Fatal insomnia and agrypnia excitata: sleep and the limbic system.

Fatal familial insomnia, a human prion disease, Morvan's chorea, an autoimmune limbic encephalopathy, and delirium tremens, the well-known alcohol (or benzodiazepine [BDZ]) withdrawal syndrome, share a clinical phenotype largely consisting in an inability to sleep associated with motor and autonomic activation. Agrypnia excitata is the term which aptly defines this clinical condition, whose pathogenetic mechanism consists in an intralimbic disconnection releasing the hypothalamus and brainstem reticular formation from corticolimbic inhibitory control. Severance of cortical-subcortical limbic structures is due to visceral thalamus degeneration in fatal familial insomnia, and may depend on autoantibodies blocking voltage-gated potassium channels within the limbic system in Morvan's chorea, and the sudden changes in gabaergic synapses down-regulated by chronic alcohol abuse within the limbic system in delirium tremens. On the basis of these findings, we suggest that a neuronal network, extending from the medulla to the limbic cortex, controls the sleep-wake cycle, operating in an integrated fashion following a caudorostral organization.

Catathrenia (nocturnal groaning): an abnormal respiratory pattern during sleep.

Catathrenia (nocturnal groaning) is a rare condition characterized by monotonous irregular groans occurring during sleep. Ten patients (five women; mean age: 27 +/- 7.4 years, range: 15-41) with sleep-related groaning persisting for years or decades and normal daytime fibreoptic laryngoscopy and respiratory function tests underwent videopolysomnographic recording (VPSG) analysing their respiratory patterns during sleep. After the VPSG, all patients were clinically followed up for a mean period of 4.9 +/- 3.5 years. On VPSG, all patients showed nocturnal groaning during NREM sleep and particularly during REM sleep stages. Groaning was associated with disproportionate prolonged expiration causing reduced breathing rate without oxygen desaturation. The breathing pattern with prolonged expiration and sound production alternated with a normal respiratory pattern without groaning. Endoesophageal pressure during groaning showed mildly positive swings at the initial phase of expiration suggesting a partial mild expiratory upper airway obstruction. At the end of the follow-up period, all patients reported persistent nocturnal groaning but no other clinical manifestations. Groaning confined to sleep alternating with normal breathing and the absence of long-term clinical consequences suggest that catathrenia is because of an abnormality of the internal respiratory drive system, possibly related to persistence of a neonatal (vestigial) type of breathing pattern.

Sleep-related breathing disorders and headache.

Obtructive sleep apnoea syndrome (OSAS) is a common disorder in the general population with an estimated prevalence in an adult population of 2% in women and 4% in men. Although several studies have suggested that headaches, particularly morning headaches, are more common in patients with OSAS than in normal subjects, others have yielded contradictory findings. When the sleep-related breathing disorder was treated with success, the headache generally disappeared, supporting a causal role of the sleep disorder for headache. Several hypotheses have been proposed to explain the relationship between OSAS and the occurrence of headache, particularly on awakening. Night-time fluctuations of oxygen saturation during the night with hypercapnia, vasodilatation, increased intracranial pressure and impaired sleep quality are all considered contributing factors. However the exact mechanisms of headache pathogenesis and the relationship between OSAS, headache and morning headaches in particular remain controversial.

Sleep and movement disorders.

Polygraphic monitoring of abnormal movements during sleep started in the 1960s in the wake of the interest in sleep and sleep disorders triggered by the discovery of REM sleep. This paper reviews the contribution of the Bologna school to the identification and understanding of motor disorders in sleep.

Hyperkinetic manifestations in nocturnal frontal lobe epilepsy. Semeiological features and physiopathological hypothesis.

Nocturnal frontal lobe epilepsy is a syndromic entity that includes paroxysmal episodes with variable semeiology, intensity and duration, representing different aspects of the same epileptic condition. In a large series studied by videopolysomnographic recording at the Department of Neurological Sciences in Bologna, we disclosed four main semeiological patterns: the paroxysmal arousals, brief simple motor phenomena, similar to a sudden arousal, recurring several times per night; the hypermotor seizures, more complex motor episodes with violent motor behaviour, vocalisation, screaming, fearful and repetitive movements of the trunk and limbs; asymmetric, bilateral tonic seizures, which can evoke the seizures from the frontal mesial area; and epileptic nocturnal wanderings, which can mimic sleepwalking episodes.

Paroxysmal arousal in epilepsy associated with cingulate hyperperfusion.

A patient with nocturnal frontal lobe epilepsy characterized by paroxysmal motor attacks during sleep had brief paroxysmal arousals (PAs), complex episodes of nocturnal paroxysmal dystonia, and epileptic nocturnal wandering since childhood. Ictal SPECT during an episode of PA demonstrated increased blood flow in the right anterior cingulate gyrus and cerebellar cortex with hypoperfusion in the right temporal and frontal associative cortices.

The neuroanatomy of sleep. Considerations on the role of the thalamus in sleep and a proposal for a caudorostral organization

This review synthetizes the most important historical contributions in sleep anatomy and the pioneer discoveries in sleep medicine in the light of our clinical observations in Fatal Familial Insomnia FFI, a genetic prion disease. Together with Morvan's chorea and Delirium Tremens, FFI is characterized by inability to sleep with severe loss of sleep spindles and delta sleep, with preserved presleep behaviour and abnormal REM sleep, associated with motor and autonomic overactivation. We labelled this pattern as Agrypnia Excitata AE. AE is due to dysfunction in thalamolimbic circuits, which emphasizes the key role of the thalamus in sleep physiology and indicates that the anatomo-functional substrate of stage 1 non-REM sleep differs from that generating slow-wave-sleep SWS, spindle and delta activity. Accordingly, the sleep-wake cycle in man should be conceptualized as consisting of 5 different behavioural and electrophysiological distinct states: active wakefulness, quiet wakefulness, drowsiness or stage 1 non-REM, SWS which incorporates spindle and delta sleep and REM sleep. An intricate neuronal network extending from the caudal brainstem to the forebrain controls these different wake and sleep behaviours with several, at least three distinct generators (AU)

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Normal sleep-wake and circadian rhythms in a case of Gerstmann-Sträussler-Sheinker (GSS) disease.

A polysomnographic study showed normal sleep patterns and circadian rhythms in a patient with ataxic type GSS. Our results suggest that sleep and circadian rhythm changes in prion diseases are due to the involvement of specific brain areas.

Agrypnia Excitata: a generalized overactivity syndrome and a useful concept in the neurophysiopathology of sleep.

OBJECTIVES: To analyse the clinicophysiological features of delirium tremens (DT), Morvan's fibrillary chorea (MC) and fatal familial insomnia (FFI) as representative of the new concept of Agrypnia Excitata (AE). METHODS: DT, MC and FFI were compared for their clinical and polysomnographic features and, for MC and FFI, post-mortem verification. RESULTS: DT, MC and FFI all display profound loss of slow-wave sleep (SWS) and abnormal rapid eye movement (REM) sleep with lack of muscular atonia and enacted dreams. Sleep spindles and K complexes are severely reduced. Motor overactivity is associated with increased sympathergic functions. Neuropathology discloses severe loss of neurons in the thalami and cingular areas in FFI, and leakage of antibodies in the thalamus in MC. CONCLUSIONS: Based on the similarities in DT, MC and FFI, we propose the new concept of AE as a clinical condition characterized by loss of SWS and abnormal REM sleep, associated with motor and autonomic sympathergic activation. AE is due to dysfunction of the thalamo-limbic system. Moreover, the preservation of light sleep in the face of severe loss of deep sleep in AE argues that 3 rather than the usually considered two (non REM and REM) independent states of sleep exist.

Familial nocturnal facio-mandibular myoclonus mimicking sleep bruxism.

A mother and son presented with a multi-decade history of nocturnal tongue biting and bleeding. In both patients, video polysomnographic recordings documented bursts of electromyographic activity originating in the masseter and spreading to orbicularis oris and oculi muscles, present only during sleep. Faciomandibular myoclonic activity during sleep mimics sleep bruxism and may be familial.

Insomnia associated with thalamic involvement in E200K Creutzfeldt-Jakob disease.

BACKGROUND: Insomnia with predominant thalamic involvement and minor cortical and cerebellar pathologic changes is not characteristic of familial Creutzfeldt-Jakob disease (CJD) but is a hallmark of fatal familial insomnia. OBJECTIVE: To report a 53-year-old woman with intractable insomnia as her initial symptom of disease. METHODS: The authors characterized clinical, pathologic, and molecular features of the disease using EEG, polysomnography, neurohistology, Western blotting, protein sequencing, and prion protein (PrP) gene (PRNP) analysis. RESULTS: The patient developed dysgraphia, dysarthria, bulimia, myoclonus, memory loss, visual hallucinations, and opisthotonos, as well as pyramidal, extrapyramidal, and cerebellar signs. Polysomnographic studies showed an absence of stages 3 and 4, and REM. She died 8 months after onset. On neuropathologic examination, there was major thalamic involvement characterized by neuronal loss, spongiform changes, and prominent gliosis. The inferior olivary nuclei exhibited chromatolysis, neuronal loss, and gliosis. Spongiform changes were mild in the neocortex and not evident in the cerebellum. PrP immunopositivity was present in these areas as well as in the thalamus. PRNP analysis showed the haplotype E200K-129M. Western blot analysis showed the presence of proteinase K (PK)-resistant PrP (PrP(sc)) with the nonglycosylated isoform of approximately 21 kd, corresponding in size to that of type 1 PrP(sc). N-terminal protein sequencing demonstrated PK cleavage sites at glycine (G) 82 and G78, as previously reported in CJD with the E200K-129 M haplotype. CONCLUSIONS: Insomnia may be a prominent early symptom in cases of CJD linked to the E200K-129M haplotype in which the thalamus is severely affected.

Polysomnographic characterization of pergolide-induced sleep attacks in idiopathic PD.

Both dopamine agonists and levodopa may induce episodes termed "sleep attacks" in patients with PD. These episodes are well detailed behaviorally, but little is known about their neurophysiologic characterization. The authors performed a 24-hour polysomnography (PSG) in a PD patient taking pergolide in combination with levodopa, in which four of these diurnal sleep episodes occurred. PSG findings were followed up after pergolide withdrawal. Sleep episodes shared with narcolepsy both behavioral and EEG findings. However, pergolide partly restored a more physiologic sleep architecture, which was disrupted during therapy with levodopa alone.

Morvan's syndrome: peripheral and central nervous system and cardiac involvement with antibodies to voltage-gated potassium channels.

Morvan's 'fibrillary chorea' or Morvan's syndrome is characterized by neuromyotonia (NMT), pain, hyperhydrosis, weight loss, severe insomnia and hallucinations. We describe a man aged 76 years with NMT, dysautonomia, cardiac arrhythmia, lack of slow-wave sleep and abnormal rapid eye movement sleep. He had raised serum antibodies to voltage-gated K(+) channels (VGKC), oligoclonal bands in his CSF, markedly increased serum norepinephrine, increased serum cortisol and reduced levels and absent circadian rhythms of prolactin and melatonin. The neurohormonal findings and many of the clinical features were very similar to those in fatal familial insomnia, a hereditary prion disease that is associated with thalamic degenerative changes. Strikingly, however, all symptoms in our MFC patient improved with plasma exchange. The patient died unexpectedly 11 months later. At autopsy, there was a pulmonary adenocarcinoma, but brain pathology showed only a microinfarct in the hippocampus and no thalamic changes. The NMT and some of the autonomic features are likely to be directly related to the VGKC antibodies acting in the periphery. The central symptoms might also be due to the direct effects of VGKC antibodies, or perhaps of other autoantibodies still to be defined, on the limbic system with secondary effects on neurohormone levels. Alternatively, changes in secretion of neurohormones in the periphery might contribute to the central disturbance. The relationship between VGKC antibodies, neurohormonal levels, autonomic, limbic and sleep disorders requires further study.

Propriospinal myoclonus at the sleep-wake transition: a new type of parasomnia.

STUDY OBJECTIVES: To describe the clinical, neurophysiological, and polysomnographic characteristics of propriospinal myoclonus (PSM) at the sleep-wake transition. DESIGN: Patients referred for insomnia due to myoclonic activity arising during relaxed wakefulness preceding sleep, or complaining of muscular jerks also during intrasleep wakefulness and upon awakening in the morning were considered. SETTING: All patients underwent EEG-EMG recordings during wakefulness and night sleep. Back-averaging of the EEG activity preceding the jerks was performed. Somatosensory evoked potentials (SEPs), transcranial magnetic stimulation (TMS) and spinal and cranial MRI were also done. PARTICIPANTS: Four patients were studied all affected with involuntary jerks arising when falling asleep, and one with jerks also during sleep and upon awakening in the morning. INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: Polysomnographic investigations revealed jerks arising during the sleep-wake transition period. Myoclonic activity was neurophysiologically documented to be of the propriospinal type. SEPs, TMS and MRI were normal CONCLUSIONS: PSM may have a peculiar relationship with the state of vigilance and represent a sleep-wake transition disorder. In this regard we consider PSM a new type of parasomnia.

Validation of symptoms related to excessive daytime sleepiness.

The aim of this study was to validate some recurring definitions of excessive daytime sleepiness (EDS) obtained from descriptive epidemiological studies. We devised questions concerning concepts such as "tiredness", "resistible sleepiness", "irresistible sleepiness" and "sudden sleep attacks". The validation was done by comparing the answers with the results of the Multiple Sleep Latency Test (MSLT), considered the gold standard, or criterion measure, for the diagnosis of EDS. The sample study comprised 73 subjects, 57 outpatients referred to our Sleep Center complaining of daytime sleepiness, snoring or sleep apnea and 16 inpatients admitted to our Neurological Institute for causes other than sleep disorders. A moderate correlation (p = -0.38, 95% confidence interval -0.57 to -0.19) was found between "irresistible sleepiness" and mean sleep latency (MSL). The best combinations of sensitivity and specificity in identifying EDS, for 5- and 8-min MSL cutoffs, were observed for the questions concerning "sudden sleep attacks" and "irresistible sleepiness" (areas under the receiver-operating characteristic curves = 66 and 67%, respectively). The subitems exploring the frequency and situations of occurrence of these symptoms improved the validity in identifying EDS. The items regarding "tiredness" and "resistible sleepiness" were not related to the results of the MSLT. In subgroup analysis, irresistible sleepiness failed to identify pathologic MSLT in sleep-disordered breathing subjects. According to previous observations, we suggest that the concept of sleepiness includes various domains heterogeneously related with MSL and that questionnaires must be tailored to the different populations studied.

Absence of sleep EEG markers in fatal familial insomnia healthy carriers: a spectral analysis study.

OBJECTIVES: Fatal familial insomnia (FFI) is linked to a mutation at codon 178 (C178) of the prion protein gene (PRNP). FFI is pathologically characterized by selective atrophy of the anteroventral and mediodorsal thalamic nuclei and clinically by loss of sleep, dysautonomia and motor signs. A key early polysomnographic sign of the disease onset is the loss of sleep spindling (sigma activity, SA). In FFI the loss of SA leads to the spectral representation of a sudden slow wave activity (SWA) increase from an awake state, the reaching of a stable plateau without oscillations, followed by abrupt fall down to REM sleep. We evaluated the presence of differences in the spectral sleep EEG pattern in FFI relatives carriers (C178(pos)) or non-carriers (C178(neg)) of the C178 mutation. METHODS: Seventeen healthy relatives of FFI patients, 8 carriers of the C178 FFI mutation in a preclinical condition and 9 non carriers, underwent two-night polysomnography. The absolute and relative EEG power of the 4 main bands (delta: SWA, 0.5-4.0 Hz; theta: TB, 4.5-8 Hz; alpha: AB, 8.5-12 Hz; sigma: SA, 12.5-16 Hz) has been studied for the total sleep time, the period of delta increase after sleep onset, and the period of delta plateau. Multiple regression has been applied to investigate relations between the power of the bands studied and 3 parameters: age, the gender of the subjects and the C178 genotype. RESULTS: Our study could not show evidence of differences in the sleep EEG composition between carriers and non-carriers of the C178 FFI mutation. CONCLUSIONS: The spectral analysis techniques we used were not able to disclose sleep EEG markers linked to the FFI C178(pos) in the preclinical condition. Key sleep EEG alteration become evident only at the clinical onset of the disease.