptoms. A 65-year-old woman was admitted to the neurology intensive care unit (ICU) with sudden onset of uncontrollable movements that were initially diagnosed as biballism. She had undergone laparoscopic pancreatic surgery 10 days prior to her current admission. Upon discharge, she was given promethazine 25 mg as required for nausea, which she was taking two–three times a day. A few days later she started experiencing pain in her right calf, which then spread to both legs and was accompanied by a ‘pins and needles’ type sensation in her legs that subsequently spread to her arms. She continued to take several doses of promethazine for nausea and started having abnormal uncontrolled movements of her legs. She presented to the ER with these symptoms and was diagnosed with acute dystonic reaction due to promethazine and given intravenous diphenhydramine. This lead to a significant worsening of the abnormal movements that led her to be admitted to the ICU. Routine blood tests for hemoglobin, blood glucose, renal and liver function tests were within normal limits. Magnetic resonance imaging of the brain showed no abnormalities. On our evaluation, the patient was in significant distress and appeared very uncomfortable while lying in bed. She was seen having uncontrollable movements in the lower extremities proximal more than distal, with minimal involvement of the upper extremities and the trunk and without orofacial involvement (Video S1). The symptoms improved with walking and mental concentration. When questioned in detail, she admitted having mildly uncomfortable sensations in her legs over the last several years when lying in bed at night. However, they were not bothersome to her and she did not mention it to her physician. She experienced no exacerbations during pregnancy that she was aware of. Her neurological examination was otherwise normal. The symptoms completely abated while awake after i.v. morphine 2 mg (Video S1). She denied having any family history of RLS, and the hemoglobin (14.4 g/dl; range: 12–16 g/dl) and serum ferritin (96.4 ng/ml; range: 7–282 ng/ml) were normal. She was diagnosed with severe exacerbation of RLS and discharged on ropinirole, and has had symptom control for over 2 years. This case illustrates several important points: severe RLS exacerbation can present in a previously undiagnosed patient in an emergency setting. The diagnosis may be missed unless one has a high index of clinical suspicion. Drugs such as dopamine-blocking agents, some antidepressants and antihistaminergics when used in patients with RLS may have a synergistic effect in worsening their RLS symptoms (in this case possibly anesthetics during surgery, diphenhydramine and promethazine) [4]. Also, severe RLS can result in profound involuntary movements that can resemble ballism. It is unlikely that the patient suffered from dopamine-blocking agentsinduced akathisia as she did not complain of inner restlessness and the movements were significantly worse in the lower extremities than other body parts. It must be stressed that RLS is also a focal akathisia and our patient did have a history of mildly uncomfortable sensations in her legs for the last several years, which suggests that she may have been suffering from RLS all along. A detailed clinical history, distribution of abnormal movements, their improvement upon walking and mental concentration, and presence of exacerbating factors such as offending medications should lead the clinician to make the correct diagnosis.

Severe exacerbation of undiagnosed restless legs syndrome presenting as a movement disorder emergency.

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Severe exacerbation of undiagnosed restless legs syndrome presenting as a movement disorder emergency.