Long-term sensitization of a defensive withdrawal reflex in Aplysia.

When a weak tactile stimulus is applied to the siphon of Aplysia californica, the animal withdraws the siphon between the parapodia. This defensive withdrawal reflex can be facilitated (sensitized) if the animal is previously given 4 days of training, consisting of four brief noxious stimuli each day. The sensitization of this reflex can last for up to 3 weeks after training and is mediated by the abdominal ganglion which also mediates long-term habituation. This preparation may provide a system for analyzing the neural mechanism of long-term behavioral modifications of complexity which is intermediate between habituation and associative learning.

Medication use in patients with restless legs syndrome compared with a control population.

Primary restless legs syndrome (RLS) is a sensorimotor disorder causing chronic sleep deprivation in those with moderate to severe symptoms. It has been associated with other medical conditions, such as high blood pressure, depression and attention deficit hyperactive disorder (ADHD). If these conditions are more prevalent for RLS patients, then it would be expected RLS patients would use relatively more of the medications treating these conditions. Current medication use was obtained from 110 RLS patients and 54 age, race and gender-matched local-community controls. Each subject was diagnosed as primary RLS or having no indications for RLS by a clinician board-certified in sleep medicine. The RLS group used more medications than the control group even when medications used for treating RLS were excluded. Significantly more of the RLS patients than controls used anti-depressants, gastro-intestinal (GI) medications and asthma/allergy medications. RLS patients compared with those without RLS are more likely to use medications not related to treating RLS. Moreover they use medications for conditions that have not previously been considered related to RLS, i.e. GI and asthma/allergy conditions.

A single question for the rapid screening of restless legs syndrome in the neurological clinical practice.

The purposes of this study were to validate the use of a single standard question for the rapid screening of restless legs syndrome (RLS) and to analyze the eventual effects of the presence of RLS on self-assessed daytime sleepiness, global clinical severity and cognitive functioning. We evaluated a group of 521 consecutive patients who accessed our neurology clinic for different reasons. Beside the answer to the single question and age, sex, and clinical diagnosis, the following items were collected from all patients and normal controls: the four criteria for RLS, the Epworth Sleepiness Scale (ESS), the Clinical Global Impression of Severity (CGI-S), and the Mini-Mental State evaluation. RLS was found in 112 patients (70 idiopathic). The single question had 100% sensitivity and 96.8% specificity for the diagnosis of RLS. ESS and CGI-S were significantly higher in both RLS patient groups than in normal controls. RLS severity was significantly higher in idiopathic than in associated/symptomatic RLS patients. RLS can be screened with high sensitivity and good reliability in large patient groups by means of the single question; however, the final diagnosis should always be confirmed by the diagnostic features of RLS and accompanied by a careful search for comorbid conditions.

Epidemiology of restless legs symptoms in adults.

BACKGROUND: Restless legs syndrome (RLS) is a disorder characterized by sleep-disrupting unpleasant leg sensations, often accompanied by daytime behavioral problems. Treatment for this condition is available, but it is suspected that most instances of RLS remain undiagnosed. The goal of this investigation was to assess the prevalence and health status correlates of restless legs symptoms (hereinafter referred to as restless legs) in the general population. METHODS: A question reflecting the clinical features of RLS was added to the 1996 Kentucky Behavioral Risk Factor Surveillance Survey. Data on the frequency of experiencing restless legs, self-rated general and mental health status, demographics, and behavioral risk factors were collected by telephone interview from 1803 men and women, 18 years and older. RESULTS: Experiencing restless legs 5 or more nights per month was reported by 3% of participants aged 18 to 29 years, 10% of those aged 30 to 79 years, and 19% of those 80 years and older. The age-adjusted prevalence for Kentucky adults is 10.0%; prevalence did not vary significantly by sex. The adjusted odds ratios (95% confidence intervals) for restless legs and diminished general health and poor mental health status were 2.4 (1.4-4.0) and 3.1 (2.0-4.6), respectively. Restless legs were significantly associated with increased age and body mass index, lower income, smoking, lack of exercise, low alcohol consumption, and diabetes. CONCLUSIONS: The prevalence of restless legs in the general adult population is high. Restless legs may be associated with decreased well-being, emphasizing the need for further research and greater medical recognition of this condition.

Dyskinesias while awake and periodic movements in sleep in restless legs syndrome: treatment with opioids.

In five unrelated patients with the restless legs syndrome, opioid drugs relieved restlessness, dysesthesias, dyskinesias while awake, periodic movements of sleep, and sleep disturbances. When naloxone was given parenterally to two treated patients, the signs and symptoms of the restless legs syndrome reappeared. Naloxone placebo had no effect. Opioid medications may offer a useful therapy for the restless legs syndrome. The endogenous opiate system may be involved in the pathogenesis of the syndrome.

Randomized, Double-Blind, Placebo-Controlled Study of Clonidine in Restless Legs Syndrome.

Ten patients with idiopathic restless leg syndrome (RLS) were asked to rate their symptoms at baseline during 2 weeks of placebo and 2 weeks of clonidine treatment by using a four-point scale. On two consecutive nights of each treatment period, polysomnography (PSG) and actigraphic studies were performed. Patients subjectively reported improvement in leg sensations (p = 0.02) and motor restlessness (p = 0.001) while receiving clonidine (mean = 0.5 mg/day). On PSG testing, sleep onset occurred faster with clonidine (12 minutes) compared with placebo (30 minutes) and baseline (47 minutes) (p = 0.006). Adverse findings associated with clonidine treatment included decreased percent REM sleep in the clonidine group (4%) compared with placebo (16%) and baseline (16%) (p = 0.001) and increased REM latency in the clonidine group (195 minutes) compared to the placebo (70 minutes) and baseline groups (89 minutes) (p = 0.028). There were no significant changes in total sleep time, stage 1 and 2 sleep, sleep efficiency, awakenings, arousals or periodic limb movements in sleep. There was a nonstatistical trend toward and increase in stage 3 and 4 sleep and a decrease in motor activity as measured by actigraphic recordings. Globally, seven out of 10 patients felt clonidine was more effective than placebo. Four patients chose to continue clonidine after the study. Clonidine may be an effective treatment for RLS patients who don't have large numbers of sleep-disrupting periodic limb movements but have delayed sleep onset due to leg sensations and subsequent motor restlessness.

Successful treatment of the idiopathic restless legs syndrome in a randomized double-blind trial of oxycodone versus placebo.

In a double-blind randomized crossover trial, oxycodone or placebo was given in divided night-time doses to 11 patients with idiopathic restless legs syndrome (RLS) for 2 weeks prior to appropriate polysomnographic studies. Under double-blinded conditions, patients were asked to do daily ratings of their leg sensations, motor restlessness and daytime alertness on a 1-4 scale for the 2 weeks prior to the polysomnographic studies and for the nights of the polysomnographic studies as well. Leg sensations (p < 0.009), motor restlessness (p < 0.006) and daytime alertness (p < 0.03) were significantly improved on oxycodone as compared to baseline or placebo. Patients were studied polysomnographically under double-blinded conditions for 2 nights in each phase of the protocol. On an average dose of 15.9 mg oxycodone (equivalent to approximately three 5-mg tablets of commercial preparation), there was a statistically significant reduction in the number of periodic limb movements in sleep [(PLMS)/hour sleep (p < 0.004)] and in the number of arousals/hour sleep (p < 0.009) on drugs as compared to baseline or placebo. A statistically significant improvement was also noted in sleep efficiency (p < 0.006) and 10 of the 11 patients preferred oxycodone over placebo. We conclude that oxycodone is an effective treatment for RLS and PLMS.

Circadian rhythm of motor restlessness and sensory symptoms in the idiopathic restless legs syndrome.

STUDY OBJECTIVES: To determine if motor restlessness in the Restless Legs Syndrome (RLS) shows a circadian rhythm with maximum at night, as previously found for subjective discomfort and periodic limb movements (PLMs), and to correlate RLS peak intensity with the core temperature cycle. DESIGN: Subjects underwent two days of normally timed wakefulness and sleep followed by a night and subsequent day of sleep deprivation. Activity was standardized through modified suggested immobilization tests (mSITs). SETTING: The study was conducted in a laboratory environment with a bedroom equipped for polysomnography during sleep and the mSITs. PATIENTS: Nine patients (mean age 59.8+/-11.3 years [range: 33-72]; 4 males, 5 females) with clinically severe idiopathic RLS. INTERVENTIONS: Patients were monitored with continuous ambulatory activity and core temperature recording. The mSITs were performed every three hours while subjects were awake. During the mSITs, subjective discomfort was measured every 15 minutes while motor restlessness was assessed through activity monitoring. MEASUREMENTS AND RESULTS: Subjective discomfort and motor restlessness increased from a trough in the morning to a maximum at night in the hours following midnight. Peak intensity was found on the falling phase of the core temperature cycle, whose circadian rhythm appeared to be within the normal range for age. CONCLUSIONS: An independent circadian factor modulates the intensity of RLS, which seems to peak on the falling phase of the core temperature cycle. Therefore, the diagnostic criteria that RLS occurs with rest and during the night have independent bases. Furthermore, RLS may be partially controlled by some process or substance whose level varies with the normal circadian rhythm.

Motorneuronal control of locomotion in Aplysia.

We have carried out a combined behavioral and cellular analysis of escape locomotion in Aplysia. Using videotape recording we obtained a detailed description of the coordinated movements of the different regions of the foot and body during locomotion. Alternating waves of extension and longitudinal contraction begin at the head and propagate caudally through each pedal segment at a constant rate. Cobalt backfill of pedal nerves indicated that certain regions of the pedal ganglia were likely to contain motor neurons for the foot and body wall musculature. We examined these areas using intracellular techniques and identified three unique cells and three regional classes of neurons having clear motor effects on the foot and body wall. We also found that locomotion is driven by a central program. The basic locomotor pattern of the identified motor neurons and regional classes of motor neurons persists even after the circumesophageal ganglia have been isolated from the periphery. The motor neurons are not synaptically interconnected; patterned bursting during locomotor activity is produced by cyclic synaptic input. Because the locomotor system has large neurons favorable for cellular analysis and because locomotion is characterized by features of both stereotypy and flexibility, Aplysia promises to be useful for investigating the mechanisms underlying both the generation and modulation of a central program.

A blinded study of the suppressibility of involuntary movements in Huntington's chorea, tardive dyskinesia, and L-dopa-induced chorea.

Videotapes of patients with Huntington's chorea, tardive dyskinesia (TD), and L-DOPA-induced chorea in Parkinson's disease were taken while the patients were seated with their legs dangling. The videotapes were scored in a blinded fashion for suppressibility of dyskinesias. Most patients with TD or L-DOPA-induced chorea substantially suppressed their involuntary movements, whereas most patients with Huntington's chorea did not. There was a small overlap between the TD and Huntington's chorea groups and suppressibility therefore could not absolutely distinguish between them. Suppressibility testing may nonetheless be a valuable clinical tool since a good, excellent, or complete suppressibility rating was highly suggestive of TD but not Huntington's chorea. TD and L-DOPA-induced chorea may be more pathophysiologically similar to each other than either is to Huntington's chorea.

Restless Legs Syndrome and the five-factor model of personality: results from a community sample.

OBJECTIVE: To examine personality characteristics as potential mediators of the association between Restless Legs Syndrome (RLS) and psychiatric disorders. METHOD: Revised NEO Personality Inventory traits are compared in respondents with (n=42) versus without (n=982) a diagnosis of RLS in a general population sample. RESULTS: RLS was associated with higher neuroticism after adjusting for potential confounders, including current psychopathology. Further analysis showed that the association between RLS and neuroticism contributes to, but does not fully explain, the relationship between RLS and either panic disorder or major depression. CONCLUSIONS: Neuroticism may mediate part of the relationship between RLS and depression or panic, but the mechanisms of these associations need further exploration.

Noise-induced psychogenic tremor associated with post-traumatic stress disorder.

Tremors in post-traumatic stress disorders have not been previously well characterized. A 67-year-old man has a 46-year history of a noise-induced exaggerated startle reflex followed by a large amplitude rest, postural and kinetic tremor that may persist for up to 3 days. This tremor is superimposed on a continuous mild organic postural/kinetic tremor whose electrophysiological characteristics are different from those of the overlying tremor. We attribute the exaggerated startle reflex and the noise-induced tremor to Post-Traumatic Stress Disorder (PTSD) and postulate a psychogenic origin for the noise-induced tremor. The patient also believes the noise-induced tremor to be psychologically based and to be produced by the fear and anxiety he experiences when he hears loud, unexpected noises. The sudden onset of the noise-induced tremor, its intermittent character, its temporary disappearance on distraction despite the patient's inability to suppress it, inconsistencies in handwriting and figure drawing, and the fact that the noise-induced tremor is stimulus specific and persists long after the offending stimulus (noise) is no longer present all suggest a tremor of psychogenic origin.

Frequent occurrence of myoclonus while awake and at rest, body rocking and marching in place in a subpopulation of patients with restless legs syndrome.

While myoclonus awake and at rest, body rocking and marching in place have been occasionally reported to occur in idiopathic restless legs syndrome (RLS), it has not been previously noted that these clinical features occur frequently in a subpopulation of severely affected older RLS patients seeking medical attention for longstanding symptoms that have become progressively worse over the years. We studied 10 unrelated patients from this subpopulation and polysomnographically documented myoclonus while awake and at rest in 8, and intermittent night-time body rocking and marching in place in 6 by history and videotape. Also occurring frequently were the well-known clinical features of floor pacing, paresthesias, sleep disturbances, periodic movements of sleep (PMS), tendency for the signs and symptoms to be worse at night, and a family history suggestive of RLS.

Beyond benzodiazepines: alternative pharmacologic agents for the treatment of insomnia.

OBJECTIVE: To review the epidemiology, etiology, and classification of insomnia and provide an overview of the pharmacologic therapy of insomnia. Novel nonbenzodiazepine hypnotics including zolpidem, zopiclone, and zaleplon, as well as nonprescription products such as valerian and melatonin, are reviewed in detail. DATA SOURCES: A MEDLINE search was performed to identify relevant clinical studies, case reports, abstracts, and review articles published between April 1992 and December 1997. Key search terms included insomnia, benzodiazepines, zolpidem, zopiclone, zaleplon, Cl 284,846, melatonin, and valerian. Additional references were obtained from the lists of review articles and textbooks. DATA EXTRACTION AND SYNTHESIS: Data concerning the safety and efficacy of the hypnotic agents were extracted from all available clinical trials and abstracts. Background information regarding insomnia, benzodiazepines, and other hypnotics was extracted from the most current literature, including review articles and textbooks. CONCLUSIONS: New developments in benzodiazepine receptor pharmacology have introduced novel nonbenzodiazepine hypnotics that provide comparable efficacy to benzodiazepines. Although they may possess theoretical advantages over benzodiazepines based on their unique pharmacologic profiles, they offer few, if any, significant advantages in terms of adverse effects. Over-the-counter agents such as valerian and melatonin may be useful in alleviating mild, short-term insomnia, but further clinical trials are required to fully evaluate their safety and efficacy.

Review and videotape recognition of idiopathic restless legs syndrome.

The motor phenomena associated with idiopathic restless legs syndrome (RLS) are infrequently seen in the physician's office because they are present only after prolonged sitting or lying and usually at night. These motor phenomena are captured on videotape in four unrelated patients with idiopathic RLS. The clinical features of idiopathic RLS are reviewed in detail, and therapeutic advances in its treatment are summarized.

A double-blind randomized crossover trial of bromocriptine and placebo in restless legs syndrome.

A double-blind randomized crossover study of 7.5 mg bromocriptine at bedtime versus placebo was conducted in 30-day phases (with a 2-week washout period between phases) in 6 patients with idiopathic restless legs syndrome. Five patients experienced partial subjective improvement in restlessness and paresthesias on bromocriptine as opposed to placebo and expressed a desire to continue on the medication. On bromocriptine, the patients showed polysomnographically a mean decrease of 43% from control and a mean decrease of 57% from placebo in the number of periodic movements of sleep per hour of sleep (p less than 0.025). Two of 3 patients with abnormally decreased total sleep time and sleep efficiency showed an improvement in these measures on therapy. The dopamine agonist bromocriptine may be a useful therapy in some patients with restless legs syndrome.

Painless legs and moving toes: a syndrome related to painful legs and moving toes?

The syndrome of painful legs and moving toes consists of continuous or semicontinuous involuntary writhing movements of the toes associated with pain in the affected extremity. We report a 57-year-old man with a 33-year history of painless and semicontinuous involuntary movements of the toes of the left foot similar to those seen in painful legs and moving toes. There was no family history of movement disorder. The history and physical examination were negative for significant trauma, radiculopathy, or peripheral neuropathy. There were no other neurological findings or involuntary movements. It is unlikely that the involuntary movements were precipitated by neuroleptics or psychosis. CT scan of the head; EEG, CT, and MRI scans of the lumbosacral spine; and EMG and nerve conduction studies of the legs showed no significant abnormalities except for a predominant cocontraction of the left foot flexors and extensors at 0.6-1.2 Hz in a pattern sometimes seen in painful legs and moving toes. We conclude that there is a condition clinically and electrophysiologically similar to painful legs and moving toes that we call painless legs and moving toes, the etiology of which remains undetermined.

Circadian rhythm of periodic limb movements and sensory symptoms of restless legs syndrome.

The symptoms of restless legs syndrome (RLS) worsen while patients are sitting or lying and also worsen at night. The current study was designed to determine if the periodic limb movements (PLMs) and sensory symptoms of RLS are modulated by an independent circadian factor. We recorded sleeping and waking PLMs and waking sensory symptoms in eight volunteers with RLS for 3 successive nights and days, starting with a polysomnographic recording of 2 nights, followed by a third night of sleep deprivation and the day after sleep deprivation. This study showed that both the PLMs and sensory symptoms were worst at night with a maximum for both between midnight and 1:00 AM and a minimum between 9:00 and 11:00 AM. Sleep and drowsiness had a tendency to worsen PLMs and sensory symptoms after the night of sleep deprivation. Circadian temperature curves were normal in all four patients with adequate data collection. The highest PLM counts occurred on the falling phase of the circadian temperature curve whereas the lowest PLM counts occurred on the rising phase of the curve. We conclude that the PLM and sensory symptoms in RLS are influenced by a circadian rhythm, and that the "worsening at night" criterion of the RLS Definition Criteria is, at least in part, distinct from the "worsening while lying or sitting" criterion.