Roberto Vetrugno

Sympathetic skin response: basic mechanisms and clinical applications.

Abstract.Sympathetic skin response (SSR), defined as the momentary change of the electrical potential of the skin, may be spontaneous or reflexively evoked by a variety of internal or by externally applied arousal stimuli. Although the suprasegmental structures influencing the SSR in humans are not well known, SSR has been proposed as a non-invasive approach to investigate the function of the sympathetic system. SSR is easy to apply but current procedures are not sufficiently reliable for diagnostic purposes, and show imperfect correlations both with clinical features and other measurements of autonomic, in particular, sudomotor dysfunction.

Motor pattern of periodic limb movements during sleep

Background: The pathophysiology of periodic limb movements in sleep (PLMS) in restless legs syndrome (RLS) is unclear. Objective: The authors neurophysiologically investigated PLMS in patients with idiopathic RLS in order to obtain information on the origin and pathophysiology of the movements. Methods: Ten patients with idiopathic RLS underwent electromyography with nerve conduction velocity (EMG-CV), somatosensory evoked potentials (SEPs), transcranial magnetic stimulation (TMS), nocturnal videopolysomnography, and multiple sleep latency test. The authors analyzed 100 consecutive PLMS for each patient to determine how frequently each muscle was involved in the PLMS; how frequently EMG activity started in a given muscle; and the time delay and pattern of activation between the first and the other activated muscles. Results: EMG-CV, SEPs, and TMS findings were all normal; in PLMS, leg muscles were those more frequently involved, often with alternation of side. Axial muscles were rarely and upper limb muscles sometimes involved. The tibialis anterior was the most frequent starting muscle. There was no constant recruitment pattern from one PLMS episode to another, even in the same patient. There was no ordinate caudal or rostral spread of the EMG activity. Conclusion: The recruitment pattern indicates the engagement of different, independent, and sometimes unsynchronized generators for each PLMS. The authors hypothesize an abnormal hyperexcitability along the entire spinal cord, especially its lumbosacral and cervical segments, as the primary cause of PLMS, triggered by sleep-related factors located at a supraspinal but still unresolved level.

Catathrenia (nocturnal groaning): A new type of parasomnia

Four patients between 15 and 25 years of age presented with exclusively expiratory groaning during sleep. Groaning usually occurred during the second part of the night, beginning at age 5 to 16 years. Patients were unaware of the nocturnal noise, but it alarmed others. Results of otorhinolaryngologic and neurologic examinations were normal. Expiratory groaning arose during REM and non-REM sleep stage 2, and was repeated in clusters. Nocturnal groaning, which the authors term catathrenia, represents a distinctive parasomnia.

Augmentation of restless legs syndrome with long‐term tramadol treatment

Restless legs syndrome (RLS) augmentation, defined as a kind of suppression of the circadian rhythm of the disease in which sensory and motor symptoms appear earlier during the day (and over previously unaffected body parts), with a progressive phase advance until, backwards, the symptoms may cover the entire day, has been described only after treatment with dopaminergic drugs. We report clinical and polysomnographic accounts of a patient developing RLS augmentation after long‐term treatment with tramadol, an opioid agonist with selectivity for μ‐receptor and added norepinephrine and serotonin reuptake inhibition properties. Polysomnographic measures showed an improvement of RLS and a disappearance of diurnal sensory and motor RLS symptoms after tramadol was stopped. Our case confirms a recent retrospective report of augmentation of RLS after treatment with tramadol, and begs the question whether augmentation is truly restricted to dopaminergic drugs.

Daytime sleepiness and neural cardiac modulation in sleep-related breathing disorders.

Sleep‐related breathing disorders are common causes of excessive daytime sleepiness, a socially and clinically relevant problem. Mechanisms responsible for daytime sleepiness are still largely unknown. We investigated whether specific alterations in autonomic cardiac modulation during sleep, commonly associated with sleep‐related breathing disorders, are related to excessive daytime sleepiness. Fifty‐three patients with sleep‐related breathing disorders underwent nocturnal polysomnography. Excessive daytime sleepiness was diagnosed as a Multiple Sleep Latency Test response less than or equal to 600 s. We explored the relation of excessive daytime sleepiness, objectively determined, with indices of autonomic cardiac regulation, such as baroreflex sensitivity and heart rate variability, with polysomnographic indices of the severity of sleep‐related breathing disorders and with quality of sleep. Patients with excessive daytime sleepiness, when compared with patients without, had significantly lower baroreflex sensitivity and significantly higher low‐to‐high frequency power ratio of heart rate variability during the different stages of nocturnal sleep. By contrast, no differences were found in indices quantifying the severity of sleep‐related breathing disorders or sleep quality. We demonstrated that excessive daytime sleepiness is accompanied by a deranged cardiac autonomic control at night, the latter probably reflecting autonomic arousals not detectable in the EEG. As abnormal autonomic regulation is also known to be associated with increased cardiovascular risk, a possible relation between excessive daytime sleepiness and cardiovascular events in patients with sleep‐related breathing disorders deserves to be investigated in future studies.

Association of restless legs syndrome with nocturnal eating: a case-control study.

We investigated the prevalence of nocturnal eating (sleep‐related eating disorder—SRED or night‐eating syndrome—NES) in patients with restless legs syndrome (RLS). One hundred RLS patients living in Emilia‐Romagna (Northern Italy) and 100 matched controls randomly selected from the general population received two telephone interviews, and were investigated for socio‐demographic characteristics, general health status, and presence of nocturnaleating. Additionally, subjects underwent interviews for psychopathological traits [by means of the Eating Disorder Inventory‐2 (EDI‐2), the Maudsley Obsessive‐Compulsive Inventory (MOCI), the Beck Depression Inventory (BDI)], excessive daytime sleepiness (EDS), and subjective sleep quality. Compared with controls, RLS patients had more frequently pathological MOCI scores (24% versus 10%, P = 0.03), used significantly more drugs for concomitant diseases and had more nocturnal sleep impairment and EDS. SRED was more prevalent in RLS patients than controls (SRED: 33% versus 1%, P < 0.001). Medication use and pathological MOCI scores were more prevalent in RLS patients with SRED than among RLS patients without SRED. Use of dopaminergic or hypnotic drugs for RLS was not correlated with the presence of SRED. We demonstrate an association between RLS and SRED. Prospective studies are needed to establish the mechanisms underlying such association and whether it is causal.

Suggestive evidence for linkage for restless legs syndrome on chromosome 19p13

Five loci for restless legs syndrome (RLS) on chromosomes 12q, 14q, 9p, 2q, and 20p (RLS1-RLS5) have been mapped in RLS families, with a recessive in the first and autosomal-dominant mode of inheritance in the latter cases. Investigations of further RLS families showed evidence for genetic locus heterogeneity. We have conducted a genome-wide linkage analysis in a large RLS family of Italian origin with 12 affected members in 3 generations using 5,861 single nucleotide polymorphisms (SNP, 6K Illumina). Linkage analysis was performed under an autosomal-dominant model with a complete penetrance, an allele frequency of 0.003 and a phenocopy rate of 0.005. The genome-wide scan resulted in suggestive evidence for linkage on chromosome 19p with maximum multipoint logarithm of the odds score of 2.61 between markers rs754292 and rs273265. The locus was replicated in a family-based association study in a set of 159 trios of European origin. This study provides evidence for a further RLS locus, thus supporting the picture of RLS as a genetically heterogenous complex trait.

Rare mtDNA variants in Leber hereditary optic neuropathy families with recurrence of myoclonus

Objective: To investigate the mechanisms underlying myoclonus in Leber hereditary optic neuropathy (LHON). Methods: Five patients and one unaffected carrier from two Italian families bearing the homoplasmic 11778/ND4 and 3460/ND1 mutations underwent a uniform investigation including neurophysiologic studies, muscle biopsy, serum lactic acid after exercise, and muscle (31P) and cerebral (1H) magnetic resonance spectroscopy (MRS). Biochemical investigations on fibroblasts and complete mitochondrial DNA (mtDNA) sequences of both families were also performed. Results: All six individuals had myoclonus. In spite of a normal EEG background and the absence of giant SEPs and C reflex, EEG-EMG back-averaging showed a preceding jerk-locked EEG potential, consistent with a cortical generator of the myoclonus. Specific comorbidities in the 11778/ND4 family included muscular cramps and psychiatric disorders, whereas features common to both families were migraine and cardiologic abnormalities. Signs of mitochondrial proliferation were seen in muscle biopsies and lactic acid elevation was observed in four of six patients. 31P-MRS was abnormal in five of six patients and 1H-MRS showed ventricular accumulation of lactic acid in three of six patients. Fibroblast ATP depletion was evident at 48 hours incubation with galactose in LHON/myoclonus patients. Sequence analysis revealed haplogroup T2 (11778/ND4 family) and U4a (3460/ND1 family) mtDNAs. A functional role for the non-synonymous 4136A>G/ND1, 9139G>A/ATPase6, and 15773G>A/cyt b variants was supported by amino acid conservation analysis. Conclusions: Myoclonus and other comorbidities characterized our Leber hereditary optic neuropathy (LHON) families. Functional investigations disclosed a bioenergetic impairment in all individuals. Our sequence analysis suggests that the LHON plus phenotype in our cases may relate to the synergic role of mtDNA variants.

A pilot double-blind placebo-controlled trial of low-dose pramipexole in sleep-related eating disorder.

Sleep‐related eating disorder (SRED) is characterized by recurrent arousals from sleep associated with compulsive ingestion of food. No controlled therapeutic trials are available for SRED. We assessed the safety, tolerability and efficacy of pramipexole, a dopamine D3‐receptor agonist, in the treatment of SRED. Eleven consecutive patients with SRED in the absence of concurrent daytime eating disorders underwent actigraphic recording and subjective sleep diary evaluation for a week before and every week for 2 weeks of treatment with pramipexole 0.18–0.36 mg or placebo, administered in a double‐blind crossover randomized sequence. The primary outcomes of the trial were actigraphic measures of night sleep parameters (sleep efficiency, motor activity mean and median, number and duration of wake episodes), secondary outcomes were the number of good sleep nights/weekly, number and duration of nocturnal awakenings/night, and visual analogue preference score. Pramipexole was well tolerated without any patient withdrawing from the study. Pramipexole reduced night‐time activity median (P = 0.02) and increased the number of nights of good sleep/week (P = 0.02). All other measurements remained unaffected. Pramipexole at low doses was well tolerated, improving some measures of sleep quality and reducing median night activity in SRED. Further studies with higher dosages and for longer time‐periods are warranted.

Status dissociatus after surgery for tegmental ponto‐mesencephalic cavernoma: A state‐dependent disorder of motor control during sleep

After surgery for a tegmental ponto‐mesencephalic cavernoma, a patient developed sleep‐related excessive fragmentary myoclonus, diffuse myoclonic jerks, simple quasipurposeful movements of the limbs, and rapid eye movement (REM) sleep behaviour disorder as motor features of status dissociatus, a condition in which elements of one state of being (wake, NREM and REM sleep) pathologically intrude into another.