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Sympathetic and cardiovascular changes during sleep in narcolepsy with cataplexy patients.

OBJECTIVEnNeural mechanisms underlying sleep-onset rapid eye movement (REM) periods (SOREMPs) in narcolepsy and the role of hypocretin in driving sympathetic changes during sleep are misunderstood. We aimed to characterize autonomic changes during sleep in narcolepsy with cataplexy (NC) patients to clarify the nature of SOREMP events and the effect of hypocretin deficiency on sympathetic activity during sleep.nnnMETHODSnWe observed 13 hypocretin-deficient NC patients and five healthy controls who underwent nocturnal video-polysomnography (v-PSG) with blood pressure (BP) recording, heart rate (HR), skin sympathetic activity (SSA), and muscle sympathetic nerve activity (MSNA) from the peroneal nerve by microneurography.nnnRESULTSnCompared to wake, control participants displayed a progressive significant decrease of BP and sympathetic activities during nonrapid eye movement (NREM) sleep and an increase of autonomic activity during REM sleep, as expected. NC patients showed: (1) a decrease of sympathetic activities during SOREMP comparable to NREM sleep stage 1 (N1) but in contrast to the increased activity typical of REM sleep; and (2) physiologic sympathetic change during the following sleep stages with a progressive decrease during NREM sleep stage 2 (N2) and NREM sleep stage 3 (N3) and a clear increase in REM sleep, though BP did not show the physiologic decrease during sleep (nondipper pattern).nnnCONCLUSIONSnSOREMPs in NC patients lack the sympathetic activation occurring during physiologic REM sleep, thus suggesting a dissociated REM sleep condition. In addition, our data indicated that hypocretin plays a limited role in the regulation of sympathetic changes during sleep.

Narcolepsy is a common phenotype in HSAN IE and ADCA-DN

We report on the extensive phenotypic characterization of five Italian patients from four unrelated families carrying dominant heterozygous DNMT1 mutations linked to two distinct autosomal dominant diseases: hereditary sensory and autonomic neuropathy with dementia and hearing loss type IE (HSAN IE) and autosomal dominant cerebellar ataxia, deafness and narcolepsy (ADCA-DN). Patients underwent genetic analysis of DNMT1 gene, neurophysiological tests investigating sleep, auditory functions and peripheral nervous system, ophthalmological studies including optical coherence tomography, lymphoscintigraphy, brain magnetic resonance and nuclear imaging, cerebrospinal fluid hypocretin-1, total tau, phosphorylated tau, amyloid-β1-42 and 14-3-3 proteins measurement, skin, muscular and sural nerve biopsies. Exome and direct sequencing studies disclosed two different point mutations affecting exon 21 of DNMT1 gene in patients with ADCA-DN, a novel heterozygous point mutation in exon 20 in two affected HSAN IE siblings, and a trinucleotide deletion in exon 20 in the latter patient with HSAN IE. Phenotypic characterization pinpoints that ADCA-DN and HSAN IE represent two discrete clinical entities belonging to the same disease spectrum, with variable degree of overlap. Remarkably, narcolepsy with or without cataplexy with low/intermediate or normal cerebrospinal fluid hypocretin-1 is present in both diseases. The human leukocyte antigen DQB1*06:02 was absent in all patients. Other common symptoms and features observed in our cases, involving the central and peripheral nervous system, include deafness, optic neuropathy-previously not reported in HSAN IE-large and small fibres polyneuropathy and lower limbs oedema. Overall, the two syndromes share more characteristics than previously recognized and narcolepsy is common to both. HSAN IE and ADCA-DN are two extreme phenotypic manifestations of a DNMT1 methylopathy.

Nocturnal eating is part of the clinical spectrum of restless legs syndrome and an underestimated risk factor for increased body mass index.

OBJECTIVESnWe aimed to investigate the prevalence of night eating syndrome (NES) in a large cohort of patients with restless legs syndrome (RLS).nnnMETHODSnOur cross-sectional study included 120 patients examined at the University of Bologna Centre for Sleep Disorders, Bologna, Italy, and met all four International RLS criteria for the diagnosis of RLS. Each patient underwent a semistructured telephone interview investigating demographic data and general health status, RLS features and severity, presence of excessive daytime sleepiness, and presence of NES.nnnRESULTSnThe sample included 37 men and 83 women with a mean age of 63.8±11.5 years. There were 31% of patients who reported episodes of nocturnal eating (NE); among them, 17% fulfilled the new diagnostic criteria for NES. Comparing RLS patients with and without NE, there were no differences in RLS features. However, RLS patients with NE were older (67.2±11.6 vs. 62.4±11; P=.038), were in a higher body mass index (BMI) range (27.7±3.8 vs. 26.1±4.1 kg/m2; P=.023), were taking more drugs for concomitant diseases (89% vs. 72%; P=.031), were more likely to report insomnia (40% vs. 23%; P=.041), and were using more hypnotic agents (37.8% vs. 19.3%; P=.050) and dopaminergic drugs (65% vs. 46%; P=.041). When comparing those RLS patients with NES diagnostic criteria and those without NES, no differences emerged in demographic, clinical, and RLS features; however, NES patients were in a higher BMI range (28.3±4.1 vs. 26.2±3.9kg/m(2), P=.037), were more frequently smokers (43% vs 17%; P=.027), and were more frequently using hypnotic agents (30% vs. 24%; P=.025). Lastly, no differences were found when comparing patients with a NES diagnosis and those with NE not fitting the diagnostic criteria for NES, except for a higher use of benzodiazepine drugs (BDZ) in this latter subgroup (29% vs. zero; P=.014).nnnCONCLUSIONSnA nocturnal compulsion to eat seems to be an intrinsic part of the clinical spectrum of RLS manifestations and an odd risk factor for increases in BMI in RLS patients. However, it is still not clear if NE in RLS would fit in one of the two known categorized syndromes of NE (i.e., sleep-related eating disorder [SRED] or NES) or if it represents a different strictly RLS-related eating behavior.

Sleep-related violence and sexual behavior in sleep: a systematic review of medical-legal case reports.

OBJECTIVEnTo review systematically medical-legal cases of sleep-related violence (SRV) and sexual behavior in sleep (SBS).nnnSEARCH METHODSnWe searched Pubmed and PsychINFO (from 1980 to 2012) with pre-specified terms. We also searched reference lists of relevant articles.nnnSELECTION CRITERIAnCase reports in which a sleep disorder was purported as the defense during a criminal trial and in which information about the forensic evaluation of the defendant was provided.nnnDATA EXTRACTION AND ANALYSISnInformation about legal issues, defendant and victim characteristics, circumstantial factors, and forensic evaluation was extracted from each case. A qualitative-comparative assessment of cases was performed.nnnRESULTSnEighteen cases (9 SRV and 9 SBS) were included. The charge was murder or attempted murder in all SRV cases, while in SBS cases the charge ranged from sexual touching to rape. The defense was based on sleepwalking in 11 of 18 cases. The trial outcome was in favor of the defendant in 14 of 18 cases. Defendants were relatively young males in all cases. Victims were usually adult relatives of the defendants in SRV cases and unrelated young girls or adolescents in SBS cases. In most cases the criminal events occurred 1-2 hours after the defendants sleep onset, and both proximity and other potential triggering factors were reported. The forensic evaluations widely differed from case to case.nnnCONCLUSIONnSRV and SBS medical-legal cases did not show apparent differences, except for the severity of the charges and the victim characteristics. An international multidisciplinary consensus for the forensic evaluation of SRV and SBS should be developed as an urgent priority.

Neuropsychological findings in childhood narcolepsy.

Narcolepsy with cataplexy is a severely disabling disorder very often arising in childhood. Data on neuropsychological impairment in children are scant. We administered standardized neuropsychological tests to 13 children with narcolepsy with cataplexy. Overall, our patients displayed multiple patterns of cognitive and behavioral dysfunction, and often academic failure (7 cases out of 13). All children had a normal full intelligence quotient (IQ), but 3 patients presented a significantly higher and 2 a significantly lower Verbal IQ compared to Performance IQ, respectively. Mean sleep latency was significantly correlated (P < .05) to alertness functions. Eight patients displayed behavioral problems: emotional symptoms and conduct problems prevailed. Childhood narcolepsy with cataplexy represents a risk factor for subtle and heterogeneous cognitive impairments potentially resulting in academic failure, despite the normal IQ. These children also have a certain psychopathological risk. All this seems to be at least partially detached from the direct effects of daytime sleepiness.

The hypocretin system and psychiatric disorders.

The hypocretin system is constituted by a small group of hypothalamic neurons with widespread connections within the entire central nervous system producing two neuropeptides involved in several key physiological functions such as the regulation of sleep and wakefulness, motor control, autonomic functions, metabolism, feeding behavior, and reward. Narcolepsy with cataplexy is a neurological disorder regarded as a disease model for the selective hypocretin system damage, and also shares several psychopatological traits and comorbidities with psychiatric disorders. We reviewed the available literature on the involvement of the hypocretin system in psychiatric nosography. Different evidences such as cerebrospinal hypocretin-1 levels, genetic polymorphisms of the neuropeptides or their receptors, response to treatments, clinical, experimental and functional data directly or indirectly linked the hypocretin system to schizophrenia, mood, anxiety and eating disorders, as well as to addiction. Future genetic and pharmacological studies will disentangle the hypocretin system role in the field of psychiatry.

The timing between REM sleep behavior disorder and Parkinson's disease.

PurposeIn Parkinson’s disease (PD) patients, REM sleep behavior disorder (RBD) might precede PD or develop with or after the onset of PD. No previous study has explored differences between these two groups. The aim of this study was therefore to compare clinical features and REM sleep chin electromyographic patterns between patients in whom RBD heralded PD and those in whom RBD occurrence coincided with or followed the clinical manifestations of PD.MethodTwenty-seven consecutive PD patients (mean age 67.9xa0years) were enrolled. Detailed clinical, laboratory, and polysomnographic studies were obtained in all participants.ResultsSixteen of the 27 patients were affected by RBD. These had a significantly higher stage of PD and took significantly higher doses of dopaminergic therapy; their disease duration tended to be longer, and their cognitive status tended to be lower. PD patients in whom RBD preceded PD (nu2009=u20096) did not differ from PD patients without RBD in disease parameters, while PD patients in whom RBD developed with or after PD (nu2009=u200910) showed a significantly higher disease stage, took significantly higher dopaminergic therapy, and had a longer disease duration.ConclusionOur findings are compatible with the hypothesis that patients in whom RBD precedes, or does not precede, PD might constitute two possibly distinct clinical and physiopathological groups, based on different progressive neuropathological sequences of events.

Primary progressive narcolepsy type 1: The other side of the coin

Narcolepsy type 1 (NT1) is characterized by hypersomnolence associated with early occurrence of REM sleep (i.e., sleep-onset REM periods [SOREMP]) and cataplexy (i.e., sudden loss of muscle tone evoked by emotions), or with CSF hypocretin-1 (CSF hcrt-1) low levels (below 110 pg/mL, undetectable in most cases). Compelling evidence indicates that NT1 is caused by an autoimmune disease affecting HLA-DQB1*06:02 carriers.1 Diagnostic workup requires a history of cataplexy and multiple SOREMP at sleep studies (nocturnal polysomnography and multiple sleep latency test [MSLT]) or CSF hcrt-1 deficiency.2 At diagnosis, most patients with NT1 already have very reduced CSF hcrt-1 levels. Hypersomnolence and cataplexy presumably become evident when hypocretin cell loss is above 85%–90%, according to postmortem studies.3 A rapid and dramatically severe picture has been documented often in childhood-onset NT1, but it is also commonly recalled by history taking that the disorder can also slowly progress, and sleepiness may anticipate cataplexy by years. In full-blown NT1 cases, CSF hcrt-1 tends to maintain stable values through the disease course, and in only one case has CSF hcrt-1 been documented by chance before and after development of NT1, showing an abrupt step down from normal to pathologic values when the disease occurs.4 We document in an adult patient the slow onset of CSF hcrt-1 deficiency paralleled by a slow clinical progression to clear-cut NT1.

Sleep–wake fluctuations and respiratory events during Cheyne–Stokes respiration in patients with heart failure

Fluctuations in sleep–wake state are thought to contribute to the respiratory instability of Cheyne–Stokes respiration in patients with heart failure by promoting the rhythmic occurrence of central apnea and ventilatory overshoot. There are no data, however, on the relationship between vigilance state and respiratory events. In this study we used a novel method to detect the occurrence of state transitions (time resolution: 0.25 s, minimum duration of state changes: 2 s) and to assess their time relationship with apnoeic events. We also evaluated whether end‐apnoeic arousals are associated with a ventilatory overshoot. A polysomnographic, daytime laboratory recording (25 min) was performed during Cheyne–Stokes respiration in 16 patients with heart failure. Automatic state classification included wakefulness and non‐rapid eye movement sleep stages 1–2. As a rule, wakefulness occurred during hyperpnoeic phases, and non‐rapid eye movement sleep occurred during apnoeic events. Ninety‐two percent of the observed central apneas (N = 272) were associated with a concurrent wakefulness → non‐rapid eye movement sleep → wakefulness transition. The delay between wakefulness → non‐rapid eye movement sleep transitions and apnea onset was −0.3 [−3.1, 3.0] s [median (lower quartile, upper quartile); P = 0.99 testing the null hypothesis: median delay = 0], and the delay between non‐rapid eye movement sleep → wakefulness transitions and apnea termination was 0.2 [−0.5, 1.2] s (P = 0.7). A positive/negative delay indicates that the state transition occurred before/after the onset or termination of apnea. Non‐rapid eye movement sleep → wakefulness transitions synchronous with apnea termination were associated with a threefold increase in tidal volume and a twofold increase in ventilation (all P < 0.001), indicating ventilatory overshoot. These findings highlight that wakefulness → non‐rapid eye movement sleepu2005→u2005wakefulness transitions parallel apnoeic events during Cheyne–Stokes respiration in patients with heart failure. The relationships between state changes and respiratory events are consistent with the notion that state fluctuations promote ventilatory instability.

Polysomnographic and neurometabolic features may mark preclinical autosomal dominant cerebellar ataxia, deafness, and narcolepsy due to a mutation in the DNA (cytosine-5-)-methyltransferase gene, DNMT1

OBJECTIVEnWe aimed to report the clinical picture of two asymptomatic daughters of a patient with autosomal dominant cerebellar ataxia, deafness, and narcolepsy (ADCA-DN) due to a mutation in the DNA (cytosine-5-)-methyltransferase gene, DNMT1.nnnMETHODSnClinical assessment based on history, neurologic examination, sleep recordings, neurophysiologic neuroimaging, and genetic tests was performed.nnnRESULTSnHistory and neurologic examination in both subjects were unremarkable. Genetic analysis disclosed in both the paternally-inherited heterozygous point mutation in the DNMT1 gene. Sleep recordings found sleep-onset rapid eye movement periods (SOREMPs) and proton magnetic resonance spectroscopy (MRS) revealed increased cerebellar myoinositol (mI) in both subjects. Auditory and ophthalmologic investigations as well as structural brain magnetic resonance imaging (MRI) scans revealed no abnormalities.nnnCONCLUSIONSnThe two asymptomatic carriers of the heterozygous DNMT1 mutation for ADCA-DN, a late-onset neurodegenerative disease, presented with SOREMPs associated with an increase of mI in the brain, a marker of glial cell activity and density characteristic of early stages of neurodegenerative diseases. Therefore, SOREMPs may precede the clinical picture of ADCA-DN as an early polysomnographic marker of central nervous system involvement detected by MRS.