A late haemorrhagic complication in an arteriovenous malformation cured with radiosurgery. Case report.

Radiosurgery is a recognized safe form of treating and usually curing arteriovenous malformations (AVMs). Complications related to radiosurgery, especially late sequelae, are rare. Such sequelae may be secondary to incomplete treatment of the original lesion such as haemorrhage, or secondary to the radiation damage to the tissue, or both. Sometimes treatment may induce new lesions. We report a patient who had an AVM cured with radiosurgery, but developed hemisensory loss acutely and had changes on MRI in keeping with a haematoma. We discuss the possible differential diagnosis that should be considered.

Functional magnetic resonance imaging neuroactivation studies in normal subjects and subjects with the narcoleptic syndrome. Actions of modafinil.

Functional magnetic resonance imaging (fMRI) can be used to detect regional brain responses to changes in sensory stimuli. We have used fMRI to determine the amount of visual and auditory cortical activation in 12 normal subjects and 12 subjects with the narcoleptic syndrome, using a multiplexed visual and auditory stimulation paradigm. In both normal and narcoleptic subjects, mean cortical activation levels during the presentation of periodic visual and auditory stimulation showed no appreciable differences with either age or sex. Normal subjects showed higher levels of visual activation at 10:00 hours than 15:00 hours, with a reverse pattern in narcoleptic subjects (P = 0.007). The group differences in spatial extent of cortical activation between control and narcoleptic subjects were small and statistically insignificant. The alerting action, and imaging response, to a single oral dose of the sleep-preventing drug modafinil 400 mg were then determined and compared with placebo in both the 12 normal (8 given modafinil, 4 placebo) and 12 narcoleptic subjects (8 modafinil, 4 placebo). Modafinil caused an increase in self-reported levels of alertness in 7 of 8 narcoleptic subjects, but there was no significant difference between mean pretreatment and post-treatment activation levels as determined by fMRI for either normal or narcoleptic syndrome subjects given modafinil. However, in the modafinil-treated group of 8 normal and 8 narcoleptic subjects, there was a clock time independent correlation between the initial level of activation as determined by the pretreatment scan and the post-treatment change in activation (visual, P = 0.002; and auditory, P = 0.001). No correlation was observed in placebo-treated subjects (P = 0.99 and 0.77, respectively). Although limited by the small number of subjects, and the lack of an objective measure of alertness, the findings of this study suggest that low cortical activation levels in both normal and narcoleptic subjects are increased following the administration of modafinil. Functional magnetic resonance imaging may be a valuable addition to established studies of attention.

Genetic factors in human sleep disorders with special reference to Norrie disease, Prader-Willi syndrome and Moebius syndrome.

Sleep-wake problems are common in specific inborn errors of metabolism and structure of the central nervous system. Psychological factors, behavioural difficulties, metabolic disturbances, and widespread rather than focal damage to the nervous system are present in many of these diseases and all influence the sleep-wake cycle. However, a number of conditions cause relatively focal damage to the neuroanatomical substrate of sleeping and waking. These include fatal familial insomnia, with involvement of the prion protein gene on chromosome 20, Norrie disease, the Prader-Willi syndrome and the Moebius syndrome. The last three important conditions, although rare, are considered in detail in this review. They result in sensory deprivation, hypothalamic and mid-brain damage, and involve the X-chromosome, chromosome 15, and chromosome 13, respectively. These conditions cause a wide variety of sleep disturbance, including parasomnias, daytime sleepiness, and a condition like cataplexy. The place of the relevant gene products in normal sleep regulation needs further exploration.

The clinical diagnosis of the narcoleptic syndrome.

Sleep-wake habits and control of postural muscle tone were investigated by self-report questionnaire in 183 subjects considered to have the narcoleptic syndrome, 62 subjects with hypersomnia and 10 with obstructive sleep apnoea. Results were compared with those in a group of 188 control subjects with normal sleep wake habits. Excessive daytime sleepiness, determined by the Epworth Sleepiness Scale (ESS), was five times greater in the narcoleptic syndrome than in control subjects (score range 0-24, mean scores +/-SD 19.6+/-3.0; and 4.5+/-3.3 respectively; P<0.001). The propensity to cataplexy, as determined by a rating scale developed to estimate the likelihood of loss of postural tone in response to sudden emotional stimuli, including laughter, was 10 times greater in narcoleptic syndrome than in control subjects (postural atonia total score range 0-600; mean + SD 334+/-122 and 28+/-45, respectively; P<0.001). Narcoleptics had more disturbances of night sleep than controls with episodes of muscle jerking, sleep walking, sleep talking and sleep terrors, as well as sleep paralysis, and higher insomnia self-rating scores. Sleep latency from bedtime to sleep-onset time was shorter in narcoleptics than controls. The hypersomniac group of 62 subjects was heterogeneous. Subsequent investigation showed that 18 subjects (29%) had idiopathic hypersomnia, four (6%) 'incomplete' narcolepsy without cataplexy and 10 (16%) hypersomnia accompanying a mood disorder. The mean ESS scores in this group and in subjects with obstructive sleep apnoea were comparable to those of the narcoleptic syndrome subject group. Mean postural atonia scores were similar to those of control subjects.

Proton spectroscopy in the narcoleptic syndrome. Is there evidence of a brainstem lesion?

There is controversy regarding the relationship of structural or biochemical brainstem lesions to "idiopathic" narcolepsy. Most cases of the narcoleptic syndrome are considered to be idiopathic because no structural lesion is detectable, although some cases of secondary narcolepsy are known to be associated with no structural brainstem lesions. Using proton spectroscopy, we determined levels of ventral pontine metabolite pools in 12 normal subjects and 12 subjects with idiopathic narcolepsy. REM sleep is generated in ventral pontine areas. Proton spectroscopy was used to study levels of N-acetyl aspartate (NAA) as a marker of cell mass, creatine and phosphocreatine (Cr + PCr), and choline (Cho). The intensity of the peaks, as determined by the area under the peak (AUP), was measured. The AUP correlates with the quantity of chemical present. In this study, the ratios of NAA to Cr + PCr were similar in normal subjects and in narcoleptic subjects with idiopathic narcolepsy. No differences in measured metabolic ratio were observed in subjects who slept during the scan procedure compared with those who remained awake. Subjects with "symptomatic" narcolepsy accompanied by an obvious structural brain lesion were not studied. Proton spectroscopy of the brain initiates a new kind of neurochemistry, allowing the noninvasive study of metabolic pools in the living human brain without the use of any kind of tracer or radioactive molecule. In this study, there was no evidence of cell loss in the ventral pontine areas of subjects with the narcoleptic syndrome.

Postprandial hypotension and parkinsonian state in Parkinson's disease.

Abnormal postprandial cardiovascular responses such as postprandial hypotension (PPH) occur in primary autonomic failure and contribute significantly to morbidity. The extent and frequency of PPH and its relationship to the parkinsonian state in idiopathic Parkinson's disease (IPD) is unknown. By studying 20 patients with IPD (without autonomic failure) and 16 age-matched controls after both groups ingested a standard isocaloric balanced liquid meal, we have shown that supine PPH complicates IPD and is related to marked worsening of the parkinsonian state as measured by a cumulative score of tremor, rigidity, bradykinesia, posture, and gait. Furthermore, significant postural hypotension is unmasked that results in postural intolerance due to presyncopal symptoms. Our study indicates that, in patients with IPD, ingestion of a meal may lead to abnormal postprandial cardiovascular responses and aggravation of the parkinsonian stage. The underlying mechanisms are unclear, although vasodilatory gut peptides released in response to food ingestion may be contributory.

Use of apomorphine in parkinsonian patients with neuropsychiatric complications to oral treatment.

Neuropsychiatric side effects often complicate anti-Parkinsonian therapy and pose a significant problem in the optimal management of idiopathic Parkinson's disease. Several publications report a relative lack of neuropsychiatric side effects in Parkinsonian patients treated with subcutaneous apomorphine. To investigate this further, we have used subcutaneous apomorphine to treat 12 non-demented IPD patients with previous oral drug-related neuropsychiatric problems. Treatment with apomorphine allowed alteration of anti-Parkinsonian medication and led to the abolition or reduction of neuropsychiatric complications in all patients. The mechanism remains unclear but may be due, in part, to a reduction in oral medication or a psychotropic action of apomorphine, possibly due to the piperidine moiety in its structure, or both.

A comparison of idiopathic hypersomnia and narcolepsy-cataplexy using self report measures and sleep diary data.

Eighteen patients with idiopathic hypersomnia (IH) were compared with 50 patients with the narcoleptic syndrome of cataplexy and daytime sleepiness (NLS) using self report questionnaires and a diary of sleep/wake patterns. The IH group reported more consolidated nocturnal sleep, a lower propensity to nap, greater refreshment after naps, and a greater improvement in excessive daytime sleepiness since onset than the NLS group. In IH, the onset of excessive daytime sleepiness was predominantly associated with familial inheritance or a viral illness. Two variable--number of reported awakenings during nocturnal sleep and the reported change in sleepiness since onset--provided maximum discrimination between the IH and NLS groups. Confusional arousals, extended naps or nocturnal sleep, autonomic nervous system dysfunction, low ratings of medication effectiveness, or side effects of medication were not associated differentially with either IH or NLS.

Melatonin and insomnia.

The hypnotic action of melatonin 5 mg p.o. was explored in 15 subjects with psychophysiological insomnia in a double-blind controlled self-report questionnaire study. Melatonin or placebo was taken at 20.00 hours for a 1-week period in random order. Effects on sleep and wakefulness were monitored by visual analogue scale and structured interview. Bedtime, sleep onset time, estimated total sleep and wake time, as well as self-rated sleep quality, were not altered by melatonin, and estimates of next-day function did not change. The period of melatonin, treatment was retrospectively correctly identified by 8 of 15 subjects. Despite unchanged ratings of night sleep quality on the last night of each treatment, 7 of 15 subjects reported that sleep had subjectively improved to a minor extent in the week of active treatment. Side-effects attributed to melatonin included headache and an odd taste in the mouth. These data indicate that melatonin is probably of no clinical value in the management of psychophysiological insomnia.

Functional echoplanar brain imaging correlates of amphetamine administration to normal subjects and subjects with the narcoleptic syndrome.

Two subjects with narcoleptic syndrome and three healthy volunteers underwent functional magnetic resonance imaging during the simultaneous presentation of periodic auditory and visual stimuli both before and after administration of amphetamine. The effect of amphetamine in control subjects was a small reduction in the extent of sensory-induced activation. In the narcoleptic subjects, amphetamine led to an increase in the extent of induced activation within primary and association sensory cortex.

Sleep paralysis.

Sleep paralysis is a common condition with a prevalence of 5-62%. Although most affected people have single or infrequent episodes, sleep paralysis may be recurrent, or occur in association with the narcoleptic syndrome. In a study of 22 subjects with frequent sleep paralysis and also excessive daytime sleepiness, episodes continued for between 5 and 35 years. In contrast to subjects with the narcoleptic syndrome, these patients did not have cataplexy, daytime sleepiness and insomnia were less severe, and there was no HLA DR2(15) or DQ1(6) association. Sleep paralysis was familial in 19 of these subjects. A non-HLA linked genetic factor, in addition to environmental factors, may thus predispose to sleep paralysis.

The delayed sleep phase syndrome: clinical and investigative findings in 14 subjects.

Fourteen subjects are described in whom a clinical diagnosis of the delayed sleep phase syndrome was made. The condition is multi-factorial, dependent on lifestyle, mood and personality, as well as on familial factors but no single factor in isolation is sufficient to explain the delay in sleep timing. Refusal to attend school may be important in some instances but will not explain cases with delayed age of onset. In half the subjects the delay in sleep phase started in childhood or adolescence. The syndrome causes severe disruption to education, work and family life. Polysomnography, motor activity monitoring of rest-activity cycles, plasma melatonin profiles and urinary melatonin metabolite excretion are normal. Different patterns of sleep phase delay seen in the syndrome include stable, progressive, irregular and non-24 hour sleep-wake cycles. These patterns may result from different social and other Zeitgebers ("time-markers", for example sunrise, sunset) in the normal environment. Treatment by forced sleep-wake phase advance or with melatonin resulted in a partial sleep-phase advance but this was not maintained on stopping treatment.

Delayed sleep phase syndrome response to melatonin.

The actions of melatonin on the sleep-wake cycle were investigated by means of a randomised, double-blind, placebo-controlled trial in 8 subjects with a delayed sleep phase syndrome attending a sleep disorders clinic. In randomised order the subjects received placebo or melatonin 5 mg daily for 4 weeks with a 1 week washout period between the treatments. Drug or placebo was given at 2200 h, 5 h before the mean time of sleep onset determined by pretrial sleep logs. In all 8 subjects sleep onset time (mean advance 82 [range 19-124] min; p less than 0.01) and wake time (117 [10-187] min; p less than 0.01) were significantly earlier during melatonin treatment than during placebo. Mean total sleep time was slightly less on melatonin (8 h 12 min) than on placebo (8 h 46 min). Alertness acrophase calculated from the subjects' ratings of alertness made every 2 h while awake was unaltered. Melatonin may act as a phase-setter for sleep-wake cycles in subjects with a delayed sleep phase syndrome.