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Biomedical subjects

E Lugaresi

Publications and source records attributed to E Lugaresi.

At least 37 records · Page 2Linked to original sources
PubMed2001

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.

Adolescent↗
PubMed2000

From nocturnal paroxysmal dystonia to nocturnal frontal lobe epilepsy.

Nocturnal paroxysmal dystonia (NPD) is the term used to describe motor attacks characterized by complex behavior, with dystonic-dyskinetic or ballic movements arising from NREM sleep. NPD together with paroxysmal arousals (PA), the briefest attacks, and episodic nocturnal wanderings (ENW), the most prolonged ones, constitute nocturnal frontal lobe epilepsy (NFLE). PA are sudden awakenings associated with stereotyped dystonic-dyskinetic movements, sometimes accompanied by screaming and a frightened expression. ENW are episodes of agitated ambulation, with complex, sometimes violent, motor behavior and dystonic postures involving head, trunk and limbs. NPD, PA and ENW coexist in most patients. NFLE is predominant in males and usually begins during adolescence. A familial recurrence of parasomnias in NFLE patients is much more common than in the general population. Autosomal dominant inheritance has been documented in 6% of our cases. Few patients present personal antecedents or positive neuroradiological findings. Seizures are frequent, occurring every or almost every night, many times per night. Interictal wake and sleep EEG tracings are often normal and ictal epileptic activity is recorded in a relatively small number of cases. Carbamazepine controls or significantly reduces seizures in about 70% of cases; the remainder are drug-resistant. Videopolysomnographic recordings, showing stereotyped abnormal movements during attacks, are mandatory to confirm the diagnosis of NFLE.

Epilepsy, Frontal Lobe↗
PubMed2000

Focal myoclonus and propriospinal propagation.

OBJECTIVE: To investigate the relationship between axial segmental myoclonus and propriospinal myoclonus. METHODS: A patient with a 3-year history of axial jerks evoked by physical effort and unexpected somesthetic and auditory stimulations was investigated. Polygraphy with multiple-channel axial and limb EMG recording was performed with off-line analysis. RESULTS: Spontaneous, somesthetic and acoustic evoked jerks always began in the left rectus abdominis muscle with a single or repetitive EMG burst that could spread to other rostral and caudal muscles without engagement of cranial nerve innervated muscles, consistent with propriospinal propagation. Spontaneous and evoked jerks could however also appear focally in abdominal muscles and remain localized without any diffusion to other muscle segments. CONCLUSION: Focal axial myoclonus and propriospinal myoclonus may coexist. Conceivably the same spinal generator responsible for a monomeric segmental myoclonus may, under conditions of heightened excitability, cause a multimeric propriospinally propagated muscular activation.

Adult↗
PubMed2000

Sleep stage-related changes in sympathetic sudomotor and vasomotor skin responses in man.

OBJECTIVES: The aim of the study was to evaluate the characteristics of the spontaneous and evoked sympathetic skin responses (SSR) during sleep and wakefulness in comparison with the skin vasomotor responses (SVR). METHODS: Five healthy subjects underwent a night of videopolysomnographic recording. Spontaneous SSR were recorded via surface electrodes placed on the dorsal and ventral aspect of the hand while SVR were evaluated by means of an infrared photoelectric transducer placed on the index finger. SSR and SVR were evoked via electrical stimuli applied to the left supraorbital nerve. RESULTS: Spontaneous SSR frequency was highest during stage 4 of NREM sleep and lowest during REM phases. On the contrary, spontaneous SVR frequency reached its lowest value during stage 4 and its highest value during stage 2 of NREM sleep, remaining at levels above waking values during REM. SSR could be elicited by stimuli inducing arousal during light sleep but it was absent during deep NREM and REM sleep. SVR could be evoked throughout NREM and REM sleep. CONCLUSIONS: Spontaneous SSR and SVR act differently during physiological modifications of vigilance. Evoked SSR is strictly dependent upon the state of vigilance, whereas evoked SVR shows no modifications during the different stages of the wake-sleep cycle.

Adult↗
PubMed1999

Studies of penetrance and anticipation in five autosomal-dominant restless legs syndrome pedigrees.

Restless legs syndrome (RLS) can occur with an autosomal-dominant mode of inheritance. To determine if there are distinguishing features of RLS pedigrees which might clarify molecular mechanisms of pathogenesis, five pedigrees with 81 affected members were analyzed for age of onset, sex ratio, and transmission pattern. One-factor analysis of variance of ages of onset between generations was carried out, and segregation ratios were calculated for each generation. These kindreds showed an autosomal-dominant mode of inheritance and a male:female ratio of 1:1.4 (p = 0.15). One of the five analyzed pedigrees shows some evidence of reduced penetrance. In two of the five analyzed pedigrees, there is statistical support for anticipation (p<0.05). These variations in penetrance and anticipation suggest possible genetic heterogeneity.

Adolescent↗
PubMed1999

Bilateral centrotemporal spikes triggered by blinking: an unusual form of sensory input with related cortical EEG activity.

OBJECTIVE: To investigate the morphology, scalp topography and temporal relationship with orbicularis oculi muscle contraction of bilateral blink related spikes (BRS) in a 7-year-old boy with chromosomopathy, mild mental retardation and left spontaneous centrotemporal spikes (SS). METHODS: The patient underwent video-polygraphic recordings with off-line analysis of SS and BRS by means of spike-averaging and orbicularis oculi contraction-locked averaging techniques respectively. EEG activity related to reflex blinking (evoked by glabellar tapping) was also studied. RESULTS: SS and BRS presented the same morphology, characterised by four peaks (P1, N1, P2, N2). SS were located over the left centroparietal regions, while BRS were placed over both left and right centrotemporoparietal regions and constantly followed the contraction of orbicularis oculi with overlapping peak latencies over C3 and C4 electrodes (P1 72 ms; N1 115 ms; P2 164 ms; N2 236 ms). Reflex blinking evoked a small waveform with the same features as BRS. CONCLUSIONS: Our findings suggest that both involuntary and reflex blinking can act as a form of sensory stimulation probably engaging similar nervous pathways and cortical sources in generating EEG abnormalities: the trigeminal system.

Action Potentials↗
PubMed1999

Fatal familial insomnia: clinical features and molecular genetics.

Fatal familial insomnia (FFI) is an autosomal dominant prion disease clinically characterized by inattention, sleep loss, dysautonomia, and motor signs and pathologically characterized by a preferential thalamic degeneration. FFI is linked to a missense mutation at codon 178 of the prion protein gene, PRNP, coupled with the presence of the codon methionine at position 129, the locus of a methionine-valine polymorphism. Homozygotes at codon 129, expressing methionine also in the nonmutated allele, have a shorter disease course (often less than 1 year), prominent sleep and autonomic disturbances at disease onset, and pathology restricted to the thalamus. Heterozygotes at codon 129, expressing valine in the nonmutated allele, have a longer disease course (often longer than 1 year), ataxia and dysarthria at disease onset, and lesions widespread to cerebral cortex. Both in the thalamus and in the cortex, the limbic structures are those most consistently and severely involved: the anterior ventral and mediodorsal thalamic nuclei, the cingulate gyrus, and the orbitofrontal cortex. FFI is thus a prion disease selectively damaging the thalamocortical limbic structures. Loss of sleep, sympathetic hyperactivity, and flattening of vegetative and hormonal circadian oscillations characterize FFI and result from a homeostatic imbalance caused by the interruption of the thalamocortical limbic circuits, the phylogenetically most advanced structures involved in the control of the sleep-wake cycle and the body's homeostasis. The selective atrophy of the limbic thalamus that characterizes FFI might be due to the binding of FFI toxic PrP or PrPres to specific receptors on thalamolimbic neurons.

Apoptosis↗
PubMed1999

Nocturnal frontal lobe epilepsy. A clinical and polygraphic overview of 100 consecutive cases.

Nocturnal frontal lobe epilepsy (NFLE) has been delineated as a distinct syndrome in the heterogeneous group of paroxysmal sleep-related disturbances. The variable duration and intensity of the seizures distinguish three non-rapid eye movement-related subtypes: paroxysmal arousals, characterized by brief and sudden recurrent motor paroxysmal behaviour; nocturnal paroxysmal dystonia, motor attacks with complex dystonic-dyskinetic features; and episodic nocturnal wanderings, stereotyped, agitated somnambulism. We review the clinical and polysomnographic data related to 100 consecutive cases of NFLE in order to define the clinical and neurophysiological characteristics of the different seizure types that constitute NFLE. NFLE seizures predominate in males (7:3). Age at onset of the nocturnal seizures varies, but centres during infancy and adolescence. A familial recurrence of the epileptic attacks is found in 25% of the cases, while 39% of the patients present a family history of nocturnal paroxysmal episodes that fit the diagnostic criteria for parasomnias. A minority of cases (13%) have personal antecedents (such as birth anoxia, febrile convulsions) or brain CT or MRI abnormalities (14%). In many patients, ictal (44%) and interictal (51%) EEGs are uninformative. Marked autonomic activation is a common finding during the seizures. NFLE does not show a tendency to spontaneous remission. Carbamazepine completely abolishes the seizures in approximately 20% of the cases and gives remarkable relief (reduction of the seizures by at least 50%) in another 48%. VideoEEG recordings confirm that NFLE comprises a spectrum of distinct phenomena, different in intensity but representing a continuum of the same epileptic condition. We believe that the detailed clinical and videoEEG characterization of patients with NFLE represents the first step towards a better understanding of the pathogenic mechanisms and different clinical outcomes of the various seizure types that constitute the syndrome.

Adolescent↗
PubMed1999

Biochemical features of mtDNA 14484 (ND6/M64V) point mutation associated with Leber's hereditary optic neuropathy.

We report the effect on complex I function of the 14484 Leber's hereditary optic neuropathy (LHON) mutation affecting the ND6 subunit gene. The same gene was also reported to carry another mutation, at position 14459, associated with the LHON/dystonia phenotype that induces a reduction of complex I-specific activity and increases the sensitivity to the product decylubiquinol. Given the proximity of both mutations in the ND6 gene, we tested the specific activity of complex I and its sensitivity to myxothiazol and nonylbenzoquinol, both inhibitors at the ubiquinol product site, in platelet submitochondrial particles from nine 14484 homoplasmic individuals, 8 Italians with Caucasian mtDNA haplogroup J (adjunctive 4216 and 13708 mutations), and 1 Tunisian with an African mtDNA haplogroup. The specific activity of complex I was not affected by the 14484 mutation, but the sensitivity to both inhibitors was significantly increased compared with control subjects regardless of the presence of haplogroup J polymorphisms. Analysis of 70 different amino acid sequences of the ND6 subunit indicated that the 14484 mutation affects an amino acid belonging to its most conserved region, which shows local similarities with cytochrome b regions interacting with ubiquinone or ubiquinol in complex III. Our results suggest that both 14484 and 14459 mutations may affect amino acids forming the interaction site of ubiquinol product, and the 14484 mutation produces a biochemical defect resembling in part that already reported for the common 11778/ND4 LHON mutation.

Adult↗
PubMed1998

Leber's Hereditary Optic Neuropathy (LHON) with 14484/ND6 mutation in a North African patient.

We report the clinical and genetic study of a Leber's Hereditary Optic Neuropathy (LHON) patient of North African origin harboring the 14484/ND6 mutation of mtDNA. For over a year we followed the ophthalmological course of this 24-year-old male with LHON treated with idebenone and vitamin B12. Serum lactate after effort was evaluated before, during and after therapy. Muscle biopsy was obtained for morphological study. Homo/heteroplasmy of 14484/ND6 mutation was studied in different tissues. Recovery of visual acuity was documented 6 months after onset and 3 months after therapy was established. Baseline serum lactate was elevated but normalized after 3.5 months of therapy. Muscle biopsy demonstrated only a few fibers with a slightly increased subsarcolemmal SDH activity. Genetic analysis showed homoplasmic 14484/ND6 mutation in all tissues investigated. The clinical phenotype of LHON/14484 in this patient closely resembles that commonly found in European patients. Even if LHON/14484 patients are reported to have a better prognosis for visual recovery, it is possible that the evolution of visual recovery in this patient could have been influenced by therapy as suggested by changes in serum lactate levels. Bioenergetic impairment of skeletal muscle was documented by lactate levels and muscle morphology. The 14484/ND6 mutation behaves as a primary mutation regardless of mtDNA population-specific backgrounds.

Adult↗
PubMed1998

Endozepine stupor. Recurring stupor linked to endozepine-4 accumulation.

Recurring stupor can be caused by repeated metabolic, toxic or structural brain disturbances. Recently, cases of recurring stupor, with fast EEG activity were shown to display increased endogenous benzodiazepine-like activity during the episodes of stupor. Patients with recurring stupor underwent extensive metabolic and toxicologic screening, EEG and brain imaging. Endozepines and exogenously administered benzodiazepines were assayed in plasma and CSF by means of mass spectrometry. Flumazenil, a benzodiazepine antagonist was administered and the behavioural and EEG responses monitored. Treatment with oral flumazenil was attempted in selected cases. Twenty patients were found with recurring stupor. Episodes had begun between ages 18 and 67 years, and in nine patients, had disappeared spontaneously after 4-6 years with symptoms. Stupor lasted hours or days. Onset of the episodes and frequency were unpredictable. Patients were normal between attacks. Stupor was characterized by initial drowsiness, staggering and behavioural changes, followed by deep sleep and spontaneous recovery with post-ictal amnesia. Biochemical screening and brain imaging were always normal. Ictal EEG showed fast background activity, and flumazenil transiently awoke the patients and normalized the EEG. In the nine cases examined, endozepine-4 levels were increased during the stupor. Oral flumazenil reduced the frequency of the attacks in three of these nine patients. Recurring episodes of stupor may be due to increased endozepine-4. We propose the term 'endozepine stupor' for such episodes. Endozepine-4 is an endogenous ligand for the benzodiazepine recognition site at the GABAA receptor, with unknown molecular structure.

Adult↗
PubMed1998

Clinical features of fatal familial insomnia: phenotypic variability in relation to a polymorphism at codon 129 of the prion protein gene.

Fatal Familial Insomnia is a hereditary prion disease characterized by a mutation at codon 178 of the prion protein gene cosegregating with the methionine polymorphism at codon 129 of the mutated allele. It is characterized by disturbances of the wake-sleep cycle, dysautonomia and somatomotor manifestations (myoclonus, ataxia, dysarthria, spasticity). PET studies disclose severe thalamic and additionally cortical hypometabolism. Neuropathology shows marked neuronal loss and gliosis in the thalamus, especially the medio-dorsal and anterior-ventral nuclei, olivary hypertrophy and some spongiosis of the cerebral cortex. Detailed analysis of 14 cases from 5 unrelated families showed that patients ran either a short (9.1 +/- 1.1 months) or a prolonged (30.8 +/- 21.3 months) clinical course according to whether they were homozygote met/met or heterozygote met/val at codon 129. Moreover, homozygotes had more prominent oneiric episodes, insomnia and dysautonomia at onset, whereas heterozygotes showed ataxia and dysarthria at onset, earlier sphincter loss and epileptic Grand Mal seizures; they also displayed more extensive cortical involvement on PET and at postmortem examination. Our data suggest that the phenotype expression of Fatal Familial Insomnia is related, at least partly, to the polymorphism at codon 129 of the prion protein-gene.

Adult↗
PubMed1998

The pathophysiology of fatal familial insomnia.

The key clinical aspects of FFI, i.e. hypovigilance and attention deficit, inability to generate EEG sleep patterns, sympathetic hyperactivity and attenuation of vegetative and hormonal circadian oscillations, are related to selective atrophy of the anteroventral and mediodorsal thalamic nuclei. These nuclei constitute the limbic part of the thalamus interconnecting limbic and paralimbic regions of the cortex and other subcortical structures in the limbic system including the hypothalamus. The hypothalamus released from cortico-limbic control is shifted to a prevalence of activating, as opposed to deactivating, functions including loss of sleep, sympathetic hyperactivity and the attendant attenuation of autonomic circadian and endocrine oscillations. These findings document that the limbic thalamus has a strategic position in the central autonomic network running from the limbic cortical regions to the lower brain stem which regulates the body's homeostasis in an integrated fashion.

Autonomic Nervous System Diseases↗
PubMed1998

Neuronal apoptosis in fatal familial insomnia.

The possibility that neuronal loss in prion diseases occurs through an apoptotic process has been postulated and is consistent with the lack of inflammation in these disorders. In order to test this hypothesis in FFI, in which neuronal loss is the predominant neuropathological feature, we examined samples of thalamus, basal ganglia, cerebral cortex, cerebellum and medulla from 10 subjects with FFI. All the patients had the characteristic 178 N mutation of the PrP gene. Eight subjects were homozygous methionine/methionine at codon 129 and 2 were heterozygous methionine/valine. Apoptotic neurons were identified by in situ end labelling in all the FFI cases and in none of the controls. They were mostly found in damaged regions and their presence and abundance seemed to correlate closely with the neuronal loss. They were particularly abundant in the thalamus and medullary olives. In heterozygous cases who had a longer disease duration and more widespread cerebral changes, apoptotic neurons were also found in the neocortex and striatum. The abundance of apoptotic neurons also correlated well with microglial activation as demonstrated by the expression of major histocompatibility complex class II antigens. PrPres immunostaining was almost invariably negative, consistent with previous data showing the lack of obvious correlation between neuronal loss and PrPres deposits in prion diseases.

Adult↗
PubMed1998

Molecular pathology of fatal familial insomnia.

Fatal familial insomnia (FFI) is linked to a mutation at codon 178 of the prion protein gene, coupled with the methionine codon at position 129, the site of a methionine/valine polymorphism. The D178N mutation coupled with the 129 valine codon is linked to a subtype of Creutzfeldt-Jakob disease (CJD178) with a different phenotype. Two protease resistant fragments of the pathogenic PrP (PrPres), which differ in molecular mass, are associated with FFI and CJD178, respectively, suggesting that the two PrPres have different conformations and hence they produce different disease phenotypes. FFI transmission experiments, which show that the endogenous PrPres recovered in affected syngenic mice specifically replicates the molecular mass of the FFI PrPres inoculated and is associated with a phenotype distinct from that of the CJD178 inoculated mice, support this idea. The second distinctive feature of the FFI PrPres is the underrepresentation of the unglycosylated PrPres form. Cell models indicate that the underrepresentation of this PrPres form results from the PrP dysmetabolism caused by the D178N mutation and not from the preferential conversion of the glycosylated forms. Codon 129 on the normal allele further modifies the FFI phenotype determining patient subpopulations of 129 homozygotes and heterozygotes: disease duration is generally shorter, insomnia more severe and histopathology more restricted to the thalamus in the homozygotes than in the heterozygotes. The allelic origin of PrPres fails to explain this finding since in both cases FFI PrPres is expressed only by the mutant allele. Despite remarkable advances, many issues remain unsolved precluding full understanding of the FFI pathogenesis.

Brain↗