Sleep disorders and the hypothalamus.

As early as the 1920s, pathological studies of encephalitis lethargica allowed Von Economo to correctly identify hypothalamic damage as crucial for the profound associated sleep-related symptoms that helped define the condition. Only over the last 3 decades, however, has the key role of the hypothalamus in sleep-wake regulation become increasingly recognized. As a consequence, a close relation between abnormal sleep symptomatology and hypothalamic pathology is now widely accepted for a variety of medical disorders. Narcolepsy is discussed in some detail as the cardinal primary sleep disorder that is caused directly and specifically by hypothalamic pathology, most notably destruction of hypocretin (orexin)-containing neurons. Thereafter, various conditions are described that most likely result from hypothalamic damage, in part at least, producing a clinical picture resembling (symptomatic) narcolepsy. Kleine-Levin syndrome is a rare primary sleep disorder with intermittent symptoms, highly suggestive of hypothalamic involvement but probably reflecting a wider pathophysiology. ROHHAD (rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation) and Prader-Willi syndrome are also covered as hypothalamic syndromes with prominent sleep-related symptoms. Finally, sleep issues in several endocrine disorders are briefly discussed.

European guideline and expert statements on the management of narcolepsy in adults and children.

BACKGROUND AND PURPOSE: Narcolepsy is an uncommon hypothalamic disorder of presumed autoimmune origin that usually requires lifelong treatment. This paper aims to provide evidence-based guidelines for the management of narcolepsy in both adults and children. METHODS: The European Academy of Neurology (EAN), European Sleep Research Society (ESRS), and European Narcolepsy Network (EU-NN) nominated a task force of 18 narcolepsy specialists. According to the EAN recommendations, 10 relevant clinical questions were formulated in PICO format. Following a systematic review of the literature (performed in Fall 2018 and updated in July 2020) recommendations were developed according to the GRADE approach. RESULTS: A total of 10,247 references were evaluated, 308 studies were assessed and 155 finally included. The main recommendations can be summarized as follows: (i) excessive daytime sleepiness (EDS) in adults-scheduled naps, modafinil, pitolisant, sodium oxybate (SXB), solriamfetol (all strong); methylphenidate, amphetamine derivatives (both weak); (ii) cataplexy in adults-SXB, venlafaxine, clomipramine (all strong) and pitolisant (weak); (iii) EDS in children-scheduled naps, SXB (both strong), modafinil, methylphenidate, pitolisant, amphetamine derivatives (all weak); (iv) cataplexy in children-SXB (strong), antidepressants (weak). Treatment choices should be tailored to each patient's symptoms, comorbidities, tolerance and risk of potential drug interactions. CONCLUSION: The management of narcolepsy involves non-pharmacological and pharmacological approaches with an increasing number of symptomatic treatment options for adults and children that have been studied in some detail.

European guideline and expert statements on the management of narcolepsy in adults and children.

BACKGROUND AND AIM: Narcolepsy is an uncommon hypothalamic disorder of presumed autoimmune origin that usually requires lifelong treatment. This paper aims to provide evidence-based guidelines for the management of narcolepsy in both adults and children. METHODS: The European Academy of Neurology (EAN), European Sleep Research Society (ESRS) and European Narcolepsy Network (EU-NN) nominated a task force of 18 narcolepsy specialists. According to the EAN recommendations, 10 relevant clinical questions were formulated in PICO format. Following a systematic review of the literature (performed in Fall 2018 and updated in July 2020) recommendations were developed according to the GRADE approach. RESULTS: A total of 10,247 references were evaluated, 308 studies were assessed and 155 finally included. The main recommendations can be summarized as follows: (i) excessive daytime sleepiness in adults-scheduled naps, modafinil, pitolisant, sodium oxybate (SXB), solriamfetol (all strong), methylphenidate, amphetamine derivates (both weak); (ii) cataplexy in adults-SXB, venlafaxine, clomipramine (all strong) and pitolisant (weak); (iii) excessive daytime sleepiness in children-scheduled naps, SXB (both strong), modafinil, methylphenidate, pitolisant, amphetamine derivates (all weak); (iv) cataplexy in children-SXB (strong), antidepressants (weak). Treatment choices should be tailored to each patient's symptoms, comorbidities, tolerance and risk of potential drug interactions. CONCLUSION: The management of narcolepsy involves non-pharmacological and pharmacological approaches with an increasing number of symptomatic treatment options for adults and children that have been studied in some detail.

Diagnosis of central disorders of hypersomnolence: A reappraisal by European experts.

The aim of this European initiative is to facilitate a structured discussion to improve the next edition of the International Classification of Sleep Disorders (ICSD), particularly the chapter on central disorders of hypersomnolence. The ultimate goal for a sleep disorders classification is to be based on the underlying neurobiological causes of the disorders with clear implication for treatment or, ideally, prevention and or healing. The current ICSD classification, published in 2014, inevitably has important shortcomings, largely reflecting the lack of knowledge about the precise neurobiological mechanisms underlying the majority of sleep disorders we currently delineate. Despite a clear rationale for the present structure, there remain important limitations that make it difficult to apply in routine clinical practice. Moreover, there are indications that the current structure may even prevent us from gaining relevant new knowledge to better understand certain sleep disorders and their neurobiological causes. We suggest the creation of a new consistent, complaint driven, hierarchical classification for central disorders of hypersomnolence; containing levels of certainty, and giving diagnostic tests, particularly the MSLT, a weighting based on its specificity and sensitivity in the diagnostic context. We propose and define three diagnostic categories (with levels of certainty): 1/"Narcolepsy" 2/"Idiopathic hypersomnia", 3/"Idiopathic excessive sleepiness" (with subtypes).

Cataplexy.

Remarkably and almost invariably, the clinical phenomenon of cataplexy results from the loss of around 40 000 hypocretin-containing neurones in the lateral hypothalamus in the context of narcolepsy type 1. Cataplexy reflects the dysregulation of rapid-eye-movement (REM) sleep, such that REM-sleep atonia intrudes inappropriately into wakefulness as brief episodes of either focal or total paralysis of voluntary muscle. The semiology of cataplexy differs between adults and children. A defining and enigmatic aspect is that certain emotional stimuli usually trigger the episodes. Cataplexy can be the most disabling symptom of the narcolepsy syndrome, severely limiting normal activities of daily living. Antidepressant drug therapy at relatively low doses is the traditional treatment; these most likely work through inhibiting REM sleep, predominantly by increasing brain monoamine concentrations. Sodium oxybate is probably the most effective drug for severe cataplexy, taken before overnight sleep and once through the night; its precise mechanism of action remains obscure. Pitolisant is a new agent for treating the excessive daytime sleepiness of narcolepsy that also helps cataplexy control by increasing histamine concentrations in the hypothalamus. Further understanding of the neurobiology of cataplexy and how it relates to hypocretin deficiency should improve our understanding of the brain's emotional processing and provide insights into REM sleep and its control.

Risk of Narcolepsy after AS03 Adjuvanted Pandemic A/H1N1 2009 Influenza Vaccine in Adults: A Case-Coverage Study in England.

STUDY OBJECTIVES: An increased risk of narcolepsy has been observed in children following ASO3-adjuvanted pandemic A/H1N1 2009 (Pandemrix) vaccine. We investigated whether this risk extends to adults in England. METHODS: Six adult sleep centers in England were visited between November 2012 and February 2014 and vaccination/clinical histories obtained from general practitioners. Suspected narcolepsy cases aged older than 17 y were selected. The risk of narcolepsy following Pandemrix was calculated using cases diagnosed by the time of the center visits and those with a diagnosis by November 30, 2011 after which there was increased awareness of the risk in children. The odds of vaccination in cases and in matched population data were compared using a case-coverage design. RESULTS: Of 1,446 possible cases identified, most had onset before 2009 or were clearly not narcolepsy. Of the 60 remaining cases, 20 were excluded after expert review, leaving 40 cases with narcolepsy; 5 had received Pandemrix between 3 and 18 mo before onset. All the vaccinated cases had cataplexy, two received a diagnosis by November 2011 and two were aged 40 y or older. The odds ratio for vaccination in cases compared to the population was 4.24 (95% confidence interval 1.45-12.38) using all cases and 9.06 (1.90-43.17) using cases with a diagnosis by November 2011, giving an attributable risk of 0.59 cases per 100,000 doses. CONCLUSIONS: We found a significantly increased risk of narcolepsy in adults following Pandemrix vaccination in England. The risk was lower than that seen in children using a similar study design.

Treating restless legs syndrome with rotigotine.

Restless legs syndrome has attracted increasing interest as a clinically significant, common and treatable disorder. Good evidence suggests that dopaminergic drugs are the most effective first-line agents when symptoms are severe.

Questionnaires for 360-degree assessment of consultant psychiatrists: development and psychometric properties.

BACKGROUND: Expert clinical judgement combines technical proficiency with humanistic qualities. AIMS: To test the psychometric properties of questionnaires to assess the humanistic qualities of working with colleagues and relating to patients using multisource feedback. METHOD: Analysis of self-ratings by 347 consultant psychiatrists and ratings by 4422 colleagues and 6657 patients. RESULTS: Mean effectiveness as rated by self, colleagues and patients, was 4.6, 5.0 and 5.2 respectively (where 1=very low and 6=excellent). The instruments are internally consistent (Cronbach's alpha >0.95). Principal components analysis of the colleague questionnaire yielded seven factors that explain 70.2% of the variance and accord with the domain structure. Colleague and patient ratings correlate with one another (r=0.39, P<0.001) but not with the self-rating. Ratings from 13 colleagues and 25 patients are required to achieve a generalisability coefficient (Erho(2)) of 0.75. CONCLUSIONS: Reliable 360-degree assessment of humane judgement is feasible for psychiatrists who work in large multiprofessional teams and who have large case-loads.

Late-onset axial jerky dystonia due to the DYT1 deletion.

We describe a 71-year-old woman who presented to the neurology department late in life with a jerky axial dystonia due to the DYT1 GAG deletion. She recalled that her symptoms began 62 years prior to study and remained unchanged for 40 years, illustrating the broad phenotype of DYT1 idiopathic torsion dystonia.