Revisione critica dei risultati e nuovi algoritmi decisionali sulla chirurgia dell'OSAS

Obstructive sleep apnoea/hypopnoea syndrome (OSAHS) is the periodic reduction or cessation of airflow during sleep. The syndrome is associated whit loud snoring, disrupted sleep and observed apnoeas. Surgery aims to alleviate symptoms of daytime sleepiness, improve quality of life and reduce the signs of sleep apnoea recordered by polysomnography. Surgical intervention for snoring and OSAHS includes several procedures, each designed to increase the patency of the upper airway. Procedures addressing nasal obstruction include septoplasty, turbinectomy, and radiofrequency ablation (RF) of the turbinates. Surgical procedures to reduce soft palate redundancy include uvulopalatopharyngoplasty with or without tonsillectomy, uvulopalatal flap, laser-assisted uvulopalatoplasty, and RF of the soft palate. More significant, however, particularly in cases of severe OSA, is hypopharyngeal or retrolingual obstruction related to an enlarged tongue, or more commonly due to maxillomandibular deficiency. Surgeries in these cases are aimed at reducing the bulk of the tongue base or providing more space for the tongue in the oropharynx so as to limit posterior collapse during sleep. These procedures include tongue-base suspension, genioglossal advancement, hyoid suspension, lingualplasty, and maxillomandibular advancement. We reviewed 269 patients undergoing to osas surgery at the ENT Department of Forlì Hospital in the last decade. Surgery was considered a success if the postoperative apnea/hypopnea index (AHI) was less than 20/h. According to the results, we have developed surgical decisional algorithms with the aims to optimize the success of these procedures by identifying proper candidates for surgery and the most appropriate surgical techniques. Although not without risks and not as predictable as positive airway pressure therapy, surgery remains an important treatment option for patients with obstructive sleep apnea (OSA), particularly for those who have failed or cannot tolerate positive airway pressure therapy. Successful surgery depends on proper patient selection, proper procedure selection, and experience of the surgeon. The intended purpose of medical algorithms is to improve and standardize decisions made in the delivery of medical care, assist in standardizing selection and application of treatment regimens, to reduce potential introduction of errors. Nasal Continuous Positive Airway Pressure (nCPAP) is the recommended therapy for patients with moderate to severe OSAS. Unfortunately this treatment is not accepted by some patient, appears to be poorly tolerated in a not neglible number of subjects, and the compliance may be critical, especially in the long term if correctly evaluated with interview as well with CPAP smart cards analysis. Among the alternative options in Literature, surgery is a long time honoured solution. However until now no clear scientific evidence exists that surgery can be considered a really effective option in OSAHS management. We have design a randomized prospective study comparing MMA and a ventilatory device (Autotitrating Positive Airways Pressure – APAP) in order to understand the real effectiveness of surgery in the management of moderate to severe OSAS. Fifty consecutive previously full informed patients suffering from severe OSAHS were enrolled and randomised into a conservative (APAP) or surgical (MMA) arm. Demographic, biometric, PSG and ESS profiles of the two group were statistically not significantly different. One year after surgery or continuous APAP treatment both groups showed a remarkable improvement of mean AHI and ESS; the degree of improvement was not statistically different. Provided the relatively small sample of studied subjects and the relatively short time of follow up, MMA proved to be in our adult and severe OSAHS patients group a valuable alternative therapeutical tool with a success rate not inferior to APAP.

Effects of ambient temperature on cardiovascular regulation during sleep in hypocretin-deficient narcoleptic mice

Hypocretin 1 and 2 (HCRT, also called Orexin A and B) are neuropeptides released by neurons in the lateral hypothalamus. HCRT neurons widely project to the entire neuroaxis. HCRT neurons have been reported to participate in various hypothalamic physiological processes including cardiovascular functions, wake-sleep cycle, and they may also influence metabolic rate and the regulation of body temperature. HCRT neurons are lost in narcolepsy, a rare neurological disorder, characterized by excessive daytime sleepiness, cataplexy, sleep fragmentation and occurrence of sleep-onset rapid-eye-movement episodes. We investigated whether HCRT neurons mediate the sleep-dependent cardiovascular adaptations to changes in ambient temperature (Ta). HCRT-ataxin3 transgenic mice with genetic ablation of HCRT neurons (n = 11) and wild-type controls (n = 12) were instrumented with electrodes for sleep scoring and a telemetric blood pressure (BP) transducer (DSI, Inc.). Simultaneous sleep and BP recordings were performed on mice undisturbed and freely-behaving at 20 °C, 25 °C, and 30 °C for 48 hours at each Ta. Analysis of variance of BP indicated a significance of the main effects of wake-sleep state and Ta, their interaction effect, and the wake-sleep state x mouse strain interaction effect. BP increased with decreasing Ta. This effect of Ta on BP was significantly lower in rapid-eye-movement sleep (REMS) than either in non-rapid-eye-movement sleep (NREMS) or wakefulness regardless of the mouse strain. BP was higher in wakefulness than either in NREMS or REMS. This effect of sleep on BP was significantly reduced in mice lacking HCRT neurons at each Ta, particularly during REMS. These data suggest that HCRT neurons play a critical role in mediating the effects of sleep but not those of Ta on BP in mice. HCRT neurons may thus be part of the central neural pathways which mediate the phenomenon of blood pressure dipping on passing from wakefulness to sleep.

La farmacogenetica della narcolessia: comorbidità psichiatriche e risvolti in sanità pubblica

La farmacogenetica fornisce un importante strumento utile alla prescrizione farmacologica, migliorando l’efficacia terapeutica ed evitando le reazioni avverse. Il citocromo P450 gioca un ruolo centrale nel metabolismo di molti farmaci utilizzati nella pratica clinica e il suo polimorfismo genetico spiega in gran parte le differenze interindividuali nella risposta ai farmaci. Con riferimento alla terapia della narcolessia, occorre premettere che la narcolessia con cataplessia è una ipersonnia del Sistema Nervoso Centrale caratterizzata da eccessiva sonnolenza diurna, cataplessia, paralisi del sonno, allucinazioni e sonno notturno disturbato. Il trattamento d’elezione per la narcolessia include stimolanti dopaminergici per la sonnolenza diurna e antidepressivi per la cataplessia, metabolizzati dal sistema P450. Peraltro, poiché studi recenti hanno attestato un’alta prevalenza di disturbi alimentari nei pazienti affetti da narcolessia con cataplessia, è stata ipotizzata una associazione tra il metabolismo ultrarapido del CYP2D6 e i disturbi alimentari. Lo scopo di questa ricerca è di caratterizzare il polimorfismo dei geni CYP2D6, CYP2C9, CYP2C19, CYP3A4, CYP3A5 e ABCB1 coinvolti nel metabolismo e nel trasporto dei farmaci in un campione di 108 pazienti affetti da narcolessia con cataplessia, e valutare il fenotipo metabolizzatore in un sottogruppo di pazienti che mostrano un profilo psicopatologico concordante con la presenza di disturbi alimentari. I risultati hanno mostrato che il fenotipo ultrarapido del CYP2D6 non correla in maniera statisticamente significativa con i disturbi alimentari, di conseguenza il profilo psicopatologico rilevato per questo sottogruppo di pazienti potrebbe essere parte integrante del fenotipo sintomatologico della malattia. I risultati della tipizzazione di tutti i geni analizzati mostrano un’alta frequenza di pazienti con metabolismo intermedio, elemento potenzialmente in grado di influire sulla risposta terapeutica soprattutto in caso di regime politerapico, come nel trattamento della narcolessia. In conclusione, sarebbe auspicabile l’esecuzione del test farmacogenetico in pazienti affetti da narcolessia con cataplessia.

Myotonic syndromes: analysis of factors with pathogenetic and prognostic significance

Background: The natural history of Myotonic Dystrophy type 1 is largely unclear, longitudinal studies are lacking. Objectives: to collect clinical and laboratory data, to evaluate sleep disorders, somatic and autonomic skin fibres, neuropsychological and neuroradiological aspects in DM1 patients. Methods: 72 DM1 patients underwent a standardized clinical and neuroradiological evaluation performed by a multidisciplinary team during 3 years of follow-up. Results: longer disease duration was associated with higher incidence of conduction disorders and lower ejection fraction; higher CVF values were predictors for a reduced risk of cardiopathy. Lower functional pulmonary values were associated with class of expansion and were negatively associated with disease duration; arterial blood gas parameters were not associated with expansion size, disease duration nor with respiratory function test. Excessive daytime sleepiness was not associated with class of expansion nor with any of the clinical parameters examined. We detected apnoea in a large percentage of patients, without differences between the 3 genetic classes; higher CVF values were predictors for a reduced risk of apnoea. Skin biopsies demonstrated the presence of a subclinical small fibre neuropathy with involvement of the somatic fibres. The pupillometry study showed lower pupil size at baseline and a lower constriction response to light. The most affected neuropsychological domains were executive functions, visuoconstructional, attention and visuospatial tasks, with a worse performance of E1 patients in the visuoperceptual ability and social cognition tasks. MRI study demonstrated a decrease in the volumes of frontal, parietal, temporal, occipital cortices, accumbens, putamen nuclei and a more severe volume reduction of the isthmus cingulate, transverse temporal, superior parietal and temporal gyri in E2 patients. Discussion: only some clinical parameters could predict the risk of cardiopathy, pulmonary syndrome and sleep disorders, while other clinical aspects proved to be unpredictable, confirming the importance of periodic clinical follow-up of these patients.

Criteri di valutazione medico-legale della narcolessia

Impairment due to narcolepsy strongly limits job performance, but there are no standard criteria to assess disability in people with narcolepsy and a scale of disease severity is still lacking. We explored: 1. the interobserver reliability among Italian Medical Commissions making disability and handicap benefit decisions for people with narcolepsy, searching for correlations between the recognized disability degree and patients’ features; 2. the willingness to report patients to the driving licence authority; 3. possible sources of variance in judgement. Fifteen narcoleptic patients were examined by four Medical Commissions in simulated sessions. Raw agreement and interobserver reliability among Commissions were calculated for disability and handicap benefit decisions and for driving licence decisions. Levels of judgement differed on percentage of disability (p<0.001), severity of handicap (p=0.0007) and the need to inform the driving licence authority (p=0.032). Interobserver reliability ranged from Kappa = - 0.10 to Kappa = 0.35 for disability benefit decision and from Kappa = - 0.26 to Kappa = 0.36 for handicap benefit decision. The raw agreement on driving licence decision ranged from 73% to 100% (Kappa not calculable). Spearman’s correlation between percentages of disability and patients’ features showed correlations with age, daytime naps, sleepiness, cataplexy and quality of life. This first interobserver reliability study on social benefit decisions for narcolepsy shows the difficulty of reaching an agreement in this field, mainly due to variance in interpretation of the assessment criteria. The minimum set of indicators of disease severity correlating with patients’ self assessments encourages a disability classification of narcolepsy.

Simulatore d’alba come possibile contromisura al social jetlag in adolescenza

L’obiettivo del presente progetto di ricerca era determinare se l’utilizzo non clinico del simulatore d’alba (un dispositivo che emette luce in graduale aumento prima del risveglio), basato su specifiche conoscenze cronobiologiche, potesse ridurre alcune delle conseguenze del social jetlag, in studenti di scuola secondaria di secondo grado. A tal fine, sono stati valutati gli effetti del simulatore d’alba su tono dell’umore (valutato soggettivamente tramite la Global and Vigor Affect Scale-GVA), livelli di attivazione (valutati soggettivamente tramite la GVA), qualità/quantità di sonno (valutate oggettivamente e soggettivamente tramite attigrafia e Mini Sleep Questionnaire-MSQ), architettura del sonno (valutata oggettivamente tramite Zeo®) ed efficienza dei tre network attentivi (alerting, orienting ed executive), valutata oggettivamente tramite l’Attention Network Test (ANT). In totale, hanno preso parte alla ricerca 56 adolescenti (24 femmine e 32 maschi), frequentanti due istituti di scuola secondaria di secondo grado nella città di Cesena, la cui età media era di 17.68 anni (range d’età 15-20 anni). Ad ogni studente è stata richiesta una partecipazione di 5 settimane consecutive ed il disegno di ricerca prevedeva 3 condizioni sperimentali: baseline, simulatore d’alba e controllo. All’MSQ, in seguito all’utilizzo del simulatore d’alba, sono state osservate una minore percezione di sonnolenza diurna, una frequenza inferiore di risvegli notturni ed una riduzione del numero di partecipanti che presentavano una cattiva qualità della veglia. All’ANT, è stato documentato un significativo miglioramento dell’efficienza del network attentivo dell’alerting, successivo all’impiego del simulatore d’alba, dovuto ad una maggiore reattività dei partecipanti in seguito alla comparsa del double cue, che anticipava la presentazione del target (freccia centrale di cui i partecipanti dovevano giudicare la direzione). Tali risultati convergono nell’evidenziare la capacità del simulatore d’alba di esercitare un effetto attivante/stimolante, mostrando dunque come esso possa essere considerato uno strumento potenzialmente utilizzabile quale contromisura al social jetlag in adolescenza.

Circadian rhythms, sleep and autonomic function in progressive supranuclear palsy: characteristic features and reciprocal interactions

Background: Progressive supranuclear palsy (PSP) is a rare neurodegenerative condition. The aims of this study were to evaluate the association between sleep, the circadian system and autonomic function in a cohort of PSP patients. Methods: Patients with PSP diagnosed according to consensus criteria were recruited prospectively and retrospectively and performed the following tests: body core temperature (BcT), sleep-wake cycle, systolic and diastolic blood pressure (SBP, DBP) continuous monitoring for 48 h under controlled environmental conditions; cardiovascular reflex tests (CRTs). The analysis of circadian rhythmicity was performed with the single cosinor method. For state-dependent analysis, the mean value of variables in each sleep stage was calculated as well as the difference to the value in wake. Results: PSP patients presented a reduced total duration of night sleep, with frequent and prolonged awakenings. During daytime, patients had very short naps, suggesting a state of profound sleep deprivation across the 24-h. REM sleep behaviour disorder was found in 15%, restless legs syndrome in 46%, periodic limb movements in 52% and obstructive sleep apnea in 54%. BcT presented the expected fall during night-time, however, compared to controls, mean values during day and night were higher. However BcT state-dependent modulation was maintained. Increased BcT could be attributed to an inability to properly reduce sympathetic activity favoured by the sleep deprivation. At CRTs, PSP presented mild cardiovascular adrenergic impairment and preserved cardiovagal function. 14% had non-neurogenic orthostatic hypotension. Only 2 PSP presented the expected BP dipping pattern, possibly as a consequence of sleep disruption. State-dependent analysis showed a partial loss of the state-dependent modulation for SBP. Discussion: This study showed that PSP presented abnormalities of sleep, circadian rhythms and cardiovascular autonomic function that are likely to be closely linked one to another.

Analysis of heat-related phenomena and their interactions at different spatio-temporal scales

This thesis analyzes the impact of heat extremes in urban and rural environments, considering processes related to severely high temperatures and unusual dryness. The first part deals with the influence of large-scale heatwave events on the local-scale urban heat island (UHI) effect. The temperatures recorded over a 20-year summer period by meteorological stations in 37 European cities are examined to evaluate the variations of UHI during heatwaves with respect to non-heatwave days. A statistical analysis reveals a negligible impact of large-scale extreme temperatures on the local daytime urban climate, while a notable exacerbation of UHI effect at night. A comparison with the UrbClim model outputs confirms the UHI strengthening during heatwave episodes, with an intensity independent of the climate zone. The investigation of the relationship between large-scale temperature anomalies and UHI highlights a smooth and continuous dependence, but with a strong variability. The lack of a threshold behavior in this relationship suggests that large-scale temperature variability can affect the local-scale UHI even in different conditions than during extreme events. The second part examines the transition from meteorological to agricultural drought, being the first stage of the drought propagation process. A multi-year reanalysis dataset involving numerous drought events over the Iberian Peninsula is considered. The behavior of different non-parametric standardized drought indices in drought detection is evaluated. A statistical approach based on run theory is employed, analyzing the main characteristics of drought propagation. The propagation from meteorological to agricultural drought events is found to develop in about 1-2 months. The duration of agricultural drought appears shorter than that of meteorological drought, but the onset is delayed. The propagation probability increases with the severity of the originating meteorological drought. A new combined agricultural drought index is developed to be a useful tool for balancing the characteristics of other adopted indices.