Efficacy of rotigotine for treatment of moderate-to-severe restless legs syndrome: a randomised, double-blind, placebo-controlled trial

BACKGROUND: Continuous administration of a dopamine agonist could be used to treat patients with restless legs syndrome. Our aim was to investigate the efficacy of transdermal rotigotine in the treatment of idiopathic restless legs syndrome. METHODS: In this randomised, double-blind, placebo-controlled trial, 458 patients with moderate-to-severe idiopathic restless legs syndrome (average baseline International Restless Legs Syndrome Study Group severity rating scale [IRLS] sum score of 28.1) were randomly assigned to receive transdermal rotigotine 1 mg over 24 h (n=115), 2 mg over 24 h (n=112), or 3 mg over 24 h (n=114), or to receive placebo (n=117). Study medication was delivered via patches, applied once a day for 6 months. Randomisation was done with a computer-generated randomisation list, stratified by centre. Primary efficacy outcomes were absolute change from baseline to end of maintenance in IRLS sum score and in the clinical global impressions (CGI) item 1 score, assessed by analysis of covariance in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT00136045. FINDINGS: Efficacy analyses were done on 112 patients in the 1 mg group, 109 in the 2 mg group, 112 in the 3 mg group, and 114 in the placebo group. Mean change in IRLS sum score from baseline at the end of the maintenance phase was -13.7 (SE 0.9) in the 1 mg group, -16.2 (0.9) in the 2 mg group, -16.8 (0.9) in the 3 mg group, and -8.6 (0.9) in the placebo group (p<0.0001 for treatment difference vs placebo with each dose). Mean change in CGI item 1 score from baseline at the end of the maintenance phase was -2.09 (0.14) in the 1 mg group, -2.41 (0.14) in the 2 mg group, -2.55 (0.14) in the 3 mg group, and -1.34 (0.14) in the placebo group (p<0.0001 for treatment difference vs placebo with each dose). Skin reactions, mostly mild or moderate, were seen in 145 (43%) of 341 patients who received rotigotine and in two (2%) of 117 who received placebo. Ten patients had serious adverse event that were deemed to be related to rotigotine: elevation of liver enzymes (one patient), worsening of tinnitus (one patient), non-response to anticoagulation (one patient), electrocardiogram changes (one patient), and application-site reactions (six patients). No admissions to hospital were needed for the application-site reactions, and they all resolved within a short time of patch removal without any other therapeutic intervention. The rate of typical dopaminergic side-effects in patients who received rotigotine was low; no signs of augmentation were noted. INTERPRETATION: 24 h transdermal delivery of low-dose rotigotine could be used to relieve the night-time and daytime symptoms of restless legs syndrome. FUNDING: Schwarz Biosciences.     

Intravenous polyclonal human immunoglobulins in multiple sclerosis

Intravenous immunoglobulin (IVIG) is an established therapy for demyelinating diseases of the peripheral nervous system. IVIG exerts a number of effects that may be beneficial in multiple sclerosis (MS). Four double-blind IVIG trials have been performed in relapsing-remitting MS. A meta-analysis of the four trials has shown that IVIG reduces the relapse rate and, possibly, disease progression. In patients with a first episode of demyelinating disease, IVIG delays the time to the second relapse and thereby to the diagnosis of definite MS. In patients with an acute MS relapse, IVIG as add-on therapy to methylprednisolone does not make remission of symptoms faster or more complete. IVIG does not seem to be of any benefit to chronic visual or motor symptoms in MS. In secondary progressive MS, IVIG has not shown any effect on disease progression, relapses or new magnetic resonance imaging lesions. Experimental studies in the MS model experimental autoimmune encephalomyelitis in rats demonstrate that IVIG has to be administered at the time of induction of a relapse in order to be effective. In conclusion, IVIG can be considered as a second-line treatment to approved therapies for relapsing-remitting MS, but the ideal dosage of IVIG still needs to be determined. In order to be a first-line treatment for MS, the beneficial effect should be confirmed in a large-scale placebo-controlled survey, or in a study comparing the effect with approved therapies for relapsing-remitting MS using appropriate clinical and magnetic resonance imaging outcome measures.     

Vascular endothelial growth factor is a strong predictor of early distant recurrences in a prospective study of premenopausal women with lymph-node negative breast cancer

We investigate the prognostic significance of the pro-angiogenic cytokine vascular endothelial growth factor (VEGF), urokinase-type plasminogen activator (uPA), plasminogen activator inhibitor 1 (PAI-1), and S-phase fraction (SPF) for distant disease free survival (DDFS) in 219 premenopausal patients with node-negative breast cancer (NNBC). In univariate analysis significantly shorter DDFS was observed for patients with high VEGF (p=0.006), high uPA (p=0.001), and high SPF (p<0.001). The prognostic significance of VEGF varied over time being very strong for early relapses (0-2.25 years follow-up) (HR=7.9; p=0.006) while no difference was seen in the subsequent follow-up period (HR=1.3; p=0.62). In a series of bivariate analyses VEGF provided prognostic information during the whole observation period (0-72 months) in addition to age, tumour size, oestrogen receptor (ER), progesterone receptor (PgR), and uPA. Also this effect was more pronounced during the first follow-up period suggesting VEGF as a marker of early recurrences.     

Clinicians' views on clinical examination and treatment of children and adolescents with obsessive-compulsive disorder (OCD). A Danish national survey study

Obsessive-compulsive disorder (OCD) is a frequently encountered disorder in children and adolescents. Several characteristics make the disorder a challenge to diagnostic methods and treatment procedures including the diversity of symptoms, the delay of referral and the occurrence of comorbidity. The aim of the present study was to examine how recent progress in assessment and treatment has influenced the Danish clinicians in their work with children and adolescents with OCD. The study was conducted as a national survey addressing a total of 14 outpatient children and adolescent departments, and 25 medical specialists in private practice. The clinicians received a questionnaire including general and specific questions on assessment scales and treatment methods towards OCD and their view on treatment efficacy and prognosis. A total of 71.8% responded to the questionnaire. Most clinicians reported the use of a general medical and social history combined with the use of OCD-specific checklists. Treatment procedures included medication, cognitive therapy or cognitive-behavioural therapy and a family approach depending on the age of the patient. Eighty-one per cent of the clinicians reported a good or very good effect of treatment. Clinical Global Improvement ratings of the last treated patient indicated a treatment response of 68.8% and a response on general improvement of 59.4%. In conclusion, the present study shows that treatment methods employed towards children and adolescents with OCD are close to the clinical recommendations and comparable with those employed in other countries. Furthermore, the general opinion of clinicians towards OCD is comparable with that described in the literature. However, a discussion of the choice of recommended assessment methods including the use of both specific and general checklists is warranted.     

Recent developments in the understanding and management of functional somatic symptoms in primary care

PURPOSE OF REVIEW: Medically unexplained or functional somatic symptoms are prevalent in primary care, but general practitioners commonly find them difficult to treat. We focus on the conceptual issues and treatment from a primary care perspective, although the field is difficult to review because of the inconsistency and multiplicity of terminology used by different authors and specialties. RECENT FINDINGS: The training of general practitioners in management techniques has been hampered by an obsolete theoretical framework and outdated diagnostic systems. Epidemiological studies, however, indicate that valid, empirically based diagnostic criteria for functional disorders may be developed. Management studies in primary care have shown disappointing effects on patient outcome, but a lot may be gained by making the training programmes more sophisticated. Recently, stepped care approaches have been introduced but they need scientific evaluation. SUMMARY: There is an immediate need for a common language and a theoretical framework of understanding of functional symptoms and disorders across medical specialties, clinically and scientifically. Any names that presuppose a mind-body dualism (such as somatization, medically unexplained) ought to be abolished. The overall ambition for treatment is to offer patients with functional somatic symptoms the same quality of professional healthcare as we offer any other patient.